A L T E R N A T I V E V I E W P I N T S _

Amlodipine PREVENTs Angina, Not Atherosclerosis

Craig Williams, Pharm.D.

(Pharmacotherapy 2002;22(3):400–402)

I would like to offer an alternative viewpointon the role of amlodipine in coronary arterydisease to the one put forth in the September2001 Pharmacotherapy supplement.1 Broadlyentitled “Pharmacologic Interventions forCoronary Artery Disease and Risk Factors,” thesupplement was in fact almost entirely a reviewof the somewhat controversial role of calciumchannel blockers in coronary artery disease. Thearticles, however,1, 2 effectively avoided anycontroversy and offered conclusions on thedisease-modifying potential of amlodipine that Ifeel are not supported by the limited clinical data.The conclusions came largely from the authors’interpretation of the recently publishedProspective Randomized Evaluation of theVascular Effects of Norvasc Trial (PREVENT).3

The trial was a 3-year study of 825 patientswith established coronary artery diseaserandomized to amlodipine or placebo. Theprimary findings were that although amlodipinedid reduce the progression of carotid arterythickening, it did not reduce mortality or theprogression of coronary artery disease as measuredby either angiography or the cardiovascularevents of myocardial infarction and stroke. Itdid, however, reduce occurrences of symptomaticcoronary artery disease as shown by a reductionin both hospitalizations for unstable angina andthe need for vascular procedures. This distinctionbetween symptomatic benefit and potentialdisease-modifying benefit is one that the authorsof PREVENT were careful to make. Whileacknowledging the early reduction in hospital-izations and vascular procedures, they concludedthat “amlodipine has no demonstrable effect onangiographic progression of coronary atherosclerosis

or the risk of major cardiovascular events.”Unfortunately, this distinction is lost in twoarticles1, 2 in the Pharmacotherapy supplement.

The first article by Dr. Pieper concludes fromPREVENT that amlodipine “significantly reducedfatal and nonfatal events and procedures.”1

Although this is technically a true statement,combining all events and procedures is ambigu-ous since the reduction seen in PREVENT wasspecifically not in major vascular events—19versus 20 myocardial infarctions and 5 versus 5strokes. Dr. Pieper acknowledges this in hisarticle and goes on to clarify that “in terms ofclinical events, amlodipine had no effect on all-cause mortality because the study was notpowered to determine potential difference.”1

Despite this admission however, he stillconcludes that “if the results [of PREVENT] canbe reproduced, they will establish amlodipine asa valuable addition to standard therapies such asaspirin, b-blockers, and lipid-lowering agents inpatients with CHD [coronary heart disease].”1

Suggesting that amlodipine may have similareffects as agents that have established mortalitybenefit in patients with coronary artery disease isan unsupported opinion, which also is at oddswith the authors of PREVENT. In theirdiscussion of the trial, the authors of PREVENTconclude that the early, symptomatic benefit ofamlodipine on hospitalizations and vascularprocedures could be complementary to thedisease-modifying benefits of angiotensin-converting enzyme (ACE) inhibitors and statinsthat often take about a year to manifest. Use ofthe two together, they conclude, might preventearly hospitalization and “allow statins or ACEinhibitors a chance to reduce ‘hard’ ischemicevents by altering the underlying pathophysiologyof atherosclerosis.”3

In the abstract of the second article by Dr.Mason, he states that “PREVENT demonstratedthat patients with documented CAD [coronary

From Purdue Pharmacy Programs, Purdue University,Indianapolis, Indiana.

Address correspondence to Craig Williams, Pharm.D.,Purdue Pharmacy Programs, D711 Myers Building, WHS,1001 West Tenth Street, Indianapolis, IN 46202-2879.

ALTERNATIVE VIEWPOINTS Williams

artery disease] treated with amlodipineexperienced marked reductions in cardiovascularevents compared with patients receiving placebo.”2

This again is misleading and only true becauseDr. Mason chose not to differentiate symptomaticanginal events from the defined vascular eventsof myocardial infarction and stroke. Thisambiguity puts his conclusion similarly at oddswith the conclusion of the authors of PREVENT.

I propose the following interpretation ofPREVENT. The observed reduction in hospital-izations and vascular procedures without areduction in myocardial infarction and strokeestablished what already was suspected about theuse of dihydropyridine calcium channel blockersin patients with established coronary arterydisease. As outlined in the current AmericanCollege of Cardiology/American Heart Associationjoint guidelines,4 dihydropyridine agents are aneffective, symptomatic treatment in patients withchronic stable angina. In PREVENT, all patientshad established coronary artery disease, and 70%had a history of angina at baseline. The averagestarting systolic blood pressure was 130 mm Hgin the placebo group. Over a 3-year period, it isreasonable to assume that a number of new andrecurrent cases of angina would develop in sucha population. It is also reasonable to assume thatuse of a dihydropyridine agent with a subsequent8-mm Hg reduction in systolic blood pressure(122 mm Hg for amlodipine vs 130 mm Hg forplacebo at the end of the study) would reducesymptomatic anginal episodes compared withplacebo. I propose that this is what PREVENTdemonstrated by the reduced need for hospital-izations and procedures with amlodipine.Whether amlodipine is superior to otherdihydropyridine agents for symptom reduction inthis population is not known and is an importantquestion given the generally higher cost ofamlodipine relative to other dihydropyridineagents.

Clearly an important trial, PREVENT bothsupports the use of a dihydropyridine agent asrecommended for established coronary arterydisease4 and suggests a potential role foramlodipine in preventing future symptomaticevents in high-risk patients. But to interpret it asevidence of disease modification by amlodipine ispremature and stands in contrast to theconclusion of the authors of the study itself.

References1. Pieper JA. Management of coronary heart disease risk factors

and progression with calcium channel blockers. Pharmacotherapy

2001;21(9 pt 2):195S–208.2. Mason RP. Mechanisms of plaque stabilization for a charged

calcium channel blocker in coronary artery disease.Pharmacotherapy 2001;21(9 pt 2):209S–15.

3. Pitt B, Byington RP, Furberg CD, et al. Effect of amlodipine onthe progression of atherosclerosis and the occurrence of clinicalevents. Circulation 2000;102:1503–10.

4. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIMguidelines for the management of patients with chronic stableangina: a report of the American College of Cardiology/American Heart Association task force on practice guidelines(committee on management of patients with chronic stableangina). J Am Coll Cardiol 1999;33:2092–7.

Author’s Reply

The comments offered by Dr. Williams areappreciated and deserve further discussion. Inthe last section of my review article,1 I provided aperspective on the literature that evaluated thepotential role of calcium channel blockers for theprevention of development and progression ofatherosclerosis. The totality of the literature,which includes the International Nifedipine Trialon Antiatherosclerotic Therapy (INTACT),2

Montreal Heart study,3 Multicenter IsradipineDiuretic Atherosclerosis Study (MIDAS),4 andProspective Randomized Evaluation of theVascular Effects of Norvasc Trial (PREVENT),5

reveal that the calcium channel blockers studiedhad no significant effect on the progression orregression of coronary lesions as assessed byquantitative coronary arteriography. However, inthe INTACT and Montreal Heart studies,nitrendipine and nicardipine, respectively,significantly reduced the rate of development ofnew lesions2 and the progression of small lesions3

compared with placebo. This effect was independentof blood pressure-lowering effects in the INTACTtrial, where there were no significant differencesin blood pressure measurements in the placeboand nifedipine groups. In the Montreal Heartstudy, baseline systolic blood pressure andchange in systolic blood pressure did correlatewith progression of minimal lesions.3 In MIDASand PREVENT, the maximum intimal-medialthickness (IMT) of the carotid artery, as assessedby quantitative B-mode ultrasound imaging,increased more in the hydrochlorothiazide(HCTZ) group when compared with theisradipine group4 and in the placebo group whencompared with amlodipine.5 In MIDAS, diastolicblood pressures were reduced similarly in theHCTZ and isradipine groups (-13 mm Hg),whereas systolic blood pressure actually wasreduced more in the HCTZ group (-19.5 vs -16mm Hg), suggesting an effect independent fromblood pressure lowering.4 In PREVENT, theamlodipine group had significantly reduced

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systolic and diastolic blood pressure measure-ments at 4 months compared with placebo(122/75 vs 130/79 mm Hg, respectively).5 Theresults of these studies are highly suggestive thatthe calcium channel blockers studied do have abeneficial disease-modifying effect on thedevelopment and progression of atherosclerosis,which has not been consistently related to theirblood pressure-lowering effects.

The significance of PREVENT is the findingthat both carotid artery IMT progression and theprespecified clinical end point of occurrence ofmajor fatal and nonfatal vascular events orprocedures were reduced significantly in theamlodipine group when compared with theplacebo group. The other prespecified end pointwas total mortality. More than 50% of thepatients in each group were receiving therapywith a b-blocker, a nitrate, and a lipid-loweringagent. The trial did not have a large enoughsample size (417 patients in the amlodipinegroup, 408 in the placebo group) to detectdifferences in the rate of mortality, myocardialinfarction, or stroke. A larger trial is required toevaluate the potential beneficial effects ofamlodipine appropriately on these “hard” endpoints. It is for this reason that the grouping ofmajor vascular events or procedures was aprespecified clinical end point. I believe thesedata support my statement that with confirmationfrom future studies, amlodipine will be a valuableaddition to standard therapies such as aspirin, b-blockers, and lipid-lowering agents in patientswith established coronary heart disease.

Dr. Williams’ interpretation that the bloodpressure-lowering effects of amlodipine inPREVENT reduced symptomatic anginal episodesthat, in turn, reduced hospitalizations andprocedures is a defensible position but ignoresthe results from INTACT and MIDAS. As weawait the results of future trials evaluating theeffects of amlodipine on hard end points (e.g.,Comparison of Amlodipine versus Enalapril toLimit Occurrences of Thrombosis [CAMELOT]study), it is reassuring for the clinician to knowthat the addition of amlodipine to contemporaryantianginal therapy reduces the need for hospital-izations for angina and vascular procedures,irrespective of the mechanism(s) for thereductions.

References1. Pieper JA. Management of coronary heart disease risk factors

and progression with calcium channel blockers. Pharmacotherapy2001;21(9 pt 2):195S–208.

2. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jost S,Deckers JW. Retardation of angiographic progression ofcoronary artery disease by nifedipine: results of the internationalnifedipine trial on antiatherosclerotic therapy (INTACT). Lancet1990;335:1109–13.

3. Waters D, Lesperance J, Francetich M, et al. A controlled trialto assess the effect of a calcium channel blocker on the progressionof coronary atherosclerosis. Circulation 1990;82:1940–53.

4. Borhani NO, Mercuri M, Borhani PA, et al. Final outcomeresults of the multicenter isradipine diuretic atherosclerosisstudy (MIDAS): a randomized controlled trial. JAMA1996;276:785–91.

5. Pitt B, Byington RP, Rurberg CD, et al. Effect of amlodipine onthe progression of atherosclerosis and occurrence of clinicalevents. Circulation 2000;102:1503–10.

John A. Pieper, Pharm.D., FCCP

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