Effects of antihypertensive drugs on cardiovascular events in patients with coronary heart disease and normal blood pressure. Randomized controlled CAMELOT study

Background. The effect of antihypertensive drugs on different cardiovascular events (CVE) in patients with coronary heart disease (CHD) and normal blood pressure (BP) remains unknown to the present day. Objective: to evaluate the effects ol amlodipine or enalapril versus placebo on the development of CVE in patients with CHD. Design, subjects, and methods: This is a double-blind, randomized, multicenter, 24-month (from April 1999 to April 2002) study evaluating the effect of amlodipine or enalapril versus placebo in 1991 patients with angiographically verified CHD (> 20 % stenosis at coronary angiography) and a diastolic BP of < 100 mm Hg. A substudy assessed the progression of atherosclerosis in 274 patients by intravascular ultrasound study (IVUSS). Therapy. The patients were randomly given amlodipine, 10 mg enalapril, 20 mg, or placebo, IVUSS was performed before and ai the end of the study. Assessment of basic outcomes. The main index of the efficacy of the drugs was the frequency CVE when amlodipine versus placebo was used. The other indices involved the comparison of amlodipine with enalapril and the latter with placebo. CVE included its related death, nonfatal myocardial infarction, resuscitated cardiac arrest, intervention for coronary revascularization, hospitalization for angina pectoris, congestive heart failure, fatal and nonfatal stroke or transient ischemic attack, and first diagnosed peripheral vascular disease. The prime objective of IVUSS was to estimate percentage changes in the volume of atherosclerotic plaques. Results. The mean BP was 129/78 mm Hg in the total sample BP increased by 0.7/0.6 mm Hg in the placebo group and by 4.8/2.5 and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (p < 0.001 for both groups versus placebo). CVE developed in 151 (23,1 %) patients in the placebo group, in 110 (16.0 %) patients receiving amlodipine [risk ratio (RR) = 0.69; 95 % confidence interval (CI) 0.54-0.88; p = 0.003 and in 136 (20.2 %) patients treated with enalapril (BR = 0.85: 95 % CI 0.67-1.07; p = 0.16). The basic parameter that was a difference in the frequency of CVE in the enalapril and amlodipine groups was statistically insignificant (RR = 0.81; 95 % CI 0.63-1.04; p = 0,10). IVUSS revealed a tendency for a decrease in progressive atherosclerosis in the amlodipine group as compared with the placebo group (p= 0,12) with a significantly less progression in the subgroup of patients with a systolic BP higher than the mean BP (p = 0.02). Comparison with the baseline IVUSS values indicated a growth of plaques in the placebo group (p < 0.001), a tendency for progressive atherosclerosis in the enalapril group (p = 0.08). and no progression in the amlodipine group (p = 0,031 ). In the amlodipine group, the relation (r) of BP lowering to the progression of atherosclerosis was 0,19 (p = 0,07). Conclusion. The use of amlodipine in patients with CHD and progressive atherosclerosis caused a reduction in the frequency of CVE. Enalapril was observed to produce the similar, but less pronounced and statistically not so significant effect. IVUSS demonstrated a stunted progression of a vascular atherosclerotic lesion when amlodipine was administered.

1. l. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effect of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115 through 129 mm Hg JAMA 1967; 202; 116-22.

2. Staessen J.A., Wang J.G., Thijs L. Cardiovascular prevention and blood pressure reduction: a metaanalysis [published correction appears in Lancet. 2002; 359:360. Lancet 2001; 358: 1305-15.

3. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000: 355: 1955-64.

4. Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145-53.

5. Fox K.M: European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary arlery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362: 782-8.

6. Pitt B., Byingfon RP., Furberg C.D. et al. PREVENT Investigators. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation 2000; 102: 1503-10.

7. Chohamian A.V., Bakris C.L., Black H.R. et al. National Heart. Lung and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Seventh report of the joint National Committee on Prevention. Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published correction appears in JAMA. 2003; 290: 197] JAMA 2003; 289: 2560-72.

8. Nissen S.E., Tuzeu E.M., Brown В.G. et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291: 1071-80.

9. Nissen S.E., Tsunoda T., Tuzen E.M. et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003; 290: 2292-300.

10. Chambers J.M., Cleveland W.S., Kleiner B., Tukey P.A. Graphical Methods for Data Analysis. Boston. Mass: Duxhury Press: 1983.

11. Lewington S., Clarke K., Qizilhash N. et al. Prospective Studies Collaboration. Age-Specific relevance of usual blood pressure to vascular mortality: a meta-analysis of Individual data for one million adults in 61 prospective studies. Lancet 2002. 360:1903-13.

12. Jorgensen B., Simonsen S., Endresen К. et al. Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the Coronary Angioplasty Amlodipine Restenosis Study (CARAPES). J Am Coll Cardiol 2000; 35: 592-9.

13. ALLHAT Officers and Сoordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin is usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002: 288: 2998-3007.

14. Julius S., Kpeldsen S.E., Weber M. et at. VALUE trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomized trial. Lancet 2004; 363: 2022-31.

15. MacFadyen R.J., Meredith P.A., Elliott H.L. Enalapril clinical pharmacokinetics and pharmacokinetic pharmacodynamic relationships: an overview. Clin Pharmacokinet 1993: 25: 274-82.

16. Poole-Wilson R.J., Lubsen J., Kirwan B.A. et al. Nifedipine Gastrointestinal therapeutic System Investigators. Effect of long-acting nifedipine and mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004: 364: 849-57.

17. Mason R.P. Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodipine: review of the evidence. Atherosclerosis 2002: 165: 194-9.

18. Cannon C.P., Brannwald E., McCuhe С.H. et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004: 350: 1495-504.