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Do calcium channel blockers increase the risk of myocardial infarction in hypertensive patients with diabetes mellitus?
Laura Park Choo Pin Por, PHARMD
Michael F Evans, MD, CCFP

cardiovascular outcomes.5'6 While evidence of this is largely based on observational studies, the general consensus among practitioners has been to avoid shortacting calcium channel blockers, especially immediaterelease nifedipine (eg, Adalat). Long-acting calcium channel blockers have raised fewer concerns. The Appropriate Blood-Pressure Control in Diabetes trial, Research question however, has now added fuel to what seems to be an Are long-acting dihydropyridines, such as nisoldipine already raging fire because it suggests that long-acting (Sular), associated with increased rates of adverse car- dihydropyridine calcium channel blockers could harm diovascular events in hypertensive patients with type 2 hypertensive diabetic patients.! diabetes? Should we continue to prescribe calcium channel blockers for hypertensive patients with type 2 diabetes? Type of article and design How can we integrate the results of this trial with the Double-blind, randomized, parallel-group study. recommendations of the JNC-6 to arrive at a bottomline decision on when to use calcium channel blockers Relevance to family physicians for our hypertensive diabetic patients, if at all? Calcium channel blockers are among the most frequently prescribed medications for treating hyperten- Overview of study and outcomes sion.' They are also widely used for patients with other The main objective of the study was to investigate the illnesses, such as angina pectoris, certain cardiac relative effects of various levels of blood pressure conarrhythmias, and Raynaud's phenomenon. Recent evi- trol on the glomerular filtration rate of hypertensive dence has shown that calcium channel blockers protect and normotensive patients with type 2 diabetes. The the renal systems of hypertensive patients with diabetic secondary objective was to compare nisoldipine with nephropathy.23 In line with this evidence, the Sixth enalapril (Vasotec) for outcomes. such as cardiovascuReport of the Joint National Committee on the lar events, neuropathy, urinary albumin excretion, and Prevention, Detection, Evaluation left ventricular hypertrophy. The and Treatment of Hypertension Critical Appraisal revviews important arti- published study reports on only UNC-6)4 named calcium channel cles in the literaturl e relevant to family a subset of the study populablockers as one of the preferred physicians. Reviews are by family physi- tion-diabetic patients with therapies for patients with hyper- cians, not experts c n the topics. They hypertension. tension and diabetes. Other assess not only the s3trength of the studIn the subset, 470 patients preferred therapies included ies but the "bottom line" clinical impor- were randomized to moderate or angiotensin-converting enzyme tance for family praictice. We invite you intensive antihypertensive regi(ACE) inhibitors, a-blockers, and to comment on theL reviews, suggest mens. All subjects were required low-dose diuretics. articles for review, c)r become a review- to have a diastolic blood pressure Concurrently, enormous con- er. Contact CoordinaLtor, Michael Evans, of at least 80mmHg not treated troversy has arisen around the by e-mail michael.ev.,ans@utoronto.ca or with antihypertensive medicasafety of calcium channel block- by fax (416) 603-58211. tions. Moderate antihypertensive ers, particularly regarding adverse treatrnent was defined as a target

Estacio RO, Jeffers BW, Hiatt WR, Biggi SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular events in patients with non-insulin-dependent diabetes and hypertension. NEngl JMed 1998;338:645-52.

Ms Park is a student in the Doctor ofPharmacy Program at the University of Toronto. Dr Choo Pin Por, a pharmacotherapy specialist the Toronto Hospital Family and Community Medicine site, is an Assistant Professor in the Doctor of Pharmacy Program. Dr Evans practises at The Toronto Hospital and teaches in the Department ofFamily and Community Medicine at the University of Toronto.

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FOR PRESCRIBING INFORMATION SEE PAGE 2556

VOL44: NOVEMBER * NOVEMBRE 1998. Canadian Family Physician . Le Medecin defamille canadien 2405

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diastolic blood pressure of 80 to 89mmHg; intensive antihypertensive treatment was defined as a target diastolic blood pressure of 75mmHg. Patients ranged in age from 40 to 74 years and had been diagnosed with type 2 diabetes. Moderate and intensive treatment groups were then further randomized to either nisoldipine or enalapril. If monotherapy with the study medication was inadequate to achieve target blood pressure control, patients could also receive open-label metoprolol (eg, Betaloc) or hydrochlorothiazide (HydroDiuril). Patients who had experienced recent myocardial infarction (MI), cerebrovascular accident (CVA), or coronary artery bypass grafting (CABG) were excluded, as were patients with recent unstable angina, with New York Heart Association functional class 3 or 4 congestive heart failure (CHF), on dialysis, and with serum creatinine levels of >265gmo/L. Baseline cardiovascular diseases (demonstrated on electrocardiogram), such as coronary artery disease (CAD), angina, CVA, CHF, abnormal ankle-brachial index, and left ventricular hypertrophy, were recorded during a placebo run-in period.

receiving nisoldipine more likely to have MIs, they were also more likely to have them earlier than the patients receiving enalapril. A high rate of discontinuations was seen in both groups: 142 patients (60%) in the nisoldipine arm and 129 patients (55%9) in the enalapril arm stopped treatment. Patients receiving nisoldipine were most likely to stop because of headaches, those receiving enalapril because of malaise, fatigue, or uncontrolled hypertension. Rates of discontinuation were not statistically different for the two groups. Analysis of methodology While this study was well-designed and equipped to respond to the intended primary research question, it is important to remember that the cardiovascular data are presented in the context of secondary end point analysis. As such, this is a hypothesis-generating trial that identifies the need for further randomized controlled trials. In addition, the study was limited by the absence of placebo control, making interpretation of the results difficult. Do the results reflect enalapril's protective effect on cardiovascular events, or is nisoldipine exerting a deleterious effect on cardiovascular outcomes? Could it be an interaction of both effects?6 Finally, we cannot exclude the possibility that the findings are a product of the higher treatment discontinuation rate in the nisoldipine group coupled with the greater diuretic or ,B blocker use in the enalapril group.

Results
Patients were followed for 67 months at which time the Drug and Safety Monitoring Committee detected a significant difference in the rate of MIs among patients treated with nisoldipine compared with those treated with enalapril. Termination of nisoldipine treatment was recommended, and patients receiving nisoldipine were switched to enalapril. The two treatment arms were relatively well balanced at entry. Slight differences in baseline characteristics included a lower high-density lipoprotein profile in the enalapril group (1.03 mmol/L vs 1.l1 mmol/L) and a higher percentage of patients with abnormal anklebrachial indices (6% enalapril vs 3% nisoldipine) and with angina (3% enalapril vs < 1% nisoldipine). The treatments provided similar blood pressure control, although more patients receiving enalapril required open-label treatment with f,Bblockers (42% enalapril vs 38% nisoldipine) and diuretics (51% enalapril vs 40% nisoldipine). A higher rate of cardiovascular events (particularly MI) was seen in the nisoldipine group: 25 patients experienced fatal or nonfatal MIs compared with only five in the enalapril arm (adjusted risk ratio 7.0; 95% confidence interval 2.3 to 21.4). These results were consistent throughout both moderate and intensive blood pressure control regimens. Kaplan-Meier survival curves also demonstrated an early split; the split was maintained throughout the study. This suggests that, not only were the patients

Application to clinical practice

The results of this trial reiterate the general consensus that, for all situations, ACE inhibitors should be preferred to calcium channel blockers for diabetic patients with hypertension. The strikingly higher rate of fatal and nonfatal MIs in patients randomized to nisoldipine should not and cannot be ignored. The findings of this trial are consistent with results of the Fosinopril versus Amlodipine Cardiovascular Events Trial,7 which found that diabetic patients randomized to fosinopril (Monopril) for hypertension had a significantly lower risk of vascular events than patients receiving amlodipine (Norvasc). Calculation of the number needed to harm reveals that only 11 patients would have to be treated with nisoldipine instead of enalapril to see one preventable MI. For patients who are intolerant of ACE inhibitors or angiotensin II-receptor antagonists, it would be prudent to avoid calcium channel blockers in favour of other well-established therapies, such as low-dose diuretics and n-blockers.

2406 Canadian Family Physician Le Medecin defamille canadien * VOL 44: NOVEMBER * NOVEMBRE 1998

Bottom line There is insufficient evidence to decide whether calcium channel blockers actually increase the risk of MI or whether the ACE inhibitors exert a cardioprotective effect. The dramatically higher cardiovascular event rate with nisoldipine, however, further confirms that ACE inhibitors should continue to be preferred over calcium channel blockers for hypertensive patients with type 2 diabetes. For diabetic patients receiving calcium channel blocker monotherapy for hypertension, it would be worthwhile to consider switching to ACE inhibitors, because treating 11 people with long-acting dihydropyridines instead of ACE inhibitors for 5 years could allow one preventable MI to occur. For diabetic patients who are ACE-inhibitor intolerant, angiotensin II-receptor antagonists, low-dose diuretics, and even ,-blockers should be initiated rather than long-acting dihydropyridines. Extrapolation of the results of this trial is difficult for diabetic patients receiving both ACE inhibitors and calcium channel blockers, but if monotherapy is even a possibility, physicians should attempt to withdraw the calcium channel blockers. 4

References
1. Beaulieu M-D, Dufresne L, LeBlanc D. Treating hypertension: are the right drugs given to the right patients? Can Fam Physician 1998;44:294-302. 2. Velussi M, Brocco E, Frigato F, Zolli M, Muollo B, Maioli M. Effects of cilazepril and amlodipine on kidney function in hypertensive NIDDM patients. Diabetes 1996;45:216-22. 3. Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM-associated nephropathy. Kidney Int 1996;50:1641-50. 4. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (NC VD. Arch Intern Med 1997;157:2413-46. 5. Psaty BM, Heckbert SR, Koepsell TD. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620-5. 6. Cutler JA. Calcium channel blockers for hypertensionuncertainty continues. N Engl J Med 1998;338:679-81. 7. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21:597-603.

Anaphylactoid reactions during membrane Other: Bioavailability of fosinoprilat not altered Anaphylactoid reactions have been with chlorthalidone, nifedipine, propranolol, in patients dialysed with high-flux hydrochlorothiazide,cimetidine, metoclopramide (e.g., polyacrylonitrile (PAN)) and and propantheline. treated concomitantly with an ACE inhibitor. ADVERSE REACTIONS: Dialysis should be stopped immediately. Severe adverse reactions occurring in 1548 reactions during desensitization: hypertensive patients treated with MONOPRIL Anaphylactoid Angitensn Covertng EzymeInhiitor There have been isolated reports of patients were. angioedema (1 case) and orthostati c INDICATIONS AND CLINICAL USE: experiencing sustained life-threatening hypotension (2.7%). Myocardial infarction Mild to moderate essential hypertension. May be anaphylactoid reactions while receiving ACE (2 cases) and cerebrovascular accident (4 casesn thiazide usedaloe o inassciaionwith used inhibitors during desensitizing treatment with occurred, possibly secondary to excessive ecsie alone in association diuretics. Use in renovascular hypertension not or hymenoptera (bees, wasps) venom. hypotension in high risk patients. In 516 heart established. Use of antihypertensive agents other Valvular Stenosis: Theoretically patients with failure patients, the severe adverse reaction than thiazide diuretics has not been established. aotcseoimihbearikoderae ocuinwthheigstfqecyasnia the management of aprticrstenosis Adjunctive treatment in heart mightpbeatbrisknofodecreasedroccurringmwithmthe:highestfrequencycwasaangina when treated with coronary perfusion failure. Initiate symptomatic congestive petri16%.Itpaeo-otole ypr tension trials (688 patients), the most frequent vasodilators as they do not develop much treatmnt undr medcal suervison Whe used clinical adverse reactions were nausea/vomiting, afterload reduction. in pregnancy during he second and third

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VOL 44: NOVEMBER * NOVEMBRE 1998+ Canadian Family Physician Le Medecin defamille canadien 2407