Lüscher, Thomas F.

Noll, Georg

Wenzel, René R.

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1920 AbstractsControversy of calcium antagonists: is there a rational differentialtherapy?Thomas F. Luscher, Rene R. Wenzel, Georg NollCardiology, University Hospital/Inselspital, Bern, SwitzerlandCalcium antagonists are among the most frequentlyused medications, particularly for the treatment ofhypertension and coronary heart disease. Three classesof calcium antagonists can be differentiated, namely(i) dyhydropyridine (e.g. nifedipine, etc.), (ii) verapa-mil, and (iii) diltiazem. All calcium antagonists arepotent vasodilators. First generation dihydropyridineincreases the heart rate while verapamil and diltiazemdecrease or do not alter the heart rate. The newdihydropyridines do not or only mildly influence heartrate. Although they are efficacious in decreasing bloodpressure and have anti-anginal effects, their safety,especially in terms of their effects on the survival ofpatients with coronary heart disease and those withhypertension, has been questioned in recent publica-tions. A meta-analysis by Curt Furberg found thatpatients with coronary heart disease treated with shortacting nifedipine had a dose dependent increase inmortality compared to the control group. This negativeeffect has only been found at very high doses of 60 mgand higher. In this meta-analysis, studies were includedwhich investigated the effects of short acting nifedipineand mortality and morbidity were not necessarily usedas endpoints in all the strains.Recently, two case controlled studies on hypertensivepatients were published. They showed that patientstreated with short acting nifedipine had a higher rateof myocardial infarction than those treated with /?-blockers. These results and the reports in the mediahave made physicians in clinic and practice, as well astheir patients extremely insecure.Calcium antagonists have an anti-hypertensive andanti-anginal effect and probably also have anti-atherosclerosis properties. Prospective, randomizedstudies regarding the effects on mortality and morbiditysuch as those carried out in the 70's and 80's for /?-blockers, diuretics and older antihypertensives, arelacking for calcium antagonists (as well as for ACE-inhibitors) in patients with hypertension and stableangina pectoris. The STONE study in China at leastindicated that hypertensive patients administered nifed-ipine had a decrease in the frequency of cerebral stroke.Less can be said regarding coronary heart disease sincethe prevalence of this disease is so low in this Asianpopulation. Nevertheless, the results of the retrospect-ive case controlled studies in hypertensive patientsshould certainly be taken seriously, even though theyCorrespondence and offprint requests to: Prof. T. F. Luscher,Inselspital, Department of Cardiology, University of Bern. CH-3010Bern. Switzerland.can not be considered as having resolved the issue.One must bear in mind that the patients in these casecontrolled studies were mostly treated with short actingnifedipine, i.e. pharmacological preparations which arehardly used any more in Europe since the introductionof slow release preparations and long acting calciumantagonists. The effects of calcium antagonists oncoronary heart disease in patients with hypertensionremains still undetermined. This question will beanswered in a few years by the ongoing ALLHATstudy and INSIGHT study.The anti-anginal effect of these substances in patientswith stable angina pectoris is uncontested. The APSISstudy proved that similar survival rates are obtainedwith verapamil as with the /?-blocker, metoprolol.Similar results were obtained for slow releasing nifedip-ine and atenolol in the TIBET study.Short acting preparations, especially those whichstimulate the sympathetic system and, therefore,increase the heart rate, should not be used, or onlytogether with a /?-blocker, in patients with coronaryheart disease. In patients with vasospastic angina pec-toris, calcium antagonists, especially nifedipine, are thefirst choice.Studies with first generation calcium antagonists donot show any positive effect on mortality in patientswith unstable angina or acute myocardial infarction.Accordingly, their use for this indication should beconsidered with great reservation and they should onlybe used for symptomatic treatment and only afterprevious beta blockade (to diminish sympatheticactivation) in specially selected cases.For secondary prevention after myocardial infarc-tion, verapamil and diltiazem appear to have a moder-ately favorable effect only in patients withoutcongestive heart failure. It should be noted that thesecondary prevention effects of cholesterol loweringdrugs and aspirin in this patient group is at least asimportant. In coronary patients with heart failure,neither verapamil nor amilodipine nor felodipine hada favorable effect on survival, while diltiazem was evenassociated with an increase in death rate. Therefore,verapamil, amlodipine and felodipine should only beadministered when symptoms are present (ischaemiaor angina pectoris) and only to patients who are notcandidates for a bypass operation or PTCA.Presently, it appears worthwhile to use the potentialof calcium antagonists and to decrease possible risksin patients with cardiovascular diseases by the use ofa differential therapy. It should be especially notedAbstracts 1921that not all calcium antagonists are the same anddepending on the diagnosis and type of therapeuticindication, i.e. symptomatic or preventive, an individu-alized differential therapy must be considered (Fig. 1).For hypertension and stable angina pectoris, calciumantagonists are effective and still may be used.However, short acting dihydropyridines should bedefinitely avoided. Until the results of prospectivestudies are available, calcium antagonists should bediscontinued and replaced by other antihypertensivedrugs before major surgery due to the increased riskof hemorrhage. In patients with unstable angina, cal-cium antagonists should not be used, or only afteradministration of/?-blockers. They are not appropriatein acute myocardial infarction. For secondary preven-tion after myocardial infarction, calcium antagonistsare not the first choice and should only be used whenadequate left ventricular function is present. Aspirin,/?-blockers, ACE inhibitors and cholesterol reducingdrugs should be given preference for this indication.In patients with compromised left ventricular functionand heart failure, verapamil, amlodipine and felodipineshould be administered only to treat symptoms andnot for secondary prevention. In this indication, theyshould only be considered in patients who are alreadytreated with an ACE inhibitor, diuretic and digitalisand in those in which invasive therapy such as PTCAor bypass for the treatment of ischemia is not possible.In hypertrophic cardiomyopathy or supraventriculararrythmias, phenylakylamine calcium antagonists (ver-apamil) or those of the benzothiazepine group (diltia-zem) are appropriate as selected first like drugs(Fig. 1).Symptoms SurvivalHypertensionAngina PectorisPrinzmetal AnginaStable AnginaAcute CoronarySyndromesUnstable AnginaAcute MyocardialInfarctionSecondaryPrevention after Ml INormal LVFunrtionCongestive HeartFailureImpairedLV FunctionDilatedCardiomyopathyHypertrophicCardiomyopathyArrhythmiasVentricularArrhythmiasSupraventricularArrhythmias^ ^ -/neutralFig. 1. Differential use of calcium antagonists in patients with cardio-vascular disease.References1. Lilscher TF, Wenzel RR, Noll G. Kalziumantagonisten in derKontroverse: Gibt es eine rationale Differentialtherapie? DtschMed Wschr 1996; 121: 532-5382. The effect of diltiazem on mortality and reinfarction aftermyocardial infarction. The Multicenter Diltiazem PostinfarctionTrial Research Group. N EnglJ Met! 1988; 319: 385-3923. Braunwald E. Mechanism of action of calcium-channel-blockingagents. N EnglJ Med 1982; 307: 1618-16274. DAVITII. Effect of verapamil on mortality and major eventsafter acute myocardial infarction (the Danish VerapamilInfarction Trial II—DAVIT II). Am J Carclio! 1990; 66: 779-7855. Furberg C, Psaty BM, Meyer JV. Nifedipine: Dose-RelatedIncrease in Mortality in Patients with Coronary Heart Disease.Circulation 1995; 92: 1326-13316. Held PH, Yusuf S, Furberg CD. Calcium channel blockers inacute myocardial infarction and unstable angina: an overview.Br MedJ 1989; 299: 1187-11927. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jost S,Deckers JW. Retardation of angiographic progression of coron-ary artery disease by nifedipine. Results of the InternationalNifedipine Trial on Antiatherosclerotic Therapy (INTACT).INTACT Group Investigators. Lancet 1990; 335: 1109-11138. Muller JE, Morrison J, Stone PH et al. Nifedipine therapy forpatients with threatened and acute myocardial infarction: arandomized, double-blind, placebo-controlled comparison.Circulation 1984; 69: 740-7479. Psaty BM, Heckbert SK, Koepsell TD, et al. The risk ofmyocardial infarction associated with antihypertensive drugtherapies. JAMA 1993; 274: 620-62510. Schroeder JS, Gao SZ, Alderman EL et al. A preliminary studyof diltiazem in the prevention of coronary artery disease inheart-transplant recipients [see comments]. N Engl J Med 1993;328: 164-17011. SPRINT. Secondary prevention reinfarction Israeli nifedipinetrial (SPRINT). A randomized intervention trial of nifedipinein patients with acute myocardial infarction. The Israeli SprintStudy Group. Eur Heart J 1988; 9: 354-364

Controversy of calcium antagonists: is there a rational differential therapy?

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