Do Calcium Channel Blockers Increase the Diagnosis of Heart

Failure in Patients With Hypertension?

Marcelo C. Shibata, MDa,*, Hernando León, MD, PhDa,e, Trish Chatterley, BA, MLISb,d,
Marlene Dorgan, BA, MLISb, and Ben Vandermeer, BSc, MScc
Calcium channel blockers (CCBs) are widely used to control hypertension. Previous work
suggested that their use could increase heart failure (HF), which is 1 of the consequences
of uncontrolled hypertension. Information about the effect of CCBs on incident HF in
patients with hypertension is scarce. A systematic review was conducted to evaluate
patients with hypertension treated with CCBs and incident HF. An electronic search of
publications was conducted using 8 major databases. Studies were eligible if they (1) were
randomized clinical trials, (2) performed comparisons of CCBs versus active control, (3)
randomized >200 patients, (4) had follow-up periods >6 months, and (5) provided data
regarding incident HF. Trials of renal transplantation patients, placebo-controlled trials,
and HF trials were excluded. A total of 156,766 patients were randomized to CCBs or
control, with a total of 5,049 events. The analysis indicated a significant increase in the
diagnosis of HF in patients allocated to CCBs (odds ratio 1.18, 95% confidence interval 1.07
to 1.31). The effect observed was independent of incident myocardial infarction. Subgroup
analyses indicated that patients with diabetes were at higher risk for developing HF (odds
ratio 1.71, 95% confidence interval 1.21 to 2.41). In conclusion, the results suggest that
patients with hypertension treated with CCBs have increased incident HF. © 2010
Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:228 –235)

The aim of this systematic review was to evaluate clinical
trials in patients with hypertension that involved calcium chan-
nel blockers (CCBs) and incident heart failure (HF).
Methods
Two librarians (MD and TC) searched Medline (1950 to
2009), Embase (1988 to 2009), the Cochrane Library,
PubMed, International Pharmaceutical Abstracts (1970 to
July 2009), Web of Science, BIOSIS Previews, and Scopus
using relevant subject headings and keywords. The search
terms used included, but were not limited to, “calcium
channel blockers,” “calcium antagonists,” “calcium inhibi-
tors,” “heart failure,” “heart disease,” and “cardiovascular
disease.” Explosion of subject headings and truncation of
terms were used as appropriate to make the search strategies
as comprehensive as possible. Validated search filters were
used when available to limit the results to randomized
controlled trials and systematic reviews. When such filters
were unavailable, text words related to desired study de-
a
EPICORE Centre, Division of Cardiology, bJohn W. Scott Health
Sciences Library, cAlberta Research Centre for Child Health Evidence,
Department of Pediatrics, University of Alberta, dInstitute of Health Eco-
nomics, and eDepartment of Medicine, General Internal Medicine Program,
University of Alberta, Edmonton, Alberta, Canada. Manuscript received
October 21, 2009; revised manuscript received and accepted February 21,
2010.
Dr. León was a recipient of a research fellowship from the Alberta
Heritage Foundation for Medical Research, Edmonton, Alberta, Canada.
*Corresponding author: Tel: 780-492-7427; fax: 780-492-6059.
E-mail address: marcelo.shibata@ualberta.ca (M.C. Shibata).
signs were used. For complete search strategies for individ-
ual databases, please contact the investigators.
Studies were eligible if they (1) were randomized clinical
trials, (2) performed comparisons of CCBs versus active
control, (3) randomized ⬎200 patients, (4) had follow-up
periods ⬎6 months, and (5) provided data regarding inci-
dent HF. Trials of renal transplantation patients and place-
bo-controlled trials were excluded, as well as trials in which
the main eligibility criteria was HF (HF trials).
Two reviewers (MCS and HL) independently assessed
the eligibility of each citation. Discrepancies were resolved
by consensus. Citations were selected according to eligibil-
ity criteria, and the full reports were retrieved for data
acquisition. Cohen’s ␬ statistic was used to evaluate the
concordance between abstractors. The quality of the re-
trieved reports was graded according to the Jadad score.1
RevMan versions 4.2.9 and 5 (Cochrane Collabora-
tion, Copenhagen, Denmark) were used for data analysis.
DerSimonian-Laird random-effects or Mantel-Haenszel fixed-
effects models were used as appropriate. Higgins’s statistical
heterogeneity test (I2) was applied to detect and quantify
heterogeneity.2
Continuous data are expressed as mean ⫾ SD or as
medians as appropriate. Categorical data are expressed as
percentages. Odds ratios (ORs) with 95% confidence inter-
vals (CIs) express treatment effects. The criterion for sta-
tistical significance was set at ␣ ⫽ 0.05.
Optimal information size has been proposed as an im-
provement in the quality of meta-analysis.3 A priori calcu-
lation of the optimal sample size to allow the detection of
clinically important differences in treatments (as in any
well-designed clinical trial) will give the reader important
information to evaluate and interpret the results properly.

0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. www.ajconline.org
doi:10.1016/j.amjcard.2010.02.031
 Review/Calcium Blockers and Heart Failure
Table 1
Sample size calculations with assumptions of power and ␣ error
Alpha Error (%) Power (%) Sample Size (per Arm)
5 70 14,200
5 80 17,955
5 90 24,041
1 90 34,123
Figure 1. Search flow of included and excluded trials with mean Jadad
score. RCT ⫽ randomized controlled trial.
Optimal information size was calculated using data from
Pahor’s meta-analysis (Table 1).4
Publication bias was minimized by carrying out an ex-
tended search in the 8 major databases mentioned previ-
ously. The reference lists of all reports retrieved were also
checked. A funnel plot was used to formally assess publi-
cation bias.
Results
After searching 8 major databases, 5,326 citations were
identified, from which 44 full reports were retrieved. Nine-
teen trials were included in the final analysis. Figure 1
shows the search flow of the trials and reasons for the
exclusions. Cohen’s ␬ coefficients for inter reviewer agree-
ment were 0.99 for the selection of the trials and 0.84 for the
quality evaluation using the Jadad score.
Particulars of the 19 trials5–23 are listed in Table 2. Seven
trials recruited patients with hypertension, and 12 trials
recruited patients with hypertension and ⱖ1 other risk fac-
tor for heart disease. Mean age varied from 54 to 76 years,
with a mean follow-up period ranging from 2 to 5 years.
Mean systolic and diastolic blood pressure at study entry
229
ranged from 146 to 194 and 82 to 102 mm Hg, respectively.
Most of the trials evaluated the dihydropyridine types of
CCBs (15 trials), 3 trials evaluated benzothiazepines (vera-
pamil), and 1 evaluated phenylalkylamine (diltiazem). Sev-
eral drugs were used for the control group: angiotensin-
converting enzyme (ACE) inhibitors, angiotensin receptor
blockers (ARB), diuretics, and ␤ blockers.
We collected information from individual trials with
regard to the criteria used to define and adjudicate HF. We
were able to obtain the definitions of HF in 11 of the 19
trials (58%). Most criteria were based on clinical features,
laboratory tests, chest imaging, and response to fluid re-
moval by either diuretics or interventions (such as dialysis
or ultrafiltration). However, clear predefined criteria were
obtained from 4 of the 19 trials included in the final analysis
(21%) (the Anglo-Scandinavian Cardiac Outcomes Trial
[ASCOT], the Japan Multicenter Investigation for Cardio-
vascular Diseases–B [JMIC-B], the Irbesartan in Diabetic
Nephropathy Trial [IDNT], and the International Verapamil-
Trandolapril Study [INVEST]). Most of the definitions were
centered on systolic HF, and no description of diastolic HF
was found.
In terms of outcome assessment, 15 of 19 trials (79%)
clearly reported that the evaluation of incident HF was
reviewed by a blinded committee. Four trials provided ei-
ther vague or no information about adjudication.
There was no significant difference between systolic
blood pressure reduction in the CCB and control arms.
Patients allocated to CCBs had slightly lower diastolic pres-
sures, with a difference of 0.66 mm Hg. This difference was
statistically significant, although clinically irrelevant, and
would not explain nor alter the interpretation of the results
(Figure 2).
A total of 156,766 patients were randomized to CCBs or
control, with a total of 5,049 events. Analysis indicated a
significant increase in the diagnosis of HF in patients allo-
cated to CCBs (OR 1.18, 95% CI 1.07 to 1.31), while results
of the test for heterogeneity were moderate (I2 ⫽ 38%). The
increase in HF was consistent among trials in that all but 4
had point estimates showing a higher risk for HF in the CCB
group (Figure 3). Incident HF was analyzed by type of
active control (ACE inhibitors or ARBs, diuretics, and ␤
blockers and/or diuretics; Figure 4). There were 47,688
patients in trials comparing CCBs to ACE inhibitors or
ARBs, with a total of 2,722 events. There was a significant
increase in incident HF in patients allocated to CCBs (OR
1.21, 95% CI 1.10 to 1.32). The magnitude of the effect was
even more pronounced when CCBs were compared with
diuretics. There was a total of 46,723 patients randomized,
with 1,859 events. The OR was 1.32 (95% CI 1.04 to 1.66).
A total of 52,714 patients were randomized to CCBs or ␤
blockers and/or diuretics, with 771 events. The OR was 1.01
(95% CI 0.82 to 1.25). Publication bias was unlikely, as
assessed by the funnel-plot method (Figure 5).
Sixteen trials published data regarding incident myocar-
dial infarction. A total of 121,404 patients were randomly
allocated to CCBs or control, with 3,612 events. The OR for
myocardial infarction was 0.96 (95% CI 0.87 to 1.07). Thus,
the increase in the diagnosis of HF in patients allocated to
CCBs cannot be explained by differences in incident myo-
cardial infarction (Figure 6).
 230
Table 2
Trials included in the meta-analysis
Trial n Setting Mean Follow-Up Men Mean BP, Baseline CCB (mg/day) Control (mg/day) End Point(s)
Age (years) (%) (mm Hg)
(years)

IDNT5 1,715 HTN ⫹ DM ⫹ 58.3 2.6 66.4 160 ⫾ 20/87 ⫾ 11 Amlodipine (10) Irbesartan (300) MI, HF, stroke, coronary
nephropathy revascularization
MIDAS6 883 HTN 58.2 3 78.3 150 ⫾ 16/96 ⫾ 5 Isradipine (2.5–5) HCTZ (12.5–25) Carotid intima-media thickness
VHAS7 1,414 HTN 54.5 2 48.9 169 ⫾ 10/102 ⫾ 5 Verapamil SR (240) Chlorthalidone (25) BP, carotid lesion
NICSEHS8 429 HTN 69 4 33.1 171 ⫾ 13/94 ⫾ 10 Nicardipine SR (20) Trichlormethiazide (2) Stroke, MI, angina, HF
STOP-29 6,614 HTN 76 4 36.2 194/98 Felodipine/isradipine† BB, diuretic, ACE inhibitor† CV mortality
INSIGHT10 6,321 HTN ⫹ 1 RF 65 3 46.3 167/96 Nifedipine GITS (30) Co-amlodipine (25/2.5) CV mortality, MI, stroke, HF
NORDIL11 10,881 HTN 60 4 48.6 173 ⫾ 17/105 ⫾ 8 Diltiazem (180–360) BB/diuretic‡ Stroke, MI, CV death
J-MIND12 464 HTN ⫹ DM 60.2 2 50.5 162 ⫾ 17/90 ⫾ 12 Nifedipine R (20–60) Enalapril (5–20) Macroalbuminuria ⬎300 mg/day

The American Journal of Cardiology (www.ajconline.org)

ALLHAT13 33,357 HTN ⫹ 1 RF 66.9 5 53.1 146 ⫾ 16/84 ⫾ 10 Amlodipine (2.5–10) Lisinopril/chlorthalidone§ CAD or MI
CONVINCE14 16,602 HTN ⫹ 1 RF 65.6 3* 44.0 150 ⫾ 15/86 ⫾ 10 Verapamil (180) Atenol/HCTZ储 Stroke, MI, CV death
INVEST15 22,576 HTN ⫹ CAD 66 3 47.9 149 ⫾ 19/86 ⫾ 12 Verapamil¶ SR (240) Atenol# (50) Death, MI, stroke
SHELL16 1,882 HTN 72 3* 38.7 178 ⫾ 10/87 ⫾ 6 Lacidipine (4) Chlorthalidone (12.5) Stroke, sudden death, MI, HF,
revascularization, CE
JMIC-B17 1,650 HTN ⫹ CAD 65 3 68.8 147 ⫾ 19/82 ⫾ 11 Nifedipine SR (10–20) ACE inhibitor** Cardiac events
VALUE18 15,245 HTN ⫹ RFs 67 4 57.6 155 ⫾ 19/87 ⫾ 10 Amlodipine (5–10) Valsartan (80–160) Cardiac mortality/morbidity
AASK19 1,094 HTN ⫹ nephropathy 54.4 3* 64.5 150 ⫾ 25/96 ⫾ 14 Amlodipine (5–10) Ramipril (5–10) Renal function
ASCOT-BPLA20 19,257 HTN ⫹ 3 RFs 63 5 76.5 164 ⫾ 18/94 ⫾ 10 Amlodipine†† (5–10) Atenolol‡‡ (50–100) MI, CAD
MOSES21 1,405 HTN ⫹ stroke 68.1 2 52.2 152 ⫾ 18/87 ⫾ 10 Nitrendipine (10) Eprosartan (600) Total mortality/CV events
CASE-J22 4,728 HTN ⫹ any RF 63.9 3.2 55.2 163.2 ⫾ 14.1/91.8 ⫾ 11.4 Amlodipine (2.5–10) Candesartan (4–12) CV events/renal disease
ACCOMPLISH23 11,506 HTN ⫹ RF 68.4 60.5 145.3 ⫾ 18.4/80.1 ⫾ 10.8 Benazepril ⫹ Benazepril ⫹ HCTZ储储 CV event/CV death
amlodipine§§

Assumptions: event control rate 2.7%, difference to be detected 20% (Table 1).30
AASK ⫽ African American Study of Kidney Disease and Hypertension; ACCOMPLISH ⫽ Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension;
ASCOT-BPLA ⫽ Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm; BP ⫽ blood pressure; CAD ⫽ coronary artery disease; CASE-J ⫽ Candesartan Antihypertensive Survival
Evaluation in Japan; CE ⫽ carotid endarterectomy; CV ⫽ cardiovascular; DM ⫽ diabetes mellitus; GITS ⫽ gastrointestinal therapeutic system; HCTZ ⫽ hydrochlorothiazide; HTN ⫽ hypertension; IDNT ⫽
Irbesartan in Diabetic Nephropathy Trial; INSIGHT ⫽ Intervention as Goal in Hypertension Treatment; JMIC-B ⫽ Japan Multicenter Investigation for Cardiovascular Diseases–B; MI ⫽ myocardial infarction;
MIDAS ⫽ Multicenter Isradipine Diuretic Atherosclerosis Study; MOSES ⫽ Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention; NICSEHS ⫽ National
Intervention Cooperative Study in Elderly Hypertensives Study; RF ⫽ risk factor; SHELL ⫽ Systolic Hypertension in the Elderly Long-Term Lacidipine; SR ⫽ sustained release; STOP-2 ⫽ Swedish Trial
in Old Patients With Hypertension–2; VALUE ⫽ Valsartan Antihypertensive Long-Term Use Evaluation; VHAS ⫽ Verapamil in Hypertension and Atherosclerosis Study.
* Median value.
†
Felodipine 2.5 mg, isradipine 2 to 5 mg, atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg.
‡
Thiazide diuretic and or ␤ blocker at the discretion of the treating physician.
§
Lisinopril 10 to 40 mg and chlorthalidone 12.5 to 25 mg.
储
Atenolol 50 mg ⫾ hydrochlorothiazide 12.5 mg.
¶
Trandolapril could be added.
#
Hydrochlorothiazide could be added.
** Enalapril 5 to 10 mg, imidapril 5 to 10 mg, lisinopril 10 to 20 mg.
††
Perindopril could be added.
‡‡
Bendroflumethiazide.
§§
Benazepril 20 to 40 mg, amlodipine 5 to 10 mg.
储储
Benazepril 20 to 40 mg, hydrochlorothiazide 12.5 to 25 mg.
 Review/Calcium Blockers and Heart Failure 231

Figure 2. Reduction in blood pressure in the CCB and control groups. Total denotes number of patients. IV ⫽ inverse variance. See Table 2 for definitions
of study acronyms.

Figure 3. Metagraph of hypertension trials using CCBs and incident HF. Total denotes number of patients. M-H ⫽ Mantzel Haenzel. See Table 2 for
definitions of study acronyms.

A subgroup analysis was conducted to evaluate the effect
of CCBs on incident HF in patients with isolated systolic
hypertension, diabetes mellitus, and coronary artery disease.
This analysis indicated that the effect of CCBs on increasing
HF was statistically significant for patients with diabetes
and isolated systolic hypertension, with ORs of 1.71 and
1.18, respectively. Although the effect was in the same
direction for patients with coronary artery disease (OR
1.11), it was not statistically significant (Figure 7).
The results were not changed by the type of CCB used in
the trials (dihydropyridines vs nondihydropyridines; Figure 8).
Discussion
The results of this meta-analysis indicate that there is an
increase in the diagnosis of HF in patients allocated to
CCBs in hypertension trials. This effect is consistent among
trials and cannot be explained by differences in incident
232 The American Journal of Cardiology (www.ajconline.org)
Figure 4. Metagraph of hypertension trials with CCBs according to type of active control. Total denotes number of patients. M-H ⫽ Mantzel Haenzel. See
Table 2 for definitions of study acronyms.
Figure 5. Funnel plot of included trials.
myocardial infarction. This effect is also observed when
comparing CCBs to ACE inhibitors or ARBs and to ␤
blockers and/or diuretics and is even more pronounced
when CCBs are compared with diuretics alone.
It is difficult to evaluate if the effect observed in our
analysis is due to a “protective effect” of ACE inhibitors,
ARBs, ␤ blockers, and/or diuretics against HF. However, it
is unwise to ignore recent publications revealing that the
treatment of hypertension with CCB increases circulating
catecholamines that could potentially be involved in the
pathogenesis of HF.24 –26 This information supports biologic
plausibility for the effect observed in our analysis and
should be tested in future trials.
Four previous systematic reviews or meta-analyses
evaluated health outcomes in patients with hypertension
treated with several types of agents.27–30 The number of
trials included varied from 9 to 42 (network meta-anal-
ysis). There was a trend suggesting that the use of CCBs
increased the diagnosis of HF compared to that of ␤
blockers, diuretics, and ACE inhibitors. Pahor’s meta-
analysis was the sole study dedicated to study the effect
of CCBs on health outcomes. It included only 9 trials, not
including the megatrial Antihypertensive Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT),
because it was ongoing at that time. When CCBs were
compared to “other” treatments, there was an increase in
HF in the CCB arm (OR 1.25, 95% CI 1.07 to 1.46). This
result was based on approximately 700 events in about
27,000 patients. Our search of the published research was
more comprehensive, surveying 8 different databases,
 Review/Calcium Blockers and Heart Failure 233

Figure 6. Exploratory analysis: incidence of myocardial infarction. Total denotes number of patients. M-H ⫽ Mantzel Haenzel. See Table 2 for definitions
of study acronyms.

Figure 7. Incidence of HF in patients with (A) isolated hypertension, (B) diabetes, and (C) hypertension and coronary artery disease. Total denotes number
of patients. M-H ⫽ Mantel-Haenszel. See Table 2 for definitions of study acronyms.

compared to only 1 database in Pahor’s work. Therefore,
our conclusions are drawn from a stronger evidence base,
resulting in a more robust, precise, and up-to-date anal-
ysis compared to previous work in this area. The lower
point estimate of the CI in our analysis is 1.07, suggest-
ing that CCBs are probably inferior to other agents in
terms of offering protection against HF, despite the same
magnitude of blood pressure reduction.
Our analysis showed that patients with diabetes are at
higher risk for developing HF under CCB treatment for
hypertension. The same applies for patients with isolated
systolic hypertension, but with a lower magnitude. The
overall effect of CCBs in increasing the diagnosis of HF
appears to be independent of the type of the CCB used
(dihydropyridines vs nondihydropyridines). Furthermore, it
is difficult to pinpoint if the increase in HF observed in our
analysis is due to increased catecholamine, negative inotro-
pic activity caused by CCBs, both, or another unclear mech-
anism. This information is hypothesis generating and should
be evaluated in future clinical trials.
234 The American Journal of Cardiology (www.ajconline.org)
Figure 8. Incidence of HF according to type of CCB. (A) No dihydropyridines; (B) dihydropyridines. Total denotes number of patients. M-H ⫽ Mantzel
Haenzel. See Table 2 for definitions of study acronyms.
Our analysis is limited by the use of tabular data. Pub-
lication bias is a common problem in meta-analyses. One of
the most effective ways of reducing it is to conduct a
thorough search using several databases, as we have done.
There was statistical heterogeneity in our analysis, which
was probably because clinical trials enrolled patients with
different degrees of cardiovascular risk. This reinforces the
random-effects model used for data analysis. Overall, most
trials were of acceptable quality, and missing data were not
significant. One important limitation is the lack of a clear
definition of HF in eligible trials. The diagnosis of HF was
left to the discretion of the investigators. Moreover, data are
limited if not inexistent with regard to the type of incident
HF, systolic, diastolic, or both. Evaluation of the ejection
fraction as a screening baseline in the trials included in our
analysis was not the norm, implying that patients with stage
B HF (asymptomatic with left ventricular dysfunction) were
not identified. We attempted to collect information regard-
ing the definition and adjudication of HF. Despite of our
best effort, including contacting investigators and perform-
ing a more comprehensive search of the published research,
we could not retrieve the necessary information from all 19
trials. At least 15 (including all the major trials) of the 19
trials showed blinded outcome assessments, thus reducing
the chance of bias. In contrast, the fact that the diagnosis of
HF was left to the discretion of the investigators may be
interpreted as a more “real world” scenario compared to
controlled clinical trials, which often are criticized in terms
of extrapolating results to the general population.
HF is a key end point in clinical trials evaluating thera-
pies for hypertension. On the basis of our results, we sug-
gest that a more stringent definition of HF and a more
careful evaluation of the ventricular function at baseline be
incorporated into future clinical trials. Our data suggest an
increase in incident HF in patients allocated to CCBs, but
because of the limitations discussed here, this effect should
be evaluated in future research.
Acknowledgment: We are thankful to Christian Funck-
Brentano, MD, PhD, for his collaboration with regard to
the data from the Intervention as Goal in Hypertension
Treatment (INSIGHT) trial.
1. Jadad AR, Moore RA, Carrol D. Assessing the quality of reports of
randomized clinical trials: is blinding necessary? Control Clin Trials
1996;17:1–12.
2. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring incon-
sistency in meta-analyses. BMJ 2003;327:557–560.
3. Pogue J, Yusuf S. Overcoming the limitations of current meta-analysis
of randomised controlled trials. Lancet 1998;351:47–52.
4. Lwanga SK, Lemeshow S. Sample Size Determination in Health
Studies: A Practical Manual. Geneva, Switzerland: World Health Or-
ganization, 1991.
5. Berl T, Hunsiker LG, Lewis JB, Pfeffer M.A., Porush JG, Rouleau J-L,
Lewis JB, Rosendorff C, Porush JG, Drury PL, Esmatjes E, Raz I,
Vanhille P, Locatelli F, Goldhaber S, Lewis EJ, Pfeffer MA. Cardio-
vascular outcomes in the Irbesartan Diabetic Nephropathy Trial of
patients with type 2 diabetes and overt nephropathy. Ann Intern Med
2003;138:542–549.
 Review/Calcium Blockers and Heart Failure
6. Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris
M, Carr AA, Kappagoda T, Rocco MV, Schnaper HW, Sowers JR,
Bond MG. Final outcome results of the Multicenter Isradipine Diuretic
Atherosclerosis Study (MIDAS). JAMA 1996;276:785–791.
7. Rosei EA, Palu CD, Leonetti G, Magnani B, Pessina A, Zanchetti A.
Clinical results of the Verapamil in Hypertension and Atherosclerosis
Study. J Hypertens 1997;15:1337–1344.
8. National Intervention Cooperative Study in Elderly Hypertensives
Study Group. Randomized double-blind comparison of a calcium
antagonist and a diuretic in elderly hypertensives. Hypertension 1999;
34:1129-1133.
9. Hansson L, Lindholm LH, Ekborn T, Dahlof B, Lanke J, Schersten B,
Wester PO, Hedner T, de Faire U. Randomised trial of old and new
antihypertensive drugs in elderly patients: cardiovascular mortality
and morbidity the Swedish Trial in Old Patients With Hypertension–2
study. Lancet 1999;354:1751–1756.
10. Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G,
Rosenthal T, Ruilope LM. Morbidity and mortality in patients ran-
domised to double-blind treatment with a long-acting calcium-channel
blocker or diuretic in the International Nifedipine GITS study: Inter-
vention as Goal in Hypertension Treatment (INSIGHT). Lancet 2000;
356:366 –372.
11. Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH,
Syverten JO Lanke J, de Faire U, Dahlöf B, Karlberg BE. Randomised
trial of effects of calcium antagonists compared with diuretics and
␤-blockers on cardiovascular morbidity and mortality in hypertension:
the Nordic Diltiazem (NORDIL) study. Lancet 2000;356:359 –365.
12. Baba S; the J-MIND Study Group. Nifedipine and enalapril equally
reduce the progression of nephropathy in hypertensive type 2 diabet-
ics. Diabetes Res Clin Pract 2001;54;191–201.
13. The ALLHAT Collaborative Research Group. Major outcomes in
high-risk hypertensive patients randomized to angiotensin-converting
enzyme inhibitor or calcium channel blocker vs diuretic. The Antihy-
pertensive and Lipid-Lowering Treatment to Prevent Heart Attack
Trial. JAMA 2002;288:2981-2997.
14. Black HR, Elliot WJ, Grandits G, Grambesh P, Lucente T, White WB,
Neaton JD, Grimm RH Jr, Hansson L, Lacourciere Y, Muller J, Sleight P,
Weber MA, Williams G, Wittes J, Zanchetti A, Anders RJ; CONVINCE
Research Group. Principal results of the Controlled Onset Verapamil
Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA
2003;289:2073–2082.
15. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P,
Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M,
Erdine S, Bristol HA, Kolb HR, Bakris GL, Cohen JD, Parmley WW.
A calcium antagonist vs a non-calcium antagonist hypertension treat-
ment strategy for patients with coronary artery disease. The Interna-
tional Verapamil-Trandolapril Study (INVEST): a randomized con-
trolled trial. JAMA 2003;290:2805–2816.
16. Malacco E, Mancia G, Rappelli A, Menotti A, Zuccaro MS, Coppini
A. Treatment of isolated systolic hypertension: the SHELL study
results. Blood Pressure 2003;12:160 –167.
17. Yui Y, Sumiyoshi T, Kodama K, Hirayama A, Nonogi H, Kanmatsuse
K, Origasa H, Iimura O, Ishii M, Saruta T, Arakawa K, Hosoda S,
Kawai C. Comparison of nifedipine retard with angiotensin converting
enzyme inhibitors in Japanese hypertensive patients with coronary
artery disease: the Japan Multicenter Investigation for Cardiovascular
Diseases–B (JMIC-B) randomized trial. Hypertens Res 2004;27;181–
191.
18. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L,
Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B,
Zanchetti A; VALUE Trial Group. Outcomes in hypertensive patients
at high cardiovascular risk treated with regimens based on valsartan or
amlodipine: the VALUE trial. Lancet 2004;363:2022–2031.
235
19. Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs
JP, Charleston J, Cheek D, Cleveland W, Douglas JG, Douglas M,
Dowie D, Faulkner M, Gabriel A, Gassman J, Greene T, Hall Y,
Hebert L, Hiremath L, Jamerson K, Johnson CJ, Kopple J, Kusek J,
Lash J, Lea J, Lewis JB, Lipkowitz M, Massry S, Middleton J,
Miller ER III, Norris K, O’Connor D, Ojo A, Phillips RA, Pogue V,
Rahman M, Randall OS, Rostand S, Schulman G, Smith W, Thorn-
ley-Brown D, Tisher CC, Toto RD, Wright JT Jr, Xu S; African
American Study of Kidney Disease and Hypertension (AASK)
Study Group. Effect of ramipril vs amlodipine on renal outcomes in
hypertensive nephrosclerosis. A randomized controlled trial. JAMA
2001;285:2719 –2728.
20. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M,
Collins R, Kjeldsen SE, Kristinsson A, Mclnnes GT, Mehlsen J,
Nieminen M, O’Brien EO, Ostergren J, for the ASCOT Investigators.
Prevention of cardiovascular events with an antihypertensive regimen
of amlodipine adding perindopril as required versus atenolol adding
bendroflumethazide as required, in the Anglo-Scandinavian Cardiac
Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA): a
multicentre randomised controlled trial. Lancet 2005;366:895–906.
21. Schrader J, Luders S, Kulschewski A, Hammersen F, Plate K, Berger
J, Zidek W, Dominiak P, Diener HC; MOSES Study Group. Morbidity
and Mortality After Stroke, Eprosartan Compared With Nitrendipine
for Secondary Prevention. Principal results of a prospective random-
ized controlled study (MOSES). Stroke 2005;36:1218 –1226.
22. Ogihara T, Nakao K, Fukui T, Fukyiyama K, Ueshima K, Oba K, Sato
T, Saruta T; Candesartan Antihypertensive Survival Evaluation in
Japan Trial Group. Effects of candesartan compared with amlodipine
in hypertensive patients with high cardiovascular risks. Candesartan
Antihypertensive Survival Evaluation in Japan Trial. Hypertension
2008;51:393–398.
23. Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, Hester
A, Gupte J, Gatlin M, Velazquez EJ; ACCOMPLISH Trial Investiga-
tors. Benazepril plus amlodipine or hydrochlorothiazide for hyperten-
sion in high risk patients. N Engl J Med 2008;359:2417–2428.
24. de Champlain J, Karas M, Assouline L, Nadeau R, LeBlanc AR, Dube
B, Larochelle P. Effects of valsartan or amlodipine alone or in com-
bination on plasma catecholamine levels at rest and during standing in
hypertensive patients. J Clin Hypertens 2007;9:168 –178.
25. Watanabe S, Okura T, Kurata M, Irita J, Manabe S, Miyoshi K,
Fukuoka T, Murakami K, Higaki J. The effect of losartan and amlo-
dipine on serum adiponectin in Japanese adults with essential hyper-
tension. Clin Ther 2006;28:1677–1685.
26. Lindqvist M, Kahan T, Melcher A, Ekholm M, Hjendahl P. Long term
calcium antagonist treatment of human hypertension with mibefradil
or amlodipine increases sympathetic nerve activity. J Hypertens 2007;
25:169 –175.
27. Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD,
Cavazzini C, Furberg CD. Health outcomes associated with calcium
antagonists compared with other first-line antihypertensive therapies: a
meta-analysis of randomised controlled trials. Lancet 2000;356:1949 –
1954.
28. Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Trialists
Collaboration. Effects of ACE inhibitors, calcium antagonists, and
other blood-pressure-lowering drugs: results of prospectively designed
overviews of randomised trials. Lancet 2000;355:1955–1964.
29. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alder-
man MH, Weiss NS. Health outcomes associated with various antihy-
pertensive therapies used as first-line agents. A network meta-analysis.
JAMA 2003;289:2534 –2544.
30. Blood Pressure Lowering Treatment Trialists Collaboration. Effects of
different blood-pressure-lowering regimens on major cardiovascular
events: results of prospective-designed overviews of randomised trials.
Lancet 2003;362:1527-1535.