Statins: The New Aspirin?
No work presented at American Heart Association’s 2001 Scientific Sessions is likely to have greater clinical impact than the Medical Research Council/British Heart Foundation Heart Protection Study, reported by Dr Rory Collins (Clinical Trial Service Unit of Oxford University, Oxford, UK). The latest guidelines from the National Cholesterol Education Program probably will have to be modified. Patients (n=20 536) were recruited in 69 UK hospitals, the entry criterion being high risk of coronary heart disease without a clear indication for cholesterol-lowering therapy. Specifically targeted were women, people >70 years of age, people with diabetes, those with noncoronary vascular disease, and those with average or below-average cholesterol levels. Patients were 40 to 80 years old (28% age ≥70 years) and one fourth were women. Two regimens were under investigation: simvastatin (40 mg daily), and a cocktail of antioxidant vitamins (vitamin E [600 mg], vitamin C [250 mg], β-carotene [20 mg daily]). Patients were randomized to 4 groups of ≈5000 each, receiving simvastatin alone, simvastatin plus vitamins, vitamins alone, or placebo. Average follow-up period was 5.5 years. In the vitamin part of the study, the results were entirely negative. No benefit or harm was evident in terms of vascular disease or any other disorders (including cancers). By contrast, striking benefits were seen with simvastatin. The primary end points for the comparison of simvastatin and placebo were all-cause mortality (12.9% versus 14.6%, respectively) and deaths from heart disease and related blood vessel disease (7.7% versus 9.2%, respectively). Secondary end points were stroke (4.4% versus 6.0%), major cardiovascular events (19.9% versus 25.4%), deaths unrelated to heart disease (5.2% versus 5.5%; not significant), and heart attack/stroke in diabetic patients without previous disease (13.9% versus 18.7%). Muscle damage was very rare and was no more common in the simvastatin group: creatine kinase >10 times the upper limit of normal, 0.09% (9 patients) versus 0.05% (5 patients); alanine aminotransferase >3 times upper limit of normal, 0.8% (77) versus 0.6% (65). Vascular events such as myocardial infarction, stroke, and arterial surgery were all reduced by about one fourth. When allowance is made for noncompliance and treatment changes during the trial, Collins concludes that simvastatin reduced these major vascular events by at least one third in a wide range of high-risk patients for whom the indication for cholesterol-lowering therapy had been uncertain—notably, women, people >70 years of age, and people with an LDL cholesterol level <200 mg/dL (≈3 mmol/L). The observation that benefits are independent of initial lipid values raises the possibility of statin prescription without cholesterol monitoring. The safety data are also impressive. Collins speaks of statins as the “new aspirin.”
Drug-eluting coronary stents were generating optimism at the Scientific Sessions. Might in-stent stenosis soon be a thing of the past? Of ≈25 candidate drugs, 9 have so far been incorporated in stents, the frontrunners being rapamycin (sirolimus), taclipaxel, and actinomyein D. In the RAVEL trial, rapamycin on the BX Velocity stent achieved a restenosis rate of zero at 6 months, but there has been concern that this success will be marred by late in-stent thrombosis, as happened with β-brachytherapy. The results at 9 months, reported by Dr J Eduardo Sousa (Dante Pazzanese Institute of Cardiology, Sao Paolo, Brazil), are reassuring; event-free survival is unaltered at 97%. The microtubule inhibitor taclipaxel has been investigated in various formulations, with and without polymer carrier, and several groups at the Scientific Sessions recorded dose-related improvements in vascular indices. The biggest study was the European Evaluation of Paclitaxel Eluting Stent (ELUTES) trial, in which 192 patients with discrete coronary lesions were randomized to received the V-Flex Plus coronary stent, either bare metal or treated with paclitaxel in 4 dose concentrations. All patients received clopidogrel for 3 months. The results at 6 months’ follow-up were reported by Dr Anthony Gershlick (Glenfield Hospital, Leicester, UK). The highest dose of paclitaxel achieved the best results. Compared with the control group (38 patients), results in the high-dose group (37 patients) were as follows: diameter stenosis, 14.2% versus 33.9% (P=0.007); late loss, 0.10 mm versus 0.73 mm (P=0.002); in-stent binary stenosis rates, 3.1% (n=1) versus 20.6% (P=0.055); and major coronary events, 3 versus 1.
ACE Inhibitor Therapy in African-Americans
African-Americans are at much higher risk of hypertension-related kidney disease than are whites, and there is a widespread belief that angiotensin-converting enzyme (ACE) inhibitors should be avoided in their treatment. At the Scientific Sessions, Dr Janice Douglas (Case Western Reserve University School of Medicine, Cleveland, Ohio) reported results from the African-American Study of Kidney Disease and Hypertension, which examined the effects of 2 intensities of blood pressure control and 3 different drugs as initial treatment (ramipril, metoprolol, and amlodipine). African-Americans with hypertensive renal disease (n=1094; glomerular filtration rate [GFR] 20 to 65 mL/min per 1.73 m2) were enrolled in 21 centers. The primary outcome was change in GFR, and the secondary outcome was a composite of clinical end points (reduction in GFR of >50% or 25 mL/min per 1.73 m2, end-stage renal disease, or death). Surprisingly, although there was a 10 mm Hg separation in mean arterial pressure between the 2 antihypertensive regimens, the slopes for decline in GFR did not differ. With the ACE inhibitor ramipril, the rate of decline was 25% slower than with metoprolol and there were 22% fewer composite events. Progression of kidney disease was particularly rapid in patients with a urinary protein to creatinine ratio >0.22 (which corresponds roughly to the level of proteinuria detectable by dipstick). In this group, the risk of composite clinical events was 46% lower with ramipril than with amlodipine and 37% lower with metoprolol than with amlodipine. The amlodipine limb of this trial was discontinued when an excess of clinical end points was seen with this calcium channel blocker (JAMA. 2001;285:2719–2728). The positive message is that an ACE inhibitor can be beneficial in this group of African-Americans.