(Hypertension. 1997;30:7-14.)
© 1997 American Heart Association, Inc.
Articles |
Safety of Nifedipine in Patients With Hypertension
A Meta-Analysis
From the Harvard School of Public Health (W.B.S.); MetaWorks, Inc (W.B.S., D.N., G.W.W., D.L., S.D.R., T.C.C.); Tufts University/New England Medical Center (C.H.S.); and Tufts University (T.C.C.), Boston, Mass.
Correspondence to William B. Stason, MD, MS, 29 Sandy Pond Rd, Lincoln, MA 01773.
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Abstract |
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Abstract Our objective was to compare cardiovascular event rates in patients with mild or moderate hypertension who received nifedipine with active drug controls. We performed a MEDLARS search using the MeSH heading "hypertension" and the text word "nifedipine" to identify all articles that were published between 1966 and August 1995 in English, French, German, Italian, and Spanish languages and that involved human subjects. The computerized search was supplemented by a manual search of article bibliographies. Review of 1880 citations revealed 98 randomized controlled clinical trials that met protocol criteria. Articles were extracted independently by two doctors who were blinded for author, institution, and treatment regimen, using a structured, pretested extraction form. Differences of opinion were resolved by consensus. Fourteen events occurred in 5198 exposures (0.27%) to nifedipine and 24 events in 5402 exposures (0.44%) to other active drug controls. Unadjusted odds ratios for nifedipine versus controls were 0.49 (95% confidence interval [CI], 0.22-1.09) for definitive events (death, nonfatal myocardial infarction or stroke, revascularization procedure) and 0.61 (95% CI, 0.31-1.17) for all events (definitive plus increased angina). The odds ratio for nifedipine monotherapy (sustained- or extended-release in 91% of exposures) was nonsignificantly higher for definitive and all events (odds ratio, 1.40; 95% CI, 0.49-4.03 and odds ratio, 1.39; 95% CI, 0.59-3.32, respectively). The odds ratio for nifedipine in combination with another drug was significantly lower for definitive and all events (odds ratio, 0.09; 95% CI, 0.01-0.66 and odds ratio, 0.15; 95% CI, 0.03-0.65, respectively). Differences in odds ratio for nifedipine monotherapy and combined therapy were statistically significant (P=.02 for definitive events and P=.001 for all events). Results support the safety of sustained- and extended-release nifedipine in the treatment of mild or moderate hypertension when it is used in combination with other drugs.
Key Words: nifedipine • meta-analysis • safety
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Introduction |
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Calcium channel blockers, including nifedipine, are widely used for the management of hypertension.1 2 Sustained- and extended-release nifedipine, alone or in combination with other agents, has been approved by the US Food and Drug Administration for the treatment of hypertension and has been endorsed in guidelines for the treatment of mild and moderate hypertension written by the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure.3
Two recent studies, however, have questioned the safety of calcium channel blockers in general and immediate-release nifedipine in particular. A meta-analysis of randomized controlled trials of nifedipine involving patients with myocardial infarction (9039 subjects in 12 trials) or unstable angina (1226 subjects in three trials) and subjects undergoing coronary angiography (425 subjects in one trial) concluded that the use of immediate-release nifedipine was associated with a significant, dose-related increase in mortality.4 A population-based case-control study of pharmacologically treated hypertensive patients enrolled in the Group Health Cooperative of Puget Sound (Seattle, Wash) found that the use of calcium channel blockers was associated with a statistically significant, dose-related increase in myocardial infarctions.5 On the basis of these findings, the authors recommended against the use of calcium channel blockers in patients with acute coronary syndromes and for restricted use in hypertensive patients until results are available from ongoing, large-scale clinical trials that are assessing cardiovascular outcomes of several antihypertensive agents, including calcium channel blockers.6 7 8 9
We performed a meta-analysis of published randomized controlled trials to assess the safety of nifedipine in hypertensive patients and to examine rates of adverse cardiovascular events in patients receiving nifedipine as monotherapy or in combination with other drugs compared with other active drugs. Outcomes of interest were definitive cardiovascular events (death, nonfatal myocardial infarction, nonfatal stroke, revascularization procedure during the study period) and episodes of new-onset or increased angina. We also examined other reasons for early withdrawal from studies.
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Methods |
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This study used techniques for meta-analysis of randomized, controlled trials described by Sacks et al.10 A prospectively designed study protocol defined the objectives of the study, eligibility criteria for the inclusion of trials, key data elements to be extracted, and analytical methods to be used. To be included, a study had to (1) be a randomized, controlled trial enrolling patients with mild or moderate hypertension, (2) be published in a peer-reviewed journal or supplement to such a journal, (3) enroll a minimum of 10 patients, (4) compare any nifedipine formulation, either as monotherapy or in combination with other agents, with a nondihydropyridine active drug or placebo control, and (5) monitor and report adverse clinical events and report them by treatment group. Eligible studies could be of either parallel or crossover design.
Studies were identified by a MEDLARS search using the MeSH heading "hypertension" and by searching for "nifedipine" as a text word. The search extended from 1966 through August 1995 and included articles published in English, French, Italian, German, and Spanish languages. CD-ROM Current Contents was searched independently. Computer-based searches were supplemented by manual searches of bibliographies of retrieved articles to detect other potentially acceptable studies. Retrieved abstracts and studies were screened by research analysts to exclude animal studies, nonqualifying languages, and nonrandomized clinical trials. Final eligibility was determined by the consensus of two independent physician reviewers.
Selected studies were blinded as to source, authors, and treatment groups.10 Each article was then extracted independently by two physicians or doctors of pharmacology using a pretested, standardized extraction form. Differences in opinions were resolved by consensus. The same reviewers assessed each study for quality using the scoring systems of Chalmers et al11 and Jadad et al.12 Administrative and treatment regimen data were extracted unblinded by an independent reviewer. Data were entered into Excel spreadsheets, verified by two research analysts, and downloaded as ASCII files for analysis with SAS software.13
Deaths, nonfatal myocardial infarctions, nonfatal strokes, and revascularization procedures that occurred during the study were classified as definitive cardiovascular events. Episodes of increased angina that led to withdrawal from the study were combined with definitive events in analyses of all cardiovascular events. Definitions of increased angina varied among studies and included unstable angina, crescendo angina, angina at rest, new angina, and increased frequency of chest pain.
Study withdrawals were classified as being due to adverse drug reactions (ADRs) or other causes. Withdrawals for ADRs included drug-related symptoms such as edema or headache as well as the cardiovascular events described above. Withdrawals for other causes included protocol violations, lost to follow-up, and inadequate therapeutic efficacy.
Because the majority of studies had no events in either the treatment or control arm, we could not compute within-study estimates of treatment effects. Heterogeneity statistics and random effects estimates could not be calculated for the same reasons.14 Incidence rates and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from the total number of events comparing nifedipine study arms with corresponding other active drug arms in the same studies. An OR less than 1.0 favors nifedipine. Placebo arms were excluded from the analysis because of the small numbers of subjects and events. We compared our results with those obtained by application of the Peto method, which discards trials in which no event occurred in any study arm.15 Results were similar. In fact, unweighted pooling and Peto's method can be shown to give equivalent OR estimates when no more than one event occurs during a study and the OR equals 1.0. The two methods give approximately equal results when the odds differ by no more than a factor of 3.0. In any event, all of these methods rely on asymptotic approximation, which is more nearly satisfied when small numbers of events are added together.
Analyses of cardiovascular events were stratified by type of nifedipine formulation (immediate-release [three or four times a day], sustained-release [twice a day], or extended-release [once a day] and by whether nifedipine was prescribed as monotherapy or in combination with other drugs (combotherapy). To test whether the unadjusted ORs differed between the type of formulation and monotherapy versus combotherapy, we fitted two logistic regression models, each including a term for type of drug (nifedipine versus other), one of the stratification factors (type of formulation or monotherapy/combotherapy), and an interaction term. The interaction term was used to determine whether the OR for drug type differed by the stratification factor.
To investigate whether treatment effects were confounded with study-level covariates, we fit multiple logistic regression models and computed the adjusted ORs for treatment.16
Covariates and rationales for their inclusion were (1) drug run-in before randomization—a proxy for case severity that indicates the reluctance of the investigator to take subjects off all active medications; (2) duration of treatment—a longer duration would be expected to be associated with an increased risk of adverse events; (3) parallel or crossover study design—carryover effects between phases of crossover studies might obscure differences between treatment regimens; (4) quality scores—a higher quality score may indicate more complete recording of adverse events and reasons for withdrawals; (5) date of publication (1987 or earlier versus 1988 or later)—a break point that coincides with the introduction of both Good Clinical Practices (GCPs) in Europe and longer-acting nifedipine formulations; and (6) study location (Europe or other versus United States) since differences in study designs, data collection strategies, or reporting conventions may influence study outcomes.
Drug regimen characteristics (nifedipine versus control drugs and monotherapy versus combotherapy) and their interaction were included in all models. Dose relationships could not be explored because most studies that titrated doses did not report the distribution of doses patients received.
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Results |
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Study Characteristics
A total of 1880 citations were retrieved for nifedipine in the treatment of hypertension. Ninety-eight were accepted for the meta-analysis and are summarized in Table 1
.17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 These studies contained 230 study
arms (111 nifedipine, 106 other active drugs, 13 placebo),
9506 subjects, and 11 020 treatment exposures (5198 to
nifedipine, 5402 to other active drugs, 420 to placebo).
The majority of studies were of parallel group design (69%), had
run-in periods with placebo or active drug controls (92%), involved at
least one monotherapy arm (81%), were of relatively short duration
(active treatment 
12 weeks in 74%) and small size (47% enrolled
50 subjects), were performed in Europe (70%), and had been published
since 1987 (61%). Mean quality scores were 29.1 (range, 5 to 56) on
the Chalmers scale and 3.0 (range, 1 to 5) on the Jadad scale. These
quality scores are average compared with other randomized controlled
trials. Subjects were predominantly male (mean for all studies, 57%)
and had a mean age of 54.6 years (range of means, 42 to 74).
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Sustained- or extended-release formulations were used in 85% of study arms and 91% of treatment exposures, and immediate-release formulations were used in 15% of study arms and 9% of treatment exposures. Starting doses were titrated upward to achieve the desired clinical response in 40% of study arms and reached a maximum of greater than or equal to 80 mg/d in 39% of study arms with sustained- and extended-release nifedipine and 35% of study arms with immediate-release nifedipine. The proportion of subjects who actually received higher doses was rarely specified.
Frequency of Cardiovascular Events
Nifedipine Versus Other Active Drugs
A cardiovascular event was reported in 0.27% of
patients in nifedipine study arms (14 events in 5198 drug
exposures) and 0.44% of patients in active drug control arms (24
events in 5402 drug exposures) (see Table 2). Overall,
there were 28 definitive events (deaths, nonfatal myocardial
infarctions or strokes, or revascularization
procedures during the study period) and 10 episodes of new or increased
angina. One or more cardiovascular events were reported
in 21% of studies. Table 3 and the
Figure present the associations between drug regimen
and the incidence of cardiovascular events. Unadjusted
ORs were nonsignificantly lower during nifedipine therapy
than during other active drugs for definitive events (OR, 0.49; 95%
CI, 0.22-1.09) and all events (OR, 0.61; 95% CI, 0.31-1.17). ORs
adjusted for type of regimen and study-level covariates increased to
0.51 (95% CI, 0.23-1.13) for definitive events and decreased to 0.57
(95% CI, 0.29-1.11) for all events. Hence, there was no apparent
confounding of treatment effects by study-level covariates. Total study
duration was significantly associated with an increased risk of
definitive events. Total study duration, location of the study in the
United States, and higher study quality were independently and
significantly associated with an increased risk of all events
controlling for drug regimen.
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Nifedipine Monotherapy Versus Combotherapy
Nifedipine was used as monotherapy in two thirds of
drug exposures and as part of combotherapy in one third of drug
exposures. In subjects on combotherapy, nifedipine was
combined with diuretics in 56% of subjects, ß-blockers in
29%, angiotensin-converting enzyme inhibitors
in 6%, and with both ß-blockers and a diuretic in 9%.
During nifedipine monotherapy, the OR for definitive events
was 1.40 (95% CI, 0.49-4.03), and during nifedipine in
combotherapy, it was 0.09 (95% CI, 0.01-0.66). Corresponding ORs for
all events were 1.39 (95% CI, 0.59-3.32) for monotherapy and 0.15
(95% CI, 0.03-0.65) for combotherapy. Differences between monotherapy
and combotherapy were statistically significant for both definitive
events and all events (P=.02 and P=.001,
respectively).
Study Withdrawals
Study withdrawal rates were significantly higher during
nifedipine than active drug controls for both ADRs (OR,
1.74; 95% CI, 1.49-2.05) and all causes (OR, 1.33; 95% CI, 1.17-1.5).
ADR withdrawal rates were significantly higher than controls for both
nifedipine monotherapy and nifedipine
combotherapy and were higher during nifedipine
monotherapy than nifedipine combotherapy. ORs were 2.36
(95% CI, 1.89-2.95) for monotherapy and 1.27 (95% CI, 1.00-1.60) for
combo-therapy. The higher ADR withdrawal rates for
nifedipine were primarily due to edema and symptoms related
to sympathetic stimulation (tachycardia, palpitations,
symptoms due to vasodilatation, dizziness, headache, and sweating).
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Discussion |
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This meta-analysis of nifedipine in the treatment of hypertension demonstrates a nonstatistically significant lower risk of cardiovascular events in subjects treated with nifedipine compared with control subjects who received other active drugs. The risk is significantly lower in patients treated with nifedipine in combination with diuretics or ß-blockers. The explanation of the latter finding may lie either in the greater efficacy of combotherapy or in an enhanced safety of using nifedipine in combination with other agents.
Our findings differ from those of the case-control study of Psaty et al5 that found increased rates of myocardial infarction in hypertensive patients treated with calcium channel blockers compared with control subjects treated with diuretics (risk ratio, 1.62) or ß-blockers (risk ratio, 1.57). In that study, the increased risk was dose related and statistically significant for diltiazem and verapamil but not for nifedipine and was present when calcium channel blockers were given as monotherapy or in combination with diuretics. One possible explanation for the differences in results lies in the shorter period of observation in our analysis—a mean of less than 12 weeks compared with a minimum of 1 year in the case-control study. Adverse effects in the latter, therefore, are more likely to reflect progression of coronary artery disease and less likely to result solely from short-term effects of the drug. Another possibility is that uncontrolled confounding by differences in case severity between cases and controls in the study of Psaty et al may influence the results. Patients treated with diuretic monotherapy in a clinical setting are likely to have less-severe hypertension and less symptomatic coexisting arteriosclerotic disease than those treated with nifedipine alone or in combination with other drugs. Finally, differences in results may reflect the fact that patients who remain on a drug regimen for a year or more are a selected population in the sense that they remain in care and are able to tolerate any side effects of their drug regimens.
Early withdrawals from studies may be due to ADRs, lack of efficacy, or protocol violations. Study withdrawal rates for ADRs were higher in subjects on both nifedipine monotherapy and nifedipine as part of combotherapy. They were more than twofold higher during nifedipine monotherapy than active drug controls. During both regimens, the symptoms that led to withdrawal reflected sympathetic stimulation or vasodilatation.
A major strength of our meta-analysis is the inclusion of the universe of relevant, published, randomized, controlled trials. The effects are to increase the generalizability of results and to minimize the likelihood of case-mix differences between study arms. Other strengths are the use of rigorous meta-analytic methods for screening studies; the blinding for author, institution, and treatment regimen of the doctors before extraction of the articles; dual extraction of articles by two physicians or doctors of pharmacology; and thorough exploration of the resulting database, including multiple logistic regression and substantiation of results by application of the fixed effects meta-analytic method proposed by Peto (Yusuf et al15 ).
Limitations relate to the relatively small number of cardiovascular events on which analyses are based; the relatively short duration of studies; the inability to adjust per-person rates for the duration of drug treatment because available information did not permit us to determine the timing of events relative to the initiation of treatment; the inability to explore dose relationships to adverse events because most studies did not provide information on actual doses received; and the paucity of patient-level data to permit case-mix adjustment across studies.
The results of our meta-analysis lend support to the safety of sustained-release and extended-release formulations of nifedipine in the treatment of hypertension, especially when they are used in combination with diuretics or ß-blockers. Evidence from the controlled clinical trials that are in progress will be required, however, to verify these conclusions.6 7 8 9
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Acknowledgments |
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This work was supported by grants from Pfizer, Inc; US Pharmaceuticals Group; and Bayer AG, Pharmaceutical Business Group.
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Footnotes |
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1 Deceased.
Received March 3, 1996; first decision March 25, 1997; accepted March 25, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Manolio TA, Cutler JA, Furberg CD, Psaty BM, Whelton PK, Applegate WB. Trends in pharmacologic management of hypertension in the United States. Arch Intern Med. 1995;155:829-837.
2.
Psaty BM, Koepsell TD, Yanez ND. Temporal
patterns of anti-hypertensive medication use among older adults,
1989-1992: an effect of major clinical trials on clinical
practice? JAMA. 1995;273:1436-1438.
3.
Joint National Committee on Detection,
Evaluation and Treatment of High Blood Pressure. The fifth report of
the Joint National Committee on Detection, Evaluation and Treatment of
High Blood Pressure (JNCV). Arch Intern Med. 1993;153:154-183.
4.
Furberg CD, Psaty BM, Meyer JV.
Nifedipine: dose-related increase in mortality in patients
with coronary heart disease. Circulation. 1995;92:1326-1331.
5.
Psaty BM, Heckbert SR, Koepsell TD,
Siscovick DS, Raghunathan TE, Weiss NS, Rosendaal FR,
Lemaitre RN, Smith NL, Wahl PW. The risk of myocardial
infarction associated with anti-hypertensive drug therapies.
JAMA. 1995;274:620-625.
6. Dahlof B, Hansson L, Lindholm LH, Schersten B, Wester PO, Ekbom T, Hedner T, de Faire V. STOP-Hypertension 2: a prospective intervention trial of newer versus older treatment alternatives in old patients with hypertension: Swedish Trial in Old Patients with Hypertension. Blood Pressure. 1993;2:136-141.[Medline] [Order article via Infotrieve]
7. Amery A, Birkenhager W, Bulpitt CJ, Clement D, De Leeuw P, Dollery CT, Fagard R, Fletcher A, Forett F, Leonetti G. Syst-Eur: a multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol and organization. Aging. 1991;3:287-302.[Medline] [Order article via Infotrieve]
8. The NORDIL Group. The Nordic Diltiazem Study (NORDIL): a prospective intervention trial of calcium antagonist therapy in hypertension. Blood Pressure. 1992;2:314-321.
9. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC, Grimm RH, LaRosa J, Whelton PK, Perry HM, Alderman MH, Ford CE, Oparil S, Francis C, Proschan M, Pressel S, Black HR, Hawkins CM. Rationale and design for the Anti-hypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens. 1996;9:342-360.[Medline] [Order article via Infotrieve]
10. Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, Chalmers TC. Meta-analysis of randomized controlled trials. N Engl J Med. 1987;316:450-455.[Abstract]
11. Chalmers TC, Smith H Jr, Blackburn B, Silverman B, Schroeder B, Reitman D, Ambroz A. A method for assessing the quality of a randomized control trial. Clin Trials J. 1981;2:31-49.
12. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds JM, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomised clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-2.[Medline] [Order article via Infotrieve]
13. SAS Institute. SAS/STAT Users Guide. 4th ed. Cary, NC: SAS Institute; 1989:1071-1126.
14. DerSimonian R, Laird NM. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-188.[Medline] [Order article via Infotrieve]
15. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of randomized trials. Prog Cardiovasc Dis. 1985;27:335-371.[Medline] [Order article via Infotrieve]
16. Hosmer DW, Lemeshow S. Applied Logistic Regression. New York, NY: John Wiley & Sons; 1989.
17. Albergati F, Paterno E, Venuti RP, Boeri D, Lombardo I, Semino S, Viviani GL, Adezati L. Comparison of the effects of carvedilol and nifedipine in patients with essential hypertension and non-insulin-dependent diabetes mellitus. J Cardiovasc Pharmacol. 1992;19(suppl 1):S86-S89.
18. Amabile G, Serradimigni A. Comparison of bisoprolol with nifedipine for treatment of essential hypertension in the elderly: comparative double-blind trial. Eur Heart J. 1987;8(suppl M):65-69.
19. Anderton JL, Vallance BD, Stanley NN, Crowe PF, Mittra B, Perks WH. Atenolol and sustained release nifedipine alone and in combination in hypertension: a randomised, double-blind, crossover study. Drugs. 1988;35(suppl 4):22-26.
20. Artigou JY, Benichou M, Berland J, Fressinaud P, Grollier G, Gueret P, Nguyen Cong Duc L. A randomized double-blind therapeutic trial of enalapril versus timed-release nifedipine in mild to moderate essential hypertension. Presse Med. 1990;19:13-16.
21. Attwood S, Bird R, Burch K, Casadei B, Coats A, Conway J, Dawes M, Ebbs D, Farmer A, Robinson J. Within-patient correlation between the antihypertensive effects of atenolol, lisinopril and nifedipine. J Hypertens. 1994;12:1053-1060.[Medline] [Order article via Infotrieve]
22. Belz GG, Spies G. Controlled study on the treatment of hypertension with verapamil in retard form. Z Kardiol. 1985;74:453-459.[Medline] [Order article via Infotrieve]
23. Bevan EG, Pringle SD, Waller PC, Herrick AL, Findlay JG, Murray GD, Carmichael HA, Reid JL, Weir RJ, Lorimer AR. Comparison of captopril, hydralazine and nifedipine as third drug in hypertensive patients. J Hum Hypertens. 1993;7:83-88.[Medline] [Order article via Infotrieve]
24. Bochicchio T, Perez-Grovas HA, Carrizosa J, Herrera-Acosta J. Evaluation of the efficacy and safety of dilevalol in the treatment of essential arterial hypertension. Arch Inst Cardiol Mex. 1989;59:181-186.[Medline] [Order article via Infotrieve]
25. Bremner AD, Fell PJ, Hosie J, James IG, Saul PA, Taylor SH. Early side-effects of antihypertensive therapy: comparison of amlodipine and nifedipine retard. J Hum Hypertens. 1993;7:79-81.[Medline] [Order article via Infotrieve]
26. Cacciapuoti F, Perrone N, Diaspro R, Galzerano D, Gentile S, Lapiello B. Slowing of mitral valve annular calcium in systemic hypertension by nifedipine and comparisons with enalapril and atenolol. Am J Cardiol. 1993;72:1038-1042.[Medline] [Order article via Infotrieve]
27. Chaignon M, Lucsko M, Rapoud JP, Aubert P, Guedon J. Comparative effects of nifedipine and indapamide in the treatment of arterial hypertension. Arch Mal Coeur Vaiss. 1985;78(Spec No):67-72.
28. Chamiec T, Zaleska T, Klos J, Pietrzykowska H, Bednarz B, Ceremuzynski L. Efficacy and tolerance of nifedipine retard vs acebutolol in patients with essential hypertension treated for 26 weeks. Mater Med Pol. 1989;21:49-52.[Medline] [Order article via Infotrieve]
29. Chan JC, Cockram CS, Nicholls MG, Cheung CK, Swaminathan R. Comparison of enalapril and nifedipine in treating non-insulin dependent diabetes associated with hypertension: one year analysis. BMJ. 1992;305:981-985.
30. Chellingsworth MC, Kendall MJ, Wright AD, Singh BM, Pasi J. The effects of verapamil, diltiazem, nifedipine and propranolol on metabolic control in hypertensives with non-insulin dependent diabetes mellitus. J Hum Hypertens. 1989;3:35-39.
31. Clamp M, Holmes B, Wilcox R. Comparative trial of nifedipine retard and atenolol in the treatment of elderly patients with mild to moderate hypertension. J Hum Hypertens. 1990;4:557-563.[Medline] [Order article via Infotrieve]
32. Corcoran JS, Perkins JE, Hoffbrand BI, Yudkin JS. Treating hypertension in non-insulin-dependent diabetes: a comparison of atenolol, nifedipine, and captopril combined with bendrofluazide. Diabet Med. 1987;4:164-168.[Medline] [Order article via Infotrieve]
33. Daniels AR, Opie LH. Atenolol plus nifedipine for mild to moderate systemic hypertension after fixed doses of either agent alone. Am J Cardiol. 1986;57:965-970.[Medline] [Order article via Infotrieve]
34. Decoulx M, Godon P, Pappo M, d'Allens H. Hypertension in the elderly: comparison of the efficacy and tolerability of labetalol and nifedipine. A multicenter, randomized, single-blind study. Ann Cardiol Angeiol (Paris). 1990;39:305-309.[Medline] [Order article via Infotrieve]
35. de Divitiis O, Petitto M, Di Somma S, Fazio S, Galderisi M, Villari B, Liguori V, Santomauro M. Acebutolol and nifedipine in the treatment of arterial hypertension: efficacy and acceptability. Arzneimittelforschung. 1984;34:710-715.[Medline] [Order article via Infotrieve]
36. de Divitiis O, Petitto M, Di Somma S, Galderisi M, Liguori V, Fazio S, Airoldi G. Therapeutic approach to arterial hypertension: comparison and combination of acebutolol with nifedipine and captopril. Cardiologia. 1985;30:469-475.[Medline] [Order article via Infotrieve]
37. Ding YA, Law HW, Chou TC. Comparison of cilazapril and nifedipine retard on ambulatory blood pressure, metabolic, rheological and platelet function in hypertensive patients. J Hum Hypertens. 1994;8:137-143.[Medline] [Order article via Infotrieve]
38.
Douglas-Jones AP, Mitchell AD. Comparison of
nifedipine (retard formulation) and mefruside in the
treatment of mild to moderate hypertension—a prospective randomized
double-blind crossover study in general practice.
Postgrad Med J. 1984;60:529-532.
39. Eber B, Brussee H, Rotman B, Kramer R, Klein W. Evaluation of the antihypertensive effect of lisinopril compared with nifedipine in patients with mild to severe essential hypertension. Angiology. 1992;43:482-489.
40. Edwards KG, Tweed JA, Saul PA, Wright FW. A comparative study of atenolol/nifedipine and atenolol/diuretic in hypertension. Pharmatherapeutica. 1986;4:637-641.[Medline] [Order article via Infotrieve]
41. Egan BM, Fleissner MJ, Stepniakowski K, Neahring JM, Sagar KB, Ebert TJ. Improved baroreflex sensitivity in elderly hypertensives on lisinopril is not explained by blood pressure reduction alone. J Hypertens. 1993;11:1113-1120.[Medline] [Order article via Infotrieve]
42. Fadayomi MO, Akinroye KK, Ajao RO, Awosika LA. Monotherapy with nifedipine for essential hypertension in adult blacks. J Cardiovasc Pharmacol. 1986;8:466-469.[Medline] [Order article via Infotrieve]
43. Feig PU, Gibson L, MacCarthy EP, Pettis PP, Schwartz L. The efficacy and safety of once-daily nifedipine coat-core in the treatment of mild-to-moderate hypertension: Adalat CC Cooperative Study Group [published erratum appears in Clin Ther. 1994;16:125]. Clin Ther. 1993;15:963-975.
44. Fletcher AE, Battersby C, Adnitt P, Underwood N, Jurgensen HJ, Bulpitt CJ. Quality of life on antihypertensive therapy: a double-blind trial comparing quality of life on pinacidil and nifedipine in combination with a thiazide diuretic. European Pinacidil Study Group. J Cardiovasc Pharmacol. 1992;20:108-114.[Medline] [Order article via Infotrieve]
45.
Fletcher AE, Bulpitt CJ, Chase DM, Collins WC,
Furberg CD,Goggin TK, Hewett AJ, Neiss AM.
Quality of life with three antihypertensive treatments: cilazapril,
atenolol, nifedipine. Hypertension. 1992;19:499-507.
46. Frishman WH, Garofalo JL, Rothschild A, Rothschild M,Greenberg SM, Soberman J. Multicenter comparison of the nifedipine gastrointestinal therapeutic system and long-acting propranolol in patients with mild to moderate systemic hypertension receiving diuretics: a preliminary experience. Am J Med. 1987;83:15-19.
47. Gavras I, Gavras H. Nifedipine in the treatment of essential hypertension. J Clin Pharmacol. 1985;25:429-432.[Abstract]
48. Gilchrist NL, Nicholls MG, Ewer TC, Livesey JH, Sainsbury R. A comparison of long acting nifedipine and enalapril in elderly hypertensives: a randomised, single-blind, cross-over study. J Hum Hypertens. 1988;2:33-39.[Medline] [Order article via Infotrieve]
49. Guazzi MD, Cipolla C, Della Bella P, Fabbiocchi F, Montorsi P, Sganzerla P. Disparate unloading efficacy of the calcium channel blockers, verapamil and nifedipine, on the failing hypertensive left ventricle. Am Heart J. 1984;108:116-123.[Medline] [Order article via Infotrieve]
50. Gueret P, Artigou JY, Benichou M, Berland J, Fressinaud P, Grollier G, Nguyen CD. Comparative efficacy and safety of enalapril and sustained-release nifedipine in patients with mild to moderate hypertension: the Enalapril vs Nifedipine French Study Group. Drugs. 1990;39(suppl 2):67-72.
51. Hallin L, Andren L, Hansson L. Controlled trial of nifedipine and bendroflumethiazide in hypertension. J Cardiovasc Pharmacol. 1983;5:1083-1085.[Medline] [Order article via Infotrieve]
52. Halperin AK, Icenogle MV, Kapsner CO, Chick TW, Roehnert J, Murata GH. A comparison of the effects of nifedipine and verapamil on exercise performance in patients with mild to moderate hypertension. Am J Hypertens. 1993;6:1025-1032.[Medline] [Order article via Infotrieve]
53. Hannedouche T, Fillastre JP, Mimran A, de Treglode D, Schardt F, Rosenthal T, Grossman F, Rocco S. Ketanserin versus nifedipine in the treatment of essential hypertension in patients over 50 years old: an international multicenter study. J Cardiovasc Pharmacol. 1987;10(suppl 3):S107-S112.
54. Harder S, Rietbrock S, Thurmann P. Antihypertensive efficacy of a slow release nifedipine tablet formulation given once daily in patients with mild to moderate hypertension: a placebo-controlled, double-blind parallel-group trial. Arzneimittelforschung. 1994;44:133-136.[Medline] [Order article via Infotrieve]
55.
Hart W, Clarke RJ. ACE inhibition versus
calcium antagonism in the treatment of mild to moderate hypertension: a
multicentre study. Ireland-Netherlands
Lisinopril-Nifedipine Study Group.
Postgrad Med J. 1993;69:450-455.
56. Henry M, Wehrlen M, Pelletier B, Capron MH. Spironolactone versus nifedipine in essential hypertension. Am J Cardiol. 1990;65:36K-38K.[Medline] [Order article via Infotrieve]
57. Hosie J, Nasar MA, Belgrave GP, Walters EG. A comparative study of long acting diltiazem (Tildiem LA) with sustained release nifedipine (nifedipine SR) and bendrofluazide in the treatment of mild to moderate hypertension. Acta Cardiol. 1994;49:251-265.[Medline] [Order article via Infotrieve]
58. Houston MC, Olafsson L, Burger MC. Effects of nifedipine GITS and atenolol monotherapy on serum lipids, blood pressure, heart rate, and weight in mild to moderate hypertension. Angiology. 1991;42:681-690.
59. Jackson G, Thirkettle JL, Taylor DJ, Jackson PG,Brennand-Roper D, Vella R, Manivannan A, Flora HK, Gupta S, Chapman CM. A double-blind crossover trial of atenolol, enalapril and the fixed combination of atenolol and nifedipine in mild and moderate hypertension. Br J Clin Pract. 1993;47:66-70.[Medline] [Order article via Infotrieve]
60. Jueng C, Halperin AK, Hashimoto F, Callender K. Nifedipine GITS and hydrochlorothiazide in essential hypertension. J Clin Hypertens. 1987;3:695-703.[Medline] [Order article via Infotrieve]
61. Klein WW, Stuhlinger W, Mahr G. Cross-over comparison between captopril and nifedipine. Postgrad Med J. 1986;62(suppl 1):108-110.
62. Landmark K, Dale J. Antihypertensive, haemodynamic and metabolic effects of nifedipine slow-release tablets in elderly patients. Acta Med Scand. 1985;218:389-396.[Medline] [Order article via Infotrieve]
63. Lederballe Pedersen O, Christensen CK, Mikkelsen E, Ramsch KD. Relationship between the antihypertensive effect and steady-state plasma concentration of nifedipine given alone or in combination with a beta-adrenoceptor blocking agent. Eur J Clin Pharmacol. 1980;18:287-293.[Medline] [Order article via Infotrieve]
64. Leon AS. Efficacy and safety of enalapril versus extended-release nifedipine for the treatment of mild-to-moderate essential hypertension: a multicenter 22-week study. Multicenter Cooperative Study Group [published erratum appears in Clin Ther. 1994;16:125]. Clin Ther. 1993;15:1094-1107.
65. Letellier P, Overlack A, Agnes E, Desche P. Perindopril plus nifedipine versus perindopril plus hydrochlorothiazide in mild to severe hypertension: a double-blind multicentre study: the Multicentre Study Group on Treatment Association with Perindopril. J Hum Hypertens. 1994;8:145-149.[Medline] [Order article via Infotrieve]
66. MacCarthy EP, Pettis PP, Gibson L, Schwartz L, Feig PU. The safety and efficacy of once-daily nifedipine coat-core in combination with atenolol in hypertensive patients: Adalat CC Cooperative Study Group. Clin Ther. 1993;15:976-987.[Medline] [Order article via Infotrieve]
67. Maclean D, Mitchell ET, Coulson RR, Fitzsimons TJ, McDevitt DG. Atenolol-nifedipine combinations compared to atenolol alone in hypertension: efficacy and tolerability. Br J Clin Pharmacol. 1988;25:425-431.[Medline] [Order article via Infotrieve]
68. Maclean D, Ramsay LE, Richardson PJ. Enalapril and nifedipine in the treatment of mild to moderate essential hypertension: a 6 month comparison. Br J Clin Pharmacol. 1990;30:203-211.[Medline] [Order article via Infotrieve]
69. Martinez de la Iglesia J, de Diego Cabrera MS, Gonzalez Santos C, Iribarren Marin MA, Calderon de la Barca Gazquez JM, Perula Torres L. Comparison of chlorthalidone and sustained-action nifedipine in the treatment of mild to moderate arterial hypertension. Aten Primaria. 1990;7:258, 260, 262-264.[Medline] [Order article via Infotrieve]
70. Midtbo K, Hals O, van der Meer J. Verapamil compared with nifedipine in the treatment of essential hypertension. J Cardiovasc Pharmacol. 1982;4(suppl 3):S363-S368.
71. Morlin C, Baglivo H, Boeijinga JK, Breckenridge AM, Clement D, Johnston GD, Klein W, Kramer R, Luccioni R, Meurer KA. Comparative trial of lisinopril and nifedipine in mild to severe essential hypertension. J Cardiovasc Pharmacol. 1987;9(suppl 3):S49-S52.
72. Murphy MB, Scriven AJ, Dollery CT. Efficacy of nifedipine as a step 3 antihypertensive drug. Hypertension. 1983;5(suppl II):II-118-II-121.
73. Myers MG, Leenen FH, Burns R, Frankel D. Nifedipine tablet vs. hydralazine in patients with persisting hypertension who receive combined diuretic and beta-blocker therapy. Clin Pharmacol Ther. 1986;39:409-413.[Medline] [Order article via Infotrieve]
74. Nifedipine-Atenolol Study Review Committee. Nifedipine and atenolol singly and combined for treatment of essential hypertension: comparative multicentre study in general practice in the United Kingdom. Br Med J. 1988;296:468-473.
75. O'Donnell MJ, Rowe BR, Lawson N, Horton A, Gyde OH, Barnett AH. Comparison of the effects of an angiotensin converting enzyme inhibitor and a calcium antagonist in hypertensive, macroproteinuric diabetic patients: a randomised double-blind study. J Hum Hypertens. 1993;7:333-339.[Medline] [Order article via Infotrieve]
76. Ohman KP, Weiner L, von Schenck H, Karlberg BE. Antihypertensive and metabolic effects of nifedipine and labetalol alone and in combination in primary hypertension. Eur J Clin Pharmacol. 1985;29:149-154.[Medline] [Order article via Infotrieve]
77. Opsahl JA, Halstenson CE, Abraham PA. Antihypertensive and humoral effects of nifedipine in essential hypertension uncontrolled by hydrochlorothiazide alone. Am J Hypertens. 1989;2:828-833.[Medline] [Order article via Infotrieve]
78. Os I, Bratland B, Dahlof B, Gisholt K, Syvertsen JO, Tretli S. Lisinopril or nifedipine in essential hypertension? A Norwegian multicenter study on efficacy, tolerability and quality of life in 828 patients [published erratum appears in J Hypertens. 1992;10:following H9]. J Hypertens. 1991;9:1097-1104.
79. Pacheco JP, Fan F, Wright RA, Corkadel LK, Horwitz LD, Reeves RL. Monotherapy of mild hypertension with nifedipine. Am J Med. 1986;81:20-24.
80. Palmer A, Fletcher A, Hamilton G, Muriss S, Bulpitt C. A comparison of verapamil and nifedipine on quality of life. Br J Clin Pharmacol. 1990;30:365-370.[Medline] [Order article via Infotrieve]
81. Palmer A, Fletcher A, Hamilton G, Muriss S, Bulpitt C. A comparison of the effects of verapamil and nifedipine on the quality of life. Wien Med Wochenschr. 1991;141:424-428.[Medline] [Order article via Infotrieve]
82. Poulter NR, Sanderson JE, Thompson AV, Sever PS, Chang CL. Comparison of nifedipine and propranolol as second line agent for hypertension in black Kenyans. BMJ. 1993;306:621-622.
83. Predel HG, Kramer HJ. Lisinopril versus slow release nifedipine in patients with essential hypertension: a multicentre study. J Hum Hypertens. 1994;8:777-780.[Medline] [Order article via Infotrieve]
84.
Ramsay LE, Parnell L, Waller PC. Comparison of
nifedipine, prazosin and hydralazine added to
treatment of hypertensive patients uncontrolled by thiazide
diuretic plus beta-blocker. Postgrad Med J. 1987;63:99-103.
85. Richardson PJ, Meany B, Breckenridge AM, Grimmer SF, Johnston GD, Kondowe G. Lisinopril in essential hypertension: a six month comparative study with nifedipine. J Hum Hypertens. 1987;1:175-179.[Medline] [Order article via Infotrieve]
86. Richardson PJ, Meany TB, Johnston GD, Kondowe G, Grimmer SF, Breckenridge AM. Comparative efficacy of lisinopril and nifedipine retard in essential hypertension: a double-blind, placebo-controlled trial. J Cardiovasc Pharmacol. 1987;10(suppl 10):S96-S98.
87. Roberts DH, Tsao Y, Linge K, McLoughlin GA, Breckenridge A. Double-blind comparison of captopril with nifedipine in hypertension complicated by intermittent claudication. Angiology. 1992;43:748-756.
88. Rogstad B. A comparison of lisinopril and nifedipine in the treatment of mild to moderate hypertension: a multicentre study. Eur J Clin Pharmacol. 1994;46:487-489.[Medline] [Order article via Infotrieve]
89. Salvetti A, Innocenti PF, Iardella M, Pambianco F, Saba GC, Rossetti M, Botta GF. Captopril and nifedipine interactions in the treatment of essential hypertensives: a crossover study. J Hypertens Suppl. 1987;5:S139-S142.[Medline] [Order article via Infotrieve]
90.
Schulte KL, Meyer-Sabellek WA, Haertenberger A,
Thiede HM, Roecker L, Distler A, Gotzen R. Antihypertensive and
metabolic effects of diltiazem and
nifedipine. Hypertension. 1986;8:859-865.
91. Senior R, Imbs JL, Bory M, Amabile G, Denis B, Zannad F, DeLuca N, Marchegiano R, Lahiri A, Raftery EB. Indapamide reduces hypertensive left ventricular hypertrophy: an international multicenter study. J Cardiovasc Pharmacol. 1993;22(suppl 6):S106-S110.
92. Serradimigni A, Perchicot E, Griener L, Kerihuel JC, Benichou M. Antihypertensive effect of a new form of nifedipine compared to a beta-blocker during chronic administration. Arch Mal Coeur Vaiss. 1985;78(Spec No):73-81.
93. Shamiss A, Meisel S, Nussinovitch N, Rosenthal T. Verapamil versus nifedipine in slow-release preparations for the treatment of mild to moderate hypertension. J Hum Hypertens. 1990;4:465-468.[Medline] [Order article via Infotrieve]
94. Singer DR, Markandu ND, Shore AC, MacGregor GA. Nifedipine and acebutolol in combination for the treatment of moderate to severe essential hypertension. J Hum Hypertens. 1987;1:31-37.[Medline] [Order article via Infotrieve]
95. Skinner MH, Futterman A, Morrissette D, Thompson LW, Hoffman BB, Blaschke TF. Atenolol compared with nifedipine: effect on cognitive function and mood in elderly hypertensive patients. Ann Intern Med. 1992;116:615-623.
96. Skoularigis J, Eitzman L, Davis J, Strugo V, Sareli P. Nifedipine versus captopril in the management of moderate hypertension in black patients. Am J Hypertens. 1994;7:440-447.[Medline] [Order article via Infotrieve]
97. Smith DH, Neutel JM, Jankelow D, Pretorius JJ, Myburgh DP. A comparative study of atenolol, nifedipine and their combination in the treatment of hypertension. S Afr Med J. 1991;79:12-15.[Medline] [Order article via Infotrieve]
98. Steiner A, Hany S, Battig B, Jenni R, Troesch M, Willimann P, Graf A, Leutenegger F, Angehm V, Beck G. Betaxolol versus nifedipine in the treatment of essential hypertension. Schweiz Rundsch Med Prax. 1988;77:1101-1103.[Medline] [Order article via Infotrieve]
99. Steiner G, Pauly NC. Comparison of the efficacy and safety of trandolapril and nifedipine SR in mild-to-moderate hypertension: Investigator Study Group. J Cardiovasc Pharmacol. 1994;23(suppl 4):S81-S85.
100. Stumpe KO, Feldhaus P, Haerlin R. Antihypertensive effect and tolerance to urapidil: comparison with nifedipine in a multicenter double-blind study. Fortschr Med. 1989;107:54-57.
101. Sullivan FM, Murray TS, Gaw N, Langan JJ, Adams-Strump BJ. Is nifedipine a suitable first-line treatment for essential hypertension in general practice? Eur Heart J. 1987;8(suppl K):21-25.
102. Svetkey LP, Weinberger MH, Gavras H, Gavras I, Brown TS, Deterding J, Klotman PE. Double-blind, placebo-controlled trial of twice-daily nifedipine as a step-2 agent in mild essential hypertension. J Clin Hypertens. 1987;3:579-588.[Medline] [Order article via Infotrieve]
103. Testa MA, Hollenberg NK, Anderson RB, Williams GH. Assessment of quality of life by patient and spouse during antihypertensive therapy with atenolol and nifedipine gastrointestinal therapeutic system. Am J Hypertens. 1991;4:363-373.[Medline] [Order article via Infotrieve]
104. Van Hoof R, Desager JP, Harvengt C, Fagard R, Lijnen P, Peerenboom P, Staessen J, Thijs L, Van Mieghem W, Amery A. Comparison of the effect of celiprolol and nifedipine on blood pressure and plasma lipids. J Cardiovasc Pharmacol. 1992;20:268-273.[Medline] [Order article via Infotrieve]
105. Waller PC, Solomon SA, Ramsay LE. Comparison of ketanserin and slow-release nifedipine added to the treatment of hypertensive patients uncontrolled by a thiazide diuretic plus beta-adrenoceptor blocker. Br J Clin Pharmacol. 1987;24:591-597.[Medline] [Order article via Infotrieve]
106. Walley T, Tsao Y, Scott A, Mackay E, Vandenburg M, Breckenridge A. Effects of dilevalol (R,R-labetalol) compared with nifedipine on heart rate, blood pressure and muscle blood flow at rest and on exercise in hypertensive patients. Br J Clin Pharmacol. 1993;35:623-628.[Medline] [Order article via Infotrieve]
107. Weir MR, Lavin PT. Comparison of the efficacy and tolerability of Prinivil and Procardia XL in black and white hypertensive patients. Clin Ther. 1992;14:730-739.[Medline] [Order article via Infotrieve]
108. Wing LM, Chalmers JP, West MJ, Bune AJ. Slow-release nifedipine as a single or additional agent in the treatment of essential hypertension: a placebo-controlled crossover study. Clin Exp Hypertens A. 1985;7:1173-1185.[Medline] [Order article via Infotrieve]
109. Witchitz S, Serradimigni A. Lisinopril versus slow-release nifedipine in the treatment of mild to moderate hypertension: a multicentre study. The Cooperative Study Group. J Hum Hypertens. 1989;3(suppl 1):29-33.
110. Woo KS, Pun CO. Long-acting nifedipine versus metoprolol as monotherapy for essential hypertension: a randomized, controlled crossover study. West J Med. 1990;152:149-152.[Medline] [Order article via Infotrieve]
111. Zachariah PK, Schwartz GL, Sheps SG, Schirger A, Carlson CA, Moore AG. Antihypertensive effects of a new sustained-release formulation of nifedipine. J Clin Pharmacol. 1990;30:1012-1019.[Abstract]
112. Zucchelli P, Zuccala A, Borghi M, Fusaroli M, Sasdelli M, Stallone C, Sanna G, Gaggi R. Long-term comparison between captopril and nifedipine in the progression of renal insufficiency. Kidney Int. 1992;42:452-458.[Medline] [Order article via Infotrieve]
113. Zusman R, Christensen D, Federman E, Kochar MS, McCarron D, Porush JG, Spitalewitz S. Comparison of nifedipine and propranolol used in combination with diuretics for the treatment of hypertension. Am J Med. 1987;82:37-41.
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