Cheung, BMY

Kumana, CR

Hong Kong Medical Journal

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Title Calcium channel blockers revisitedAuthor(s) Cheung, BMY; Kumana, CRCitation Hong Kong Medical Journal, 2002, v. 8 n. 4, p. 300-301Issued Date 2002URL http://hdl.handle.net/10722/45135Rights Creative Commons: Attribution 3.0 Hong Kong License300      Hong Kong Med J Vol 8 No 4 August 2002COMMENTARYCalcium channel blockers (CCBs) are a major class of drugsused in the treatment of hypertension, angina, and cardiacarrhythmias. Among the CCBs, there is much heterogen-eity in terms of their effect on heart rate, cardiac contractility,peripheral vascular tone, and with respect to half-life. TheCCBs can be broadly divided into the dihydropyridines(eg nifedipine) and the non-dihydropyridines (eg verapamil).Short-acting dihydropyridines, such as immediate-releasenifedipine, cause a rapid decrease in blood pressure anda reflex tachycardia as they do not suppress heart rate.Long-acting formulations and CCBs with longer half-liveswere thus developed to overcome large fluctuations in bloodpressure.Although CCBs are undoubtedly effective in loweringblood pressure, until the last few years, there have notbeen substantial clinical outcome data demonstrating theirimpact on cardiovascular events. Indeed, earlier case-control studies from Furberg et al1 and others raised doubtsabout the safety of this class of drugs,1-4 which were ap-proved and marketed on the basis of their effect on bloodpressure as a surrogate end-point. These studies suggestedthat CCBs were associated with increased risk of myocar-dial infarction,1 cancer,2 and gastrointestinal haemorrhage.3The lack of prospective data from large clinical trialsmeant that these doubts were hard to dismiss.Fortunately, in the last few years, several importantclinical trials—STONE (Shanghai Trial of Nifedipine inthe Elderly),5 Syst-Eur (The Systolic Hypertension inEurope),6 and Syst-China (Systolic Hypertension inChina)7—involving CCBs, have been completed andpublished. On the whole, these have been reassuring withregard to the safety of CCBs. The incidence of strokes wasreduced in these trials. The major question is, however, notwhether CCBs are better than placebo, since diuretics andbeta-blockers are already proven therapy for hyperten-sion, but whether or not CCBs are equivalent to diureticsand beta-blockers. The STOP-2 (Swedish Trial in OldPatients with Hypertension-2 study),8 NORDIL (NordicDiltiazem study),9 and INSIGHT (Intervention as a Goalin Hypertension Treatment10) trials addressed this questionwith head-to-head comparisons of drug classes. In essence,CCBs were not shown to be significantly better or worsethan older treatments. Whilst CCBs have been vindicatedto a large extent, the fact is that they tend to be moreexpensive than diuretics and beta-blockers. From a publichealth perspective therefore, one must question whether itis justifiable to prescribe CCBs rather than cheaper,older treatments.The WHO-ISH (World Health Organization-International Society of Hypertension) guidelines on themanagement of hypertension published in 1999 endorsedthe use of any of six classes of antihypertensive drugs,including CCBs, as first-line agents.11 This differs from theAmerican Joint National Committee-VI guidelines whichcontinue to recommend diuretics and beta-blockers asfirst-line treatment because of their demonstrated efficacyin numerous trials.12 Pooling recent clinical trials involvingcomparisons of CCBs with other classes have shown adisturbing pattern.13,14 Whereas CCBs appeared slightlysuperior to angiotensin-converting enzyme inhibitors(ACEIs) in the prevention of strokes, and no difference inoverall mortality between the two classes was seen, CCBsappeared notably inferior to ACEIs in the prevention ofcoronary events.13 These findings are consistent with thedemonstrated beneficial effect of beta-blockers and ACEIsafter myocardial infarction and in heart failure, and thefailure to demonstrate such benefits of CCBs. This has ledto the suggestion that CCBs should not be the first choice inpatients at cardiovascular risk unless multiple drugs areneeded to control their blood pressure.15In this new decade, things have turned full circle.Although CCBs regained favour when the placebo-controlled trials were completed, with more clinical trialdata comparing different antihypertensive drug classes,they have been found wanting. Interestingly, alpha-blockershave also emerged as inferior agents to diuretics in theALLHAT (The Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial) study.16Though there was ‘more heat than light’ in the debateover CCBs a few years ago, we now have hard clinicalevidence on which to base our judgements. From theclinician’s point of view, CCBs will continue to be usefulfor those patients primarily at risk of stroke rather thancoronary heart disease, and for those with severe hyper-tension requiring combination therapy. For those with mildhypertension requiring monotherapy, diuretics and beta-blockers are proven and very cost-effective treatments; theyshould be used unless contraindicated or not tolerated bythe patient. Angiotensin-converting enzyme inhibitorsshould be considered, especially in the light of the HOPE(Heart Outcomes Prevention Evaluation) study,17 for pa-tients who have coronary artery disease, cerebrovasculardisease, peripheral vascular disease, or diabetes mellitus withat least one other risk factor.In the Far East where strokes are common and coronaryheart disease is less prevalent than in Caucasian popu-lations, the benefits of CCBs may be more pronounced. Interms of lowering of blood pressure, CCBs are very effect-ive for Chinese patients.18-20 There has been a trend towardslower blood pressure treatment targets, especially in pa-tients with diabetes or nephropathy.11,12 The best way ofoptimising blood pressure control is to use a combinationCalcium channel blockers revisitedHong Kong Med J Vol 8 No 4 August 2002      301of antihypertensive drugs. In this clinical scenario, CCBsare useful and safe agents.BMY Cheung, PhD, FHKAM (Medicine)CR Kumana, FRCP, FHKAM (Medicine)Department of MedicineThe University of Hong KongQueen Mary Hospital102 Pokfulam RoadHong KongReferences1. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increasein mortality in patients with coronary heart disease. Circulation 1995;92:1326-31.2. Pahor M, Guralnik JM, Ferrucci L, et al. Calcium-channel blockadeand incidence of cancer in aged populations. Lancet 1996;348:493-7.3. Pahor M, Guralnik JM, Furberg CD, Carbonin P, Havlik R. Risk ofgastrointestinal haemorrhage with calcium antagonists in hypertensivepersons over 67 years old.  Lancet 1996;347:1061-5.4. Cheung BM. Is it safe to use calcium channel blockers in hypertension?Hong Kong Med J 1996;2:107-8.5. Gong L, Zhang W, Zhu Y, et al. Shanghai trial of nifedipine in theelderly (STONE). J Hypertens 1996;14:1237-45.6. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blindcomparison of placebo and active treatment for older patients withisolated systolic hypertension. The Systolic Hypertension in Europe(Syst-Eur) Trial Investigators. Lancet 1997;350:757-64.7. Liu L, Wang JG, Gong L, Liu G, Staessen JA. Comparison of activetreatment and placebo in older Chinese patients with isolated systolichypertension. Systolic Hypertension in China (Syst-China) Collabo-rative Group. J Hypertens 1998;16:1823-9.8. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of oldand new antihypertensive drugs in elderly patients: cardiovascularmortality and morbidity in the Swedish Trial in Old Patients withHypertension-2 study. Lancet 1999;354:1751-6.9. Hansson L, Hedner T, Lund-Johansen P, et al. Randomised trial ofeffects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension:the Nordic Diltiazem (NORDIL) study. Lancet 2000;356:359-65.10. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality inpatients randomised to double-blind treatment with a long-actingcalcium-channel blocker or diuretic in the International NifedipineGITS study: Intervention as a Goal in Hypertension Treatment(INSIGHT). Lancet 2000;356:366-72.11. 1999 World Health Organization-International Society of Hyperten-sion Guidelines for the Management of Hypertension. GuidelinesSubcommittee. J Hypertens 1999;17:151-83.12. The sixth report of the Joint National Committee on prevention,detection, evaluation, and treatment of high blood pressure. ArchIntern Med 1997;157:2413-46.13. Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associatedwith calcium antagonists compared with other first-line antihyperten-sive therapies: a meta-analysis of randomised controlled trials. Lancet2000;356:1949-54.14. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors,calcium antagonists, and other blood-pressure-lowering drugs: resultsof prospectively designed overviews of randomised trials. BloodPressure Lowering Treatment Trialists’ Collaboration. Lancet 2000;356:1955-64.15. He J, Whelton PK. Selection of initial antihypertensive drug therapy.Lancet 2000;356:1942-3.16. ALLHAT Collaborative Research Group. Major cardiovascular eventsin hypertensive patients randomized to doxazosin vs chlorthalidone:the antihypertensive and lipid-lowering treatment to prevent heartattack trial (ALLHAT). JAMA 2000;283:1967-75.17. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effectsof an angiotensin-converting-enzyme inhibitor, ramipril, on cardio-vascular events in high-risk patients. The Heart Outcomes PreventionEvaluation Study Investigators. N Engl J Med 2000;342:145-53.18. Chan JC, Cockram CS, Nicholls MG, Cheung CK, Swaminathan R.Comparison of enalapril and nifedipine in treating non-insulin depend-ent diabetes associated with hypertension: one year analysis. BMJ1992;305:981-5.19. Lau CP, Cheung BM. Relative efficacy and tolerability of lacidipineand amlodipine in patients with mild-to-moderate hypertension:a randomized double-blind study. J Cardiovasc Pharmacol 1996;28:328-31.20. Cheung BM, Lau CP, Wu BZ. Amlodipine, felodipine, and isradipinein the treatment of Chinese patients with mild-to-moderatehypertension. Clin Ther 1998;20:1159-69.

Calcium channel blockers revisited

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Calcium channel blockers revisited

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