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Prevention of Atherosclerotic Cardiovascular Disease:

Guideline Updates on Blood Pressure and Cholesterol


Control

Nicholas B Norgard, Pharm.D., BCPS!


Clinical Assistant Professor, Cardiology!
University at Buffalo, SPPS

Objectives
Identify specific blood pressure thresholds and
goals for antihypertensive pharmacologic therapy!
Construct an individualized blood pressure
lowering regimen based on patient characteristics!
Identify groups of patients who will benefit
frompharmacological lipid-lowering therapy!
Devise an appropriate intensity lipidloweringtreatment and monitoring regimen

This is Bob
Bob is a 50-year old male who has not seen a
health care professional for many years. His
father (age 70) recently had a myocardial
infarction. That has led Bob to think he should
start taking care of himself better.!
Family History:
!
Dad (70) - alive, HTN, MI at age 70
!
Mom (69) - alive, diabetes
!
2 brothers - alive and healthy
Smokes cigarettes (20 pack/yr history) and drinks alcohol socially
Weight: 220 lbs, Height: 68 inches
BMI: 34 kg/m2, Waist circumference 44 inches
His blood pressure today is 150/106 mm Hg (left arm), 151/107 (right arm)
Fasting lipid panel: total cholesterol 215; LDL 136; HDL 35; triglycerides 220.
PMH: He has no past medical history or surgeries.
Medications: Famotidine 20 mg as needed.

JNC 8 is not just JNC 7 Retooled or Repainted ,


but Imploded and Reconstructed

Questions Guiding JNC 8


At what level should you treat BP? !
Does initiating antihypertensive pharmacological
therapy at specific BP thresholds improve health
outcomes?!
To what level should BP be treated?!
Does treatment with antihypertensive pharmacological
therapy to a specific BP goal lead to improvements in
health outcomes?!
How do you do it? !
Do various antihypertensive drugs or drug classes
differ in comparative benefits and harms on specific
health outcomes?

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 60

Age 18-59

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

At what level should


you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

How do you do it?

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 60

Age 18-59

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

At what level should


you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

How do you do it?

Is >60 elderly or is >80 elderly?


HTN patients > 80 years with SBP 160 mm Hg prior to randomization
180

Total Mortality!
(21% reduction)

170

Blood Pressure (mmHg)

160
150
140

P=0.019

130
120

Placebo
Indapamide SR +/- perindopril
Placebo
Indapamide SR +/- perindopril

110
100
90
80
70

Follow-up (years)
N Engl J Med 2008;358/ACC 2008

Does the absence of evidence lead to the


conclusion of evidence of absence?
Systolic Hypertension in the Elderly Program (SHEP)
Population: HTN patients age > 60
Average blood pressure

Fatal plus nonfatal stroke rate


B 10

200
190
180
170 rj
160

RR 0.63 (0.49-0.82)

it:

150-1
140
130
120
110
100
90
80
70.

! feg--g-g-

60
0<

12

I I I I I I I I I

60

24

Follow-up,

I I I I 1 I I I I

mo

lin

11111111 iiniiiii up 1111111111111 ni 111111111 un 1111111111111


12

24

36

Follow-up,

48

60

mo

The
5-year average SBP was 143 mmHg Figin2.Cumulative
treatment
group and 155 mmHg in
fatal plus nonfatal stroke rate per 100 participants in the
Fig 1. Average systolic and diastolic blood pressure during the Systolic Hyper
tension in the Elderly Program follow-up plotted at 1, 3, 6, and 12 months and
active treatment (solid line) and placebo (broken line) groups during the Systolic
placebo
group
therafter.
with
indicates
blood
Solid line
open squares
average systolic
Hypertension in the Elderly Program.
yearly
-

pressure for the active treatment group; broken line with closed circles, average
systolic blood pressure for the placebo group; solid line with triangles, average
JAMA.
1991;265:3255-3264
diastolic
blood pressure for the active treatment group; and broken line with open

the definitive end point,


all causes of
had similar
Per 1,000
6.8 and
(4.510.0)
7.4death
(4.910.7)
0.77
0.338 patient-years (95% CI)
rates
in
the
2
target
groups.
The
subanalysis
of
the
prespeciRenal failure, n (%)
8 (0.36)
9 (0.41)
0.80
ACE inhibitors
%88 (%5.7)
%85 (%5.5)
0.567
fied subgroups
on (0.94.1)
sex, age, BMI,2.4and
complications
Per 1,000 patient-years
(95% CI)based 2.1
(1.14.5)
0.80
Others
50 (3.2)
58 (3.8)
0.411
revealed no
difference in the primary end point rate
JATOS Study
Group: Treatment forsimilarly
Elderly Hypertension
2119
* 2 test.
Data are mean$SD unless otherwise specified. ACE indicates angiotensinbetween the 2 target groups.
converting enzyme.
In general, cardiovascular risk reduction by antihypertenStrict-treatment
*The averaged dose at the end of the study was calculated
from allPopulation:
ofgroup
the
patients
age
- 85 of the BP decrease.
sive HTN
treatment
is related
to the65
magnitude
8.0
patients with and without other antihypertensives.
!-Blockers

22 (1.4)

1.6 (0.63.4)
0 (0.00)
0.0 (0.00.8)

16 (1.0)

1.1 (0.32.7)
1 (0.05)
0.3 (0.01.5)

Does the absence of evidence lead to the conclusion


of evidence of absence?

Blood pressure (mmHg)

24

patients of the strict control group and 733 patients of the


160
moderate* control group). The incidences
of the primary
Systolic
composite end point were 2.4% (8.2 per 1000 patient-years)
140
in the strict control group and 2.3% (7.8 per 1000 patientyears) in the moderate control group (hazard ratio: 1.04 [95%
120
CI: 0.56 to 1.93]; P!0.89).
Figure 4 shows the primary composite end point and
100
individual
end points. There were no significant differences
in any end point
between the strictDiastolic
and moderate control
*
80 The relative risk of the primary end point in each
groups.
prespecified subgroup by baseline variables is shown in
60 5. No significant heterogeneity of variance for possiFigure
0
3
6
9
12
15
18
21
ble interactions between treatment and
baseline variables was
Months
detected in any of the variables.

On the basis of a meta-analysis conducted by Staessen et al3


Strict-treatment group
on the magnitude of BP lowering by antihypertensive drugs
and the degree of cardiovascular hazard riskMild-treatment
reduction, agroup
6.0
BP reduction of 5 mm Hg will lead to an #20% reduction
p = 0.98 (Log-rank test)
in9.7total
mmHgcardiovascular risk, a 30% reduction in stroke, and
a 25% reduction in myocardial infarction. The present
4.0 in no difference in the primary end
study, VALISH, resulted
point rate between the moderate and strict control groups,
although the difference in achieved systolic BP between 2
groups was 5.6 mm 2.0
Hg. Therefore, we simply assume that
moderate control of BP, for example, "150 mm Hg, as in this
3.3 mmHg
study,
may be sufficient to reduce cardiovascular events in
elderly hypertensive patients.
0.0
In a subanalysis
the Candesartan
Antihypertensive
4
8
12
16
200 of Hypertension
August
2010
24
Survival
in Japan, the cardiovascular risk
Months
Number atEvaluation
risk
hazard ratio in patients over age 65 years began to rise

Cumulative incidence (%)

Mild-treatment group

180

Strict-treatment
Blood pressure during treatment. *Intergroup differences were significant from this point (p<
0.001). Systolicgroup
and dias- 2212
group
s were lower by 9.7 mmHg and 3.3 mmHg, respectively, in the strict-treatment group than inMild-treatment
the mild-treatment
group at 2206
Population:
HTN
patients
age 70
of treatment mmHg
(both p< 0.001).

Events

140

Strict treatment Mild treatment


(n=2,212)
(n=2,206)

1883
1885

1815
1797

1755
1742

1482
1500

Incidence rate of events

160
Incidences
of Nonfatal and Fatal Components of
mary Endpoint

- 85

1964
1959

24

0.10
0
10
Moderate control group (12.0/1000patients-year)
Fig. 3. The Kaplan-Meier time-to-event analyses for the primary
endpoint.
cumulative rates of morbidity from the p
Strict control
groupThe
(10.6/1000patients-year)
Strict
control
group
endpoint were similar in the two groups. To estimate cumulative incidence rates of morbidity, data up to 2 years after ad
vival maytration
vary around
75used.
years of
age (24),
anmore
age of than
75 years
were
Data
from
2 0.08
years after treatment were excluded.
Moderate control group

180

2055
2042

20

was chosen as the cutoff point between younger patients and


older patients.
p=0.383 (log-rank test)
All tests were two-sided, and the significance level was set0.06
Baseline
Characteristics
Treatment
at 5%.
Hazard
Figure 2. Changes in BP during treatment. The
BP ratio (95%CI): 0.89 (0.60-1.31)
differences
between the 2 groups were
p<0.001
(ANOVA)differences
There were
no significant
between
Atstatistically
the end of the study, 4,094 subjects (92.7%) were
0.04the two groups

endpoint 120
86 (9)
86 (8)
vascular disease
52 (3)
49 (3)
significant during the follow-up period.
Organization
in sex, age, body mass index, smoking status, baseline BP, the
ing efonidipine alone or in combination with other ant
al infarction
36 (2)
30 (0)
100
prevalence
of study
an enlarged
or LVH, a past history (6
tensive drugs. One thousand thirteen subjects (45.8%)
al hemorrhage
7 (0)
8 (1)
The details
of the JATOS
group andheart
the investigators
p<0.001
<0 001
(ANOVA)
0 02
0.02
achnoid hemorrhage
1 (1)
4 (2)
or more before enrollment) of cerebrovascular
disstrict-treatment group and 1,246 (56.5%) in the mild
are shownmonths
in the Appendix.
ent ischemic80
attack
8 (0)
7 (0)
ease or cardiac and vascular disease, prevalence of renal disment group were receiving monotherapy with efonidi
and vascular disease
26 (6)
28 (4)
ease, diabetesResults
mellitus or hyperlipidemia, or
the proportion of
another antihypertensive drug (p < 0.001). As shown in
0.00
a pectoris
9 (0)
10 (0)
2, at the end of treatment, a combination of antihyper
patients who had received prior antihypertensive treatment
60
ardial infarction
6 (1)
6 (0)
0
3
6
9 12 15 18 21Study
24 Profile
27 301). 33
39rates
42 of various antihypertensive
0
0 strict-treatmen
6
12
18 more frequently
24
36
42
drugs was
used in3the
(Table
The 36
usage
drugs
stive heart failure
8 (4)
7 (1)
than in the mild-treatment
(40.7% vs. 30.9% for
did not differmonths
significantly betweenexcluded
the twoofgroups.
months ofgroup
follow-up
ctive arterial disease
2 (0)
1 (0)
patients followed
Although 4,508 subjects were registered, 50 wereNumber
N
tensin-converting enzyme [ACE] inhibitors or angiote
minalJATOS
aortic rupture
0
(0)
1
(1)
because
they
did
not
return
for
follow-up
appointments,
and
Study Group. Hypertens Downloaded
Res. 2008;31(12):21152127.
1545
1482
1408
1336
1306
1295
336
from http://hyper.ahajournals.org/ by guestStrict
on July 18, 2014
S
aneurysm enlargement
0 (0)
2 (1)
14.3%924
vs. 11.6%
for adre
receptor
blockers,
p < 0.001;
40 were excluded because of violations of the study protocol

Ogihara T, et al. Hypertension. 2010;56(2):196202.

Moderate

1534

1461

1375

1304

1279

1265

902

335

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 60

Age 18-59

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

At what level should


you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

Treatment to SBP <140 is OK if well


tolerated and without adverse
effects on health or quality of life

How do you do it?

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 60

Age 18-59

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

At what level should


you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

How do you do it?

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 60

Age 18-59

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

At what level should


you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

How do you do it?

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 60

Age 18-59

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

At what level should


you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

How do you do it?

the evidence is insufficient to


determine if there is a benefit in
mortality or vascular health
outcomes with antihypertensive
drug therapy to a lower BP goal.

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

Age 18-59

Age 60
At what level should
you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


SBP < 140 !
DBP
< 90
DBP < 90
7 Antihypertensive Therapies
226

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

CENTRAL AGENTS
! Clonidine
! Reserpine
! Moxonidine

CATECHOLAMINE
INHIBITORS

How do you do it?


ALDOSTERONE
BLOCKERS

DIURETICS

SVR

Na+ loss
RENIN

? Vasodilation

ANGIOTENSIN II
ACE INHIBITORS

VASODILATORS
! DHPs: nifedipine,
amlodipine, others
! Verapamil, diltiazem
! Prazosin, doxazosin
! Hydralazine (direct)
Opie 2012

AT-1 BLOCKERS
(ARBs)

Figure 7-2 Different types of antihypertensive agents act at different sites.

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 60

Age 18-59

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

At what level should


you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

JAMA 2002;288: 1981-97

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 60

Age 18-59

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

At what level should


you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

JAMA 2002;288: 1981-97

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 60

Age 18-59

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

At what level should


you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

Wright JT et al. JAMA. 2005;293:1595-1608.

JNC Management Guideline Algorithm


General Population (no diabetes or CKD)

Age 60

Age 18-59

Age 18!

Age 18!

Diabetes!

CKD!

No CKD

Diabetes

At what level should


you treat BP?

SBP 150 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

SBP 140 !
DBP 90

To what level should


BP be treated?

SBP < 150 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

SBP < 140 !


DBP < 90

Nonblack
How do you do it?

Initiate thiazide or ACEI


or ARB or CCB, alone
or in combination.

Black
Initiate thiazide or
CCB, alone or in
combination.

All Races
Initiate ACEI or ARB,
alone or in combination
with other drug class.

Strategies to Dose Antihypertensive Drugs


Strategy Description
A

Details

Start one drug,


If goal BP is not achieved with the initial drug, titrate the dose of the initial drug up to the
titrate to maximum
maximum recommended dose to achieve goal BP!
dose, and then add If goal BP is not achieved with the use of one drug despite titration to the maximum
a second drug!
recommended dose, add a second drug (thiazide, CCB, ACEI, or ARB) and titrate up to the
maximum recommended dose of the second drug to achieve goal BP!
If goal BP is not achieved with 2 drugs, select a third drug (thiazide, CCB, ACEI, or ARB),
avoiding the combined use of ACEI and ARB. Titrate the third drug up to the maximum
recommended dose to achieve goal BP!

Start one drug and Start with one drug then add a second drug before achieving the maximum recommended
then add a second
dose of the initial drug, then titrate both drugs up to the maximum recommended doses of
before achieving
both to achieve goal BP !
maximum dose of If goal BP is not achieved with 2 drugs, select a third drug from the list (thiazide, CCB, ACEI,
the initial drug!
or ARB), avoiding the combined use of ACEI and ARB. Titrate the third drug up to the
maximum recommended dose to achieve goal BP

Begin with 2 drugs Initiate therapy with 2 drugs simultaneously, either as 2 separate drugs or as a single pill
at the same time,
combination. !
either as 2
Start therapy with 2 drugs when SBP is >160 mm Hg and/or DBP is >100 mm Hg, or if SBP
separate pills or
is >20 mm Hg above goal and/or DBP is >10 mm Hg above goal. !
single pill
If goal BP is not achieved with 2 drugs, select a third drug from the list (thiazide, CCB, ACEI,
combination!
or ARB), avoiding the combined use of ACEI and ARB. Titrate the third drug up to the
maximum recommended dose.

MANN Report
Special Report

WHY DO WE USE HCTZ?


Hydrochlorothiazide

(HCTZ) is most commonly


prescribed agent for BP reduction in North America

Trials

showing thiazide vascular protection used


chlorthalidone
-

No evidence for HCTZ as first-line hypertension


monotherapy

Chlorthalidone

and indapamide are more potent and


provide 24-hr BP reduction
- HCTZ lowers BP during day but loses effect at night

HCTZ

is a paltry antihypertensive

Antihypertensive HCTZ Efcacy as Assessed by


24-h ABP Monitoring

Messerli, F. H. et al. J Am Coll Cardiol 2011;57:590-600

MANN Report !
Special Report

Select a drug treatment titration strategy!


A.!!Maximize first medication before adding second or!
B.!!Add second medication before reaching maximum dose of first medication or!
C.!!Start with 2 medication classes separately or as fixed-done combination

1 Month follow-up

At goal BP?
No

Strategies for Reaching


BP Goal

Yes

Reinforce medication and lifestyle adherence!


For strategies A and B, add and titrate thiazide-type diuretic or ACEI or ARB or CCB !
For strategy C, titrate doses of initial medications to maximum.

1 Month follow-up

At goal BP?
No

Yes

Reinforce medication and lifestyle adherence!


Add and titrate thiazide-type diuretic or ACEI or ARB or CCB

1 Month follow-up

At goal BP?
No

Yes

Reinforce medication and lifestyle adherence!


Add additional medication class and/or refer to physician with expertise in hypertension
management.

No

At goal BP?

James PA, et al. JAMA. 2014;311:507-520.

Yes

Continue! current
treatment and
monitoring

Blood Pressure Recommendations for Bob


Age 18-59

SBP 140 !
DBP 90

SBP < 140 !


DBP < 90

Initiate thiazide or ACEI


or ARB or CCB, alone
or in combination.

His blood pressure today:


150/106 (left arm)!
151/107 (right arm)

Blood Pressure Recommendations for Bob


Age 18-59

SBP 140 !
DBP 90

SBP < 140 !


DBP < 90

Initiate thiazide or ACEI


or ARB or CCB, alone
or in combination.

His blood pressure today:


150/106 (left arm)!
151/107 (right arm)

Strategy C!
Start therapy with 2 drugs when SBP is >160 mm
Hg and/or DBP is >100 mm Hg, or if SBP is >20 mm
Hg above goal and/or DBP is >10 mm Hg above
goal.

Blood Pressure Recommendations for Bob


Age 18-59

SBP 140 !
DBP 90

SBP < 140 !


DBP < 90

Initiate thiazide or ACEI


or ARB or CCB, alone
or in combination.

His blood pressure today:


150/106 (left arm)!
151/107 (right arm)

Strategy C!
Start therapy with 2 drugs when SBP is >160 mm
Hg and/or DBP is >100 mm Hg, or if SBP is >20 mm
Hg above goal and/or DBP is >10 mm Hg above
goal.

Example regimen:!
Benazepril 20 mg Daily!
Amlodipine 5 mg Daily

JNC 8 - soon outdated?

Risk reduction is proportional to


LDL lowering from statin therapy !
Therefore, more intensive statin
therapy could reduce risk more
than moderate- or lowerintensity statin therapy

RR for ASCVD (log scale)

CHOLESTEROL CONCEPT #1
3.7
2.9
2.2
1.7
1.3
1.0

40

70

100

130

LDL-C (mg/dL)

ASCVD = atherosclerotic cardiovascular disease!


Adapted from Grundy SM, et al. Circulation. 2004;110:227-239.

160

190

CHOLESTEROL CONCEPT #2
Absolute benefit from statin
therapy is proportional to baseline
ASCVD risk!
Patients with lower baseline
ASCVD risk have lower absolute
benefit from statin therapy that
may approach the risk for
adverse effects

Four Statin Benet Groups


Clinical ASCVD

LDL cholesterol greater


than 190 mg/dL

Diabetes !
Age 40-75!
LDL cholesterol 70-189*

No diabetes or ASCVD !
Age 40-75!
LDL 70-189*!
Estimated 10-yr ASCVD
risk >7.5%

ASCVD = atherosclerotic cardiovascular disease!


* = mg/dL

Four Statin Benet Groups


Clinical ASCVD

Yes
High-intensity statin

Clinical ASCVD includes:!


Acute coronary syndromes, or history of MI, stable or unstable angina, coronary
or other arterial revascularization, stroke, TIA, or peripheral arterial disease
presumed to be of atherosclerotic origin

ASCVD = atherosclerotic cardiovascular disease!


* = mg/dL

Intensity of Statin Therapy *Individual

There migh
Evidence
Intensity
of
Statin
Therapy
High-Intensity Statin
Moderate-Intensity Statin
Low-Intensity Statin
Although
Daily dose lowers LDL on
Daily dose lowers LDL on
Daily dose lowers LDL on
recomm
average by 50%
average by 30% to <50%
average bynot
<30%

Atorvastatin (40)-80 mg!


Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20-40 mg
Pravastatin 40 (80) mg
Lovastatin 40 mg!
Fluvastatin XL 80 mg
Pitavastatin 2-4 mg

Simvastatin 10 mg
Pravastatin 10-20 mg!
Lovastatin 20 mg!
Pitavastatin 1 mg

Specific statins and doses noted in bold were evaluated in RCTs


*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice.
There might be a biologic basis for a less-than-average response.
Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).
Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is
not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.

Clinical ASCVD:

Initiating Statin Therapy


Clinical ASCVD!
Not currently on statin therapy!

Initial evaluation prior to statin initiation!


Fasting lipid panel!
ALT!
CK (if indicated)!
Consider evaluation for other secondary
causes or conditions that may influence
statin safety

Age 75 y!
without contraindications,
conditions or drug-drug interactions
influencing statin safety, or a
history of statin intolerance

Initiate high-intensity statin therapy!


Counsel on healthy-lifestyle habits

*Fasting lipid panel preferred.


In a nonfasting individual, a
nonfasting non-HDL
mg/dL may indicate genetic
hypercholesterolemia that
requires further evaluation or a
secondary etiology. If
nonfasting triglycerides are

panel is required.
It is reasonable to evaluate
the potential for ASCVD
benefits and for adverse
effects, and to consider patient
Age >75 y!
preferences, in initiating or
OR!
with conditions or drug-drugcontinuing a moderate- or highintensity statin, in individuals
interactions influencing statin safety,
with ASCVD >75 years of age.
or a history of statin intolerance

Initiate moderate-intensity statin therapy!


Counsel on healthy-lifestyle habits

Monitor statin therapy


Clinical ASCVD includes:!
acute coronary syndromes, or history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke,
TIA, or peripheral arterial disease presumed to be of atherosclerotic origin

PRIMARY PREVENTION

LDL cholesterol greater


than 190 mg/dL

Diabetes
Age 40-75
LDL cholesterol 70-189*

No diabetes or ASCVD
Age 40-75
LDL 70-189*
Estimated 10-yr ASCVD
risk >7.5%

ASCVD = atherosclerotic cardiovascular disease!


* = mg/dL

Evidence for Statin Benet in


in adults in the general population who had one risk factor (see evidence statements
Primary Prevention

therapy, across the range of LDLC levels in primary-prevention individuals aged >40 years and

38)(21,82,107-110).

Effects of statin therapy on major CVD events per 39 mg/dL


Figure 3. Effects of statin therapy on major CVD events per 1.0 mmol/L reduction in LDLC, by clinical
reduction in LDL, by clinical CVD status!
CVD status

Similar RRR in ASCVD and major CVD events between primary- and secondary-prevention populations!

(CHD and non-CHD vascular = secondary prevention; None= primary prevention)


[Adapted from CTT 2010(21)] [published with permission]
Lancet. Nov 13, 2010; 376(9753): 16701681.

STATINS IN PRIMARY PREVENTION


No Clinical ASCVD!
Not currently on statin therapy!

Initial evaluation prior to statin initiation!


Fasting lipid panel!
ALT!
HbA1C!
CK (if indicated)!
Consider evaluation for other
secondary causes or conditions that
may influence statin safety

LDL-C > 190


mg/dL?

High intensity statin!

Yes

(Moderate-intensity if not candidate for


high-intensity)

Screen for secondary causes of elevated LDL


Secondary Cause

Elevated LDL

Diet

Saturated or trans fats, weight


gain, anorexia

Drugs

Diuretics, cyclosporine,
glucocorticoids, amiodarone

Diseases

Biliary obstruction, nephrotic


syndrome

Disorders and altered


states of metabolism

Hypothyroidism, obesity, pregnancy

STATINS IN PRIMARY PREVENTION


No Clinical ASCVD!
Not currently on statin therapy!

Initial evaluation prior to statin initiation!


Fasting lipid panel!
ALT!
HbA1C!
CK (if indicated)!
Consider evaluation for other
secondary causes or conditions that
may influence statin safety

LDL-C > 190


mg/dL?

Yes

High intensity statin!


(Moderate-intensity if not candidate for
high-intensity)

Screen for secondary causes of hyperlipidemia


- If primary, screen family for familial hypercholesterolemia
Those with an LDL-C 190 mg/dl should receive high-intensity statin therapy
regardless of estimated ASCVD risk
- Goal 50% LDL reduction
- Moderate-intensity statin therapy can be used if patient is not a
candidate for high-intensity statin therapy
- Addition of other cholesterol-lowering agents can be considered to
further lower LDL-C

Non-Statin Lipid Lowering Agents for


Severe Elevations in LDL-C
For additional LDL lowering on top of maximally
tolerated statin therapy:!
- Ezetimibe!
- Bile Acid Sequestrants!
- Niacin!
- Lomitapide!
- Mipomersen
Fibrates and Omega-3 fatty acids have little or no
LDL lowering effects

STATINS IN PRIMARY PREVENTION


No Clinical ASCVD!
Not currently on statin therapy!

Initial evaluation prior to statin initiation!


Fasting lipid panel!
ALT!
HbA1C!
CK (if indicated)!
Consider evaluation for other
secondary causes or conditions that
may influence statin safety

LDL-C > 190


mg/dL?

Yes

(Moderate-intensity if not candidate for


high-intensity)

No
Diabetes?

High intensity statin!

Moderate-intensity statin!
if 10-yr ASCVD risk < 7.5%

Yes
High-intensity statin!
if 10-yr ASCVD risk > 7.5%

10 mg

Lancet. 2004 Aug 21-27;364(9435):685-96

ASCVD Risk Prediction


Web Version

Mobile Version

http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/
Prevention-Guidelines_UCM_457698_SubHomePage.jsp

INDIVIDUALS NOT

IN A

STATIN BENEFIT GROUP

Diabetes with Age <40

Risk for ASCVD increases with the duration of diabetes!


Individuals could be at increased ASCVD risk before age 40 if they
have developed type 1 or type 2 diabetes during childhood or early
adulthood!

10-year risk cannot be calculated in individuals <40


Clinician judgment and patient
preferences should be used in
decisions to initiate statin therapy in
patients younger than 40 with
diabetes!
Statin therapy should not be initiated
among women who may become or
are pregnant or are nursing.

Additional factors that may be considered


in treatment decision making: !
Primary LDL >160 mg/dl or evidence of
genetic hyperlipidemia!
Family history of premature ASCVD !
- < 55 years in a first degree male relative!
- < 65 years in a first degree female relative!
High sensitivity C-Reactive Protein >2 mg/L!
Coronary artery calcium score 300!
Ankle-brachial index (ABI) <0.9!
Lifetime risk of ASCVD

STATINS IN PRIMARY PREVENTION


No Clinical ASCVD!
Not currently on statin therapy!

Initial evaluation prior to statin initiation!


Fasting lipid panel!
ALT!
HbA1C!
CK (if indicated)!
Consider evaluation for other
secondary causes or conditions that
may influence statin safety

LDL-C > 190


mg/dL?

Yes

High intensity statin!


(Moderate-intensity if not candidate for
high-intensity)

No
Diabetes?

Yes

Moderate-intensity statin!

Yes

Moderate-to-high
intensity statin

(High-intensity if 10-yr
ASCVD risk > 7.5%)

No
Calculate 10-yr
ASCVD risk using
Pooled Cohort
Equations

> 7.5% 10-yr


ASCVD risk?

Statin Selection in Individuals


Without Diabetes and LDL <190
Primary Prevention RCTs of Moderate-to-High Intensity Statins!
Randomized
Controlled Treatment vs. placebo
Trial

AFCAPS

JUPITER

Lovastatin 2040 mg

Rosuvastatin 20 mg

Mean percent LDL reduction


and mean reduction vs.
placebo at 1 year

27%
115 vs. 156 (41 mg/dL)

50%
55 vs. 110 (55 mg/dL)

RRR for ASCVD

NNT to prevent
1 ASCVD event

26%

56

44%

30

STATINS IN PRIMARY PREVENTION


No Clinical ASCVD!
Not currently on statin therapy!

Initial evaluation prior to statin initiation!


Fasting lipid panel!
ALT!
HbA1C!
CK (if indicated)!
Consider evaluation for other
secondary causes or conditions that
may influence statin safety

LDL-C > 190


mg/dL?

Yes

High intensity statin!


(Moderate-intensity if not candidate for
high-intensity)

No
Diabetes?

Yes

Moderate-intensity statin!

Yes

Moderate-to-high
intensity statin

(High-intensity if 10-yr
ASCVD risk > 7.5%)

No
Calculate 10-yr
ASCVD risk using
Pooled Cohort
Equations

> 7.5% 10-yr


ASCVD risk?

No
ASCVD prevention benefit less clear, but may be considered

INDIVIDUALS NOT IN A STATIN BENEFIT GROUP


Baseline ASCVD Risk 5.0% to <7.5%
There is still net absolute benefit with moderateintensity statin therapy

For high-intensity statin therapy, the potential for


harm exceeds the potential for ASCVD benefit
HIGH!INTENSITY!STATIN!TREATMENT!

MODERATE!INTENSITY!STATIN!TREATMENT!
Assumes a 35% relative risk reduction in ASCVD from moderate intensity statin treatment
NNT to prevent 1 ASCVD event varies by baseline estimated 10-year ASCVD risk.
NNH based on 1 excess case of incident diabetes per 100 individuals* treated with statins for 10 years.

Assumes a 45% relative risk reduction in ASCVD from high intensity statin treatment
NNT to prevent 1 ASCVD event varies by baseline estimated 10-year ASCVD risk
NNH based on 3 excess cases of incident diabetes* per 100 individuals treated with statins for 10 years.!

120!

NNT(to(prevent(1(ASCVD(event(over(10(years(

110%
100%

2.5%%

NNH=100%

90%
80%
70%
60%

5.0%(

50%
40%
30%

7.5%(
10.0%%

20%

15.0%%

10%
0%
0.0%%

5.0%%

10.0%%

15.0%%

20.0%%

20.0%%

25.0%%

25.0%%

10Ryear(ASCVD(risk(

*A conservative estimate of adverse events includes excess cases of incident diabetes, myopathy, and hemorrhagic
stroke. The NNH is dominated by excess cases of diabetes, with minimal contribution by myopathy (approximately
0.01 excess case per 100) and hemorrhagic stroke (approximately 0.01 excess case per 100 for hemorrhagic stroke)
(90,114,116)

NNT!to!prevent!1!ASCVD!event!over!10!years!

120%

110!
100!
90!
80!

2.5%!

70!
60!
50!

5.0%!

40!

NNH=33!

30!
20!

7.5%!
10.0%!

10!
0!
0.0%!

15.0%!
5.0%!

10.0%!

15.0%!

20.0%!
20.0%!

25.0%!
25.0%!

10?yearASCVD!risk!!

*A conservative estimate of adverse events includes excess cases of incident diabetes, myopathy, and
Clinician-Patient discussion
regarding
:! by excess cases of diabetes, with minimal contribution by
hemorrhagic stroke.
The NNH is dominated
myopathy (approximately 0.01 excess case per 100) and hemorrhagic stroke (approximately 0.01
ASCVD indicates atherosclerotic cardiovascular disease
ASCVD risk reduction
benefits !
excess case per 100 for hemorrhagic stroke) (90,114,116).
Adverse
Figure 6. Visual aid to illustrate relationship between NNT and NNH for high-intensity
statin: Teneffects!
-year
ASCVD indicates atherosclerotic cardiovascular disease
ASCVD risk and number- NNT to prevent 1 ASCVD event over 10 years compared with the NNH from
Drug-drug interactions!
adverse events* over 10 years for high-intensity statins
Patient preferences

INDIVIDUALS NOT

IN A

STATIN BENEFIT GROUP

Baseline ASCVD Risk <5% or Age <40 or >75

Lower-risk patients might be able to avoid


crossing the threshold for statin therapy if they
can achieve and sustain improvements in other
ASCVD risk factors:!
- smoking cessation!
- adhering to a heart healthy dietary pattern!
- engaging in regular physical activity!
- controlling hypertension!
- losing weight

MAXIMIZE STATIN SAFETY

Evaluation for conditions that may influence statin safety

Characteristics predisposing individuals to statin adverse


effects include, but are not limited to:!
-

Multiple or serious comorbidities, including impaired renal,


thyroid, or hepatic function!
History of previous statin intolerance or muscle disorders!
Unexplained ALT elevations >3 times ULN!
Patient characteristics or concomitant use of drugs affecting
statin metabolism!
>75 years of age!
History of hemorrhagic stroke!
Asian ancestry!

High-intensity statin !
! ! ! ! ! ! moderate-intensity statin when
predisposing characteristics present

MAXIMIZE STATIN SAFETY


Evaluate and Treat Muscle Symptoms

CK should not be routinely measured in individuals


receiving statin therapy!

Baseline measurement of CK is reasonable for individuals


believed to be at increased risk for adverse muscle events !
- Personal or family history of statin intolerance or muscle disease!
- Concomitant drug therapy that might increase the risk for
myopathy!

During statin therapy, it is reasonable to measure CK in


individuals with muscle symptoms, including pain,
tenderness, stiffness, cramping, weakness, or generalized
fatigue

MAXIMIZE STATIN SAFETY


Evaluate and Treat Muscle Symptoms

No constant relationship between cholesterol-lowering effect and myotoxicity

http://www.fda.gov/cder/drug/infopage/rosuvastatin/crestor_cp.pdf

EVALUATE

AND

TREAT MUSCLE SYMPTOMS


Obtain a history of prior or current muscle symptoms to
establish a baseline

Mild to moderate
muscle symptoms
Discontinue the statin until the
symptoms can be evaluated.
Evaluate the patient for other
conditions that might increase the
risk for muscle symptoms

Hypothyroidism!
Renal or hepatic dysfunction!
Rheumatologic disorders
such as polymyalgia
rheumatica!
Steroid myopathy!
Vitamin D deficiency!
Primary muscle diseases!
Drug-drug interactions

Muscle symptoms resolve

Muscle symptoms persist for


2 months without statin

Give the patient the original or a


lower dose of the same statin

Consider other causes of muscle


symptoms

Muscle symptoms return


Discontinue the original statin and
once muscle symptoms resolve, use
a low dose of a different statin

If persistent muscle symptoms from


condition unrelated to statin therapy, or!
If predisposing condition has been
treated
Resume statin therapy at the original
dose

Unexplained, severe
muscle symptoms
Discontinue the statin and
evaluate for rhabdomyolysis
(CK, creatinine, urine
myoglobin)

Evaluate the patient for other


conditions that might increase
the risk for muscle symptoms
Rhabdomyolysis resolves

Consultation with a lipid


specialist for re-initiation of
statin therapy

MAXIMIZE STATIN SAFETY


Evaluate and Treat Muscle Symptoms

Statin-related events are commonly reported and


often lead to statin discontinuation. !
Most patients who are rechallenged can tolerate
statins long-term. !
Many of the statin-related events may have other
causes, are tolerable, or may be specific to
individual statins rather than the entire drug class
Zhang H, et al. Statin discontinuation and intolerance: the challenge of lifelong therapy. Ann. Intern. Med. 2013;158(7):526534.

EVALUATE

AND

TREAT MUSCLE SYMPTOMS


Obtain a history of prior or current muscle symptoms to
establish a baseline

Mild to moderate
muscle symptoms

Unexplained, severe
muscle symptoms

Discontinue the statin until the


symptoms can be evaluated.

Discontinue the statin and


evaluate for rhabdomyolysis
(CK, creatinine, urine
myoglobin)

Evaluate the patient for other


conditions that might increase the
risk for muscle symptoms

Muscle symptoms resolve

Muscle symptoms persist for


2 months without statin

Give the patient the original or a


lower dose of the same statin

Consider other causes of muscle


symptoms

Muscle symptoms return


Discontinue the original statin and
once muscle symptoms resolve, use
a low dose of a different statin

If persistent muscle symptoms from


condition unrelated to statin therapy, or!
If predisposing condition has been
treated
Resume statin therapy at the original
dose

Evaluate the patient for other


conditions that might increase
the risk for muscle symptoms
Rhabdomyolysis resolves

Consultation with a lipid


specialist for re-initiation of
statin therapy

EVALUATE

AND

TREAT MUSCLE SYMPTOMS


Obtain a history of prior or current muscle symptoms to
establish a baseline

Mild to moderate
muscle symptoms

Unexplained, severe
muscle symptoms

Discontinue the statin until the


symptoms can be evaluated.

Discontinue the statin and


evaluate for rhabdomyolysis
(CK, creatinine, urine
myoglobin)

Evaluate the patient for other


conditions that might increase the
risk for muscle symptoms

Muscle symptoms resolve

Muscle symptoms persist for


2 months without statin

Give the patient the original or a


lower dose of the same statin

Consider other causes of muscle


symptoms

Muscle symptoms return


Discontinue the original statin and
once muscle symptoms resolve, use
a low dose of a different statin

If persistent muscle symptoms from


condition unrelated to statin therapy, or!
If predisposing condition has been
treated
Resume statin therapy at the original
dose

Evaluate the patient for other


conditions that might increase
the risk for muscle symptoms
Rhabdomyolysis resolves

Consultation with a lipid


specialist for re-initiation of
statin therapy

EVALUATE

AND

TREAT MUSCLE SYMPTOMS


Obtain a history of prior or current muscle symptoms to
establish a baseline

Mild to moderate
muscle symptoms

Unexplained, severe
muscle symptoms

Discontinue the statin until the


symptoms can be evaluated.

Discontinue the statin and


evaluate for rhabdomyolysis
(CK, creatinine, urine
myoglobin)

Evaluate the patient for other


conditions that might increase the
risk for muscle symptoms

Muscle symptoms resolve

Muscle symptoms persist for


2 months without statin

Give the patient the original or a


lower dose of the same statin

Consider other causes of muscle


symptoms

Muscle symptoms return


Discontinue the original statin and
once muscle symptoms resolve, use
a low dose of a different statin

If persistent muscle symptoms from


condition unrelated to statin therapy, or!
If predisposing condition has been
treated
Resume statin therapy at the original
dose

Evaluate the patient for other


conditions that might increase
the risk for muscle symptoms
Rhabdomyolysis resolves

Consultation with a lipid


specialist for re-initiation of
statin therapy

MAXIMIZE STATIN SAFETY


Statin-Associated Diabetes

Risk of developing diabetes is limited to patients who are already at high risk
of developing diabetes

MAXIMIZE STATIN SAFETY


Statin-Associated Diabetes

Statin intensity

Fewer major CVD


Excess cases of
events/1,000
incident diabetes/
individuals treated 1,000 individuals
for 1 year vs.
treated for 1 year
placebo
vs. placebo

NNT per year

NNH per year

Moderateintensity statin vs.


placebo/control

5.4

189

1,002

High-intensity vs.
moderateintensity statin

6.5

155

498

High-intensity
(rosuvastatin) vs.
placebo

5.9

169

332

An incident case of CVD reflects a more serious and immediate change


in health status than does an incident case of diabetes mellitus

MONITORING STATIN RESPONSE AND ADHERENCE


Yes

Expected
Response?

Assess adherence with fasting


lipid panel

No
No

Statin
Intolerance?

Reinforce medication
adherence

No

Yes

Manage Intolerance

Expected
Response?

Reinforce Improved Adherence!


Increase intensity OR consider
addition of non-statin therapy

Yes

Reinforce continued
adherence!
Follow-up in 3-12 months

Cholesterol Recommendations for Bob

Moderate to High-Intensity Statin Recommended!


Adults 40 to 75 years of age with LDL-C 70 to 189 mg/dL with no diabetes and estimated 10year ASCVD risk 7.5% should be treated with moderate to high-intensity statin therapy.!

Lifestyle Recommendations!
AHA/ACC guidelines stress the importance of lifestyle modifications to lower cardiovascular
disease risk. This includes eating a heart-healthy diet, regular aerobic exercises, maintenance
of desirable body weight and avoidance of tobacco products.

Cholesterol Recommendations for Bob

Moderate to High-Intensity Statin Recommended!


Adults 40 to 75 years of age with LDL-C 70 to 189 mg/dL with no diabetes and estimated 10year ASCVD risk 7.5% should be treated with moderate to high-intensity statin therapy.!

Lifestyle Recommendations!
AHA/ACC guidelines stress the importance of lifestyle modifications to lower cardiovascular
disease risk. This includes eating a heart-healthy diet, regular aerobic exercises, maintenance
of desirable body weight and avoidance of tobacco products.

Example regimen:!
Benazepril 20 mg Daily!
Atorvastatin 20 mg/Amlodipine 5 mg Daily

Diverging Guideline Philosophies


Cholesterol:!
Emphasis on risk assessment and treating
those at greatest overall risk with more
aggressive therapy!
Hypertension:!
Focus on a single risk factor (BP) and
recommend less aggressive treatment of BP in
older individuals!
These differences may be rationally based on the
adverse effect profiles of the 2 interventions

Implications

Practitioner

Questions?
Contact me:!
Nicholas B. Norgard, Pharm.D. BCPS!
University at Buffalo School of Pharmacy &
Pharmaceutical Sciences!
Office: 716-645-4779!
nnorgard@buffalo.edu