|arznei-telegramm 2004; 35: 93|
CARD STUDY: ATORVASTATIN (SORTIS) IN DIABETES?
Current evidence is inconclusive on benefit of statins in diabetic patients without manifest atherosclerotic diseases. Only one of three long-term interventional trials with large diabetic subgroups allows a clear advantage for these patients to be identified - the Heart Protection Study (1,2) (HPS) with simvastatin (e.g. ZOCOR), but not the ALLHAT-LLT* study (3) with pravastatin (e.g. PRAVASIN) and the ASCOT-LLA* study (4) with atorvastatin (SORTIS; a-t 2004, 35: 56-60). Now for the fist time a statin trial has appeared on the prevention of cardiovascular diseases exclusively in diabetic patients (CARDS*). Between 1997 and 2001 2.838 40 to 75 year old patients with type 2 diabetes for at least six months were included in the randomised double-blind investigation financed partially by Pfizer, the manufacturer of atorvastatin, and the UK Department of Health. The average LDL-cholesterol of the patients had to be below 4.14 mmol/l (160 mg/dl) after several baseline measurements. At least one other cardiovascular risk factor or marker had to be present - arterial hypertension, retinopathy, micro- or macroalbuminuria or smoking. Exclusion criteria included previous history of myocardial infarction, unstable angina, coronary angioplasty or bypass, cerebrovascular event or severe peripheral vascular disease with potential indication for surgery, creatinine above 1.7 mg/dl, HbA1c above 12% and a compliance of less than 80% in a placebo run-in phase.(5,6)
The study compared the use of 10 mg atorvastatin daily with placebo in addition to the previous treatment. The study was stopped early because of a clear difference in favour of atorvastatin after about four years. The LDL fell by an average of 40% with atorvastatin compared to placebo. The primary endpoint - a combination of symptomatic or silent myocardial infarction, unstable angina, acute coronary death, resuscitation after cardiac arrest, coronary revascularisation or stroke - decreased from 9% to 5.8% on atorvastatin (relative risk [RR] 0.63; 95% confidence interval [CI] 0.48 to 0.83; number needed to treat [NNT] = 122/year). Strokes were reduced from 2.8% to 1.5% (RR 0.52, 95% CI 0.31 to 0.89; NNT = 300/year). For severe coronary events - nonfatal myocardial infarction and acute coronary death - only the rate per 100 patient years is given. It fell from 1.31 to 0.88 (RR 0.67; 95% CI 0.47-0.97; NNT = 233/year). Mortality was also lower on atorvastatin but statistically this was only a trend (5.8% versus 4.3%; RR 0.73% 95% CI 0.52 to 1.01).(5) As in the HPS, patients with an LDL of 120 mg/dl or lower also benefit.
Rhabdomyolysis was not observed in the study. A rise in the GOT to three times the upper limit of normal or above affected 1.2% of patients on atorvastatin, and there was a corresponding rise in GPT in 0.4%.(5)
Contrary to what the authors suggest the CARD study does not justify an expansion of the indication for a statin to all patients with diabetes.(7) The study participants are a high risk group with an average age of 62 years, a duration of diabetes for an average of eight years and high blood pressure in 84%, retinopathy in 30% and albuminuria in 17%. Two thirds smoke (23%) or have smoked (43%)(5). In these patients there is a high probability that they already have (hitherto not diagnosed) coronary heart disease. As far as can be seen from the published data (5,6), even overt vascular diseases are not reliably excluded by the exclusion criteria. 15% of the patients take acetylsalicylic acid (ASA; e.g. ASPIRIN) or other platelet aggregation inhibitors, also an indication of atherosclerotic disease in at least some. The CARD study, however, confirms the results of the Heart Protection Study in diabetic patients without known vascular diseases (a-t 2003; 34: 65-6), with the advantage that the profile of the participants in CARDS is identifiable, albeit with limitations. Only simvastatin is licenced for the prevention of subsequent cardiovascular diseases in coronary heart disease or diabetes. Furthermore, overall evidence of benefit in these indications is better for simvastatin.
(R = randomised study)
ALLHAT-LLT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial-Lipid-Lowering Trial
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