Linköping University Medical Dissertations No 1562

Improving management of STEMI patients treated with primary PCI: Pharmacotherapy,

renal function estimation and gender perspective.

Dimitrios Venetsanos

Department of Medical and Health Sciences

Linköping University, Sweden
Linköping 2017
Dimitrios Venetsanos, 2017

Cover/picture/Illustration/Design: Dimitrios Venetsanos

Articles II and IV are published under the terms of the Creative Commons Attribution
Non-Commercial License which permits use, distribution, and reproduction in any me-
dium, provided the original work is properly cited and is not used for commercial pur-
poses.

Published material has been reprinted with the permission of the copyright holder.

Printed in Sweden by LiU-Tryck, Linköping, Sweden, 2017

ISBN 978-91-7685-577-5
ISSN 0345-0082
To my father

To Despina, Silia and Anastasia.

“Ignoramuset ignorabimus”
("we do not know and will not know", “On the limits of our understanding
of nature”, Emil Du Bois Reymond, 1872)

or

“wir müssen wissen wir werden wissen”

(“We must know. We will know”, David Hilbert, 1930)
Contents
Abstract .................................................................................................................. 1
List of Papers .......................................................................................................... 3
Populärvetenskaplig sammanfattning ..................................................................... 4
Abbreviations .......................................................................................................... 6
Introduction ............................................................................................................ 8
Background ................................................................................................................... 8
Pathogenesis of Acute Coronary Syndromes .................................................................. 8
Thrombosis – the fundamental role of platelets and coagulation system ...................... 11
Management of STEMI patients - Timely reperfusion therapy .................................... 14
Anticoagulation and antiplatelet therapy in STEMI patients during PPCI .................. 15
Oral antiplatelet therapy in STEMI patients ................................................................ 17
Bleeding events – the Achilles heel of invasive management and antithrombotic
treatment ..................................................................................................................... 19
Prevention of bleeding complications and improvement of outcomes ........................... 23
Gender differences in patients with ACS...................................................................... 25
Reperfusion therapy in STEMI patients from a gender perspective ............................. 25
Gender differences in the effectiveness and safety of antiplatelet therapy .................... 26
Chronic kidney disease in patients with ACS ............................................................... 27
Measurements and estimations of glomerular filtration rate ........................................ 27
Aims ...................................................................................................................... 29
Material and methods ........................................................................................... 30
Sample size calculation .......................................................................................... 35
Statistical analysis ................................................................................................. 36
Ethical considerations ........................................................................................... 39
Results ................................................................................................................... 40
Paper I ......................................................................................................................... 40
Paper II ........................................................................................................................ 43
Paper III ...................................................................................................................... 45
Paper IV ...................................................................................................................... 46
Conclusions clinical implications .......................................................................... 56
Future Directions .................................................................................................. 57
Acknowledgements ................................................................................................ 58
References ............................................................................................................. 60
 Abstract

ABSTRACT

This thesis focused on the acute management of patients with ST-segment elevation
myocardial infarction (STEMI) in an effort to provide information that may improve
outcome. The aim was to evaluate the efficacy and safety of bivalirudin versus
unfractionated heparin (UFH) in STEMI patients during primary PCI. Furthermore, to
provide pharmacodynamic data of novel ways of ticagrelor administration.
Additionally, to identify subgroups of patients, such as women who may derive greater
benefit from specific antithrombotic strategies due to their risk/benefit profile. Finally,
to evaluate current formulas for estimation of renal function in the acute phase of
STEMI, due to the importance of renal function estimation for dose adjustments of
antithrombotic agents.
In Paper I, all STEMI patients in Sweden between 2008 and 2014, presenting
within 12 hours from symptom onset, treated with primary PCI and UFH or bivalirudin
(both with or without glycoprotein IIb/IIIa inhibitors, GPI) were included in our
analysis.
Of the total population of 23 800 patients, 8783 (36.9%) were included in the UFH
group and 15 017 (63.1%) in the bivalirudin group. Concomitant GPI administration
was 68.5% in the UFH arm compared to 3.5% in the bivalirudin arm (p<0.01).The
adjusted incidence of 30-day mortality was not significant different between the two
groups (UFH vs bivalirudin, adjusted HR 0.94; 95% CI 0.82 -1.07). The adjusted risk
for 1-year mortality, 30-day and 1-year stent thrombosis and re-infarction did not differ
significantly between the two groups. In contrast, patients treated with UFH had a
significantly higher incidence of major in-hospital bleeding (adjusted OR 1.62; 95%CI
1.30 -2.03).
In Paper II pharmacodynamic data of chewed or crushed ticagrelor compared to
standard ticagrelor loading dose (LD) was assessed in 99 patients with stable angina.
Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60 minutes after
LD. High Residual platelet reactivity (HRPR) was defined as > 208 P2Y12 reaction
units (PRU).
Chewed ticagrelor tablets resulted in significantly lower PRU values compared to
crushed or integral tablets at 20 and 60 minutes. Crushed ticagrelor LD resulted in
significantly lower PRU values compared to integral tablets at 20 minutes whereas no
difference was observed at 60 minutes. At 20 minutes, no patients had HRPR with
chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD
(p<0.01).
In Paper III we presented a pre-specified gender analysis of the ATLANTIC trial
including 1 862 STEMI patients that were randomly assigned to pre-hospital versus in-
hospital administration of 180mg ticagrelor.
Women were older and had higher TIMI risk score. Women had a 3-fold higher risk for
all-cause mortality compared to men (5.7% vs 1.9%, HR 3.13, 95% CI 1.78 – 5.51).
However, after adjustment for baseline characteristics, the difference was lesser and no
longer significant (HR 1.98, 95% CI 0.97 – 4.04). Female gender was not an
independent predictor of risk for bleeding after multivariable adjustments (BARC type
3-5 HR 1.52, 95% CI 0.74-3.09). There was no interaction between gender and efficacy
or safety of randomised treatment.
In Paper IV, forty patients with PCI- treated STEMI were included between November

1
 Abstract

2011 and February 2013. We validated the performance of the Cockcroft-Gault (CG),
the Modification of Diet in Renal Disease (MDRD-IDMS), the Chronic Kidney Disease
Epidemiology (CKD-EPI) and the Grubb relative cystatin C (rG-CystC) equations for
estimation of GFR against measured GFR (mGFR) during the index hospitalisation for
STEMI.
MDRD-IDMS and CKD-EPI demonstrated a good performance to estimate GFR with
accuracy within 30% (P30) 82.5% vs 82.5%, respectively. CKD was best classified by
CKD-EPI (Kappa 0.83). CG showed the worst performance with the lowest P30. The
rG-CystC equation had a marked bias of -17.8% and significantly underestimated
mGFR (p=0.03).
Conclusions – In STEMI patients treated with primary PCI, bivalirudin should be
preferred in patients at high risk for bleeding. With crushed or chewed ticagrelor tablets
a more rapid platelet inhibition may be achieved, compared with standard integral
tablets. In STEMI patients, fast and potent platelet inhibition with chewed ticagrelor
may reduce the risk of early stent thrombosis and patients treated with a less aggressive
antithrombotic strategy, such as UFH or bivalirudin monotherapy, may derive a greater
benefit. Although gender differences in adverse outcomes could mainly be explained by
older age and clustering of comorbidities in women, a bleed-reduction strategy in
women with high risk characteristics is warranted in order to improve their outcome.
Regardless the choice of antithrombotic strategy, dose adjustment of drugs cleared by
kidneys based on GFR estimation is of crucial importance. MDRD and CKD-EPI
should be the formulas used for estimation of GFR in STEMI patients.

2
 List Of Papers

LIST OF PAPERS

Paper I
D. Venetsanos, S. Sederholm Lawesson, Stefan James, Sasha Koul, David Erlinge, E
Swahn, J. Alfredsson
Bivalirudin versus heparin with or without GP IIb/IIIa inhibitors in ST-elevation
myocardial infarction patients treated with primary PCI. A report from the
SWEDEHEART registry.
Submitted
Paper II
D. Venetsanos, S. Sederholm Lawesson, E. Swahn, J. Alfredsson
Chewed ticagrelor tablets provide faster platelet inhibition compared to integral
tablets.
The Inhibition of Platelet Aggregation after Administration of three Different
TicagreIor formulations (IPAAD-Tica) Study, a randomised controlled trial.
Thrombosis research. 2017 Jan; 149:88-94.
Paper III
D. Venetsanos, S. Sederholm Lawesson, J. Alfredsson, M. Janzon, A. Cequier, M.
Chettibi, S.G. Goodman, A.W. van‘t Hof, G. Montalescot, E. Swahn
Association between gender and short term outcome in STEMI patients planned for
primary PCI and treated with novel antiplatelet therapy.
A pre-specified gender analysis of the Administration of Ticagrelor in the Cath Lad or
in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary
artery (ATLANTIC) trial – a multicenter, randomised, placebo-controll study.
Submitted
Paper IV
Dimitrios Venetsanos, MD, Joakim Alfredsson, MD, PhD, Mårten Segelmark, MD,
PhD, Eva Swahn, MD, PhD, Sofia Lawesson, MD, PhD
Glomerular Filtration Rate (GFR) during and after STEMI –A single-centre,
methodological study comparing estimated and measured GFR.
BMJ open. 2015 Sep 23; 5(9):e007835.

3
 Populär Vetenskaplig Sammanfattning

POPULÄRVETENSKAPLIG SAMMANFATTNING

Kranskärlssjukdom förorsakar ca 25 % av alla dödsfall i Sverige och är en vanligare

dödsorsak än alla cancersjukdomar. Dessutom är det en av de vanligaste orsakerna till
läkemedelsanvändning, sjukhusinläggningar, sjukbidrag och förtidspension.
Akuta manifestationer av kranskärlssjukdom består av ST-höjningsinfarkt (STEMI),
icke-ST-höjningsinfarkt (NSTEMI) och instabil kärlkramp. Den underliggande orsaken
är oftast en bristning i ett åderförfettnings-plack i något av hjärtats kranskärl, följt av en
pålagrad blodpropp (trombos) som förtränger blodflödet till den del av hjärtmuskeln
som försörjs av det kärlet vilket leder till en hjärtmuskelskada på grund av blodbrist
(hjärtinfarkt).
Vid STEMI är orsaken så gott som alltid att trombosen orsakat en total igentäppning av
kranskärlet. Därför är den akuta behandlingen inriktad på att omedelbart öppna det
tilltäppta kranskärlet (reperfusion) och återställa det normala blodflödet för att begränsa
utbredningen av infarkten. Detta kan åstadkommas med antingen kateterburet
kranskärlsingrepp (PCI) eller läkemedel som kan lösa upp proppen (trombolys). De
senaste åren har studier visat att omedelbar behandling med PCI plus inläggning av ett
ståltrådsnät (stent) förbättrar överlevnaden och minskar risken för allvarliga blödningar
jämfört med trombolys. Därför har PCI blivit den dominerade behandlingen av STEMI i
Sverige. Blodförtunnande behandling som ges i injektion direkt i blodet eller i tablett-
form under PCI hämmar fortsatt trombos-utveckling och minskar risken för återbildning
av proppar i framtiden men ökar samtidigt risken för blödningar.
Denna avhandling fokuserar på STEMI patienter och deras akuta omhändertagande och
farmakologiska behandling. I arbete I jämförde vi effektivitet och säkerhet hos de två
vanligaste blodförtunnande läkemedlen som ges under PCI ingreppet, bivalirudin och
heparin med eller utan glycoprotein IIb/IIIa hämmare (GPI) i båda grupper. Vi använde
data från det nationella hjärt-registret (SWEDEHEART). Studien visade att behandling
med bivalirudin ± GPI gav färre blödningskomplikationer under vårdtillfället jämför
med heparin ± GPI. Dödlighet, återinsjuknande i hjärtinfarkt och stent trombos skiljde
sig inte mellan grupperna vare sig vid kort eller lång uppföljning.
I arbete II testade vi och studerade farmakodynamiken av två nya sätt att ge ticagrelor,
en stark och snabbverkande blodförtunnande tablett. Patienterna lottades slutmässigt till
engångs behandling med 180 mg tuggade, krossade eller hela ticagrelor tabletter.
Tuggad och krossad ticagrelor gav en snabbare och effektivare blockering av
blodplättarna jämfört med hel tablett 30 minuter efter intag av tabletterna. Dessutom,
visade sig tuggade ticagrelor-tabletter vara effektivare än krossade ticagrelor-tabletter i
hämning av blodplättar.
I arbete III använde vi data från den internationella, randomiserade studien som kallas
ATLANTIC. Studien inkluderade patienter med STEMI och jämförde effektivitet och
säkerhet av ticagrelor-behandling som påbörjades i ambulansen jämfört med start av
behandlingen på sjukhuset strax före PCI. Vårt syfte var att se om könsskillnader i
dödlighet och blödningskomplikationer existerar och om behandling med ticagrelor är
lika effektiv och säker hos båda könen. Vår studie visade att kvinnor hade betydligt
högre risk för död och blödningar inom 30 dagar efter STEMI men dessa skillnader
kunde förklaras av åldersskillnaden mellan män och kvinnor och högre samtidig
förekomst av andra sjukdomar hos kvinnorna. Behandling med ticagrelor i ambulansen
var lika säkert hos bägge könen.

4
 Populär Vetenskaplig Sammanfattning

I den sista studien, arbete IV, utvärderade vi de fyra vanligaste ekvationerna som
används för att beräkna njurfunktion (eGFR), i förhållande till mätt njurfunktion hos
STEMI patienter. Njurfunktionen är mycket viktig för att kunna justera dosen av
blodförtunnande läkemedel, t.ex. bivalirudin, GPI eller heparin. Överdosering av dessa
läkemedel ökar kraftigt risken för blödningar. Våra resultat visade att ” MDRD-IDMS”
och ” CKD-EPI” - ekvationerna presterade mycket bra och bör företrädesvis användas i
klinisk praxis medan CG-ekvationen visade sig vara sämst på att bedöma
njurfunktionen och borde därmed inte användas . Ett intressant fynd var att cystatin C
steg kraftigt under vårdtillfälle och ledde till en felaktig bedömning av njurfunktionen
när cystatin C ekvation användes.
Sammanfattning
Hos STEMI-patienter som behandlas med PCI, bör blodförtunnande behandling med
bivalirudin föredras, fram för allt hos patienter som löper hög risk för blödning. Snabb
och högst verksam blockering av blodplättarna med tuggade ticagrelortabletter kan
minska risken för återbildning av propp i stentet (stenttrombos) och bivalirudin-
behandlade patienter kan dra en större fördel av detta. Könsskillnader i dödlighet och
blödningar efter STEMI kan förklaras av högre ålder och högre samtidig förekomst av
andra sjukdomar hos kvinnor. Rätt val av blodförtunnande behandling hos kvinnor med
hög risk-för blödningar är stark motiverat för att förbättra resultat och därför bör
behandling med bivalirudin alltid övervägas. Oavsett val av antitrombotisk strategi, är
dosjustering av läkemedel som utsöndras via njurarna, av yttersta vikt och baseras på
den njurfunktion som uppskattas med använd GFR-formel. MDRD och CKD-EPI är de
formler som bör användas för beräkning av GFR hos STEMI patienter.

5
 Abbreviations

ABBREVIATIONS

ACC/AHA American College of Cardiology/American Heart Association

ACE-I Angiotensin Converting Enzyme Inhibitors
ACS Acute Coronary Syndrome
ADP Adenosine Diphosphate Receptor
AF Atrial Fibrillation
BARC Bleeding Academic Research Consortium
BMI Body Mass Index
CAD Coronary Artery Disease
CCU Coronary Care Unit
CI Confidence Interval
CKD Chronic Kidney Disease
CKD-EPI Chronic Kidney Disease-Epidemiology Collaboration
COPD Chronic Obstructive Pulmonary Disease
DAPT Double Antiplatelet Therapy
DES Drug Eluting Stent
DM Diabetes Mellitus
ECG Electrocardiogram
eGFR Estimated Glomerular Filtration Rate (mGFR)
GPI Glycoprotein IIb/IIIa receptor Inhibitors
GPIb Glycoprotein Ib
GPIIb/IIIa Glycoprotein IIb/IIIa receptors
HF Heart Failure
HR Hazard Ratio
HRPR High Residual Platelet Reactivity
IHD Ischemic Heart Disease
IRA Infarct Related Artery
LD Loading Dose
MACE Major Adverse Cardiovascular Events,
MDRD-IDMS Modification of Diet in Renal Disease
mGFR Measured Glomerular Filtration Rate
MI Myocardial Infarction
MVD Multivessel Disease
NACE Net Adverse Clinical Event
NPR National Patient Registry
NSTE ACS Non-ST Segment Elevation Acute Coronary Syndromes
NSTEMI Non-ST Segment Elevation Myocardial Infarction
OCT Optical Coherence Tomography
OR Odds Ratio
PPCI Primary Percutaneous Coronary Intervention
PR Platelet Reactivity
rG-CystC relative Grubb cystatin C
RR Relative Risk
SAP Stable Angina Pectoris
STEMI ST segment Elevation Myocardial Infarction
SWEDEHEART Swedish Web-system for Enhancement and Development of

6
 Abbreviations

Evidence-based care in Heart Disease Evaluated According to

Recommended Therapies
TCFA Thin-Cap Fibroatheroma
TLR Target Lesions Revascularisation
UA Unstable Angina
UFH Unfractionated Heparin
vWF Von Willebrand factor

7
 Background

INTRODUCTION

The term acute coronary syndrome (ACS) includes the three different types of acute
clinical manifestations of ischemic heart disease (IHD), i.e. unstable angina (UA), non-
ST segment elevation myocardial infarction (NSTEMI) and ST segment elevation
myocardial infarction (STEMI). These clinical manifestations share a common
pathophysiologic mechanism but have different diagnostic criteria and management.
Symptoms suggesting myocardial ischemia and ST segment elevation on the
electrocardiogram (ECG), obtained soon after the first medical contact, set the diagnosis
of STEMI and mandate immediate reperfusion therapy. When the diagnosis of STEMI
has been excluded, clinical assessment of symptoms, repeated ECGs and analysis of
cardiac biomarkers, preferably high sensitive troponin, are necessary to rule out or to
confirm the diagnosis of an ACS.1, 2

The incidence rate of STEMI has slightly declined over the last decades, but has
remained stable the last years, and a concomitant rise in the incidence rates of NSTEMI
has been observed. STEMI still represents around 30% of patients with ACS with 66
hospital admissions/100.000 inhabitants/year in Sweden. 3, 4
Coronary artery disease (CAD) remains the leading cause of death, worldwide, and
accounts for 12.8% of all deaths. 5 In STEMI patients, age, time delay to treatment,
mode of reperfusion therapy, history of prior myocardial infarction (MI), diabetes
mellitus (DM), chronic kidney disease (CKD) and number of diseased coronary arteries,
are some of the most powerful predictors of adverse outcome. Female gender has also
emerged as an independent predictor of early mortality and bleeding complications.6, 7
The management of patients with ACS has underwent dramatic changes the last three
decades. At the same time, a significant decrease of IHD mortality in older patients and
to a lesser extent in subgroups such as young women has been observed. 8 However,
mortality remains substantial with approximately 6% of STEMI patients dying within
the first 6 months after the index event. Therefore, additional efforts to optimise the
management of STEMI patients are needed.
This thesis focuses on the acute management of STEMI patients in an effort to improve
outcome and potentially lead to an individualised treatment based on patients risk
profile. Especially, this thesis will focus on 1) the pharmacologic therapy during
primary percutaneous coronary intervention (PPCI) 2) the effectiveness and safety of
current treatment in both genders as well as on the potential importance of gender as a
predictor of outcome and 3) methods to estimate renal function in STEMI patients
during the index hospitalisation.

Background

Pathogenesis of Acute Coronary Syndromes

In Greek, Athére means gruel or porridge and refers to the lipid-rich core, and scleros
means hard, which describes the fibrotic and often calcified encapsulating tissue. In
1786, Edward Jenner proposed atherosclerosis in coronary vessels as the cause of
angina pectoris, a disease described some years before by William Heberden. It took
8
 Background

many years before Constantinides, Chapman, and Friedman described the mechanism
linking coronary atherosclerosis to myocardial infarction. They found that plaque
rupture exposing thrombogenic plaque components to the blood flow led to thrombus
formation in the coronary vessels and to myocardial infarction.9, 10 Furthermore, non-
ruptured plaques with surface irregularities may have superimposed thrombus, that was
later recognised as plaque erosion and as an alternative mechanism to myocardial
infarction.11
It is now well recognised that ACS is caused by coronary artery thrombosis. Thrombus
is usually occlusive and sustained in STEMI, leading to transmural ischemia and typical
ECG changes whereas it is non-occlusive, dynamic or even absent in UA and
NSTEMI.12 Rupture of an atherosclerotic plaque remains the main cause of coronary
thrombosis and occurs in the presence of a thin fibrous cap, abundant inflammatory
cells and a large lipid core in the plaque. These observations led to the definition of the
vulnerable plaque or thin-cap fibroatheroma (TCFA) which can thus be assumed to
encompass the majority of plaques at risk for rupture.13 Although the absence of a
TCFA in a patient indicates a low imminent risk for plaque rupture and thrombosis, the
presence of a TCFA does not inevitably lead to plaque rupture and to a thrombotic
event. Studies using intravascular imaging, intravascular ultrasound or optical
coherence tomography (OCT) have clearly shown that only 5% of TCFA caused
coronary events over a 3.4 years follow-up, weaken the rationale for an interventional
targeted therapeutic approach to rupture-prone plaques. 14, 15 Additionally, a significant
proportion of thrombotic lesions found on autopsy are not associated with a plaque
rupture. 13 Superficial erosion and calcified nodules have emerged as underlying
mechanism of ACS with increasing frequency.16 Lesions underlying superficial erosions
differ in their histological characteristics compared to lesions associated with plaque
rupture (figure 1). They lack thin cap, large lipid pool and inflammatory cells but
accumulate abundant extracellular matrix, notably proteoglycans and
glycosaminoglycans.17

Figure 1. Contrasts between superficial erosion and fibrous cap rupture as causes of arterial
thrombosis. LDL, low-density lipoprotein (Libby, Requiem for the ‘vulnerable plaque’,
European Heart Journal (2015) 36, 2984–2987. Reprinted with permission)

9
 Background

The mechanism leading to thrombus formation without rupture remains an unsolved

question and different hypotheses have been provided, e.g. vasospasm that may be a
cause of the endothelial damage and subsequent thrombosis. Calcified nodules are
pathologically defined as the presence of fracture of a calcified plate, interspersed fibrin,
and a disrupted fibrous cap with an overlying thrombus 13 and are the less common
identifiable mechanism of coronary thrombosis with an incidence of around 8% (figure
2, 3 and figure 4).16

Figure 2. Plaque rupture is identified on cross-sectional

optical coherence tomography (OCT) images by the
disrupted fibrous-cap (arrowheads) and a cavity (*)
formation inside the plaque (Haibo Jia, J Am Coll Cardiol
2013; 62:1748–58. Reprinted with permission from
Elsevier).

Figure 3 Superficial erosion. Serial optical coherence tomography (OCT) cross-sectional im-
ages from proximal to distal of the culprit lesion indicate that no rupture is detected. Cross-sec-
tional images indicate fibrous plaque (homogeneous high signal region) proximal (A) and distal
(D) to thrombus. OCT-erosion is identified as an irregular lumen surface with attached mural
thrombus (arrows) overlying a fibrous plaque (B and C) (Haibo Jia, J Am Coll Cardiol 2013;
62:1748–58. Reprinted with permission from Elsevier).

The increasing frequency of superficial erosions as the underlying mechanism of ACS

may be explained by the increasing use of statin treatment and less active smoking that
may lead to stabilisation of vulnerable plaques and reduce their risk for rupture.18
Erosions are more frequently associated with NSTEMI whereas plaque rupture is more
common in STEMI.16 The increasing frequency of plaque erosions may have
contributed to the increasing frequency of NSTEMI. Noteworthy, plaque rupture is
particularly infrequent in premenopausal young women 19 whereas superficial erosions
occur more frequently in women, in diabetics and the elderly.

10
 Background

Figure 4 Optical coherence tomography (OCT)-calcified nodule is identified as a nodular calci-

fication (A) protruding into lumen through a disrupted fibrous cap (arrowheads) overlying su-
perficial calcification with red thrombus (B and C, arrows) attached to the disrupted site.
*Guidewire (Haibo Jia, J Am Coll Cardiol 2013; 62:1748–58. Reprinted with permission from
Elsevier).

Thrombosis – the fundamental role of platelets and coagulation system

The thrombotic response following the plaque rupture or erosion varies considerably
and may range from a small mural thrombus sealing the plaque to a large occlusive
thrombus causing a STEMI. Determinants of the thrombotic magnitude are probably
those of the classic triad of Virchow: 1) thrombogenicity of the exposed plaque
material; 2) local flow disturbances due to coronary stenosis; and 3) systemic
thrombotic propensity. In the setting of plaque rupture, thrombogenicity of the exposed
plaque material is probably the main determinant. Collagen from the cap and the
thrombogenic lipid-rich core are exposed to blood flow and initiate the thrombotic
process.20 In the case of plaque erosion, endothelial denudation is a weak thrombogenic
stimulus. Therefore flow disturbances and systemic thrombotic factors such as platelet
hyperaggregability and hypercoagulability or depressed fibrinolysis may play the most
important role.21, 22
Normally, platelets do not interact with other cells or the intact vessel wall. In case of
vessel injury a cascade of biochemical and cellular processes leads to thrombus
formation that, depending on the initiating event, may represent protective hemostasis
or an ACS. This process can be divided into five steps: platelet translocation, activation,
secretion, adhesion and aggregation (figure 5).

11
 Background

Figure 5. Distinct steps of platelet adhesion, activation, and aggregation following endothelial
injury (Kraft P et al; Next-generation antithrombotics in ischemic stroke: preclinical perspective
on 'bleeding-free antithrombosis' J Cereb Blood Flow Metab. 2012 Oct;32(10):1831-40.
Reprinted with permission)

The initial adhesion of platelets (tethering, A) is mediated by the binding of the

glycoprotein (GP) Ib-V–IX receptor complex to the A1 domain of the von Willebrand
factor (VWF) on endothelial cells. Additionally, binding to P-Selectin can enhance
platelet recruitment to the intact vessel wall.23, 24 In a second step (B) interactions
between GPVI and collagen stabilise the thrombus. Moreover, translocation is followed
by platelet activation, mainly initiated by collagen and thrombin, that produces a platelet
monolayer that promote further thrombin generation and adhesion of new platelets.25
Platelet activation prompts secretion of platelet storage granules that leads to the release
of ADP, thrombin and other activating factors. Through this sustaining autocrine circuit
further platelet activation is achieved.26 The two final steps towards stable thrombus
formation and growth are adhesion and aggregation. Binding of fibrinogen and vWf via
activated GPIIb/IIIa receptors are the key components of this process (figure 6). 27

12
 Background

Figure 6. Platelet activation mechanism (Wallentin et al; P2Y12 inhibitors: differences in

properties and mechanisms of action and potential consequences for clinical use. European
Heart Journal (2009) 30, 1964–1977, reprinted with permission)

Despite the crucial role of platelets in thrombosis, the importance of the coagulation
system should not be overlooked (figure 7). Exposure of tissue factor activates
coagulation cascade that leads to a burst of thrombin generation. Thrombin has a critical
role by converting soluble fibrinogen into a network of fibrin, by activating platelets
through PAR receptors and contributing to vessel constriction.

Figure 7. The cell-based

model of coagulation
highlights the initiation of
events on tissue-factor
bearing cells, followed by
an amplification step
wherein events transition to
activated platelets. The
propagation state is
characterised by a burst of
thrombin generation. (From
Hoffman M: A cell-based
model of hemostasis.
Thromb Haemost 2001;
85:958-965. Reprinted with
permission)

13
 Background

Management of STEMI patients - Timely reperfusion therapy

Patients with STEMI usually have an occluded coronary artery. Therefore reperfusion
therapy in order to restore patency and to reduce infarct size is the cornerstone of the
management. Timely diagnosis and reperfusion are key components since the greatest
benefit gained from reperfusion therapy occurs within 2-3 hours from symptom onset.28
In order to reduce time between symptom onset and provision of reperfusion therapy
and improve outcome, organisation of local networks including ambulances, referral
hospital or emergency departments and the receiving hospital is crucial. Still, one third
of STEMI patients do not receive reperfusion therapy within 2 hours after the first
medical contact.29 Early diagnosis, in a prehospital setting, triage and initiation of
pharmacologic reperfusion therapy or transfer to a PCI capable center have been shown
to reduce delays and improve clinical outcomes. 30
Two main reperfusion therapies exist, fibrinolytic therapy and primary PCI. Fibrinolytic
therapy was a major advance in the treatment of STEMI. In the late 1980s thrombolytic
therapy with streptokinase significantly reduced mortality compared to placebo.31
Results were further improved when recombinant tissue-type plasminogen activator,
such as alteplase, was used.32 The main benefit was observed when thrombolytic
therapy was administrated within 2-3 hours after symptom onset and diminished with
time.33 Concerns about risk for bleeding complications, mainly intracranial bleeding and
absolute or relative contraindications to treatment, resulted in relatively low rates of
provided reperfusion therapy in STEMI.
In 1974, at the Medical Policlinic of the University of Zürich, Andreas Grüntzig (1939–
1985) for the first time used a balloon-tipped catheter to re-open a severely stenosed
femoral artery, a procedure, which he called “percutaneous transluminal dilatation”. In
1977, Dr. Grüntzig performed the first coronary angioplasty on a 38-year-old man
suffering from angina due to a stenosis in the LAD.34 Balloon angioplasty became one
of the most successful examples of translational medicine in the twentieth century for
which Grüntzig and Charles T. Dotter (1920–1985) received a nomination for the Nobel
Prize in Physiology or Medicine in 1978.
Since then PCI has undergone continued advances and has become one of the most
frequently performed therapeutic interventions. Primary PCI is defined as PCI in the
setting of STEMI, without previous fibrinolysis. Compared to fibrinolysis, reperfusion
with PPCI significantly reduced the risk for mortality, re-infarction and intracranial
bleeding. 35, 36 These results led to an international shift from fibrinolytic therapy to
PPCI and an overall increase in reperfusion rates. PPCI is the preferred reperfusion
strategy in STEMI patients and is used in Sweden in more than 80% of patients under
the age of 80.
Thrombolytic therapy still remains an option due to limited availability of timely PPCI
in some areas. Only 5% of STEMI patients are treated with fibrinolytic therapy in
Sweden. (figure 8)

14
 Background

Figure 8. Trends in reperfusion treatment in Sweden, in patients with STEMI, <80 years, 1995-
2015 (SWEDEHEART annual report 2015)

Anticoagulation and antiplatelet therapy in STEMI patients during PPCI

STEMI represents a highly thrombotic state and therefore adjunctive antithrombotic

therapy as a complement to PPCI is of crucial importance. The ideal antithrombotic
therapy should reduce the risk for ischemic complications such as stent thrombosis and
distal embolisation and at the same time minimise the risk of bleeding events, providing
a net clinical benefit for the patient.
The glycoprotein IIb/IIIa receptor inhibitors (GPI) are potent antiplatelet agents that
after intravenous administration, rapidly inhibit platelet aggregation and thrombus
formation and may dissolve fresh thrombus already formed (figure 6). 37 For many
years, unfractionated heparin (UFH) with upfront or peri-procedural administration of
GPI during PPCI was the standard treatment, as early reports showed a significant
reduction in mortality. 38, 39 However, in the era of potent P2Y12 receptor blockers
including high loading dose of clopidogrel the role of adjunctive GPI administration is
controversial. The ON-TIME-2 trial showed a lower incidence of 30 day death,
recurrent MI or urgent vessel revascularisation with pre-hospital administration of
tirofiban compared with placebo (5.8% vs 8.6%, p=0.043) without a significant increase
in bleeding (3.4% vs 2.9%, p=0.58).40 Conversely, the ASSIST trial and the BRAVE 3
showed no benefit with routine eptifibatide or upstream abciximab, respectively.41, 42 A
significantly higher risk for major or minor bleeding was observed in the ASSIST trial
but not in BRAVE. The randomised FINESSE trial included almost 2 500 STEMI
patients presented within 6 hours from symptom onset and compared the efficacy and
safety of facilitated PPCI with upfront administration of abciximab, abciximab plus
15
 Background

reteplase versus PPCI only. Although the combination of abciximab and reteplase was
associated with significantly higher rates of ST-segment resolution, the primary
outcome, a combination of death, ventricular fibrillation, cardiogenic shock and
congestive heart failure, did not significantly differ between the three groups.43 The rate
of bleeding, intracranial haemorrhage and transfusion was significantly higher in the
facilitated PPCI groups. However, a sub study showed a benefit in the primary outcome
in high risk patients. 44
The HORIZON-AMI trial, published almost 10 years ago, was a landmark trial
comparing the efficacy and safety of UFH + routine GPI versus bivalirudin
monotherapy with bailout administration of GPI in 3 602 STEMI patients. At 30 days
and 1 year the rate of net adverse clinical outcome (NACE) (death, re-infarction, target
lesion revascularisation (TLR), stroke or major bleeding) as well as the individual
endpoint of cardiac mortality and major bleeding were significantly lower with
bivalirudin (30 day NACE rate 9.2% versus 12.1% with UFH+GPI, RR 0.76, p<0.01).45,
46
While there was no difference in major adverse cardiovascular events (MACE), the
superiority in NACE was mainly driven by a reduction in major bleeding (4.9% versus
8.3%, p<0.01), cardiac mortality (1.8% versus 2.9%, p=0.03) and all-cause mortality
(2.1% versus 3.1%, p=0.046). Notably, a significantly higher risk of acute stent
thrombosis was noted with bivalirudin (1.3% versus 0.3%, p<0.01). The benefits were
sustained and continued to increase through 3 years follow-up.47 This study caused an
international shift in the antithrombotic strategy during PPCI towards increased
bivalirudin use (figure 9).

Figure 9. Anticoagulation and proportion of GPI and /or bivalirudin before/during PPCI in
STEMI patients in Sweden, 2006-2015 (SWEDEHEART annual report 2015).

In the era of potent P2Y12 receptor blockers and early mechanical reperfusion, GPI is
no longer assumed as a frontline therapy but only as an adjunctive therapy in selected
cases. This is reflected by current recommendations for GPI use from the European
society of cardiology and ACC/AHA guidelines.48 GPI use is mainly recommended as
bailout treatment in patients with giant thrombus, no reflow or slow flow and as
upstream treatment in high risk patients undergoing transfer for primary PCI. Recent
trials comparing different antithrombotic strategies is STEMI patients have reported
very low rates of GPI use, when GPI was restricted to bailout use by the study protocol
49, 50
but considerably higher rates when the decision was left to the operators´
discretion.51 However, GPIs may still have an important role in our armamentarium of
contemporary PCI 52, 53 and the optimal rate of administration certainly depends on the
population studied.

16
 Background

The initial enthusiasm for bivalirudin following HORIZON-AMI trial, has been
dampened by subsequent studies comparing bivalirudin with UFH and provisional or
bailout GPI showing conflicting results. The HEAT-PCI, was a single centre trial of
1 812 patients randomised to UFH versus bivalirudin monotherapy without post-PCI
infusion.49 This trial reflected current PCI techniques, with high rate of DES
implantation (80%) and radial access (81%) Furthermore novel P2Y12 blockers were
used in 89% of the patients. The GPI use was 15% in both groups. In contrast with
previous studies, the composite outcome of death, re-infarction, stroke or unplanned
TLR was higher in the bivalirudin group (8.7% versus 5.7%, p=0.01) mainly driven by
higher re-infarction and TLR, where both were attributed to the higher rate of stent
thrombosis in the bivalirudin arm (2.9% versus 0.9%, p<0.01). The incidence of major
bleeding, according to Bleeding Academic Research Consortium (BARC) definition,
did not significantly vary between the two groups (3.5% versus 3.1%, p=0.59).54 The
study was critisised for the single centre design and the activated clotting time
monitoring system that was utilised and generating the hypothesis of potential under
dosing of bivalirudin used. Following this study the BRIGHT study included patients
with ACS (88% STEMI) randomly assigned to three different treatment strategies:
bivalirudin monotherapy (n=735), UFH monotherapy (n=729) and UFH plus tirofiban
(n=730). 50 Compared to HEAT-PCI trial, the UFH dose was higher in the UFH-
monotherapy arm (100U/kg versus 70U/kg) but the GPI use was lower (only 5%).
Clopidogrel was used and bivalirudin infusion was continued after PCI. Bivalirudin was
associated with a significantly lower rate of BARC major bleeding compared to UFH
monotherapy or UFH+ tirofiban (0.5% versus 1.5% versus 2.1%). The incidence of
death, myocardial infarction or TLR did not differ between the three groups whereas the
incidence of stent thrombosis was very low (0.3%) in all the groups. The most recent
MATRIX trial included 7 000 ACS patients (56% STEMI) and compared radial versus
femoral access and bivalirudin versus UFH and provisional GPI administration. 51 The
use of GPI significantly differed between the two groups and was 4.6% with bivalirudin
and 25.8% with UFH. Bivalirudin use was associated with significantly lower incidence
of BARC major bleeding (1.4% versus 2.5%) and all-cause mortality (1.7% versus
2.3%) whereas the rate of stent thrombosis was significantly higher in the bivalirudin
group (1.0% versus 0.6%).

Oral antiplatelet therapy in STEMI patients

In STEMI patients, dual antiplatelet therapy with aspirin and an adenosine diphosphate
receptor (ADP) antagonist at the time of first medical contact is highly recommended
(Ib recommendation according to ESC guidelines on myocardial revascularisation) to
prevent ischemic complications. 48, 55 Clopidogrel, a thienopyridine ADP receptor
blocker was the drug of choice in ACS care for more than a decade. However,
clopidogrel has some important limitations: a slow onset of action due to the need of
metabolism to produce the active thienopyridine metabolites, mild potency and large
inter-individual variability in response. 56, 57 A 75-mg o.d. clopidogrel maintenance dose
requires at least 5 days and a 600-mg loading dose (LD) of clopidogrel requires up to 8
hours to achieve around 50% steady state of inhibition of ADP-induced platelet
aggregation in stable patients. 58, 59 Furthermore, approximately 15- 30% of patients
have been reported to be nonresponsive. Of importance, several studies have
highlighted a link between high residual platelet reactivity (HRPR) or suboptimal
inhibition of platelet reactivity (PR), as measured by platelet assays after a clopidogrel

17
 Background

LD, and the occurrence of thrombotic events after PCI.60 Those limitations could only
partially be overcome by high LD or maintenance dose of clopidogrel that improves
pharmacodynamics properties of the drug.61 In the pre-specified analysis of CURRENT-
OASIS 7 trial including 17 263 individuals with ACS who underwent PCI, high LD
clopidogrel (600mg) was associated with a significant reduction in cardiovascular
events and stent thrombosis compared to standard LD. 62 The rate of definite or
probable stent thrombosis was 31% lower and definite stent thrombosis was 46% lower
with double dose clopidogrel. CURRENT-defined major bleeding was more common
with high LD than with the standard dose clopidogrel but the incidence of TIMI-major
bleeding was similar between the two groups.54 Furthermore, upstream administration
of clopidogrel prior to arrival at the catheterisation laboratory compared to
administration after coronary angiography have shown to significantly reduce the risk of
re-infarction and stent thrombosis and improved survival. 63, 64
Ticagrelor is a direct acting and reversibly binding P2Y12 receptor inhibitor that is
highly recommended in clinical guidelines for treatment of patients with ACS. 65-67 In
patients with stable angina pectoris (SAP), administration of 180 mg LD of ticagrelor
resulted in a more rapid and stronger inhibition of PR compared to clopidogrel. Within
30 minutes, ticagrelor administration led to the same degree of inhibition of PR as that
achieved 8 hours after a 600 mg LD of clopidogrel. 59 In the PLATO trial, including
18 624 patients with ACS, ticagrelor as compared with clopidogrel was associated with
a reduction of cardiovascular death (4% versus 5.1%, p<0.01) and MI (5.8% versus
6.9%, p<0.01) without increasing the rate of overall major bleeding but with an increase
of non-CABG-related major bleeding (4.5% versus 3.8%, p=0.03). 68 In the pre-
specified analysis of the PLATO trial in patients with STEMI, a significant reduction of
definite stent thrombosis was observed (HR 0.58; 95% CI 0.37-0.89) without any
increase in the incidence of major bleeding events.69 The faster and more potent platelet
inhibition with ticagrelor compared to clopidogrel is the main explanation for the lower
occurrence of ischemic events observed in the PLATO trial. The last years, ticagrelor
has become the main oral antiplatelet therapy for treatment of patients with ACS in
Sweden. About 90% of STEMI patients are treated with ticagrelor (figure 10).

Figure 10. Trend in the use of P2Y12 receptor blockers at discharge, in patients with STEMI
<80 years in Sweden (SWEDEHEART annual rapport 2015).

18
 Background

Despite the predictable pharmacodynamics properties of ticagrelor in patients with SAP,

in patients with STEMI, where fast and effective platelet inhibition is even more
important, a delayed onset of action of platelet inhibitors and a wider variability of drug
response have been demonstrated. 70-72 Beside the higher baseline PR in STEMI
patients, a limited or delayed intestinal absorption of orally administered drugs is
another major contributor to this observation. 71, 72. More than half of the STEMI
patients treated with LD of integral ticagrelor still have HRPR up to 4 hours after
administration of the drug 71 and are at increased risk of ischemic complications.73 In
the ATLANTIC trial, despite a short median time between pre-hospital and in-hospital
administration of ticagrelor, prehospital administration significantly reduced the risk of
stent thrombosis, suggesting that fast and strong platelet inhibition at the time of PCI is
clinically important. 74 Previous pharmacokinetic studies have demonstrated that
chewable aspirin and crushed clopidogrel administration increased the rate of drug
absorption compared to integral tablets, when administered orally. 75, 76 Recently,
crushed ticagrelor tablets, administered orally or via a naso-gastric tube, has been shown
to be feasible and resulted in increased plasma concentration of ticagrelor and its active
metabolite at an earlier time point compared to integral tablets.77, 78 As the plasma
concentration of ticagrelor and its active metabolite is linearly associated with the
degree of platelet inhibition, 65 administration of crushed or chewed ticagrelor may
provide a more rapid onset of drug action. The MOJITO trial showed that crushed
ticagrelor tablet administration in STEMI patients is feasible and provides faster platelet
inhibition compared with standard integral tablets. 79 However, data about the
pharmacodynamics properties of novel ways of ticagrelor administration are limited.

Bleeding events – the Achilles heel of invasive management and antithrombotic

treatment

Advances in the care, increasingly efficacious antithrombotic therapy and early invasive
management have led to a significant improvement in outcomes in patients with ACS. 8
However, the anti-ischemic benefit obtained with a more aggressive antithrombotic
therapy has been associated with a concomitant risk for bleeding and blood transfusion.
The addition of clopidogrel to aspirin for the treatment of ACS in the CURE trial was
associated with reductions in ischemic events but at the expense of an increased risk of
bleeding (3.7% versus 2.7%, RR, 1.38; p =0.001).80 Compared to clopidogrel, the use of
more potent antiplatelet therapy such as prasugrel or ticagrelor resulted in significant
improvement in ischemic outcomes in the TRITON—TIMI 38 and PLATO studies.68, 81
That improvement came at a cost, as prasugrel increased major bleeding (HR 1.32; 95%
CI 1.03 – 1.68, p=0.01) and life-threatening bleeding (1.4% versus 0.9%, p=0.01).
Similarly, but to a less extent, ticagrelor increased the risk of non-CABG major
bleeding compared to clopidogrel in the PLATO trial. In a meta-analysis enrolling
31 402 patients with ACS, treatment with GPI significantly reduced the occurrence of
death and myocardial infarction (10.8% versus 11.8%, p=0.02) and the greatest benefit
was observed in patients at high risk for thrombotic complications. 82 However, major
bleeding complications were significantly increased with GPI (2.4% versus 1.4%,
p<0.01).
Recent analyses and clinical trials have clearly shown a strong independent association
between bleeding complications, blood transfusion and poor outcomes in patients with
ACS (figure 11).83-87 Given the high efficacy of the current antithrombotic treatment to

19
 Background

reduce ischemic complications, strategies reducing the risk of bleeding have the
potential to further improve outcome in patients with ACS.

Figure 11. Independent predictors of mortality in patients with ACS (Manoukian et al. Major
Bleeding in ACS. JACC Vol. 49, No. 12, 2007. Reprinted with permission)

The incidence of major bleeding significantly varies in clinical trials between 1 and
10%. Variations in the utilisation of invasive treatment, combination of various
antiplatelet and anticoagulation agents at different doses and differences in underlying
risk of bleeding are some plausible explanations for the disparity of the reported rate of
bleeding. Utilisation of different bleeding definitions in ACS trials is another
explanation. Multiple bleeding definitions exist with considerable differences in their
bleeding severity classification criteria (figure 12). A main difference between various
definitions is the use of clinical or laboratory parameters for classification of bleeding
severity. The GUSTO bleeding definition uses clinical outcome whereas the TIMI
definition is based on laboratory parameters such as haemoglobin drop for
discrimination of bleeding.32, 88 The BARC definition arose from the need to overcome
the drawbacks of the myriad of the bleeding definitions currently in use in clinical trials,
including TIMI and GUSTO and combined both clinical and laboratory criteria.54 The
PRODIGY trial was the first prospective study to use the BARC bleeding scale and
provided evidence that BARC >2 bleeding events carry prognostic implications with
respect to overall mortality at 2 years to a similar range compared to TIMI major or
minor as well as GUSTO moderate to severe events.89 Although a significant
association between different definitions and adverse clinical outcome has been
demonstrated, 84, 86, 90 data indicate that bleeding defined by clinical events is more
important in terms of prognosis rather than bleeding defined solely on the basis of
reductions in haemoglobin concentration.83

20
 Background

Figure 12a. Bleeding Academic Research Consortium (BARC) definition for bleeding

21
 Background

Figure 12b. Major-bleeding definitions (continues)

22
 Background

Regardless of the bleeding definition used, advanced age, female gender, lower body
weight, use of invasive procedures and renal insufficiency have consistently been found
to be strong independent predictors of bleeding complications in patients with ACS
(figure 13).

Figure 13. Predictors of bleeding in acute coronary syndrome (Moscucci et al, Predictors of
major bleeding in acute coronary syndromes. EHJ (2003) 24, 1815–1823. Reprinted with
permission).

Women had a 43% higher risk for developing a major in-hospital bleeding compared to
men in the GRACE registry. 91 Smaller body and vessel size, reduced creatinine
clearance (for a given weight and serum creatinine), higher prevalence of comorbidities
and higher risk of drug overdosing were main contributors to this observation. 92 In
women, excess dosing of antithrombotic agents may account for up to 25% of the
bleeding risk.93 Apart from female gender, older age and renal insufficiency were strong
predictors of excess dosing of antithrombotic agents. A rapport from the CRUSADE
registry of more than 140 000 ACS patients showed that 42% of patients received at
least one excess dose of antithrombotic agent during their hospitalisation and had
significantly higher risk of bleeding and prolonged length of hospital stay.92 Careful
adjustment of doses of pharmacological agents cleared by kidneys, based on the
estimated renal function, is of crucial importance in order to reduce the risk for
bleeding.

Prevention of bleeding complications and improvement of outcomes

Despite the strong association between bleeding and adverse outcome in patients with
ACS the causal relationship between bleeding complications and adverse outcome
remains uncertain.94 Bleeding complications may be a surrogate marker of
comorbidities and identify patients at high risk for adverse events given the overlapping
23
 Background

between predictors of bleeding and predictors of ischemic complications. However,

consequences of bleeding including hemodynamic instability, anemia, blood transfusion
and early discontinuation of antiplatelet and anticoagulation therapies may have a direct
negative impact on outcomes (figure 14). 86, 95, 96

Figure 14. Hypothetical mechanisms linking bleeding and mortality (Steg et al; Bleeding in
ACS and PCI. European Heart Journal (2011) 32, 1854–1864. Reprinted with permission)

Interventional studies have provided some evidence about a causal relationship between
bleeding and adverse outcome. In the OASIS-5 trial including 20 078 patients with
NSTEMI, treatment with fondaparinux compared to enoxaparin, significantly reduced
the incidence of 9-day major bleeding (2.2 % vs 4.1 %, p<0.01). At 30 days, the number
of deaths was significantly lower among patients assigned to fondaparinux (295 vs. 352,
p=0.02).97 In the HORIZON-AMI trial enrolling 3 602 patients with STEMI and
comparing bivalirudin vs UFH+GPI, treatment with bivalirudin was associated with a
significant reduction in major bleeding at 30 days (4.9% vs.8.3 %, p<0.01) and
mortality at 30 days (2.1% vs. 3.1 %, p=0.047). In the WOEST trial of 573 patients
undergoing PCI with an indication for oral anticoagulation, the bleeding rate as well as
the all-cause mortality rate was significantly lower in patients who received double
therapy compared to patients who received triple therapy.98 Finally, in the MATRIX
study, a reduction of major bleeding by radial access was associated with lower all-
cause mortality compared to femoral access. 99
Prevention of bleeding complications in STEMI patients undergoing PPCI should
always take into consideration: 1) choice of antithrombotic strategy 2) kidney function
and 3) access site. An antithrombotic strategy that reduces the risk of bleeding while
maintaining anti-ischemic efficacy should be preferred especially in a subgroup of
patients with high risk of bleeding such as elderly, women and patients with renal
insufficiency. Careful attention when dosing antiplatelet and anticoagulation agents that
are cleared by kidneys is warranted. Finally, reducing access site bleeding can be
achieved by using the radial instead of femoral approach.

24
 Background

Gender differences in patients with ACS

Coronary artery disease is the leading cause of mortality for women and afflicts 6.6
million women annually in the US. 100, 101In Sweden, 26 600 patients were diagnosed
with MI in 2015. Despite a significant improvement in cardiovascular disease (CVD)
mortality in both genders, the annual CVD mortality rate has remained higher for
women than for men the last 30 years.100 Within 1 and 5 years of a first MI, regardless
of age, the mortality is significantly higher in women compared to men (women vs men:
26% vs 19% and 47% vs 36%, respectively). Furthermore, data suggest a significant
interaction between age and gender whereby younger women are at particularly higher
risk of mortality after MI compared to men.102, 103
Women are older when they present with their first MI and have more often
comorbidities such as DM, hypertension and CKD, compared to men. 102, 104 The older
age onset of IHD in women is mainly attributed to the protective role of circulating
estrogen on the endothelium. 105 However the exact mechanism by which estrogen
protects against atherosclerosis is incompletely understood. Traditional risk factors for
IHD are similar in both genders. In the INTERHEART study, 9 potentially modifiable
risk factors (smoking, hypertension, DM, waist-to-hip ratio, dietary patterns, physical
activity, alcohol consumption, plasma apolipoproteins, and psychosocial factors)
accounted for 96% of the population-attributable risk of MI in women. 106 Clustering of
risk factors in women at the time of the first MI may be explained by older age.
However, a recent study in young women with MI showed that women fail to assess
their personal risk for IHD and they reported limited access to preventive cardiac care
before MI.107
Pathophysiological mechanisms of MI may significantly differ between men and
women. Plaque rupture remains the most common mechanism of MI but a recent study
showed that only 56% of fatal MI in women was found to be due to a plaque rupture
compared to 76% in men. 108 Plaque rupture is particularly infrequent in premenopausal
women 19 whereas autopsy studies have shown an increased prevalence of plaque
erosion compared to men and postmenopausal women.109 These findings may explain
the higher incidence of non-obstructive coronary artery disease in women with MI. 110
Additionally, unusual pathophysiological mechanisms of MI such as spontaneous
coronary artery dissection as well as Takotsubo cardiomyopathy mimicking ACS are
more common in women. 111, 112.
Gender differences in clinical presentation are evident in patients with ACS and may
influence both time to presentation and outcomes.113 Despite the fact that chest pain
remains the most common symptom in both genders, women more often have atypical
chest pain, angina-equivalent such as dyspnoea or more general symptoms such as
fatigue and indigestion. Women present later to treatment for AMI than men, a
difference that has remained unchanged over the last two decades despite educational
initiatives to increase awareness of the symptoms suggesting MI. 114, 115

Reperfusion therapy in STEMI patients from a gender perspective

Fibrinolytic therapy is still an important reperfusion strategy when timely reperfusion

with PPCI is not available. 48 Fibrinolytic therapy, especially when administrated early,
significantly improves outcomes, regardless of gender and age.116 However, the short-
and long-term mortality in STEMI patients treated with fibrinolysis is about twice as
high in women than in men.117, 118 The incidence of complications such as shock, heart

25
 Background

failure (HF), re-infarction, stroke and bleeding is significantly higher in women. 118
Furthermore, female gender is an independent predictor of intracranial bleeding with
fibrinolytic therapy. Moreover, relative contraindications to fibrinolytic therapy such as
advance age, uncontrolled hypertension and small body weight are more often present
in women than in men and contributed to the lower rate of reperfusion therapy provided
in women with STEMI in the fibrinolytic era.
Because women have higher risk for complications with fibrinolytic therapy they
derived a greater benefit from PPCI. Use of PPCI as reperfusion strategy reduces the
risk for intracranial bleeding and is an independent predictor of survival in women with
STEMI.119 In the GUSTO II-B angioplasty sub study, PPCI compared to fibrinolytic
therapy prevented 56 deaths in women and 49 in men per 1 000 treated. 120 Despite the
improvement in outcomes in women in the era of PPCI, controversy still remains as to
why short and long term mortality after STEMI is reported to be higher in women than
men.102, 121, 122 It remains unclear if gender is an independent predictor of outcome due
to differences in the biology of the disease in men and women with STEMI or if this is a
confounded observation due to baseline differences in cardiovascular risk profile and/or
health care utilisation between genders.7, 123-125
Pre-specified gender analysis of RCTs have shown that the observed unadjusted higher
short- and long-term mortality in women compared to men are attenuated and no longer
significant after adjustment for age and other baseline characteristics. 126, 127 In addition
to higher age and comorbidities in women, disparities in the management between
genders may further contribute to the higher risk for adverse outcomes in women
compared to men. Women are less likely to receive primary reperfusion therapy despite
the higher survival advantage in women than in men and less likely to get newer
evidence based-therapies such as thienopyridines and angiotensin converting enzyme
inhibitors (ACEI).128 Also, women are more likely to have a prehospital missed
diagnosis of STEMI and a higher risk for inter hospital transfer to a PCI-capable facility
and hence are at risk for reperfusion delay.129 Ambulance service may give lower
priority for transporting women than men with possible STEMI diagnosis, resulting in
potentially longer ischemic time.130 While the reasons for these disparities are unclear,
they may significantly contribute to increase mortality in women, presented with
STEMI.

Gender differences in the effectiveness and safety of antiplatelet therapy

Treatment with DAPT (aspirin and an ADP receptor blocker), improves outcomes in
patients with an ACS. A meta-analysis of all the most important randomised trials on
clopidogrel, with focus on gender differences, showed that clopidogrel significantly
reduced the risk for adverse cardiovascular outcomes by 14% with similar efficacy in
both genders. Clopidogrel significantly increases the risk of bleeding in both genders.
131
However, limited data exist in terms of the efficacy and safety of clopidogrel in men
and women with STEMI treated with PPCI.
In the PLATO trial, ticagrelor significantly reduced the combined ischemic endpoints
compared to clopidogrel. In a pre-specified gender analysis, women showed similar
absolute and relative reduction of the primary endpoint within the ticagrelor arm and
similar effects were also seen in terms of major bleedings.132 Notably, the PLATO trial
included STEMI patients planned for PPCI as well as patients with NSTEMI intended
for either invasive or medical treatment.

26
 Background

Chronic kidney disease in patients with ACS

It is assumed that more than 20% of patients with ACS have at least moderate CKD and
almost 40% have some renal impairment.133, 134 Based on estimated glomerular filtration
rate (eGFR), previous studies have shown a powerful relationship between the severity
of CKD and poor outcomes in ACS and STEMI patients.135-141 Multiple possible
mechanisms for the cardio-renal syndrome, the strong association between CKD and
increased risk for death and cardiovascular disease, exist. A high prevalence of known
risk factors for cardiovascular disease and death such as DM, HT and heart failure is
observed in patients with CKD. 134 CKD is also associated with increased levels of
inflammatory factors, abnormal apolipoprotein levels, enhanced coagulability, anemia,
left ventricular hypertrophy and increased arterial calcification, factors that may
contribute to the higher risk for cardiovascular disease. 142, 143 Furthermore, there is an
association between the risk of bleedings and eGFR.144 CKD is one of strongest
predictors of bleeding events 92 and overdosing of antithrombotic agents significantly
contributes to these results.93 A rapport from the CRUSADE registry of more than
140 000 ACS patients showed that 42% of patients received at least one excess dose of
antithrombotic agent during their hospitalisation and had significantly higher risk of
bleeding.92 Another important contributor to the worse prognosis of CKD patients is
under treatment. In Gulf Registry of Acute Coronary Events prospective registry,
including 6 518 consecutive patients with an ACS, patients with CKD were less likely
to receive antiplatelet agents, ACEI, beta blockers and statins and were less likely to
undergo invasive management. 145 Concerns for further worsening of renal function
and/or therapy-related toxic effects in patients with CKD are possible explanations for
this observation. However, the benefit of revascularisation may well exceed the risk
associated with the invasive management. A report from the SWEDEHEART registrer
including 23 262 NSTEMI patients showed that the adjusted risk for death at 1 year was
36% lower in patients with CKD who underwent early invasive management with PCI
compared with those who did not. The benefit from early invasive strategy was not
uniform across the five CKD stages and declined with lower renal function. 146

Measurements and estimations of glomerular filtration rate

The best overall index of renal function is considered to be the glomerular filtration rate
(GFR) and the gold standard method for its assessment is the measurement of renal
inulin clearance or other methods using radiolabeled isotopes or nonradioactive contrast
agents such as iohexol.147, 148 Unfortunately, these methods cannot be used routinely in
daily practice because of their complexity and cost. Therefore, formulas to estimate
GFR, based on creatinine, have been developed. The Cockcroft-Gault (CG), and the
Modification of Diet in Renal Disease (MDRD) 149, 150 are the most widely used.
However, their performance significantly varies in populations not similar to the one
from which the equations were derived.151 During the last years, new equations such as
the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) 152 based on
creatinine has emerged and challenged the older formulas due to its higher accuracy.
Nevertheless, all creatinine based equations share a main limitation, the unpredictable
production and tubular secretion of creatinine in various individuals and populations.
Cystatin C is a proteinase inhibitor, eliminated mainly via glomerular filtration, without
tubular reabsorption and degradation and is a more reliable predictor of GFR than
creatinine.153 The relative Grubb cystatin C equation (rG-CystC) 154 has shown a high

27
 Background

accuracy, comparable to MDRD, using the cystatin C concentration, and has probably
overcome many limitations of the creatinine based estimates in different populations.
However, measurements of cystatin C have suffered from a lack of universal
standardisation. Furthermore, it remains unclear if inflammation, myocardial necrosis
and atherosclerosis affect cystatin C levels in patients with MI.155, 156
As significant disagreements in CKD classification between formulas have been proven
in MI populations and overestimation of GFR by formulas may have led to overdosing
of antithrombotic drugs and contributed to the observed higher bleeding rate.151 Despite
the crucial role of renal function in the management of STEMI patients, GFR estimates
have not been validated against mGFR in that population during the acute phase.
Therefore, it is still unclear if their prognostic impact only depends on their accuracy to
estimate GFR or the coefficients that are included in the formulas.

28
 Aims

AIMS

The aims of the research program on which this thesis is based were to

 compare the efficacy and safety of the two most commonly used antithrombotic
strategies, bivalirudin vs UFH with or without GPI in both groups, in STEMI
patients treated with PPCI in a large real world population

 provide pharmacodynamic data of two novel ways of ticagrelor administration,

crushed and chewed tablets, in comparison with administration of the standard
integral tablets

 study the association between gender and risk of short term mortality and
bleeding in STEMI patients planned for PPCI and treated with ticagrelor

 validate the performance of the most commonly used creatinine and cystatin C
based equations for the estimation of GFR against measured GFR during the
index hospitalisation of a STEMI population.

29
 Material and Methods

MATERIAL AND METHODS

Paper I
Source data
In the study for paper I we used data from The Swedish Web-system for enhancement
and development of evidence-based care in heart disease evaluated according to
recommended therapies (SWEDEHEART). Details about the register have been
previously published. 157 The SWEDEHEART register includes the former separate
registers RIKS-HIA, SCAAR, SEPHIA and the Swedish Thoracic Surgery Registry.
SWEDEHEART registers all patients admitted to a coronary care unit (CCU) and all
patients undergoing coronary catheterisation in Sweden. More than 100 variables,
including patient demographics, past medical history, medical treatment before
admission, medical treatment and interventions during CCU care, in-hospital outcomes
and complications, discharge diagnosis and discharge medication are collected.
Source data have continuously been validated by comparison of the register information
with the hospitals´ patient records by an external monitor with over 95% agreement.
Data from the SWEDEHEART register was merged with the National Patient Registry
(NPR) to obtain information on previous medical history and readmission for a new MI
and the Swedish population register to obtain information on mortality, by using each
patient’s unique personal identification number. NPR provides all discharge diagnoses
for patients admitted to a hospital in Sweden.
Peri-procedural characteristics and in-hospital complications including bleedings were
obtained from the SWEDEHEART register. Mortality and stent thrombosis data were
available for all patients from the National Board of Health and
Welfare’s Cause of Death Register and the SWEDEHEART register, respectively. Data
on readmission due to a new MI were collected from the NPR register.

Study population
From January 1𝑠𝑡 2008 to October 10𝑡ℎ 2014 we selected patients using the following
inclusion criteria: 1) patients with STEMI presenting within 12 hours after symptom
onset, 2) treated with PPCI 3) received UFH or bivalirudin as adjunctive anticoagulant.
Inclusion dates were chosen to coincide with the presentation of the HORIZONS AMI
trial. Only the first time an individual appeared in the register with STEMI was included
for analysis. The included population was 23 800 patients.
Based on the adjunctive antithrombotic regimen patients were coded into two treatment
groups: (i) UFH with or without GPI (will be referred as UFH group) and (ii)
bivalirudin with or without GPI or UFH (will be referred as bivalirudin group).
Information about death and stent thrombosis were collected up to November 14𝑡ℎ 2014
(all patients had at least 30 days of follow up) whereas information about readmission
for a new MI were available up to December 31𝑠𝑡 2013.

Outcome definition
The primary efficacy outcome of the study was all-cause mortality during 30 days after
the index procedure. Secondary efficacy outcomes included 1-year all-cause mortality,
30-day and 1-year definite stent thrombosis and re-infarction at 30-day and 1 year after
discharge. Primary safety outcome was the rate of non-CABG major in-hospital

30
 Material and Methods

bleeding and secondary outcome was the composite of non-CABG major or minor in-
hospital bleedings.
Definite stent thrombosis (ST) was defined according to the Academic Research
Consortium definition.158 Standardised clinical and biochemical criteria for the
diagnosis of acute MI and STEMI has been used in the register in accordance with the
European guidelines 159 and diagnoses have been coded according to the International
Classification of Disease at the treating physician’s discretion. In-hospital major
bleeding was defined as any fatal or cerebral bleeding, required surgical intervention or
blood transfusion or leading to a decrease in hemoglobin > 5.0 g/dL. Minor in-hospital
bleeding included any bleeding that led to hemoglobin drop > 2.0 g/dL, led to early
discontinuation of antithrombotic treatment or any pseudo-aneurysm at the access site
that required treatment other than manual compression.

Paper II
Study design and population
This was a single center, open-label, randomised, investigator initiated,
pharmacodynamic study. Patients > 18 years of age, with stable angina pectoris,
scheduled for outpatient coronary angiography, were randomly assigned, at least 90
minutes before the intervention, in a 3:1:1 fashion (according to a computer generated
randomisation list) to one of the following treatment modalities: A) Integral ticagrelor
tablets, 180 mg LD B) Crushed ticagrelor tablets, 180 mg LD or C) Chewed ticagrelor
tablets, 180 mg LD. The allocation sequence was concealed from the researcher
enrolling and assessing participants in sequentially numbered, sealed envelopes.
Exclusion criteria were: pregnancy or lactation, known allergy to the study medication,
chronic therapy with ticagrelor, prasugrel, clopidogrel or ticlopidine, treatment with
warfarin or new oral anticoagulants (NOAC) within 4 days before admission, active
bleeding, bleeding diathesis or coagulopathy, history of gastrointestinal or genitourinary
bleeding in the last 2 months, history of intracranial bleeding, major surgery in the last 4
weeks, known relevant hematological deviation (severe anemia, severe
thrombocytopenia), known severe liver disease or severe renal failure, increased risk of
bradycardia or inability to chew tablets.

Administration of the different ticagrelor formulations.

All three groups received two tablets of ticagrelor (180 mg) and 150 mL of water. In the
first group (A), two integral ticagrelor tablets were administered as an oral dose,
followed by 150 mL of water. In the second group (B), two ticagrelor tablets (180 mg)
were placed in a point-of-care (POC) crushing device and crushed. The total content of
the crushed tablets was transferred to a dosing cup, 50 mL of water was added and the
suspension was mixed before drinking. Afterwards, 100 mL of water was administered.
In the third group (C), the patient was instructed to chew two tablets of ticagrelor for at
least 10-15 seconds followed by oral administration of 150 mL of water.

Blood sampling for platelet aggregation measurements

Platelet aggregation assessment was performed at three time-points: before
administration of ticagrelor (baseline, sample 1) 20 ± 5 minutes (sample 2) and 60 ± 10
minutes (sample 3) after administration of ticagrelor. In all cases, the blood samples
were drawn from a recently inserted venous catheter for repeated sampling or by direct
venipuncture. The first 2-3 mL of blood was discarded to avoid platelet aggregation and
then blood was collected in 3.2 % citrated tubes. Platelet aggregation was measured
with the VerifyNow P2Y12 (Accumetrics Inc, San Diego, CA) POC test. The test has

31
 Material and Methods

been described in detail earlier.160 Briefly, VerifyNow is a turbidimetric test which

measures agonist-induced aggregation as an increase in light transmittance. The system
contains a lyophilised preparation of human fibrinogen-coated beads, which causes a
change in light transmittance by agonist-induced platelet aggregation.
Platelet reactivity (PR) results are reported in arbitrary P2Y12 reaction units (PRU). The
percent inhibition of platelet reactivity (IPR) was defined as: [(PRU baseline – PRU
sample 1 or 2)/PRU baseline] X 100. Based on a recently published consensus
document, high residual platelet reactivity (HRPR) was defined as PR > 208 PRU (non-
responders).161 Patients with PR values ≤ 208 were considered as responders to the
drug.

Outcome
We report residual platelet reactivity, percent IPR and proportion of patients with HRPR
at baseline, 20 and 60 minutes.
Safety outcomes include TIMI major, minor or minimal bleeding within 24 hours after
randomization.

Paper III
The ATLANTIC study was an international, randomised, double-blind, placebo-
controlled study with 30 days follow-up. The design of the study, inclusion and
exclusion criteria, outcome definitions and principal results have previously been
described.74, 162 Briefly, 1 862 patients presenting with STEMI, less than 6 hours after
symptom onset, were included and randomised to pre-hospital (in the ambulance) versus
in-hospital (in the catheterisation laboratory) treatment with a loading dose of ticagrelor
(180mg) in addition to aspirin and standard clinical care. All patients were to
subsequently receive ticagrelor 90 mg twice daily for 30 days, after which it was
recommended that ticagrelor should be continued for up to 12 months. Pre-hospital
administration of a GP IIb/IIIa inhibitor was left to the physician’s discretion. Peri-
procedural use of parenteral anticoagulants was also left to the physician’s discretion,
according to the local practice.
The proportion of patients who did not have ≥70% resolution of ST segment elevation
before PCI and / or did not meet the criteria for TIMI flow 3 in the infarct related artery
(IRA) at initial angiography was the primary outcome of the ATLANTIC trial.
Secondary outcomes (clinical efficacy outcomes) included the composite of death, MI,
stent thrombosis, stroke, or urgent revascularisation at 30 days and definite stent
thrombosis at 30 days. Safety outcomes included major and minor bleeding over the 30-
day treatment period. Bleeding risk was evaluated using the TIMI (The Thrombolysis In
Myocardial Infarction), BARC (Bleeding Academic Research Consortium) and PLATO
(Study of Platelet Inhibition and Patient Outcomes) bleeding definitions.162
The main objective of our analysis was to study the association between gender and
primary and secondary outcomes of the main study with a special focus on the clinical
efficacy and safety outcomes. The interaction of gender subgroups with randomised
treatment effects was also investigated.

Paper IV
Design and Study Population
This was a single center, prospective observational study including patients with STEMI
treated with primary PCI (PPCI). Patients with known advanced renal failure (on
dialysis), cardiogenic shock at arrival or known allergy to iodine were excluded.
Between November 2011 and February 2013, forty patients were successfully included.

32
 Material and Methods

GFR, plasma Creatinine and Cystatin C measurements

Blood samples were obtained via a direct venous puncture at the time of randomisation
(before coronary angiography) and before discharge (between day 4 and 7 after
admission). Plasma creatinine and cystatin C were analysed at the central laboratory of
Östergötland County Concil (at Linköping University Hospital and at Norrköping
Hospital).
Furthermore, from patient records we retrospectively collected high sensitive Troponin
T that was routinely measured six to eight hours after admission as a marker of infarct
size.

Determination of GFR
GFR was determined by measurement of the plasma clearance of iohexol, 163 a non-
radioactive radiographic contrast medium (Omnipaque 300 mg I/ml; Nycomed
Amersham AB, Sweden) before discharge, soon after blood samples for creatinine and
Cystatin C measurements were obtained. Four millilitres of iohexol were injected
intravenously in an antecubital vein and clearance was calculated from the remaining
iohexol concentration in two plasma samples. The sampling time-point was determined
from eGFR, using MDRD-IDMS. If eGFR was > 40 mL/min/1.73 𝑚2 sampling was
performed at 3 and 4 hours after injection. For eGFR < 40 mL/min/1.73 𝑚2 samples
were drawn 6 and 8 hours after injection. Plasma iohexol concentration was determined
by high-performance liquid chromatography (HPLC). The total coefficient of variation
(CV) for the analysis method, during a three months period was 4.0 % for a control
sample with an assigned value of 31 mg/L and 3.7% for a control sample with an
assigned value of 62 mg/L (n=56). For a person weighing 70 kg and sampling at 4
hours, these iohexol concentrations corresponded to GFR values of approximately 100
mL/min and 60 mL/min, respectively, without correction for body surface area (BSA).
GFR was expressed in relative values: mL/min/1.73 𝑚2 using the DuBois-DuBois
formula for calculation of BSA.

Determination of plasma creatinine

Plasma creatinine was analysed by a kinetic alkaline picrate colometric method, a
modification of the original method described by Jaffe using Advia 1650 and 1800
instruments (Siemens Healthcare Diagnostics). Precision measured during a three
months period on four instruments showed a total CV of 4.3% at a creatinine level of 86
µmol/L and of 3.2% at a creatinine level of 380 µmol/L (reference values used: 60 - 105
for adult males and 45 - 90 for adult females). Calibration is traceable to a primary
reference material (SRM 967) with values assigned by isotope dilution mass
spectrometry (IDMS) and a zero-point calibrator was used.

Measurement of cystatin C
Plasma cystatin C was measured by an automated particle-enhanced
immunoturbidimetric method on Advia 1650 and 1800 analysis system (Siemens
Healthcare Diagnostics) with reagents obtained from DakoCytomation and according to
the procedure recommended by the reagent producer. Precision measured during a three
months period on two instruments showed a total CV of 4.2 % at a cystatin C
concentration of 1.2 mg/L and 3.2% at 4.6 mg/L (reference values used, 0.55 - 1.15
mg/L for persons 1-50 years of age and 0.63 - 1.44 mg/L for persons > 50years). All
samples were analysed within one day after collection.

33
 Material and Methods

Definition and staging of Chronic Kidney Disease

According to the National Kidney Foundation Kidney/Disease Outcome Quality
Initiative (NKF K/DOQI) CKD is defined as kidney damage persisting for more than 3
months.164 Patients with reduced kidney function should be staged into five CKD stages
based on GFR. Patients in stage 1 (GFR ≥90 mL/min/1.73 𝑚2 , normal kidney function)
and stage 2 (GFR 60-89 mL/min/1.73 𝑚2 , mild CKD) must have signs of kidney
damage such as albuminuria or pathological imaging in order to be staged into CKD.
Patients in stage 3 (GFR 30-59 mL/min/1.73 𝑚2 ) and stage 4 (GFR 15-29
mL/min/1.73 𝑚2 ) have moderate or severe CKD, respectively. Dialysis or GFR <15
mL/min/1.73 𝑚2 is defined as end-stage renal failure (stage 5). In this article, from now
on CKD is defined as CKD stage 3-5, i.e. GFR less than 60 mL/min/1.73 𝑚2 .

Objectives
The objective of this study was to validate the performance of the most commonly used
equations for estimation of GFR against mGFR during the index hospitalisation in a
STEMI population. We used the Cockcroft-Gault (CG), the abbreviated Modification of
Diet in Renal Disease (MDRD-IDMS), the Chronic Kidney Disease-Epidemiology
Collaboration (CKD-EPI) based on creatinine and the relative Grubb cystatin C (rG-
CystC) equations to estimate GFR (figure 15).

Figure 15. Equations for estimation of Glomerular Filtration Rate (eGFR).The Cockcroft-Gault
(CG), the abbreviated Modification of Diet in Renal Disease (MDRD-IDMS), the Chronic
Kidney Disease-Epidemiology Collaboration (CKD-EPI) based on creatinine and the relative
Grubb cystatin C (rG-CystC) equations

34
 Sample size calculation

SAMPLE SIZE CALCULATION

Sample size calculation was not performed in paper I and paper III that were
retrospective analyses of prospectively collected data. The study for paper IV was a
methodological, observational study and sample size calculation was not performed. In
the study for paper II, previous studies showed that around 50% of patients had HRPR
30 minutes after LD ticagrelor (integral tablets).59 A recent study165 has shown that
administration of crushed ticagrelor tablets resulted in a mean plasma concentration of
ticagrelor that was four to five times higher at 30 minutes compared with plasma
concentration after administration of integral tablets. We assumed that chewed
ticagrelor tablets would have at least as fast uptake as crushed ones. Given that the
antiplatelet effect of ticagrelor is linearly related to the blood concentration of
ticagrelor,65 we also assumed that 20% of patients with the novel ways of ticagrelor
administration (crushed and chewed) would have HRPR 20 minutes after administration
of LD. A sample of 100 patients (60 patients in the integral, 20 patients in the crushed
and 20 patients in the chewed group) would give an 80% power to detect statistically
significant differences in the HRPR rates.

35
 Statistical analysis

STATISTICAL ANALYSIS

In paper I and III, continuous variables were presented by their mean and standard
deviation (SD) or median and 25th -75th percentiles as appropriate. Categorical
variables were presented as counts and percentages. Baseline and peri-procedural
characteristics were compared according to treatment or gender by Chi-square tests for
categorical variables and Student`s t-test or Mann Whitney U test for continuous
variables, depending on if the variable of interest was normally distributed or not. In
paper II, the Kolmogorov-Smirnov test was used to test for normality of the
distribution of PR values. Baseline characteristics were compared according to
randomised treatment by Fisher`s exact test for categorical variables and Kruskal-Wallis
test for continuous variables. Friedman’s test was used for within group comparisons of
PR over time. PR and IPR of the three groups of patients were compared using Kruskal-
Wallis test. Pairwise comparisons of the groups were performed with Mann Whitney U
test. Percentage of HRPR in the three groups was compared using Chi-squared test.
Pairwise comparisons were also performed using the same test. A p-value <0.05 was
considered to indicate statistical significance. Due to the relatively small number of
hypotheses being tested under the pairwise comparison, the likelihood of type I error
was estimated as low and adjusted p values were not used. A p-value <0.05 was
considered to indicate statistical significance.

Paper I
Given the observational nature of our study, methods for risk-adjusted outcomes, such
as multivariable analyses, propensity score adjustments and propensity score matched
analyses were used. In order to study the association between treatment and efficacy
outcomes, hazard ratios (HR) with 95% confidence intervals (CI) were derived from
Cox proportional hazard models. In the unadjusted (crude) model, treatment was the
only explanatory variable. In the first adjusted model (Model 1), we used a backward
stepwise selection algorithm with a significant cut-off level of 0.05 for variable
inclusion. Treatment was forced into the model. The selection of the other variables
possibly associated with the efficacy outcomes was based on results from previous
studies as well as clinical experience; year of the index procedure, gender, age, smoking
status, history of HTN, dyslipidemia, DM, HF, MI, previous PCI, CABG, stroke,
history of atrial fibrillation (AF), cancer within 3 years of admission, COPD, history of
gastrointestinal bleeding, treatment with warfarin, time from symptom onset to
diagnostic ECG, BMI, baseline hemoglobin, eGFR according to the MDRD formula,
cardiogenic shock at arrival, aspirin and ADP receptor blockers before or during PCI,
access site, MVD, IRA, PCI with stent, PCI with DES, thrombectomy and successful
revascularisation.
To assess the association between treatment and safety outcome logistic regression
models were constructed, including the same variables as above using a backward
stepwise selection algorithm with a significance level of less than 0.05 for inclusion.
Odds ratios (OR) with 95% CI were presented.
We calculated an individual propensity score, reflecting the individual probability for a
patient to be treated with bivalirudin based on available covariates within a multiple
logistic regression model. All covariates included in the multivariable analysis were also
included in the propensity score model. As a linear relationship between propensity

36
 Statistical analysis

score and outcomes cannot be assumed, we divided subjects into five equal-size groups
using the quintiles of the estimated propensity score and performed a multivariable
analysis of outcomes including treatment and the propensity score as a categorical
variable according to the method described by Austin (Model 2). 166 Furthermore, based
on the individual propensity score we matched patients in the UFH group with patients
in the bivalirudin group using 1:1 nearest neighbor matching without replacement and
caliper width of 0.1. We evaluated the success of matching by using standardized
difference between the two groups. In the propensity matched population we used
multivariable Cox proportional hazard models to assess efficacy outcomes and
multivariable logistic regression models to assess bleeding complications. Treatment
and the four covariates that significantly differed between the two groups (year of the
index procedure, thrombectomy, PCI with DES, and ADP receptor blockers before or
during PCI), were included in the multivariable model (Model 3).

Paper II
A forward stepwise binary logistic regression analysis was used to identify independent
predictors of HRPR at 20 minutes after administration of ticagrelor. Known and
potential predictors of HRPR were included in the model, in accordance with previous
studies. 167, 168 Variables included in the model were age, gender, DM, BMI, smoking
status, eGFR by the MDRD formula, platelet count, treatment with beta blockers or
diuretics, PR at baseline and randomization group as a dichotomous variable (integral
tablets versus crushed or chewed tablets).167, 169. Odds ratios with 95% CI were
presented for the significant predictors.

Paper III
In order to study the association between gender and the clinical efficacy and safety
outcomes, independent of randomised treatment as well as the possible interactions
between gender and randomised treatment with respect to the outcomes, hazard ratios
with 95% CI were derived from Cox proportional-hazards models. In the unadjusted
(crude) model, gender was the only explanatory variable whereas in the adjusted
multivariable model, gender was forcibly included and the other variables were chosen
by using a forward stepwise selection algorithm with a significant cut-off level of 0.05
for inclusion. Adjustment variables included age, weight, prior MI, prior PCI, history of
DM, HTN, non-hemorrhagic stroke, gastrointestinal bleeding, time from symptom onset
to pre-PCI ECG, admission Killip class (as a dichotomous variable 1 / >1), baseline
hemoglobin, eGFR according to the MDRD formula, use of GP IIIb/IIa inhibitor and
location of MI. To evaluate the importance of early mortality, a landmark analysis of the
clinical efficacy outcomes was also performed from 48 hours after randomisation
(arbitrarily defined) to the end of the study. In order to explore the importance of
bleeding on the clinical efficacy outcomes, a separate analysis was also performed by
censoring the patients who reported a PLATO major bleeding at the time of the onset of
a bleeding event.
A comparable statistical process was used to compare gender differences in the effect of
randomised treatment by constructing logistic regression models. Odds ratios with 95%
CI were presented. The above process for Cox regression and logistic regression was
also used to explore any interaction between gender and treatment.

Paper IV
The percentage of CKD patients obtained with the four formulas and mGFR was
compared with the McNemar test. Agreement between GFR estimates and between

37
 Statistical analysis

mGFR and eGFR regarding CKD classification to discriminate GFR greater and less
than 60mL/min1.73𝑚2 was assessed by Cohen’s kappa statistics. A kappa value of 0.20
or less was considered slight agreement; 0.21 – 0.40, fair agreement; 0.41 – 0.60,
moderate agreement; 0.61 – 0.80 substantial agreement; and 0.81 – 1.00, almost perfect
agreement.170
Furthermore, we constructed Bland-Altman plots according to the original article by
Bland and Altman.171 Because iohexol clearance was considered as the gold standard
method, differences between eGFR and mGFR were plotted.
We assessed the diagnostic performance of the eGFR equations compared to mGFR
with respect to correlation, bias, precision and accuracy.172 Correlation between eGFR
and mGFR was obtained from Pearson correlation and reported as correlation
coefficient (R). Bias was defined as the median percentage error between eGFR and
mGFR, positive values indicating an overestimation of mGFR. A bias of less than 10%
was considered as clinically acceptable.173 Precision was assessed as the interquartile
range (IQR) expressed in mL/min/1.73 𝑚2 of the difference eGFR – mGFR. Accuracy
within 30% (P30) was the percentage of estimates within 30% of mGFR. A P30 of more
than 75% was accepted sufficient for clinical decisions.174 Differences in accuracy
between 0 – 2% were regarded as equivalent accuracy, between 3 – 4% as slightly
higher accuracy and ≥ 5% as significant higher accuracy. The 95% of P30 was
calculated according to the formula:
(1−𝑃30) 0.5
95%𝐶𝐼 = 𝑃30 ± 1.96 𝑥 [𝑃30 𝑥 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑚𝑒𝑛𝑡𝑠] .

We used the Cockcroft-Gault (CG), the abbreviated Modification of Diet in Renal

Disease (MDRD-IDMS), the Chronic Kidney Disease-Epidemiology Collaboration
(CKD-EPI) based on creatinine and the relative Grubb cystatin C (rG-CystC) equations
to estimate GFR. P-values < 0.05 were considered to indicate statisticall significance.

Missing values

Paper I
For the variables included in the multivariable analyses 28% of the patients had at least
one missing value and 1.5% of the total values were missing. Multiple missing values
imputation was performed by using SPSS and an automatic imputation method was
used based on a scan of our data source.

Paper III
For most of the variables included in the multivariable models, only few patients had
missing data (<10 patients). However, 7% of patients had missing values for creatinine,
5% for hemoglobin and 4% for Killip class. The number of patients with complete data
for multivariable Cox proportional-hazard models of the primary outcome was 1613
(88%). To investigate the influence of missing values, multivariable analysis was
performed before and after simple missing values imputation as well as with only
gender and age as explanatory variables (because these variables had no missing
values).

38
 Ethical Considerations

ETHICAL CONSIDERATIONS

All studies were approved by the Ethical review board in Linköping, conformed to the
Declaration of Helsinki and followed the principles of good clinical practice.
The study for paper I was a retrospective analysis of prospectively collected data in the
SWEDEHEART register. All patients were informed about the inclusion in the register
and had the right to decline participation, but informed consent for participation in our
study was not judged to be possible. The merge of the registers was approved by the
National Board of Health and Welfare. Analysis of data was performed with
anonymised data only and the possible risk of revealing confidential medical records
was minimised.
The study for paper II was a randomised clinical trial, approved by the Regulatory
Authorities. Participants in this study were treated according to our standard clinical
praxis. They received only a loading dose ticagrelor before catheterisation followed by
maintenance clopidogrel dose if PCI was performed. The antiplatelet effect of
clopidogrel administered the day before the intervention is equivalent to the effect of
ticagrelor administrated at arrival to the outpatient clinic. Therefore the risk for bleeding
complication and ischemic complications (e.g. acute stent thrombosis or myocardial
infarction) in our participants should not be higher compare to patients pre-treated with
clopidogrel. We hypothesised that chewed or crushed ticagrelor administration would
result in a faster inhibition of platelet aggregation at 20 minutes compared with the
intact tablets. Nevertheless, ticagrelor was given at least 1.5 hour before the coronary
angiography and no difference in the degree of platelet aggregation was expected at the
time of angiography or angioplasty between the three different group 59. Therefore
patients randomised to one of the three different routes of ticagrelor administration were
not expected to have any additional risk. The risk for allergic reaction to ticagrelor is
very low and probably not higher compared to the risk for allergic reaction to
clopidogrel. The risk for other common side-effects of ticagrelor such as dyspnea or
bradycardia was assessed to be very low after administration of a single dose ticagrelor.
The study for paper III was a pre-specified analysis of the ATLANTIC trial, a
randomised double blind clinical trial, with central randomisation, 100% local
monitoring of the medical records in the centers, CRF cross-checking, declaration of all
adverse events, mandatory pharmacovigilance declarations when AE were related to the
drug, adjudication of all the events declared by the investigators by an independent
clinical endpoint committee international randomised control trial. Our analysis could
be performed without any additional risk for the patients.
The study for paper IV was an observational, methodological study. This study could be
performed safe and without any significant risk for the patients. Considering blood
samples and iohexol clearance measurement the discomfort and risks were considered
limited to mild temporal discomfort and a very small risk of local complications due to
venous puncture.

39
 Results

RESULTS

Paper I

Baseline and peri-procedural characteristics

Of the total population of 23 800 patients, 8,783 (36.9%) were included in the UFH
group and 15 017 (63.1%) in the bivalirudin group. The UFH group had more men,
higher prevalence of dyslipidemia, previous MI and PCI whereas patients in the
bivalirudin group were older and more often had a history of cancer. The rate of
cardiogenic shock at arrival was significantly higher in the UFH group (5.1% vs 3.6%,
p<0.01).
Angiographic findings including culprit vessel were similar in the two groups while PCI
success rate was higher in the bivalirudin group. Stents, radial access and thrombectomy
were significantly more often used in the bivalirudin arm. Almost 80% of the
bivalirudin treated patients received at least one dose of UFH before/during PPCI.
Concomitant GPI administration was 68.5% in the UFH arm compared to 3.5% in the
bivalirudin arm (p<0.01).

Mortality
The primary efficacy outcome, 30-day all-cause mortality, occurred in 5.3% in the UFH
group and in 5.5% in the bivalirudin group, respectively (crude HR 0.97; 95% CI 0.86 -
1.08). After multivariable adjustment (model 1), there was no significant difference
(HR 0.94; 95% CI 0.82 -1.07). Similarly with short-term mortality, 1-year all-cause
mortality rate did not significantly differ between groups (HR 0.93; 95% CI 0.84 -1.03
in the multivariable model 1). Propensity score adjusted models (model 2 and 3) showed
similar results (figure 16).

Stent thrombosis
The rate of definite stent thrombosis within 30 days was 0.6% in the UFH group and
0.5% in the bivalirudin group (crude HR 1.35; 95% CI 0.95 -1.91). After multivariable
adjustment, no significant difference was detected.
At one year, the incidence of stent thrombosis was significantly higher in the UFH
group 1.1% vs 0.7%, (crude HR 1.56; 95% CI 1.19 -2.04). However, after multivariable
adjustment, no significant difference remained, regardless which risk-adjusted model
was applied (figure 17).

Myocardial infarction
The incidence of re-infarction, within 30 days after discharge, was 2.9% in the UFH
group and 2.1% in the bivalirudin group, HR 1.33; 95% CI 1.18 -1.59. However, after
adjustment, the difference was no longer statistically significant. The adjusted incidence
of re-infarction within 1 year after the index procedure did not significantly differ
between groups (figure 18).

40
 Results

Figure 16. Association between treatment and all-cause mortality Crude hazard ratio (HR) and
p-value for UFH versus bivalirudin (with or without glycoproteins IIb/IIIa inhibitors in both
groups) was calculated from Cox proportional hazard model with only treatment as explanatory
variable. Additionally, three different risk adjusted models (multivariable model, propensity
score adjusted model and propensity matching) were developed to calculate adjusted HR and p-
value

Figure 17. Association between treatment and definite stent thrombosis. Crude hazard ratio
(HR) and p-value for UFH versus bivalirudin (with or without glycoproteins IIb/IIIa inhibitors
in both groups) was calculated from Cox proportional hazard model with only treatment as ex-
planatory variable. Additionally, three different risk adjusted models (multivariable model, pro-
pensity score adjusted model and propensity matching) were developed to calculate adjusted HR
and p-value

41
 Results

Figure 18. Association between treatment and readmission for myocardial infarction. Crude
hazard ratio (HR) and p-value for UFH versus bivalirudin (with or without glycoproteins
IIb/IIIa inhibitors in both groups) was calculated from Cox proportional hazard model with only
treatment as explanatory variable. Additionally, three different risk adjusted models (multivaria-
ble model, propensity score adjusted model and propensity matching) were developed to calcu-
late adjusted HR and p-value

Bleeding
The incidence of in-hospital major bleeding was 1.8% in the UFH group compared to
1.1% in the bivalirudin group (HR 1.65; 95% CI 1.33 -2.05). After adjustment, the risk
for major bleeding remained significantly higher in the UFH group, compared to the
bivalirudin group (47% to 65% higher risk depending on the risk-adjusted model used).
The composite of major or minor in-hospital bleeding was significantly higher in the
UFH group (3.1%) compared to the bivalirudin group (2.4%) (Crude HR 1.35; 95% CI
1.15 -1.58). The risk remained significantly higher after adjustment, regardless of the
risk-adjusted model used (figure 19).

42
 Results

Figure 19. Association between treatment and readmission for myocardial infarction. Crude
hazard ratio (HR) and p-value for UFH versus bivalirudin (with or without glycoproteins
IIb/IIIa inhibitors in both groups) was calculated from Cox proportional hazard model with only
treatment as explanatory variable. Additionally, three different risk adjusted models
(multivariable model, propensity score adjusted model and propensity matching) were
developed to calculate adjusted HR and p-value

Paper II

Baseline characteristics
There were no significant differences in baseline characteristics and medication between
the groups.

Residual Platelet reactivity

There was no difference in PRU values at baseline between groups. At 20 and 60
minutes after the LD, chewed ticagrelor resulted in significantly lower PRU values
compared to other two treatment modalities. Crushed ticagrelor achieved significantly
lower PRU values compared to integral tablets 20 minutes after the LD whereas no
difference was observed at 60 minutes (figure 20).

High Residual Platelet Reactivity

The percentage of patients with HRPR at different time points in the integral, crushed
and chewed ticagrelor groups are presented in Figure 4. HRPR rates differed
significantly between the three groups 20 and 60 minutes after the LD. No patient in the
chewed ticagrelor group had HRPR 20 minutes after the LD. At the same time point,
68.3% of patients in the integral ticagrelor group and 30% of patients in the crushed
ticagrelor groups had HRPR. After 60 minutes, none of the patients in the crushed or the
chewed ticagrelor groups had HRPR compared to 20% of patients in the integral
ticagrelor group, a significantly higher rate than the two other groups (figure 21).

43
 Results

Figure 20. Mean values (standard deviation) of P2Y12 platelet reactivity unit (PRU) for integral
vs crushed vs chewed ticagrelor: 274 (54), 279 (43), 271 (50) at baseline, 227 (100), 142 (90),
81 (56) 20 minutes after loading dose and 96 (106), 59 (46), 28 (41) 60 minutes after loading
dose of 180 mg ticagrelor. No significant reduction in PRU was observed in the integral ticagre-
lor group within 20min (p = 0.52). PRU was significantly reduced between 20 and 60 min in the
integral ticagrelor group (p < 0.01) and between all the time points in the crushed and chewed
ticagrelor group, (p values not shown). Comparisons by using Friedman’s test. Reprinted with
permission

In a multivariate analysis including potential predictors of HRPR, integral ticagrelor

administration (vs. crushed/chewed tablets combined) was the most powerful predictor
of HRPR (OR for HRPR: 12.63; 95% CI: 4.22 - 37.76). The other significant predictors
of HRPR had a modest effect; PRU value at baseline (OR: 1.01; 95% CI: 1.00 – 1.02)
and BMI (OR: 1.15; 95% CI: 1.00 – 1.32).

Figure 21. High Residual platelet reactivity (defined as > 208 platelet reactivity units) at base-
line and 20 and 60 minutes after ticagrelor administration.*P-values for comparison of the three
groups by Chi-squared test. Pairwise comparison between groups by chi-squared. Reprinted
with permission.

44
 Results

Paper III

Demographic and clinical characteristics stratified by gender

The study population consisted of 369 (20 %) women. They were older (mean age 69
vs. 59 years, p<0.01), had lower BMI, higher TIMI risk score, more often had a history
of HTN, COPD or stroke. Men had more frequent prior PCI.

Time delays
Women had significantly longer delay times, both from symptom onset to prehospital
ECG (median 88 vs 70 minutes, p<0.01)

Procedural characteristics, angiographic findings, and medication during the index

event
Coronary angiography was more often performed by femoral access in women (39.7%
vs 30.4%, p<0.01). The genders did not differ according to IRA, with the left anterior
descending artery involved in 38% of women and 39% of men. PPCI, with or without
stent, was performed significantly more often in men (88.5% vs 83.7%, p<0.01)
whereas the use of DES was similar. Thromboaspiration, GP IIb/IIIa inhibitors and
intravenous anticoagulants were used less often in women

Association between gender and outcomes independent of randomised treatment

Female gender was associated with significantly higher risk for the composite outcome
of death, MI, stroke, urgent revascularisation or definite acute stent thrombosis com-
pared to male gender (6.8% vs 3.9%, crude HR 1.79, 95% CI 1.12 – 2.86). This differ-
ence was mainly driven by a 3-fold higher risk for all-cause mortality in women com-
pared to men (5.7% vs 1.9%, HR 3.13, 95% CI 1.78 – 5.51). However, in the multivari-
able model, the gender effect was lower and not significantly associated with the com-
posite primary outcome (HR 1.34, 95% CI 0.77 – 2.32) or with all-cause mortality (HR
1.98, 95% CI 0.97 – 4.04) (figure 22).

Figure 22. Association between gender and clinical outcomes independent of randomised treat-
ment.

45
 Results

Women had significantly higher risk for major bleeding complications compared to
men, irrespective of the bleeding definition used. However, after adjustment for baseline
and clinical characteristics, female gender was no longer an independent predictor of
risk for bleeding at 30 days (figure 22).
Female gender was associated with lower risk for TIMI flow < 3 in the IRA at initial an-
giography (OR 0.64, 95% CI 0.46-0.91). The risk of incomplete ST-segment elevation
resolution (<70%) before PCI did not differ significantly between the genders (adjusted
OR 1.15, 95% CI 0.75-1.76). The risk of abnormal TIMI flow in the IRA and incom-
plete ST segment elevation resolution after PCI was similar in both genders (figure 23).

Association between gender and efficacy and safety of randomised treatment

Pre-hospital administration of ticagrelor compared to in-hospital administration resulted
in a non- significant difference in the primary, secondary and safety outcomes. No
significant interactions between randomised treatment and gender in terms of these
outcomes were found in the unadjusted or adjusted (data not shown).

Figure 23. Association between gender and efficacy outcomes independent of randomised treat-
ment

Paper IV

The median creatinine on arrival was 86 µmol/L and the median cystatin C was 1.1
mg/L. Cystatin C increased by 19% during hospitalisation whereas a 6% increase in
creatinine value was observed (median values).

CKD prevalence
On arrival, the CG showed a tendency to overestimate the CKD prevalence compared to
other formulas but no statistical significant differences could be detected. The lowest
prevalence of CKD was obtained when the CKD-EPI and the rG-CystC formulas were
used.
At discharge, the rG-CystC significantly overestimated the prevalence of CKD

46
 Results

compared to mGFR whereas the CG showed a similar tendency. The CKD prevalence
according to the CKD-EPI and the MDRD-IDMS formulas were comparable to that
obtained by mGFR. The rG-CystC formula significantly overestimated the prevalence
of CKD compared to the CKD-EPI (p=0.02) and the MDRD (p=0.07) (table 1).

Table 1. Prevalence of moderate-severe CKD on arrival and at discharge

CKD, % (n) p-value†
On arrival †p values for comparison of
percentage of moderate-severe
CG 35 (14)
Chronic Kidney disease (CKD)
MDRD-IDMS 27.5 (11) patients obtained with the four
CKD-EPI 25 (10) formulas compared to mGFR
rG-CystC 25 (10) by using McNemar test.
At discharge CG (Cockcroft-Gault), MDRD-
IDMS (Modification of Diet in
CG 42.5 (17) 0.3 Renal Disease - Isotope
MDRD-IDMS 32.5 (13) 1.0 Dilution Mass Spectrometry),
CKD-EPI 30 (12) 1.0 rG-CystC (relative Grubb
rG-CystC 47.5 (19) 0.03 cystatin C), CKD-EPI (Chronic
Iohexol 32.5 (13) Kidney Disease-Epidemiology
Collaboration). n number.

Level of agreement between eGFR and mGFR to discriminate GFR <60

mL/min/1.73 𝑚2 is illustrated in table 2. At discharge, the CKD-EPI had an almost
perfect agreement with mGFR according to the Cohen’s kappa value, followed by the
MDRD-IDMS. The rG-CystC formula had a substantial agreement but lower than the
MDRD-IDMS whereas the CG achieved the lowest agreement among the formulas
tested (moderate agreement). When agreement between different GFR estimates, both
on arrival and at discharge, was examined, the creatinine-based formulas had an
essentially unchanged agreement to each other whereas rG-CystC showed an almost
perfect agreement with MDRD-IDMS and CKD-EPI on arrival but a substantially lower
agreement at discharge (table 2).

Table 2. Agreement between different estimates and mGFR to discriminate GFR greater and
less than 60 mL/min/1.73 𝑚2

Correlation, bias, precision and accuracy

The MDRD-IDMS, the CKD-EPI and the rG-CystC estimates had better correlation to
47
 Results

mGFR, compared to the CG. The rG-CystC estimates yielded the best correlation with
mGFR. All creatinine-based estimates showed a low bias. The rG-CystC formula had a
marked bias of -17.8%. The rG-CystC formula had the highest precision, followed by
the CKD-EPI and the MDRD-IDMS that yielded an almost equal value, whereas the CG
showed the lowest precision between the formulas tested. The CKD-EPI and the
MDRD-IDMS formulas had the highest accuracy. The rG-CystC formula had a slightly
lower accuracy compared with the CKD-EPI and the MDRD-IDMS. The CG formula
showed a considerably lower accuracy compared to the other equations (table 3).
We found a moderate correlation between the cystatin C rise during hospitalisation
(absolute values) and troponin values 6-8 h after admission (R=0.51, p=0.01).

Table 3. Correlation, bias, precision and accuracy (P30) of prediction equations to estimate
relative m-GFR (mL/min/1.73 𝑚2 )
At Correlation Bias, me- Precision P30 (95%CI)
discharge (R) dian error (IQR),
(%) ml/min/1.73
𝑚2
CG 0.73 -1.2 (-1.3) 22.5 75.0% (62 – 88%)

MDRD- 0.78 -0.8 (-1.3) 17.9 82.5% (70.5 – 94.5%)

IDMS
CKD-EPI 0.81 0.9 (1.5) 17.1 82.5% (70.5 – 94.5%)

rG-CystC 0.89 -12.2 (-17.8) 14.8 80.0% (68 – 92%)

Bias was defined as the median percentage error between eGFR and mGFR, positive values
indicate an overestimation of mGFR. Precision was assessed as the interquartile range (IQR)
expressed in mL/min/1.73 𝑚2 of the difference eGFR – mGFR. Accuracy within 30% (P30)
was the percentage of estimates within 30% of mGFR. Correlation between eGFR and mGFR
was reported as correlation coefficients (R).
CG (Cockcroft-Gault), MDRD-IDMS (Modification of Diet in Renal Disease - Isotope Dilution
Mass Spectrometry), rG-CystC (relative Grubb cystatin C), CKD-EPI (Chronic Kidney Disease-
Epidemiology Collaboration).

48
 Discussion

DISCUSSION

Despite recent advantages in the management of STEMI patients, including

implementation of PPCI as the reperfusion therapy of choice, short and long term
mortality after the index event remains high (figure 24)

Figure 24. 30-day and 1-year mortality after PCI in STEMI patients in Sweden, 2007-2015
(Swedeheart annual report 2016)

Therefore, actions to further improve outcomes are warranted. In this direction,

judicious choice of antithrombotic drugs in order to obtain a balance between the risk
for ischemic and bleeding complication is crucial. Novel ways of orally administrated
antiplatelet agents may improve their pharmacodynamic properties and reduce the risk
for acute stent thrombosis. The effectiveness and safety of new treatment strategies
should be tested in both genders. Furthermore, identification of gender as an
independent predictor of adverse events may lead to target therapeutic interventions that
will improve outcomes. Finally, accurate estimation of renal function in STEMI patients
during the initial hospitalisation is important to avoid overdosing of antithrombotic
agents and contrast media as well as making decisions about use of other life-saving
therapies and additional risk stratification.
Our results showed that bivalirudin monotherapy with bailout use of GPI significantly
reduced the risk for major in-hospital bleeding with no difference for the risk of short
and long term mortality compared to UFH with or without GPI. Novel ways of
ticagrelor administration resulted in a faster and stronger platelet inhibition compared to
standard ticagrelor administration that may have a clinical implication in STEMI
patients, especially those treated with bivalirudin. Prehospital administration of
ticagrelor showed similar efficacy and safety in both genders. Women had a
significantly higher risk for early mortality and bleeding complication compared to men
49
 Discussion

but this difference was significantly attenuated after adjustment for age and baseline
characteristics. Finally, the CKD-EPI followed by the MDRD-IDMS formula more
precisely estimated renal function in STEMI patients during the acute phase compared
to other formulas whereas further research is needed to clarify the role of cystatin C.

Bivalirudin versus UFH, with or without GPI (Paper I)

In this large real-world study of STEMI patients treated with PPCI, we found no signif-
icant difference in 30-day or one-year mortality, myocardial infarction or stent throm-
bosis in patients treated with bivalirudin±GPI compared with UFH±GPI. Bleeding com-
plication rates were significantly higher with UFH±GPI.
Our study showed no difference in short or long-term mortality between the two treat-
ment groups. The mortality benefit associated with bivalirudin in the HORIZONS-AMI
trial was mainly attributed to the reduced risk for bleeding complications, 45 but the
mortality benefit persisted even when patients with a major bleeding were excluded. 175
Despite a significant reduction in the risk of major bleeding in the BRIGHT 50 and EU-
ROMAX trial 176, no difference in mortality was observed in accordance with our re-
sults. The recent HEAT-PCI showed no significant difference in 30-day mortality and
bleeding complications between the two treatment strategies.49 In the EUROMAX trial,
UFH was combined with GPI in a similar proportion of cases as in our trial (69%)
whereas in the BRIGHT trial and the HEAT-PCI trial, GPI was used as bailout treat-
ment in both bivalirudin and UFH group. Recently, the MATRIX study became the first
RCT after HORIZONS-AMI suggesting a mortality benefit with bivalirudin over
UFH±GPI.51 However, there was no difference in the primary outcome, hence the ob-
served difference in mortality may have been a play of chance. Reasons for the ob-
served differences between these studies are incompletely understood but may, at least
partially be explained by differences in UFH dose, bivalirudin infusion time, use of
modern P2Y12-inhibitors, access site and rate of GPI use between groups. Notably,
none of the earlier studies was powered to detect differences in mortality. Consistently
with our results, a recent meta-analysis, including the five most recent RCTs with more
than 10 000 patients, 177 showed no difference in short term mortality between bivaliru-
din±GPI and UFH±GPI. In concordance with the BRIGHT trial, lack of difference be-
tween the two treatment strategies persisted at one-year follow-up.
In our study, the mortality rates were substantially higher than in RCTs, but similar to
observational STEMI trials, 178 emphasising the importance of post-marketing studies in
real-world high-risk populations, which include patients that are usually not included in
RCTs. In our analysis we used three different risk-adjustment models to compensate for
the observational nature of our data and the findings strongly concurred.
Bleeding complications have been associated with worse outcome 179, 180, but the mech-
anisms are not clarified. In our study Bivalirudin ± GPI reduced the unadjusted risk of
non-CABG major in-hospital bleeding by 65%, a difference that remained after adjust-
ment. An abundance of evidence from observational and randomised trials support our
findings, demonstrating a safety benefit with bivalirudin over UFH, with various de-
grees of GPI administration. 50, 51, 178, 181-183 Bivalirudin’s predictable biological activity,
short half-life and the absence of thrombocytopenia are plausible explanations for the
reduced bleeding risk. More frequent use of GPIs with UFH in our study, may obvi-
ously have contributed to the increased bleeding rate. 177 Anyhow, GPIs may have still
have a role in selected patients, but the optimal rate remains unclear. 52, 53, 184
In contrast to previous studies we did not observe higher rate of ST associated with bi-
valirudin, after adjustment for baseline differences 49, 51, 176. The rate of early ST in the

50
 Discussion

UFH±GPI group is consistent previously reported reported, 49, 51, 176 but the rate in the
bivalirudin±GPI group was substantially lower in our study. Lower rate of ST associ-
ated with bivalirudin in our data may, at least partially, be explained by: 1. Initial pre-
hospital treatment with UFH is common practice in Sweden (79.5% in our study) irre-
spective of later treatment strategy, which has been shown to lower ST rate. 185, 186 2.
Early implementation and high rate of third generation P2Y12-inhibitors. 3. Widespread
use of bivalirudin infusion. In the BRIGHT trial, 50 with a high dose post-PCI bivaliru-
din infusion in all patients treated with bivalirudin, the risk of early stent thrombosis
was 0.4% in bivalirudin compared to 0.6% in UFH, which is in accordance with our re-
sults. Similar trends were observed in a subgroup analysis of the EUROMAX trial in
patients receiving a post-PCI bivalirudin infusion.187
In contrast to the HORIZONS-AMI trial, we found a significantly higher rate of re-in-
farction in the UFH group. However, after adjustment, the difference was not statisti-
cally significant. In accordance with our results, recent studies and meta-analyses have
not confirmed a lower re-infarction rate with bivalirudin compared to UFH± GPI, de-
spite the superior safety profile of bivalirudin.177, 188
Given the current conflicting evidence, our study provides important information re-
garding the efficacy and safety (short and long-term) of the most commonly used an-
tithrombotic strategies during PPCI in a large real-world population with STEMI.

Novel ways of orally administrated ticagrelor - The IPAAD-Tica study (Paper II)

Our study shows that a LD of crushed or chewed ticagrelor tablets achieved a more
rapid and more effective platelet inhibition compared to LD of standard integral tablets.
In addition, and to the best of our knowledge, for the first time, we show that
administration of chewed ticagrelor tablets is feasible and may provide a faster and
stronger platelet inhibition than administration of either crushed or integral tablets.
Within 20 minutes after chewed ticagrelor LD, no patient had HRPR and a very low
residual PR was observed (median PR 84 PRU). As the degree of platelet inhibition by
ticagrelor is linearly related to the plasma concentration of the drug,65 our data indicate
that chewed ticagrelor achieved the most rapid and the highest rate of drug absorption.
Furthermore, the faster and stronger platelet inhibition with chewed ticagrelor compared
to crushed ticagrelor implies that other mechanisms than the mechanical “fractioning”
of the tablets may have contributed to the improved absorption of the chewed ticagrelor.
Initiation of enzymatic metabolic degradation of the tablet in the mouth due to the
prolonged contact of the drug with the saliva as well as enhanced oral transmucosal
absorption of the drug may be explanations for our results.
In this study we confirm earlier knowledge regarding pharmacodynamic properties of
integral and crushed ticagrelor LD. In a previous study,59 patients with stable angina
were randomised to ticagrelor versus clopidogrel LD. Within 60 minutes, 80%
inhibition of PR was observed in the ticagrelor group in accordance with our results in
the integral ticagrelor group. A recent study compared crushed versus integral ticagrelor
tablets in STEMI patients.168 Crushed ticagrelor provided earlier inhibition of platelet
aggregation than integral tablets. At 60 minutes, 63% in the integral ticagrelor group
and 35% in the crushed ticagrelor group had HRPR. In our study, compared to integral
ticagrelor, 50% lower rate of HRPR was observed with crushed ticagrelor at 20 minutes.
Lower baseline PRU values and earlier onset of drug action in our stable population
may explain the difference between the two studies.

51
 Discussion

Our findings may be of clinical importance in STEMI patients. According to an earlier

trial, more than half of the STEMI patients treated with LD of integral ticagrelor still
have HRPR up to 4 hours after administration of the drug.71 Given the fact that
suboptimal platelet inhibition is an important predictor of ischemic complications, such
as stent thrombosis,73 there is a time window after PPCI, in which patients are at
increased risk for ischemic complications. In the ATLANTIC trial, despite a short
median time between pre-hospital and in-hospital administration of ticagrelor,
prehospital administration significantly reduced the risk of stent thrombosis, suggesting
that fast and strong platelet inhibition at the time of PCI is clinically important.74. A
significantly faster and stronger platelet inhibition, by overcoming the delayed intestinal
absorption of orally administrated drugs, with chewed ticagrelor administration may
improve clinical outcomes compared to integral tablets. A recent study in STEMI
patients confirmed the superior pharmacodynamic properties of crushed ticagrelor
compared to integral tablets.168 Crushed tablet preparation in the prehospital setting,
such as in the ambulance, may be cumbersome whereas chewed ticagrelor
administration is more comfortable and according to our data, may provide a more
effective platelet inhibition compared to crushed ticagrelor administration.
Theoretically, a stronger platelet inhibition at the time of PCI may increase the risk of
bleeding. In the ATLANTIC trial, prehospital administration of ticagrelor appeared to
be safe, compared to in hospital administration. In our study, the risk of bleeding was
not increased with crushed or chewed ticagrelor administration.

Association between gender and risk for short term mortality and bleeding in
STEMI patients treated with primary PCI and novel antiplatelet therapy (Paper
III).

In the present analysis, unadjusted data showed a significantly higher risk of the
composite outcome of death, MI, stroke, urgent revascularisation or definite acute stent
thrombosis in women, mainly driven by a three times higher risk for short-term
mortality. After multivariable adjustment female gender was not an independent
predictor of worse outcome.
Undoubtedly, older age and clustering of comorbidities in women could explain a large
part of the observed difference in short term clinical outcomes in our study. However,
the adjusted risk for death, while not statistically significant, was still considerably
higher in women, generating the hypothesis that gender could be an independent
predictor of early mortality if the population of the study was larger. Any possible
contribution of gender, as independent risk factor, on adverse outcome may depend on
the population studied. The age gap between genders in our population was
substantially higher compared to previous studies, with a mean age difference of 10
years.127, 189 In spite of appropriate statistical methods that were used for adjustment,
adjustment for such age-difference is awkward. Additionally, the age difference may
indicate a selection bias. As identification and randomisation took place in the
ambulance, young women with suspected STEMI were possibly not included in the
study as alternative reasons for ST-segment elevation on prehospital ECG may have
been considered more plausible in this group. These factors may explain the observed
trend toward increased adjusted risk for early mortality in women.
Previous observational studies in STEMI cohorts, without focus on PPCI treated
patients have shown a higher risk for early mortality in women.102, 190, 191 Significant
differences in the rate of reperfusion therapy between genders and hidden confounders
such as frailty in elderly women with STEMI may have influenced their results. Recent

52
 Discussion

observational studies including patients treated with PPCI122, 192, 193and pre-specified
gender analysis of RCTs126, 127, 132, 189, 194 have shown that the impact of gender on
mortality could mainly be explained by differences in age and comorbidities between
genders, in accordance with our results. On the contrary, another observational studiy
and a meta-analysis have reported higher multivariable adjusted risk of early mortality
in women with STEMI treated with PPCI.7, 121 Differences in the covariates included in
the multivariable analysis between studies may explain the conflicting results. Previous
studies have clearly demonstrated the importance of body surface area and the eGFR on
prognosis.195, 196 In a meta-analysis, Berger et al showed that female gender was an
independent predictor of early mortality in STEMI patients. However, 30-day mortality
was not statistically significant different between genders after additional adjustment for
angiographic disease severity.197
In the present study, women had a 2-3 times higher unadjusted risk for non-CABG
related bleedings, depending on the definition used. After adjustment for baseline
characteristics, no significant difference remained. Female gender has previously been
associated with higher risk for bleeding complications in patients with ACS.6, 179, 198, 199
Known predictors of bleedings like advanced age, diabetes, hypertension, renal
insufficiency and anemia, are usually more often encountered in women with STEMI.86
Additionally, smaller body and vessel size, higher use of femoral access and overdosing
of antithrombotic medication in women may explain the higher observed risk for
bleeding. Procedural-related improvement such as increased use of radial access or
smaller femoral sheaths and careful dose adjustment of antithrombotic medication, have
resulted in a significant decline in the risk of bleeding/vascular complication during
cardiovascular interventions the last years and have probably contributed to our
results.200
In terms of ST-segment elevation resolution and TIMI flow 3 rates before and after PCI,
no significant difference between genders was observed apart from a lower risk of
abnormal coronary flow in IRA at initial angiography in women. The higher rate of
TIMI flow 3 at initial angiography may be explained by the higher rate of normal
coronary arteries as well as less obstructive coronary artery disease in women with
STEMI, which is in concordance with previous data.201
The analysis of the effect of gender on outcomes dependent on the randomised
treatment showed no statistically significant interactions. Pre-hospital administration of
ticagrelor did not improve pre- or post-PCI coronary reperfusion as assessed by TIMI
flow in IRA and resolution of ST elevation pre-PCI. Clinical efficacy outcomes were
not significantly improved either. However, prehospital administration of ticagrelor was
safe in both genders with similar rate of major and minor bleedings.

GFR estimations in STEMI patients during the initial hospitalisation.

In our study, CKD-EPI followed by the MDRD-IDMS formula showed a good overall
performance to estimate GFR.
Validation of the most widely used creatinine based GFR estimates, in the acute phase
after a STEMI, showed largely confirmatory result. The similar overall accuracy of the
MDRD-IDMS and the CKD-EPI equations was consistent with the original CKD-EPI
external validation cohort, where P30 was 84% for the CKD-EPI formula and 81% for
the MDRD-IDMS formula.152 The low bias for the MDRD-IDMS and the CKD-EPI
formulas was comparable with the results in previous studies.202 The CKD-EPI showed
the best ability to discriminate patients with CKD and that can be explained by the

53
 Discussion

population studied. The CKD-EPI performs better in patients with GFR≥60

ml/min/1.73 𝑚2 and reduces the rate of false-positive diagnosis of CKD (eGFR<60
ml/min/1.73 𝑚2 ).152 The original MDRD formula was developed by studying 1628
patients with non-diabetic CKD using the Jaffe method of creatinine measurement but
was re-expressed for use with the standardised serum creatinine assay.203 The best
accuracy is obtained in patients with CKD whereas the formula has a tendency to
underestimate the mGFR in patients without CKD.150 As in previous studies,151, 204, 205
the CG formula had a tendency to overestimate the prevalence of CKD compared to
other GFR estimates. The CG formula has many limitations. First, it was derived from a
small population, predominantly men and an arbitrary correction for women was
proposed. Second, it calculates creatinine clearance that may significantly differ from
GFR. Third, the formula has not been re-expressed for use with the standardised serum
creatinine assay. However, the CG has extensively been used and previous studies have
shown that the eGFR based on CG is a better predictor of adverse outcomes than that
based on the MDRD-IDMS and probably the CKD-EPI equations in patients with
myocardial infarction.204-206 According to our results, the predictive ability of the CG
formula should be attributed to the coefficients included in the formula and not to the
better estimation of GFR, as other authors have previously suggested.204
Validation of the rG-CystC formula in our STEMI population showed inconsistent
results with previous studies. In the development and validation population, the rG-
CystC equation showed a very good performance, at least as good as the MDRD-
IDMS.154, 207
In the absence of a universal calibrator for cystatin C, the choice of the cystatin C
measurement method is of crucial importance 208 and can importantly affect the
performance of a cystatin C-based equation that is not derived by using the same
calibrator and method, resulting in significant methodological error in GFR
estimations.209 In our study, we calculated eGFR by using a rG-CystC formula that was
recommended by the manufacturer. Therefore an important methodological error in the
cystatin C measurements was considered improbable.
It should be noticed that the performance of the rG-CystC equation altered during the
study period. At arrival, CKD-EPI and rG-CystC showed an almost perfect agreement,
classified almost the same patients as having CKD but at discharge their agreement was
substantially lower and they showed an important discrepancy in CKD classification
that reached statistical significance. During hospitalisation, cystatin C increased by
19%, disproportional to creatinine rise. Theoretically, that could be attributed to the
early detection of renal injury by cystatin C and not by creatinine. Nevertheless, that can
be ruled out as the rG-CystC considerably overestimated the CKD prevalence compared
to mGFR and the CKD-EPI showed an almost perfect agreement with mGFR at
discharge.
Our findings suggest that other pathophysiological events were probably involved in the
rise of cystatin C and the observed bias of the rG-CystC, e.g. plaque rapture,
inflammation and myocardial necrosis. Cystatin C has been shown to be an independent
predictor of mortality and MI in patients with stable angina, ACS and STEMI 140, 210-212
and previous studies have suggested that cystatin C is not only a marker of renal
function but is also correlated with atherosclerosis, inflammation, plaque vulnerability
and rupture.155, 156 Cystatin C, independently of the estimated renal function, has been
shown to be associated with increased risk of developing cardiovascular disease.213 It is
an endogenous inhibitor of cathepsins that are cysteine proteases secreted by all
nucleated cells and played an important role in the extracellular matrix degradation. An
imbalance between cystatin C and cathepsins may trigger a pathophysiological cascade

54
 Discussion

leading to atherosclerosis 214 and collagen degradation in the cap of the atherosclerotic
plaque, increasing the risk of rupture.215, 216 Levels of cathepsins are elevated in STEMI
patients at arrival.217 Additionally, cathepsins are probably involved in healing process
after STEMI and cathepsin-mediated turnover of collagen is increased during the first
days following the myocardial infarction.218 The observed increase of cystatin C in our
population may represent a response to the highly activated cathepsins, trying to
counterbalance the effect of those enzymes. This hypothesis is supported by
experimental studies showing that cystatin C is produced by cardiomyocytes as a
response to myocardial ischemia and elevated cystatin C results in inhibition of
cathepsins.219 We examined a possible relationship between cystatin C increase and
troponin level in our population. We found a significant but moderate correlation
between cystatin C rise and troponin and a weaker correlation between creatinine rise
and troponin. This partially reflects the cardio-renal syndrome but could also indicate a
relationship between the infarct size and the cystatin C elevation. Apart from an
elevated production of cystatin C during the acute phase of myocardial infarction, an
altered glomerular endothelial permeability due to infarct-related inflammation may
impair the filtration rate of cystatin C that is a more than 100 times larger molecule than
creatinine, leading to an accumulation of cystatin C in the blood.220

55
 Conclusions – Clinical implications

CONCLUSIONS – CLINICAL IMPLICATIONS

In STEMI patients treated with PPCI, bivalirudin was the optimal antithrombotic
therapy compared to UFH with or without GPI. Treatment with bivalirudin and low
rates of concomitant GPI administration was associated with a significant reduction in
the risk of non-CABG major and major or minor in-hospital bleeding compared to UFH
and high rates of GPI administration. This safety benefit with bivalirudin was not
associated with a significant reduction in mortality. Furthermore, it is still a matter of
debate if bivalirudin increases the risk for early stent thrombosis compared to UFH and
provisional GPI administration. Taking into account the substantially higher financial
cost with bivalirudin compared to UFH, physicians may consider individualised
selection of antithrombotic drug during PPCI guided by the estimated risk of acute stent
thrombosis and bleeding based on risk scores or clinical experience. 6, 221 In patients
with high risk of bleeding, treatment with bivalirudin should always be preferred. In
patients at increased risk of stent thrombosis but low risk of bleeding UFH with bailout
GPI administration remains an option.

Novel ways of orally administrated ticagrelor were feasible and provided a faster and a
more effective platelet inhibition compared to standard ticagrelor tablets. Our findings
may have an important clinical implication in STEMI patient in whom insufficient
platelet inhibition at the time of PPCI has been associated with an increased risk of stent
thrombosis. In bivalirudin treated patients, early administration of chewed ticagrelor
tablets may mitigate the risk for early stent thrombosis and further improve outcomes.

Women with STEMI treated with PPCI and ticagrelor had a significantly higher
unadjusted risk of early mortality and bleeding complications compared to men.
However, these differences were significantly attenuated after adjustment for baseline
characteristics and age. Scores for bleeding risk estimation incorporate female gender
together with baseline and procedural characteristics such as advanced age, anemia and
reduced renal failure that are more often presented in women than in men with STEMI.
In women with high risk of bleeding, bivalirudin use and cautious antithrombotic dose-
adjustment based on estimated renal function are some of the actions warranted in order
to reduce the bleeding risk and improve outcomes.

According to our results MDRD and CKD-EPI should be the formulas used for
estimation of GFR in the acute phase of STEMI. On the other hand, CG should be
abandoned as it overestimates the prevalence of CKD. Finally cystatin C based formulas
should be used with cations in the acute phase of STEMI until more studies confirm or
reject our findings. Due to the crucial role of renal function on the acute management,
risk stratification, avoidance of overdosing of drug cleared by the kidneys and early
initiation of other life-savings therapies, accurate estimation of GRF by formulas may
have a significant influence on outcomes.

56
 Future Directions

FUTURE DIRECTIONS

Bivalirudin is superior to UFH and provisional GPI in the reduction of bleeding.

However, UFH monotherapy at the lower recommended dose with bailout GPI
administration appears as a promising alternative. It remains unclear if bivalirudin
monotherapy has a superior safety profile compared to UFH monotherapy. Furthermore,
it is still unclear if premedication with a single dose UFH, prolonged post-PCI infusion
of bivalirudin and early administration of ticagrelor may mitigate the risk of early stent
thrombosis in bivalirudin treated patients. Results from the VALIDATE-
SWEDEHEART trial, a register-based RCT, randomised 7 000 ACS patients to
bivalirudin or UFH monotherapy, are awaited to provide further evidence in this area

The superior pharmacodynamic properties of chewed ticagrelor compared to crushed

ticagrelor should be confirmed in a new study. The efficacy and safety of chewed or
crushed ticagrelor compared to integral ticagrelor in STEMI patients should be tested in
a RCT.

The association between gender and the risk of early mortality and bleeding in STEMI
patients treated with PPCI, novel antiplatelet therapy and bivalirudin or UFH
monotherapy with bailout-only GPI administration should be evaluated in a large study.
A pre-specified gender analysis of the VALIDATE-SWEDEHEART is planned.

Our findings suggested that inflammation and myocardial necrosis were involved in the
observed rise of cystatin C during the acute phase in STEMI patients. Further research
is needed to confirm our finding and provide pathophysiologic explanations for this
observation.

57
 Acknowledgements

ACKNOWLEDGEMENTS

This thesis could not have been completed without the great support of so many people
during these past four years. I would like to express my sincere gratitude to all of you
who have helped, supported and inspired me during these years. In particular, I wish to
express my gratitude to:
All patients who participated in our studies.
Linköping University and “Institution of Medicine and Health” for giving me the
opportunity to perform my PhD training.
Professor Eva Swahn - my main supervisor. Thank you for “dragging” me into clinical
research, I do not really know if I had been engaged without you. For sharing with me
your deep knowledge about research. I am grateful for your support all these years and
your generous attitude. For your inspiring enthusiasm that you succeed to share with
your colleagues. For always being available and providing rapid feedback. For giving
me the opportunity to choose my own scientific paths. For good advice, not just about
scientific questions but also about life. For opening your home and creating a welcom-
ing atmosphere for me. For offering me your friendship.
Joakim Alfrdsson, my co-supervisor. Thank you for your great contribution to my the-
sis. For constructive, valid and valuable remarks regarding my projects. For keeping me
on tracks many times by supporting or discouraging new ideas and there have been
many. For your vast knowledge about registry-based research and statistic that you have
generously shared with me. Thank you for your patience and your time. It was a pleas-
ure and a privilege to have you and Sofia as fellow passengers during this exciting trip.
Sofia Sederholm-Lawesson, my co-supervisor -.Thank you for your deep involvement
in my thesis. For your important contribution in the design, performance, analysis and
presentation of my projects. For introducing me to SPSS and to mystics “syntaxes”. For
your tremendous generosity, kindness and enthusiasm. For your linguistic and editorial
revision of all my articles. For your efforts to promote research in our department. It has
been a pleasure to travel with you to international congresses presenting our results.
Magnus Janzon, head of the department of Cardiology at University Hospital in Linkö-
ping. Thank you for your kind support, encouragement and for giving me the oppor-
tunity to participate in international congresses as well as to take time off for my re-
search. “Research at the centre” has been the department’s moto and Magnus has an im-
portant contribution to that.
Elisabeth Logander your skills makes you the best research nurse ever. Thank you for
successfully guiding me in the labyrinth of different applications and advising me about
Good Clinical Praxis. Your advices will follow me in the future.

58
 Acknowledgements

Maria Eriksson, research nurse, for your help with IPAAD-Tica study and editorial re-
vision of my abstracts.
All my co-authors, in all papers for their invaluable remarks and recommendations.
My colleague Anders Björkholm for teaching me fundamentals in coronary angi-
ography and PCI.
My colleague Tim Tödt for pushing me to break my limits.
My friend and colleague Manolis Charitakis, who recently defended his thesis, for
your friendship, support and for our endless discussions about statistics and new re-
search projects.
My friend and colleague Giorgios Panayi for always taking time to listen.
My good friend Andreas Bousios for your friendship and help to organise the party.
All my past and present colleagues in the Cardiology department and catheterisation
laboratory at Linköping for their friendship, support and involvement in my projects.
All nurses in the catheterisation laboratory at Linköping and Norrköping for participat-
ing in my projects and for pleasant times at work and outside the hospital.
All nurses in the Seldinger outpatient clinic at Linkoping University Hospital for their
participation in the data collection of the IPAAD-Tica study.
Richard Cairns from Worldwide Clinical Trials UK who performed the statistical anal-
ysis of the ATLANTIC gender analysis and Liz Anfield, Prime Medica Ltd, Knutsford,
Cheshire, for editorial support of the ATLANTIC gender analysis.
My parents, for the principles and the unconditional love you gave me.
To my beloved family. My wife Despina for your love and endurance and for showing
me what is truly meaningful in life. My wonderful daughters, Silia and Anastasia for
the joy and happiness you give me every day.

59
 References

REFERENCES

1. Task Force on the management of STseamiotESoC, Steg PG, James SK, Atar
D, Badano LP, Blomstrom-Lundqvist C, Borger MA, Di Mario C, Dickstein K,
Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P, Halvorsen S, Huber
K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW, Valgimigli M, van 't
Hof A, Widimsky P, Zahger D. Esc guidelines for the management of acute
myocardial infarction in patients presenting with st-segment elevation. European
heart journal. 2012;33:2569-2619
2. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ,
Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti
P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S, Baumgartner
H, Gaemperli O, Achenbach S, Agewall S, Badimon L, Baigent C, Bueno H,
Bugiardini R, Carerj S, Casselman F, Cuisset T, Erol C, Fitzsimons D, Halle M,
Hamm C, Hildick-Smith D, Huber K, Iliodromitis E, James S, Lewis BS, Lip GY,
Piepoli MF, Richter D, Rosemann T, Sechtem U, Steg PG, Vrints C, Luis
Zamorano J, Management of Acute Coronary Syndromes in Patients Presenting
without Persistent STSEotESoC. 2015 esc guidelines for the management of acute
coronary syndromes in patients presenting without persistent st-segment elevation:
Task force for the management of acute coronary syndromes in patients presenting
without persistent st-segment elevation of the european society of cardiology (esc).
European heart journal. 2016;37:267-315
3. Widimsky P, Wijns W, Fajadet J, de Belder M, Knot J, Aaberge L,
Andrikopoulos G, Baz JA, Betriu A, Claeys M, Danchin N, Djambazov S, Erne P,
Hartikainen J, Huber K, Kala P, Klinceva M, Kristensen SD, Ludman P, Ferre JM,
Merkely B, Milicic D, Morais J, Noc M, Opolski G, Ostojic M, Radovanovic D,
De Servi S, Stenestrand U, Studencan M, Tubaro M, Vasiljevic Z, Weidinger F,
Witkowski A, Zeymer U, European Association for Percutaneous Cardiovascular
I. Reperfusion therapy for st elevation acute myocardial infarction in europe:
Description of the current situation in 30 countries. European heart journal.
2010;31:943-957
4. Jernberg T. Årsrapport swedeheart 2015. Available at
http://www.Ucr.Uu.Se/swedeheart/arsrapport-2015

5. Roth GA, Huffman MD, Moran AE, Feigin V, Mensah GA, Naghavi M,
Murray CJ. Global and regional patterns in cardiovascular mortality from 1990 to
2013. Circulation. 2015;132:1667-1678
6. Mehran R, Pocock SJ, Nikolsky E, Clayton T, Dangas GD, Kirtane AJ, Parise
H, Fahy M, Manoukian SV, Feit F, Ohman ME, Witzenbichler B, Guagliumi G,
Lansky AJ, Stone GW. A risk score to predict bleeding in patients with acute
coronary syndromes. Journal of the American College of Cardiology.
2010;55:2556-2566

60
 References

7. Pancholy SB, Shantha GP, Patel T, Cheskin LJ. Sex differences in short-term
and long-term all-cause mortality among patients with st-segment elevation
myocardial infarction treated by primary percutaneous intervention: A meta-
analysis. JAMA internal medicine. 2014;174:1822-1830
8. Gupta A, Wang Y, Spertus JA, Geda M, Lorenze N, Nkonde-Price C,
D'Onofrio G, Lichtman JH, Krumholz HM. Trends in acute myocardial infarction
in young patients and differences by sex and race, 2001 to 2010. Journal of the
American College of Cardiology. 2014;64:337-345
9. Friedman M, Van den Bovenkamp GJ. The pathogenesis of a coronary
thrombus. The American journal of pathology. 1966;48:19-44
10. Chapman I. Morphogenesis of occluding coronary artery thrombosis. Archives
of pathology. 1965;80:256-261
11. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal
rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized
by an inflammatory process irrespective of the dominant plaque morphology.
Circulation. 1994;89:36-44
12. Davies MJ. The pathophysiology of acute coronary syndromes. Heart.
2000;83:361-366
13. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from
sudden coronary death: A comprehensive morphological classification scheme for
atherosclerotic lesions. Arteriosclerosis, thrombosis, and vascular biology.
2000;20:1262-1275
14. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, Mehran
R, McPherson J, Farhat N, Marso SP, Parise H, Templin B, White R, Zhang Z,
Serruys PW, Investigators P. A prospective natural-history study of coronary
atherosclerosis. The New England journal of medicine. 2011;364:226-235
15. Kubo T, Maehara A, Mintz GS, Doi H, Tsujita K, Choi SY, Katoh O, Nasu K,
Koenig A, Pieper M, Rogers JH, Wijns W, Bose D, Margolis MP, Moses JW,
Stone GW, Leon MB. The dynamic nature of coronary artery lesion morphology
assessed by serial virtual histology intravascular ultrasound tissue characterization.
Journal of the American College of Cardiology. 2010;55:1590-1597
16. Jia H, Abtahian F, Aguirre AD, Lee S, Chia S, Lowe H, Kato K, Yonetsu T,
Vergallo R, Hu S, Tian J, Lee H, Park SJ, Jang YS, Raffel OC, Mizuno K, Uemura
S, Itoh T, Kakuta T, Choi SY, Dauerman HL, Prasad A, Toma C, McNulty I, Zhang
S, Yu B, Fuster V, Narula J, Virmani R, Jang IK. In vivo diagnosis of plaque
erosion and calcified nodule in patients with acute coronary syndrome by
intravascular optical coherence tomography. Journal of the American College of
Cardiology. 2013;62:1748-1758
17. Kolodgie FD, Burke AP, Wight TN, Virmani R. The accumulation of specific
types of proteoglycans in eroded plaques: A role in coronary thrombosis in the
absence of rupture. Current opinion in lipidology. 2004;15:575-582
18. Libby P, Pasterkamp G. Requiem for the 'vulnerable plaque'. European heart
journal. 2015;36:2984-2987
19. Burke AP, Farb A, Malcom GT, Liang Y, Smialek J, Virmani R. Effect of risk
factors on the mechanism of acute thrombosis and sudden coronary death in
women. Circulation. 1998;97:2110-2116

61
 References

20. Tedgui A, Mallat Z. Apoptosis as a determinant of atherothrombosis.

Thrombosis and haemostasis. 2001;86:420-426
21. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J,
Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman
S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS,
de Korte CL, Aikawa M, Airaksinen KE, Assmann G, Becker CR, Chesebro JH,
Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic
J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A,
Boerwinkle E, Ballantyne C, Insull W, Jr., Schwartz RS, Vogel R, Serruys PW,
Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R,
Ridker PM, Zipes DP, Shah PK, Willerson JT. From vulnerable plaque to
vulnerable patient: A call for new definitions and risk assessment strategies: Part
ii. Circulation. 2003;108:1772-1778
22. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J,
Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman
S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS,
de Korte CL, Aikawa M, Juhani Airaksinen KE, Assmann G, Becker CR,
Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March
K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran
R, Colombo A, Boerwinkle E, Ballantyne C, Insull W, Jr., Schwartz RS, Vogel R,
Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE,
Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT. From vulnerable plaque
to vulnerable patient: A call for new definitions and risk assessment strategies: Part
i. Circulation. 2003;108:1664-1672
23. Carvalho D, Savage CO, Black CM, Pearson JD. Igg antiendothelial cell
autoantibodies from scleroderma patients induce leukocyte adhesion to human
vascular endothelial cells in vitro. Induction of adhesion molecule expression and
involvement of endothelium-derived cytokines. The Journal of clinical
investigation. 1996;97:111-119
24. Nieswandt B, Watson SP. Platelet-collagen interaction: Is gpvi the central
receptor? Blood. 2003;102:449-461
25. Dubois C, Panicot-Dubois L, Gainor JF, Furie BC, Furie B. Thrombin-
initiated platelet activation in vivo is vwf independent during thrombus formation
in a laser injury model. The Journal of clinical investigation. 2007;117:953-960
26. Jackson SP. The growing complexity of platelet aggregation. Blood.
2007;109:5087-5095
27. Ruggeri ZM, Orje JN, Habermann R, Federici AB, Reininger AJ. Activation-
independent platelet adhesion and aggregation under elevated shear stress. Blood.
2006;108:1903-1910
28. Gershlick AH, Banning AP, Myat A, Verheugt FW, Gersh BJ. Reperfusion
therapy for stemi: Is there still a role for thrombolysis in the era of primary
percutaneous coronary intervention? Lancet. 2013;382:624-632
29. Miedema MD, Newell MC, Duval S, Garberich RF, Handran CB, Larson DM,
Mulder S, Wang YL, Lips DL, Henry TD. Causes of delay and associated mortality
in patients transferred with st-segment-elevation myocardial infarction.
Circulation. 2011;124:1636-1644

62
 References

30. Terkelsen CJ, Sorensen JT, Maeng M, Jensen LO, Tilsted HH, Trautner S,
Vach W, Johnsen SP, Thuesen L, Lassen JF. System delay and mortality among
patients with stemi treated with primary percutaneous coronary intervention.
JAMA : the journal of the American Medical Association. 2010;304:763-771
31. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither
among 17,187 cases of suspected acute myocardial infarction: Isis-2. Isis-2
(second international study of infarct survival) collaborative group. Lancet.
1988;2:349-360
32. An international randomized trial comparing four thrombolytic strategies for
acute myocardial infarction. The gusto investigators. The New England journal of
medicine. 1993;329:673-682
33. Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic
treatment in acute myocardial infarction: Reappraisal of the golden hour. Lancet.
1996;348:771-775
34. Short R. In search of andreas roland gruntzig, md (1939-1985). Circulation.
2007;116:f49-53
35. Grines CL, Browne KF, Marco J, Rothbaum D, Stone GW, O'Keefe J, Overlie
P, Donohue B, Chelliah N, Timmis GC, et al. A comparison of immediate
angioplasty with thrombolytic therapy for acute myocardial infarction. The
primary angioplasty in myocardial infarction study group. The New England
journal of medicine. 1993;328:673-679
36. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous
thrombolytic therapy for acute myocardial infarction: A quantitative review of 23
randomised trials. Lancet. 2003;361:13-20
37. Goto S, Tamura N, Ishida H. Ability of anti-glycoprotein iib/iiia agents to
dissolve platelet thrombi formed on a collagen surface under blood flow
conditions. Journal of the American College of Cardiology. 2004;44:316-323
38. De Luca G, Suryapranata H, Stone GW, Antoniucci D, Tcheng JE, Neumann
FJ, Van de Werf F, Antman EM, Topol EJ. Abciximab as adjunctive therapy to
reperfusion in acute st-segment elevation myocardial infarction: A meta-analysis
of randomized trials. JAMA : the journal of the American Medical Association.
2005;293:1759-1765
39. Montalescot G, Antoniucci D, Kastrati A, Neumann FJ, Borentain M,
Migliorini A, Boutron C, Collet JP, Vicaut E. Abciximab in primary coronary
stenting of st-elevation myocardial infarction: A european meta-analysis on
individual patients' data with long-term follow-up. European heart journal.
2007;28:443-449
40. ten Berg JM, van 't Hof AW, Dill T, Heestermans T, van Werkum JW,
Mosterd A, van Houwelingen G, Koopmans PC, Stella PR, Boersma E, Hamm C,
On TSG. Effect of early, pre-hospital initiation of high bolus dose tirofiban in
patients with st-segment elevation myocardial infarction on short- and long-term
clinical outcome. Journal of the American College of Cardiology. 2010;55:2446-
2455
41. Le May MR, Wells GA, Glover CA, So DY, Froeschl M, Marquis JF, O'Brien
ER, Turek M, Thomas A, Kass M, Jadhav S, Labinaz M. Primary percutaneous
coronary angioplasty with and without eptifibatide in st-segment elevation

63
 References

myocardial infarction: A safety and efficacy study of integrilin-facilitated versus

primary percutaneous coronary intervention in st-segment elevation myocardial
infarction (assist). Circulation. Cardiovascular interventions. 2009;2:330-338
42. Mehilli J, Kastrati A, Schulz S, Frungel S, Nekolla SG, Moshage W, Dotzer
F, Huber K, Pache J, Dirschinger J, Seyfarth M, Martinoff S, Schwaiger M,
Schomig A, Bavarian Reperfusion Alternatives Evaluation-3 Study I. Abciximab
in patients with acute st-segment-elevation myocardial infarction undergoing
primary percutaneous coronary intervention after clopidogrel loading: A
randomized double-blind trial. Circulation. 2009;119:1933-1940
43. Ellis SG, Tendera M, de Belder MA, van Boven AJ, Widimsky P, Janssens L,
Andersen HR, Betriu A, Savonitto S, Adamus J, Peruga JZ, Kosmider M, Katz O,
Neunteufl T, Jorgova J, Dorobantu M, Grinfeld L, Armstrong P, Brodie BR,
Herrmann HC, Montalescot G, Neumann FJ, Effron MB, Barnathan ES, Topol EJ,
Investigators F. Facilitated pci in patients with st-elevation myocardial infarction.
The New England journal of medicine. 2008;358:2205-2217
44. Herrmann HC, Lu J, Brodie BR, Armstrong PW, Montalescot G, Betriu A,
Neuman FJ, Effron MB, Barnathan ES, Topol EJ, Ellis SG, Investigators F. Benefit
of facilitated percutaneous coronary intervention in high-risk st-segment elevation
myocardial infarction patients presenting to nonpercutaneous coronary
intervention hospitals. JACC. Cardiovascular interventions. 2009;2:917-924
45. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D,
Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Kirtane
AJ, Parise H, Mehran R, Investigators H-AT. Bivalirudin during primary pci in
acute myocardial infarction. The New England journal of medicine.
2008;358:2218-2230
46. Mehran R, Lansky AJ, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR,
Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Wong SC, Nikolsky
E, Gambone L, Vandertie L, Parise H, Dangas GD, Stone GW, Investigators H-
AT. Bivalirudin in patients undergoing primary angioplasty for acute myocardial
infarction (horizons-ami): 1-year results of a randomised controlled trial. Lancet.
2009;374:1149-1159
47. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D,
Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Fahy M,
Parise H, Mehran R, Investigators H-AT. Heparin plus a glycoprotein iib/iiia
inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-
metal stents in acute myocardial infarction (horizons-ami): Final 3-year results
from a multicentre, randomised controlled trial. Lancet. 2011;377:2193-2204
48. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G,
Hamm C, Head SJ, Juni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U,
Laufer G, Neumann FJ, Richter DJ, Schauerte P, Uva MS, Stefanini GG, Taggart
DP, Torracca L, Valgimigli M, Wijns W, Witkowski A, Grupa Robocza
Europejskiego Towarzystwa K, Europejskie Stowarzyszenie Chirurgii Serca i
Klatki Piersiowej do spraw rewaskularyzacji miesnia s, European Association for
Percutaneous Cardiovascular I. [2014 esc/eacts guidelines on myocardial
revascularization]. Kardiologia polska. 2014;72:1253-1379

64
 References

49. Shahzad A, Kemp I, Mars C, Wilson K, Roome C, Cooper R, Andron M,

Appleby C, Fisher M, Khand A, Kunadian B, Mills JD, Morris JL, Morrison WL,
Munir S, Palmer ND, Perry RA, Ramsdale DR, Velavan P, Stables RH,
investigators H-Pt. Unfractionated heparin versus bivalirudin in primary
percutaneous coronary intervention (heat-ppci): An open-label, single centre,
randomised controlled trial. Lancet. 2014;384:1849-1858
50. Han Y, Guo J, Zheng Y, Zang H, Su X, Wang Y, Chen S, Jiang T, Yang P,
Chen J, Jiang D, Jing Q, Liang Z, Liu H, Zhao X, Li J, Li Y, Xu B, Stone GW,
Investigators B. Bivalirudin vs heparin with or without tirofiban during primary
percutaneous coronary intervention in acute myocardial infarction: The bright
randomized clinical trial. JAMA : the journal of the American Medical Association.
2015;313:1336-1346
51. Valgimigli M, Frigoli E, Leonardi S, Rothenbuhler M, Gagnor A, Calabro P,
Garducci S, Rubartelli P, Briguori C, Ando G, Repetto A, Limbruno U, Garbo R,
Sganzerla P, Russo F, Lupi A, Cortese B, Ausiello A, Ierna S, Esposito G,
Presbitero P, Santarelli A, Sardella G, Varbella F, Tresoldi S, de Cesare N,
Rigattieri S, Zingarelli A, Tosi P, van 't Hof A, Boccuzzi G, Omerovic E, Sabate
M, Heg D, Juni P, Vranckx P, Investigators M. Bivalirudin or unfractionated
heparin in acute coronary syndromes. The New England journal of medicine.
2015;373:997-1009
52. De Luca G, Navarese E, Marino P. Risk profile and benefits from gp iib-iiia
inhibitors among patients with st-segment elevation myocardial infarction treated
with primary angioplasty: A meta-regression analysis of randomized trials.
European heart journal. 2009;30:2705-2713
53. Safley DM, Venkitachalam L, Kennedy KF, Cohen DJ. Impact of
glycoprotein iib/iiia inhibition in contemporary percutaneous coronary
intervention for acute coronary syndromes: Insights from the national
cardiovascular data registry. JACC. Cardiovascular interventions. 2015;8:1574-
1582
54. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S,
Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P,
Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H.
Standardized bleeding definitions for cardiovascular clinical trials: A consensus
report from the bleeding academic research consortium. Circulation.
2011;123:2736-2747
55. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK,
Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA,
Clopidogrel in Unstable angina to prevent Recurrent Events trial I. Effects of
pretreatment with clopidogrel and aspirin followed by long-term therapy in
patients undergoing percutaneous coronary intervention: The pci-cure study.
Lancet. 2001;358:527-533
56. Jaremo P, Lindahl TL, Fransson SG, Richter A. Individual variations of
platelet inhibition after loading doses of clopidogrel. Journal of internal medicine.
2002;252:233-238
57. Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, Bhatt
DL, Cattaneo M, Collet JP, Cuisset T, Gachet C, Montalescot G, Jennings LK,

65
 References

Kereiakes D, Sibbing D, Trenk D, Van Werkum JW, Paganelli F, Price MJ,

Waksman R, Gurbel PA, Working Group on High On-Treatment Platelet R.
Consensus and future directions on the definition of high on-treatment platelet
reactivity to adenosine diphosphate. Journal of the American College of
Cardiology. 2010;56:919-933
58. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US.
Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: Results of
the clopidogrel loading with eptifibatide to arrest the reactivity of platelets (clear
platelets) study. Circulation. 2005;111:1153-1159
59. Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R,
Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson
V, Ledley GS, Storey RF. Randomized double-blind assessment of the onset and
offset of the antiplatelet effects of ticagrelor versus clopidogrel in patients with
stable coronary artery disease: The onset/offset study. Circulation.
2009;120:2577-2585
60. Aradi D, Komocsi A, Vorobcsuk A, Rideg O, Tokes-Fuzesi M, Magyarlaki T,
Horvath IG, Serebruany VL. Prognostic significance of high on-clopidogrel
platelet reactivity after percutaneous coronary intervention: Systematic review and
meta-analysis. American heart journal. 2010;160:543-551
61. von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A,
Schomig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and
900-mg loading doses of clopidogrel: Results of the isar-choice (intracoronary
stenting and antithrombotic regimen: Choose between 3 high oral doses for
immediate clopidogrel effect) trial. Circulation. 2005;112:2946-2950
62. Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB,
Faxon DP, Rupprecht HJ, Budaj A, Avezum A, Widimsky P, Steg PG, Bassand
JP, Montalescot G, Macaya C, Di Pasquale G, Niemela K, Ajani AE, White HD,
Chrolavicius S, Gao P, Fox KA, Yusuf S, investigators C-Ot. Double-dose versus
standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals
undergoing percutaneous coronary intervention for acute coronary syndromes
(current-oasis 7): A randomised factorial trial. Lancet. 2010;376:1233-1243
63. Koul S, Smith JG, Schersten F, James S, Lagerqvist B, Erlinge D. Effect of
upstream clopidogrel treatment in patients with st-segment elevation myocardial
infarction undergoing primary percutaneous coronary intervention. European
heart journal. 2011;32:2989-2997
64. Zeymer U, Arntz HR, Mark B, Fichtlscherer S, Werner G, Scholler R, Zahn
R, Diller F, Darius H, Dill T, Huber K. Efficacy and safety of a high loading dose
of clopidogrel administered prehospitally to improve primary percutaneous
coronary intervention in acute myocardial infarction: The randomized cipami trial.
Clinical research in cardiology : official journal of the German Cardiac Society.
2012;101:305-312
65. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G.
Pharmacodynamics, pharmacokinetics, and safety of the oral reversible p2y12
antagonist azd6140 with aspirin in patients with atherosclerosis: A double-blind
comparison to clopidogrel with aspirin. European heart journal. 2006;27:1038-
1047

66
 References

66. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger
CB, Lange RA, Mack MJ, Mauri L, Mehran R, Mukherjee D, Newby LK, O'Gara
PT, Sabatine MS, Smith PK, Smith SC, Jr. 2016 acc/aha guideline focused update
on duration of dual antiplatelet therapy in patients with coronary artery disease: A
report of the american college of cardiology/american heart association task force
on clinical practice guidelines. Journal of the American College of Cardiology.
2016;68:1082-1115
67. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G,
Hamm C, Head SJ, Juni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U,
Laufer G, Neumann FJ, Richter DJ, Schauerte P, Uva MS, Stefanini GG, Taggart
DP, Torracca L, Valgimigli M, Wijns W, Witkowski A. [2014 esc/eacts guidelines
on myocardial revascularization]. Kardiologia polska. 2014;72:1253-1379
68. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C,
Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg
PG, Storey RF, Harrington RA, Investigators P, Freij A, Thorsen M. Ticagrelor
versus clopidogrel in patients with acute coronary syndromes. The New England
journal of medicine. 2009;361:1045-1057
69. Velders MA, Abtan J, Angiolillo DJ, Ardissino D, Harrington RA, Hellkamp
A, Himmelmann A, Husted S, Katus HA, Meier B, Schulte PJ, Storey RF,
Wallentin L, Gabriel Steg P, James SK, Investigators P. Safety and efficacy of
ticagrelor and clopidogrel in primary percutaneous coronary intervention. Heart.
2016;102:617-625
70. Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC,
Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G.
Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in
patients with st-segment-elevation myocardial infarction. Circulation.
Cardiovascular interventions. 2012;5:797-804
71. Parodi G, Valenti R, Bellandi B, Migliorini A, Marcucci R, Comito V,
Carrabba N, Santini A, Gensini GF, Abbate R, Antoniucci D. Comparison of
prasugrel and ticagrelor loading doses in st-segment elevation myocardial
infarction patients: Rapid (rapid activity of platelet inhibitor drugs) primary pci
study. Journal of the American College of Cardiology. 2013;61:1601-1606
72. Kubica J, Adamski P, Ostrowska M, Sikora J, Kubica JM, Sroka WD,
Stankowska K, Buszko K, Navarese EP, Jilma B, Siller-Matula JM, Marszall MP,
Rosc D, Kozinski M. Morphine delays and attenuates ticagrelor exposure and
action in patients with myocardial infarction: The randomized, double-blind,
placebo-controlled impression trial. European heart journal. 2016;37:245-252
73. Bonello L, Pansieri M, Mancini J, Bonello R, Maillard L, Barnay P, Rossi P,
Ait-Mokhtar O, Jouve B, Collet F, Peyre JP, Wittenberg O, de Labriolle A,
Camilleri E, Cheneau E, Cabassome E, Dignat-George F, Camoin-Jau L, Paganelli
F. High on-treatment platelet reactivity after prasugrel loading dose and
cardiovascular events after percutaneous coronary intervention in acute coronary
syndromes. Journal of the American College of Cardiology. 2011;58:467-473
74. Montalescot G, van 't Hof AW, Lapostolle F, Silvain J, Lassen JF, Bolognese
L, Cantor WJ, Cequier A, Chettibi M, Goodman SG, Hammett CJ, Huber K,
Janzon M, Merkely B, Storey RF, Zeymer U, Stibbe O, Ecollan P, Heutz WM,

67
 References

Swahn E, Collet JP, Willems FF, Baradat C, Licour M, Tsatsaris A, Vicaut E,

Hamm CW, Investigators A. Prehospital ticagrelor in st-segment elevation
myocardial infarction. The New England journal of medicine. 2014;371:1016-
1027
75. Nordt SP, Clark RF, Castillo EM, Guss DA. Comparison of three aspirin
formulations in human volunteers. The western journal of emergency medicine.
2011;12:381-385
76. Zafar MU, Farkouh ME, Fuster V, Chesebro JH. Crushed clopidogrel
administered via nasogastric tube has faster and greater absorption than oral whole
tablets. Journal of interventional cardiology. 2009;22:385-389
77. Crean B, Finnie C, Crosby A. Evaluation of crushed ticagrelor tablet doses:
Recovery following crushing and naso-gastric tube passage ex vivo. Drugs in
R&D. 2013;13:153-157
78. Teng R, Carlson G, Hsia J. An open-label, randomized bioavailability study
with alternative methods of administration of crushed ticagrelor tablets in healthy
volunteers. International journal of clinical pharmacology and therapeutics.
2015;53:182-189
79. Parodi G, Xanthopoulou I, Bellandi B, Gkizas V, Valenti R, Karanikas S,
Migliorini A, Angelidis C, Abbate R, Patsilinakos S, Baldereschi GJ, Marcucci R,
Gensini GF, Antoniucci D, Alexopoulos D. Ticagrelor crushed tablets
administration in stemi patients: The mojito study. Journal of the American
College of Cardiology. 2015;65:511-512
80. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, Clopidogrel
in Unstable Angina to Prevent Recurrent Events Trial I. Effects of clopidogrel in
addition to aspirin in patients with acute coronary syndromes without st-segment
elevation. The New England journal of medicine. 2001;345:494-502
81. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb
S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody
G, Gibson CM, Antman EM, Investigators T-T. Prasugrel versus clopidogrel in
patients with acute coronary syndromes. The New England journal of medicine.
2007;357:2001-2015
82. Boersma E, Harrington RA, Moliterno DJ, White H, Theroux P, Van de Werf
F, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, Simes J, Califf RM,
Topol EJ, Simoons ML. Platelet glycoprotein iib/iiia inhibitors in acute coronary
syndromes: A meta-analysis of all major randomised clinical trials. Lancet.
2002;359:189-198
83. Rao SV, O'Grady K, Pieper KS, Granger CB, Newby LK, Mahaffey KW,
Moliterno DJ, Lincoff AM, Armstrong PW, Van de Werf F, Califf RM, Harrington
RA. A comparison of the clinical impact of bleeding measured by two different
classifications among patients with acute coronary syndromes. Journal of the
American College of Cardiology. 2006;47:809-816
84. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse
impact of bleeding on prognosis in patients with acute coronary syndromes.
Circulation. 2006;114:774-782
85. Rao SV, Jollis JG, Harrington RA, Granger CB, Newby LK, Armstrong PW,
Moliterno DJ, Lindblad L, Pieper K, Topol EJ, Stamler JS, Califf RM.

68
 References

Relationship of blood transfusion and clinical outcomes in patients with acute

coronary syndromes. JAMA : the journal of the American Medical Association.
2004;292:1555-1562
86. Manoukian SV, Feit F, Mehran R, Voeltz MD, Ebrahimi R, Hamon M,
Dangas GD, Lincoff AM, White HD, Moses JW, King SB, 3rd, Ohman EM, Stone
GW. Impact of major bleeding on 30-day mortality and clinical outcomes in
patients with acute coronary syndromes: An analysis from the acuity trial. Journal
of the American College of Cardiology. 2007;49:1362-1368
87. Mehran R, Pocock S, Nikolsky E, Dangas GD, Clayton T, Claessen BE,
Caixeta A, Feit F, Manoukian SV, White H, Bertrand M, Ohman EM, Parise H,
Lansky AJ, Lincoff AM, Stone GW. Impact of bleeding on mortality after
percutaneous coronary intervention results from a patient-level pooled analysis of
the replace-2 (randomized evaluation of pci linking angiomax to reduced clinical
events), acuity (acute catheterization and urgent intervention triage strategy), and
horizons-ami (harmonizing outcomes with revascularization and stents in acute
myocardial infarction) trials. JACC. Cardiovascular interventions. 2011;4:654-
664
88. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT,
Francis CK, Hillis D, Ludbrook P, et al. Thrombolysis in myocardial infarction
(timi) trial, phase i: A comparison between intravenous tissue plasminogen
activator and intravenous streptokinase. Clinical findings through hospital
discharge. Circulation. 1987;76:142-154
89. Vranckx P, Leonardi S, Tebaldi M, Biscaglia S, Parrinello G, Rao SV, Mehran
R, Valgimigli M. Prospective validation of the bleeding academic research
consortium classification in the all-comer prodigy trial. European heart journal.
2014;35:2524-2529
90. Segev A, Strauss BH, Tan M, Constance C, Langer A, Goodman SG,
Canadian Acute Coronary Syndromes Registries I. Predictors and 1-year outcome
of major bleeding in patients with non-st-elevation acute coronary syndromes:
Insights from the canadian acute coronary syndrome registries. American heart
journal. 2005;150:690-694
91. Moscucci M, Fox KA, Cannon CP, Klein W, Lopez-Sendon J, Montalescot
G, White K, Goldberg RJ. Predictors of major bleeding in acute coronary
syndromes: The global registry of acute coronary events (grace). European heart
journal. 2003;24:1815-1823
92. Alexander KP, Chen AY, Roe MT, Newby LK, Gibson CM, Allen-LaPointe
NM, Pollack C, Gibler WB, Ohman EM, Peterson ED, Investigators C. Excess
dosing of antiplatelet and antithrombin agents in the treatment of non-st-segment
elevation acute coronary syndromes. JAMA : the journal of the American Medical
Association. 2005;294:3108-3116
93. Alexander KP, Chen AY, Newby LK, Schwartz JB, Redberg RF, Hochman
JS, Roe MT, Gibler WB, Ohman EM, Peterson ED, Investigators C. Sex
differences in major bleeding with glycoprotein iib/iiia inhibitors: Results from the
crusade (can rapid risk stratification of unstable angina patients suppress adverse
outcomes with early implementation of the acc/aha guidelines) initiative.
Circulation. 2006;114:1380-1387

69
 References

94. Lopes RD, Subherwal S, Holmes DN, Thomas L, Wang TY, Rao SV, Magnus
Ohman E, Roe MT, Peterson ED, Alexander KP. The association of in-hospital
major bleeding with short-, intermediate-, and long-term mortality among older
patients with non-st-segment elevation myocardial infarction. European heart
journal. 2012;33:2044-2053
95. Reinecke H, Trey T, Wellmann J, Heidrich J, Fobker M, Wichter T, Walter
M, Breithardt G, Schaefer RM. Haemoglobin-related mortality in patients
undergoing percutaneous coronary interventions. European heart journal.
2003;24:2142-2150
96. Hill SR, Carless PA, Henry DA, Carson JL, Hebert PC, McClelland DB,
Henderson KM. Transfusion thresholds and other strategies for guiding allogeneic
red blood cell transfusion. The Cochrane database of systematic reviews.
2002:CD002042
97. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes I, Yusuf
S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, Budaj A, Peters RJ,
Bassand JP, Wallentin L, Joyner C, Fox KA. Comparison of fondaparinux and
enoxaparin in acute coronary syndromes. The New England journal of medicine.
2006;354:1464-1476
98. Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herrman JP,
Adriaenssens T, Vrolix M, Heestermans AA, Vis MM, Tijsen JG, van 't Hof AW,
ten Berg JM, investigators Ws. Use of clopidogrel with or without aspirin in
patients taking oral anticoagulant therapy and undergoing percutaneous coronary
intervention: An open-label, randomised, controlled trial. Lancet. 2013;381:1107-
1115
99. Valgimigli M, Gagnor A, Calabro P, Frigoli E, Leonardi S, Zaro T, Rubartelli
P, Briguori C, Ando G, Repetto A, Limbruno U, Cortese B, Sganzerla P, Lupi A,
Galli M, Colangelo S, Ierna S, Ausiello A, Presbitero P, Sardella G, Varbella F,
Esposito G, Santarelli A, Tresoldi S, Nazzaro M, Zingarelli A, de Cesare N,
Rigattieri S, Tosi P, Palmieri C, Brugaletta S, Rao SV, Heg D, Rothenbuhler M,
Vranckx P, Juni P, Investigators M. Radial versus femoral access in patients with
acute coronary syndromes undergoing invasive management: A randomised
multicentre trial. Lancet. 2015;385:2465-2476
100. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman
M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE,
Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH,
Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME,
Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ,
Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ,
Woo D, Yeh RW, Turner MB, American Heart Association Statistics C, Stroke
Statistics S. Heart disease and stroke statistics--2015 update: A report from the
american heart association. Circulation. 2015;131:e29-322
101. Gholizadeh L, Davidson P. More similarities than differences: An
international comparison of cvd mortality and risk factors in women. Health care
for women international. 2008;29:3-22
102. Lawesson SS, Alfredsson J, Fredrikson M, Swahn E. A gender
perspective on short- and long term mortality in st-elevation myocardial infarction-

70
 References

-a report from the swedeheart register. International journal of cardiology.

2013;168:1041-1047
103. Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM. Sex-
based differences in early mortality after myocardial infarction. National registry
of myocardial infarction 2 participants. The New England journal of medicine.
1999;341:217-225
104. de Boer SP, Roos-Hesselink JW, van Leeuwen MA, Lenzen MJ, van
Geuns RJ, Regar E, van Mieghem NM, van Domburg R, Zijlstra F, Serruys PW,
Boersma E. Excess mortality in women compared to men after pci in stemi: An
analysis of 11,931 patients during 2000-2009. International journal of cardiology.
2014;176:456-463
105. Chakrabarti S, Morton JS, Davidge ST. Mechanisms of estrogen
effects on the endothelium: An overview. The Canadian journal of cardiology.
2014;30:705-712
106. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F,
McQueen M, Budaj A, Pais P, Varigos J, Lisheng L, Investigators IS. Effect of
potentially modifiable risk factors associated with myocardial infarction in 52
countries (the interheart study): Case-control study. Lancet. 2004;364:937-952
107. Lichtman JH, Leifheit-Limson EC, Watanabe E, Allen NB, Garavalia
B, Garavalia LS, Spertus JA, Krumholz HM, Curry LA. Symptom recognition and
healthcare experiences of young women with acute myocardial infarction.
Circulation. Cardiovascular quality and outcomes. 2015;8:S31-38
108. Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute
coronary syndromes: The pathologists' view. European heart journal.
2013;34:719-728
109. Farb A, Burke AP, Tang AL, Liang TY, Mannan P, Smialek J,
Virmani R. Coronary plaque erosion without rupture into a lipid core. A frequent
cause of coronary thrombosis in sudden coronary death. Circulation.
1996;93:1354-1363
110. Chokshi NP, Iqbal SN, Berger RL, Hochman JS, Feit F, Slater JN,
Pena-Sing I, Yatskar L, Keller NM, Babaev A, Attubato MJ, Reynolds HR. Sex
and race are associated with the absence of epicardial coronary artery obstructive
disease at angiography in patients with acute coronary syndromes. Clinical
cardiology. 2010;33:495-501
111. Ghadri JR, Cammann VL, Jurisic S, Seifert B, Napp LC, Diekmann
J, Bataiosu DR, D'Ascenzo F, Ding KJ, Sarcon A, Kazemian E, Birri T, Ruschitzka
F, Luscher TF, Templin C, Inter TAKc-i. A novel clinical score (intertak
diagnostic score) to differentiate takotsubo syndrome from acute coronary
syndrome: Results from the international takotsubo registry. European journal of
heart failure. 2016
112. Thompson EA, Ferraris S, Gress T, Ferraris V. Gender differences
and predictors of mortality in spontaneous coronary artery dissection: A review of
reported cases. The Journal of invasive cardiology. 2005;17:59-61
113. Rubini Gimenez M, Reiter M, Twerenbold R, Reichlin T, Wildi K,
Haaf P, Wicki K, Zellweger C, Hoeller R, Moehring B, Sou SM, Mueller M,
Denhaerynck K, Meller B, Stallone F, Henseler S, Bassetti S, Geigy N, Osswald

71
 References

S, Mueller C. Sex-specific chest pain characteristics in the early diagnosis of acute

myocardial infarction. JAMA internal medicine. 2014;174:241-249
114. Lawesson SS, Alfredsson J, Fredrikson M, Swahn E. Time trends in
stemi--improved treatment and outcome but still a gender gap: A prospective
observational cohort study from the swedeheart register. BMJ open.
2012;2:e000726
115. Sadowski M, Gasior M, Gierlotka M, Janion M, Polonski L. Gender-
related differences in mortality after st-segment elevation myocardial infarction:
A large multicentre national registry. EuroIntervention : journal of EuroPCR in
collaboration with the Working Group on Interventional Cardiology of the
European Society of Cardiology. 2011;6:1068-1072
116. Indications for fibrinolytic therapy in suspected acute myocardial
infarction: Collaborative overview of early mortality and major morbidity results
from all randomised trials of more than 1000 patients. Fibrinolytic therapy trialists'
(ftt) collaborative group. Lancet. 1994;343:311-322
117. Simon T, Mary-Krause M, Cambou JP, Hanania G, Gueret P,
Lablanche JM, Blanchard D, Genes N, Danchin N, Investigators U. Impact of age
and gender on in-hospital and late mortality after acute myocardial infarction:
Increased early risk in younger women: Results from the french nation-wide usic
registries. European heart journal. 2006;27:1282-1288
118. Weaver WD, White HD, Wilcox RG, Aylward PE, Morris D, Guerci
A, Ohman EM, Barbash GI, Betriu A, Sadowski Z, Topol EJ, Califf RM.
Comparisons of characteristics and outcomes among women and men with acute
myocardial infarction treated with thrombolytic therapy. Gusto-i investigators.
JAMA : the journal of the American Medical Association. 1996;275:777-782
119. Stone GW, Grines CL, Browne KF, Marco J, Rothbaum D, O'Keefe
J, Hartzler GO, Overlie P, Donohue B, Chelliah N, et al. Comparison of in-hospital
outcome in men versus women treated by either thrombolytic therapy or primary
coronary angioplasty for acute myocardial infarction. The American journal of
cardiology. 1995;75:987-992
120. Tamis-Holland JE, Palazzo A, Stebbins AL, Slater JN, Boland J, Ellis
SG, Hochman JS, Investigators GI-BAS. Benefits of direct angioplasty for women
and men with acute myocardial infarction: Results of the global use of strategies
to open occluded arteries in acute coronary syndromes angioplasty (gusto ii-b)
angioplasty substudy. American heart journal. 2004;147:133-139
121. Benamer H, Tafflet M, Bataille S, Escolano S, Livarek B, Fourchard
V, Caussin C, Teiger E, Garot P, Lambert Y, Jouven X, Spaulding C, Investigators
C-AR. Female gender is an independent predictor of in-hospital mortality after
stemi in the era of primary pci: Insights from the greater paris area pci registry.
EuroIntervention : journal of EuroPCR in collaboration with the Working Group
on Interventional Cardiology of the European Society of Cardiology. 2011;6:1073-
1079
122. Suessenbacher A, Doerler J, Alber H, Aichinger J, Altenberger J,
Benzer W, Christ G, Globits S, Huber K, Karnik R, Norman G, Siostrzonek P,
Zenker G, Pachinger O, Weidinger F. Gender-related outcome following
percutaneous coronary intervention for st-elevation myocardial infarction: Data

72
 References

from the austrian acute pci registry. EuroIntervention : journal of EuroPCR in

collaboration with the Working Group on Interventional Cardiology of the
European Society of Cardiology. 2008;4:271-276
123. Birkemeyer R, Schneider H, Rillig A, Ebeling J, Akin I, Kische S,
Paranskaya L, Jung W, Ince H, Nienaber CA. Do gender differences in primary
pci mortality represent a different adherence to guideline recommended therapy?
A multicenter observation. BMC cardiovascular disorders. 2014;14:71
124. Kunadian V, Qiu W, Bawamia B, Veerasamy M, Jamieson S, Zaman
A. Gender comparisons in cardiogenic shock during st elevation myocardial
infarction treated by primary percutaneous coronary intervention. The American
journal of cardiology. 2013;112:636-641
125. Vakili BA, Kaplan RC, Brown DL. Sex-based differences in early
mortality of patients undergoing primary angioplasty for first acute myocardial
infarction. Circulation. 2001;104:3034-3038
126. De Luca G, Gibson CM, Gyongyosi M, Zeymer U, Dudek D, Arntz
HR, Bellandi F, Maioli M, Noc M, Zorman S, Gabriel HM, Emre A, Cutlip D,
Rakowski T, Huber K, van't Hof AW. Gender-related differences in outcome after
st-segment elevation myocardial infarction treated by primary angioplasty and
glycoprotein iib-iiia inhibitors: Insights from the egypt cooperation. Journal of
thrombosis and thrombolysis. 2010;30:342-346
127. Motovska Z, Widimsky P, Aschermann M, Investigators PSG. The
impact of gender on outcomes of patients with st elevation myocardial infarction
transported for percutaneous coronary intervention: Analysis of the prague-1 and
2 studies. Heart. 2008;94:e5
128. Radovanovic D, Nallamothu BK, Seifert B, Bertel O, Eberli F, Urban
P, Pedrazzini G, Rickli H, Stauffer JC, Windecker S, Erne P, Investigators AP.
Temporal trends in treatment of st-elevation myocardial infarction among men and
women in switzerland between 1997 and 2011. European heart journal. Acute
cardiovascular care. 2012;1:183-191
129. Mahmoud KD, Gu YL, Nijsten MW, de Vos R, Nieuwland W, Zijlstra
F, Hillege HL, van der Horst IC, de Smet BJ. Interhospital transfer due to failed
prehospital diagnosis for primary percutaneous coronary intervention: An
observational study on incidence, predictors, and clinical impact. European heart
journal. Acute cardiovascular care. 2013;2:166-175
130. Melberg T, Kindervaag B, Rosland J. Gender-specific ambulance
priority and delays to primary percutaneous coronary intervention: A consequence
of the patients' presentation or the management at the emergency medical
communications center? American heart journal. 2013;166:839-845
131. Berger JS, Bhatt DL, Cannon CP, Chen Z, Jiang L, Jones JB, Mehta
SR, Sabatine MS, Steinhubl SR, Topol EJ, Berger PB. The relative efficacy and
safety of clopidogrel in women and men a sex-specific collaborative meta-
analysis. Journal of the American College of Cardiology. 2009;54:1935-1945
132. Husted S, James SK, Bach RG, Becker RC, Budaj A, Heras M,
Himmelmann A, Horrow J, Katus HA, Lassila R, Morais J, Nicolau JC, Steg PG,
Storey RF, Wojdyla D, Wallentin L, group Ps. The efficacy of ticagrelor is
maintained in women with acute coronary syndromes participating in the

73
 References

prospective, randomized, platelet inhibition and patient outcomes (plato) trial.

European heart journal. 2014;35:1541-1550
133. Reddan DN, Szczech LA, Tuttle RH, Shaw LK, Jones RH, Schwab
SJ, Smith MS, Califf RM, Mark DB, Owen WF, Jr. Chronic kidney disease,
mortality, and treatment strategies among patients with clinically significant
coronary artery disease. Journal of the American Society of Nephrology : JASN.
2003;14:2373-2380
134. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic
kidney disease and the risks of death, cardiovascular events, and hospitalization.
The New England journal of medicine. 2004;351:1296-1305
135. Holzmann MJ, Ivert T, Jungner I, Nordqvist T, Walldius G, Ostergren
J, Hammar N. Renal function assessed by two different formulas and incidence of
myocardial infarction and death in middle-aged men and women. Journal of
internal medicine. 2010;267:357-369
136. Bae EH, Lim SY, Cho KH, Choi JS, Kim CS, Park JW, Ma SK, Jeong
MH, Kim SW. Gfr and cardiovascular outcomes after acute myocardial infarction:
Results from the korea acute myocardial infarction registry. American journal of
kidney diseases : the official journal of the National Kidney Foundation.
2012;59:795-802
137. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L,
Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S,
Leimberger JD, Califf RM, Pfeffer MA. Relation between renal dysfunction and
cardiovascular outcomes after myocardial infarction. The New England journal of
medicine. 2004;351:1285-1295
138. Sederholm Lawesson S, Alfredsson J, Szummer K, Fredrikson M,
Swahn E. Prevalence and prognostic impact of chronic kidney disease in stemi
from a gender perspective: Data from the swedeheart register, a large swedish
prospective cohort. BMJ open. 2015:In press
139. Fox KA, Antman EM, Montalescot G, Agewall S, SomaRaju B,
Verheugt FW, Lopez-Sendon J, Hod H, Murphy SA, Braunwald E. The impact of
renal dysfunction on outcomes in the extract-timi 25 trial. Journal of the American
College of Cardiology. 2007;49:2249-2255
140. Akgul O, Uyarel H, Ergelen M, Pusuroglu H, Gul M, Turen S, Bulut
U, Baycan OF, Ozal E, Cetin M, Yildirim A, Uslu N. Predictive value of elevated
cystatin c in patients undergoing primary angioplasty for st-elevation myocardial
infarction. Journal of critical care. 2013;28:882 e813-820
141. Orvin K, Eisen A, Goldenberg I, Farkash A, Shlomo N, Gevrielov-
Yusim N, Iakobishvili Z, Hasdai D. The proxy of renal function that most
accurately predicts short- and long-term outcome after acute coronary syndrome.
American heart journal. 2015;169:702-712 e703
142. Muntner P, Hamm LL, Kusek JW, Chen J, Whelton PK, He J. The
prevalence of nontraditional risk factors for coronary heart disease in patients with
chronic kidney disease. Annals of internal medicine. 2004;140:9-17
143. Shlipak MG, Fried LF, Crump C, Bleyer AJ, Manolio TA, Tracy RP,
Furberg CD, Psaty BM. Elevations of inflammatory and procoagulant biomarkers
in elderly persons with renal insufficiency. Circulation. 2003;107:87-92

74
 References

144. Santopinto JJ, Fox KA, Goldberg RJ, Budaj A, Pinero G, Avezum A,
Gulba D, Esteban J, Gore JM, Johnson J, Gurfinkel EP, Investigators G. Creatinine
clearance and adverse hospital outcomes in patients with acute coronary
syndromes: Findings from the global registry of acute coronary events (grace).
Heart. 2003;89:1003-1008
145. El-Menyar A, Zubaid M, Sulaiman K, Singh R, Al Thani H, Akbar
M, Bulbanat B, Al-Hamdan R, Almahmmed W, Al Suwaidi J. In-hospital major
clinical outcomes in patients with chronic renal insufficiency presenting with acute
coronary syndrome: Data from a registry of 8176 patients. Mayo Clinic
proceedings. 2010;85:332-340
146. Szummer K, Lundman P, Jacobson SH, Schon S, Lindback J,
Stenestrand U, Wallentin L, Jernberg T, Swedeheart. Influence of renal function
on the effects of early revascularization in non-st-elevation myocardial infarction:
Data from the swedish web-system for enhancement and development of evidence-
based care in heart disease evaluated according to recommended therapies
(swedeheart). Circulation. 2009;120:851-858
147. Levey AS. Measurement of renal function in chronic renal disease.
Kidney international. 1990;38:167-184
148. Gaspari F, Perico N, Remuzzi G. Application of newer clearance
techniques for the determination of glomerular filtration rate. Current opinion in
nephrology and hypertension. 1998;7:675-680
149. Cockcroft DW, Gault MH. Prediction of creatinine clearance from
serum creatinine. Nephron. 1976;16:31-41
150. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen
S, Kusek JW, Van Lente F, Chronic Kidney Disease Epidemiology C. Using
standardized serum creatinine values in the modification of diet in renal disease
study equation for estimating glomerular filtration rate. Annals of internal
medicine. 2006;145:247-254
151. Melloni C, Peterson ED, Chen AY, Szczech LA, Newby LK,
Harrington RA, Gibler WB, Ohman EM, Spinler SA, Roe MT, Alexander KP.
Cockcroft-gault versus modification of diet in renal disease: Importance of
glomerular filtration rate formula for classification of chronic kidney disease in
patients with non-st-segment elevation acute coronary syndromes. Journal of the
American College of Cardiology. 2008;51:991-996
152. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd,
Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J, Ckd EPI. A
new equation to estimate glomerular filtration rate. Annals of internal medicine.
2009;150:604-612
153. Dharnidharka VR, Kwon C, Stevens G. Serum cystatin c is superior
to serum creatinine as a marker of kidney function: A meta-analysis. American
journal of kidney diseases : the official journal of the National Kidney Foundation.
2002;40:221-226
154. Grubb A, Nyman U, Bjork J, Lindstrom V, Rippe B, Sterner G,
Christensson A. Simple cystatin c-based prediction equations for glomerular
filtration rate compared with the modification of diet in renal disease prediction

75
 References

equation for adults and the schwartz and the counahan-barratt prediction equations
for children. Clinical chemistry. 2005;51:1420-1431
155. Antoniadis AP, Chatzizisis YS, Giannoglou GD. Pathogenetic
mechanisms of coronary ectasia. International journal of cardiology.
2008;130:335-343
156. Ge C, Ren F, Lu S, Ji F, Chen X, Wu X. Clinical prognostic
significance of plasma cystatin c levels among patients with acute coronary
syndrome. Clinical cardiology. 2009;32:644-648
157. Jernberg T, Attebring MF, Hambraeus K, Ivert T, James S, Jeppsson
A, Lagerqvist B, Lindahl B, Stenestrand U, Wallentin L. The swedish web-system
for enhancement and development of evidence-based care in heart disease
evaluated according to recommended therapies (swedeheart). Heart.
2010;96:1617-1621
158. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA,
Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M,
Krucoff MW, Serruys PW, Academic Research C. Clinical end points in coronary
stent trials: A case for standardized definitions. Circulation. 2007;115:2344-2351
159. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White
HD, Writing Group on behalf of the Joint ESCAAHAWHFTFftUDoMI. Third
universal definition of myocardial infarction. Global heart. 2012;7:275-295
160. Price MJ. Bedside evaluation of thienopyridine antiplatelet therapy.
Circulation. 2009;119:2625-2632
161. Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ,
Stone GW, Curzen N, Geisler T, Ten Berg J, Kirtane A, Siller-Matula J, Mahla E,
Becker RC, Bhatt DL, Waksman R, Rao SV, Alexopoulos D, Marcucci R, Reny
JL, Trenk D, Sibbing D, Gurbel PA, Working Group on On-Treatment Platelet R.
Consensus and update on the definition of on-treatment platelet reactivity to
adenosine diphosphate associated with ischemia and bleeding. Journal of the
American College of Cardiology. 2013;62:2261-2273
162. Montalescot G, Lassen JF, Hamm CW, Lapostolle F, Silvain J, ten
Berg JM, Cantor WJ, Goodman SG, Licour M, Tsatsaris A, van't Hof AW.
Ambulance or in-catheterization laboratory administration of ticagrelor for
primary percutaneous coronary intervention for st-segment elevation myocardial
infarction: Rationale and design of the randomized, double-blind administration of
ticagrelor in the cath lab or in the ambulance for new st elevation myocardial
infarction to open the coronary artery (atlantic) study. American heart journal.
2013;165:515-522
163. O'Reilly PH, Brooman PJ, Martin PJ, Pollard AJ, Farah NB, Mason
GC. Accuracy and reproducibility of a new contrast clearance method for the
determination of glomerular filtration rate. British medical journal. 1986;293:234-
236
164. National Kidney F. K/doqi clinical practice guidelines for bone
metabolism and disease in chronic kidney disease. American journal of kidney
diseases : the official journal of the National Kidney Foundation. 2003;42:S1-201

76
 References

165. G Carlson RT, J Hsia. Crushing ticagrelor tablets accelerates exposure

compared with intact tablets. J Am Coll Cardiol.
2014;63(12_S):doi:10.1016/s0735-1097(14)60229-1. April 2014
166. Austin PC. An introduction to propensity score methods for reducing
the effects of confounding in observational studies. Multivariate behavioral
research. 2011;46:399-424
167. Verdoia M, Sartori C, Pergolini P, Nardin M, Rolla R, Barbieri L,
Schaffer A, Marino P, Bellomo G, Suryapranata H, De Luca G, Novara
Atherosclerosis Study G. Prevalence and predictors of high-on treatment platelet
reactivity with ticagrelor in acs patients undergoing stent implantation. Vascular
pharmacology. 2015
168. Alexopoulos D, Barampoutis N, Gkizas V, Vogiatzi C, Tsigkas G,
Koutsogiannis N, Davlouros P, Hahalis G, Nylander S, Parodi G, Xanthopoulou I.
Crushed versus integral tablets of ticagrelor in st-segment elevation myocardial
infarction patients: A randomized pharmacokinetic/pharmacodynamic study.
Clinical pharmacokinetics. 2015
169. Alexopoulos D, Gkizas V, Patsilinakos S, Xanthopoulou I, Angelidis
C, Anthopoulos P, Makris G, Perperis A, Karanikas S, Koutsogiannis N,
Davlouros P, Deftereos S, Chiladakis J, Hahalis G. Double versus standard loading
dose of ticagrelor: Onset of antiplatelet action in patients with stemi undergoing
primary pci. Journal of the American College of Cardiology. 2013;62:940-941
170. Landis JR, Koch GG. The measurement of observer agreement for
categorical data. Biometrics. 1977;33:159-174
171. Bland JM, Altman DG. Statistical methods for assessing agreement
between two methods of clinical measurement. Lancet. 1986;1:307-310
172. National Kidney F. K/doqi clinical practice guidelines for chronic
kidney disease: Evaluation, classification, and stratification. American journal of
kidney diseases : the official journal of the National Kidney Foundation.
2002;39:S1-266
173. Spinler SA, Nawarskas JJ, Boyce EG, Connors JE, Charland SL,
Goldfarb S. Predictive performance of ten equations for estimating creatinine
clearance in cardiac patients. Iohexol cooperative study group. The Annals of
pharmacotherapy. 1998;32:1275-1283
174. Goolsby MJ. National kidney foundation guidelines for chronic
kidney disease: Evaluation, classification, and stratification. Journal of the
American Academy of Nurse Practitioners. 2002;14:238-242
175. Stone GW, Clayton T, Deliargyris EN, Prats J, Mehran R, Pocock SJ.
Reduction in cardiac mortality with bivalirudin in patients with and without major
bleeding: The horizons-ami trial (harmonizing outcomes with revascularization
and stents in acute myocardial infarction). Journal of the American College of
Cardiology. 2014;63:15-20
176. Steg PG, van 't Hof A, Hamm CW, Clemmensen P, Lapostolle F,
Coste P, Ten Berg J, Van Grunsven P, Eggink GJ, Nibbe L, Zeymer U, Campo
dell' Orto M, Nef H, Steinmetz J, Soulat L, Huber K, Deliargyris EN, Bernstein D,
Schuette D, Prats J, Clayton T, Pocock S, Hamon M, Goldstein P, Investigators E.

77
 References

Bivalirudin started during emergency transport for primary pci. The New England
journal of medicine. 2013;369:2207-2217
177. Navarese EP, Schulze V, Andreotti F, Kowalewski M, Kolodziejczak
M, Kandzari DE, Rassaf T, Gorny B, Brockmeyer M, Meyer C, Berti S, Kubica J,
Kelm M, Valgimigli M. Comprehensive meta-analysis of safety and efficacy of
bivalirudin versus heparin with or without routine glycoprotein iib/iiia inhibitors
in patients with acute coronary syndrome. JACC. Cardiovascular interventions.
2015;8:201-213
178. Hibbert B, MacDougall A, Labinaz M, O'Brien ER, So DY, Dick A,
Glover C, Froeschl M, Marquis JF, Wells GA, Blondeau M, Le May MR.
Bivalirudin for primary percutaneous coronary interventions: Outcome assessment
in the ottawa stemi registry. Circulation. Cardiovascular interventions.
2012;5:805-812
179. Steg PG, Huber K, Andreotti F, Arnesen H, Atar D, Badimon L,
Bassand JP, De Caterina R, Eikelboom JA, Gulba D, Hamon M, Helft G, Fox KA,
Kristensen SD, Rao SV, Verheugt FW, Widimsky P, Zeymer U, Collet JP.
Bleeding in acute coronary syndromes and percutaneous coronary interventions:
Position paper by the working group on thrombosis of the european society of
cardiology. European heart journal. 2011;32:1854-1864
180. Pinto DS, Stone GW, Shi C, Dunn ES, Reynolds MR, York M,
Walczak J, Berezin RH, Mehran R, McLaurin BT, Cox DA, Ohman EM, Lincoff
AM, Cohen DJ, Investigators A. Economic evaluation of bivalirudin with or
without glycoprotein iib/iiia inhibition versus heparin with routine glycoprotein
iib/iiia inhibition for early invasive management of acute coronary syndromes.
Journal of the American College of Cardiology. 2008;52:1758-1768
181. Wise GR, Schwartz BP, Dittoe N, Safar A, Sherman S, Bowdy B,
Hahn HS. Comparative effectiveness analysis of anticoagulant strategies in a large
observational database of percutaneous coronary interventions. Journal of
interventional cardiology. 2012;25:278-288
182. Marso SP, Amin AP, House JA, Kennedy KF, Spertus JA, Rao SV,
Cohen DJ, Messenger JC, Rumsfeld JS, National Cardiovascular Data R.
Association between use of bleeding avoidance strategies and risk of
periprocedural bleeding among patients undergoing percutaneous coronary
intervention. JAMA : the journal of the American Medical Association.
2010;303:2156-2164
183. Stone GW, White HD, Ohman EM, Bertrand ME, Lincoff AM,
McLaurin BT, Cox DA, Pocock SJ, Ware JH, Feit F, Colombo A, Manoukian SV,
Lansky AJ, Mehran R, Moses JW, Acute C, Urgent Intervention Triage strategy
trial i. Bivalirudin in patients with acute coronary syndromes undergoing
percutaneous coronary intervention: A subgroup analysis from the acute
catheterization and urgent intervention triage strategy (acuity) trial. Lancet.
2007;369:907-919
184. Plent S, Mitchell M, Fan W, Werner R. Utilization of anticoagulants
and outcomes in stemi patients undergoing ppci in the us hospitals: Bivalirudin,
heparin plus gpi or heparin alone? Hospital practice. 2015;43:164-171

78
 References

185. Koutouzis M, Lagerqvist B, James S, Omerovic E, Matejka G, Grip

L, Albertsson P. Unfractionated heparin administration in patients treated with
bivalirudin during primary percutaneous coronary intervention is associated lower
mortality and target lesion thrombosis: A report from the swedish coronary
angiography and angioplasty registry (scaar). Heart. 2011;97:1484-1488
186. Dangas GD, Mehran R, Nikolsky E, Claessen BE, Lansky AJ, Brodie
BR, Witzenbichler B, Guagliumi G, Peruga JZ, Dudek D, Mockel M, Caixeta A,
Parise H, White H, Stone GW, Investigators H-AT. Effect of switching
antithrombin agents for primary angioplasty in acute myocardial infarction: The
horizons-switch analysis. Journal of the American College of Cardiology.
2011;57:2309-2316
187. Clemmensen P, Wiberg S, Van't Hof A, Deliargyris EN, Coste P, Ten
Berg J, Cavallini C, Hamon M, Dudek D, Zeymer U, Tabone X, Kristensen SD,
Bernstein D, Anthopoulos P, Prats J, Steg PG. Acute stent thrombosis after primary
percutaneous coronary intervention: Insights from the euromax trial (european
ambulance acute coronary syndrome angiography). JACC. Cardiovascular
interventions. 2015;8:214-220
188. Capodanno D, Gargiulo G, Capranzano P, Mehran R, Tamburino C,
Stone GW. Bivalirudin versus heparin with or without glycoprotein iib/iiia
inhibitors in patients with stemi undergoing primary pci: An updated meta-analysis
of 10,350 patients from five randomized clinical trials. European heart journal.
Acute cardiovascular care. 2016;5:253-262
189. Wijnbergen I, Tijssen J, van 't Veer M, Michels R, Pijls NH. Gender
differences in long-term outcome after primary percutaneous intervention for st-
segment elevation myocardial infarction. Catheterization and cardiovascular
interventions : official journal of the Society for Cardiac Angiography &
Interventions. 2013;82:379-384
190. Champney KP, Frederick PD, Bueno H, Parashar S, Foody J, Merz
CN, Canto JG, Lichtman JH, Vaccarino V, Investigators N. The joint contribution
of sex, age and type of myocardial infarction on hospital mortality following acute
myocardial infarction. Heart. 2009;95:895-899
191. Jneid H, Fonarow GC, Cannon CP, Hernandez AF, Palacios IF, Maree
AO, Wells Q, Bozkurt B, Labresh KA, Liang L, Hong Y, Newby LK, Fletcher G,
Peterson E, Wexler L, Get With the Guidelines Steering C, Investigators. Sex
differences in medical care and early death after acute myocardial infarction.
Circulation. 2008;118:2803-2810
192. Jakobsen L, Niemann T, Thorsgaard N, Nielsen TT, Thuesen L,
Lassen JF, Jensen LO, Thayssen P, Ravkilde J, Tilsted HH, Mehnert F, Johnsen
SP. Sex- and age-related differences in clinical outcome after primary
percutaneous coronary intervention. EuroIntervention : journal of EuroPCR in
collaboration with the Working Group on Interventional Cardiology of the
European Society of Cardiology. 2012;8:904-911
193. Jackson EA, Moscucci M, Smith DE, Share D, Dixon S, Greenbaum
A, Grossman PM, Gurm HS. The association of sex with outcomes among patients
undergoing primary percutaneous coronary intervention for st elevation
myocardial infarction in the contemporary era: Insights from the blue cross blue

79
 References

shield of michigan cardiovascular consortium (bmc2). American heart journal.

2011;161:106-112 e101
194. Lansky AJ, Pietras C, Costa RA, Tsuchiya Y, Brodie BR, Cox DA,
Aymong ED, Stuckey TD, Garcia E, Tcheng JE, Mehran R, Negoita M, Fahy M,
Cristea E, Turco M, Leon MB, Grines CL, Stone GW. Gender differences in
outcomes after primary angioplasty versus primary stenting with and without
abciximab for acute myocardial infarction: Results of the controlled abciximab and
device investigation to lower late angioplasty complications (cadillac) trial.
Circulation. 2005;111:1611-1618
195. Peterson ED, Lansky AJ, Kramer J, Anstrom K, Lanzilotta MJ,
National Cardiovascular Network Clinical I. Effect of gender on the outcomes of
contemporary percutaneous coronary intervention. The American journal of
cardiology. 2001;88:359-364
196. Sederholm Lawesson S, Todt T, Alfredsson J, Janzon M, Stenestrand
U, Swahn E. Gender difference in prevalence and prognostic impact of renal
insufficiency in patients with st-elevation myocardial infarction treated with
primary percutaneous coronary intervention. Heart. 2011;97:308-314
197. Berger JS, Elliott L, Gallup D, Roe M, Granger CB, Armstrong PW,
Simes RJ, White HD, Van de Werf F, Topol EJ, Hochman JS, Newby LK,
Harrington RA, Califf RM, Becker RC, Douglas PS. Sex differences in mortality
following acute coronary syndromes. JAMA : the journal of the American Medical
Association. 2009;302:874-882
198. Becker RC, Bassand JP, Budaj A, Wojdyla DM, James SK, Cornel
JH, French J, Held C, Horrow J, Husted S, Lopez-Sendon J, Lassila R, Mahaffey
KW, Storey RF, Harrington RA, Wallentin L. Bleeding complications with the
p2y12 receptor antagonists clopidogrel and ticagrelor in the platelet inhibition and
patient outcomes (plato) trial. European heart journal. 2011;32:2933-2944
199. Mathews R, Peterson ED, Chen AY, Wang TY, Chin CT, Fonarow
GC, Cannon CP, Rumsfeld JS, Roe MT, Alexander KP. In-hospital major bleeding
during st-elevation and non-st-elevation myocardial infarction care: Derivation
and validation of a model from the action registry(r)-gwtg. The American journal
of cardiology. 2011;107:1136-1143
200. Ahmed B, Piper WD, Malenka D, VerLee P, Robb J, Ryan T, Herne
M, Phillips W, Dauerman HL. Significantly improved vascular complications
among women undergoing percutaneous coronary intervention: A report from the
northern new england percutaneous coronary intervention registry. Circulation.
Cardiovascular interventions. 2009;2:423-429
201. Otten AM, Maas AH, Ottervanger JP, Kloosterman A, van 't Hof AW,
Dambrink JH, Gosselink AT, Hoorntje JC, Suryapranata H, de Boer MJ, Zwolle
Myocardial Infarction study G. Is the difference in outcome between men and
women treated by primary percutaneous coronary intervention age dependent?
Gender difference in stemi stratified on age. European heart journal. Acute
cardiovascular care. 2013;2:334-341
202. Bjork J, Jones I, Nyman U, Sjostrom P. Validation of the lund-malmo,
chronic kidney disease epidemiology (ckd-epi) and modification of diet in renal
disease (mdrd) equations to estimate glomerular filtration rate in a large swedish

80
 References

clinical population. Scandinavian journal of urology and nephrology.

2012;46:212-222
203. Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van
Lente F, Chronic Kidney Disease Epidemiology C. Expressing the modification of
diet in renal disease study equation for estimating glomerular filtration rate with
standardized serum creatinine values. Clinical chemistry. 2007;53:766-772
204. Szummer K, Lundman P, Jacobson SH, Lindback J, Stenestrand U,
Wallentin L, Jernberg T, Swedeheart. Cockcroft-gault is better than the
modification of diet in renal disease study formula at predicting outcome after a
myocardial infarction: Data from the swedish web-system for enhancement and
development of evidence-based care in heart disease evaluated according to
recommended therapies (swedeheart). American heart journal. 2010;159:979-986
205. Tomaszuk-Kazberuk A, Kozuch M, Malyszko J, Bachorzewska-
Gajewska H, Dobrzycki S, Musial WJ. Which method of gfr estimation has the
best prognostic value in patients treated with primary pci: Cockcroft-gault formula,
mdrd, or ckd-epi equation?--a 6-year follow-up. Renal failure. 2011;33:983-989
206. Kontos MC, Jamal SM, Ornato JP, Tatum JL, Jesse RL, Anderson FP.
Comparison of the modification of diet in renal disease and the cockcroft-gault
equations for predicting mortality in patients admitted for exclusion of myocardial
ischemia. The American journal of cardiology. 2008;102:140-145
207. Sterner G, Bjork J, Carlson J, Grubb A, Nyman U. Validation of a
new plasma cystatin c-based formula and the modification of diet in renal disease
creatinine-based formula for determination of glomerular filtration rate.
Scandinavian journal of urology and nephrology. 2009;43:242-249
208. Tidman M, Sjostrom P, Jones I. A comparison of gfr estimating
formulae based upon s-cystatin c and s-creatinine and a combination of the two.
Nephrology, dialysis, transplantation : official publication of the European
Dialysis and Transplant Association - European Renal Association. 2008;23:154-
160
209. Delanaye P, Pieroni L, Abshoff C, Lutteri L, Chapelle JP, Krzesinski
JM, Hainque B, Cavalier E. Analytical study of three cystatin c assays and their
impact on cystatin c-based gfr-prediction equations. Clinica chimica acta;
international journal of clinical chemistry. 2008;398:118-124
210. Akerblom A, Wallentin L, Siegbahn A, Becker RC, Budaj A, Buck
K, Giannitsis E, Horrow J, Husted S, Katus HA, Steg PG, Storey RF, Asenblad N,
James SK. Cystatin c and estimated glomerular filtration rate as predictors for
adverse outcome in patients with st-elevation and non-st-elevation acute coronary
syndromes: Results from the platelet inhibition and patient outcomes study.
Clinical chemistry. 2012;58:190-199
211. Silva D, Cortez-Dias N, Jorge C, Marques JS, Carrilho-Ferreira P,
Magalhaes A, Martins SR, Goncalves S, da Silva PC, Fiuza M, Diogo AN, Pinto
FJ. Cystatin c as prognostic biomarker in st-segment elevation acute myocardial
infarction. The American journal of cardiology. 2012;109:1431-1438
212. Ichimoto E, Jo K, Kobayashi Y, Inoue T, Nakamura Y, Kuroda N,
Miyazaki A, Komuro I. Prognostic significance of cystatin c in patients with st-

81
 References

elevation myocardial infarction. Circulation journal : official journal of the

Japanese Circulation Society. 2009;73:1669-1673
213. Eriksson P, Deguchi H, Samnegard A, Lundman P, Boquist S,
Tornvall P, Ericsson CG, Bergstrand L, Hansson LO, Ye S, Hamsten A. Human
evidence that the cystatin c gene is implicated in focal progression of coronary
artery disease. Arteriosclerosis, thrombosis, and vascular biology. 2004;24:551-
557
214. Lutgens SP, Cleutjens KB, Daemen MJ, Heeneman S. Cathepsin
cysteine proteases in cardiovascular disease. FASEB journal : official publication
of the Federation of American Societies for Experimental Biology. 2007;21:3029-
3041
215. Barascuk N, Skjot-Arkil H, Register TC, Larsen L, Byrjalsen I,
Christiansen C, Karsdal MA. Human macrophage foam cells degrade
atherosclerotic plaques through cathepsin k mediated processes. BMC
cardiovascular disorders. 2010;10:19
216. Libby P. Collagenases and cracks in the plaque. The Journal of
clinical investigation. 2013;123:3201-3203
217. Shalia KK, Mashru MR, Shah VK, Soneji SL, Payannavar S. Levels
of cathepsins in acute myocardial infarction. Indian heart journal. 2012;64:290-
294
218. Stansfield R, Gossiel F, Morton A, Newman C, Eastell R. Type i
collagen degradation during tissue repair: Comparison of mechanisms following
fracture and acute coronary syndromes. Bone. 2014;69C:1-5
219. Xie L, Terrand J, Xu B, Tsaprailis G, Boyer J, Chen QM. Cystatin c
increases in cardiac injury: A role in extracellular matrix protein modulation.
Cardiovascular research. 2010;87:628-635
220. Park M, Vittinghoff E, Ganz P, Peralta CA, Whooley M, Shlipak MG.
Role of soluble endothelial cell-selective adhesion molecule biomarker in
albuminuria and kidney function changes in patients with coronary artery disease:
The heart and soul study. Arteriosclerosis, thrombosis, and vascular biology.
2014;34:231-236
221. Dangas GD, Claessen BE, Mehran R, Xu K, Fahy M, Parise H,
Henriques JP, Ohman EM, White HD, Stone GW. Development and validation of
a stent thrombosis risk score in patients with acute coronary syndromes. JACC.
Cardiovascular interventions. 2012;5:1097-1105

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 Papers
The articles associated with this thesis have been removed for copyright
reasons. For more details about these see:

http://urn.kb.se/resolve? urn:nbn:se:liu:diva-136532