|IDEAL STUDY: HIGH-DOSE ATORVASTATIN (SORTIS) WITHOUT ADVANTAGE
The benefit of a therapy with 20 mg to 40 mg simvastatin daily (ZOCOR etc.) or 40 mg pravastatin daily (PRAVASIN etc.) has been confirmed in patients with stable coronary heart disease (a-t 2004, 35: 56-60). In contrast, evidence for the benefit of atorvastatin (SORTIS) in coronary heart disease is sparse (a-t 2004; 35: 135-6). The recently published randomised IDEAL* study, sponsored by Pfizer, compares atorvastatin at a high dose of 80 mg daily with 20 mg simvastatin designated as the usual dose in patients with a previous history of myocardial infarction and a statin indication according to national guidelines. When patients were on statin treatment previously the dose could be equivalent to a maximum of 20 mg simvastatin. If the cholesterol level was over 190 mg/dl 24 weeks after the start of the study, the simvastatin dose was allowed to be increased to 40 mg daily. The atorvastatin dose could be reduced to 40 mg daily if there were problems of tolerability. The study was open-label; only the analysis of the endpoints was performed by a central evaluation committee without knowledge of group allocation (PROBE** design) (1).
8,888 patients with an average age of 62 years were recruited between March 1999 and March 2001. 81% were men. 76% were previously treated with a statin, 79% with aspirin and 75% with a beta-blocker. After 24 weeks the simvastatin dose was increased to 40 mg daily in 21% of the patients and the atorvastatin dose was reduced to 40 mg daily in 6%. At the end, 23% and 13% respectively were taking 40 mg of either statin per day.
After 4.8 years coronary deaths, hospital admissions because of myocardial infarction or resuscitation because of cardiac arrest (primary combined endpoint) were not at all significantly rarer with atorvastatin than with simvastatin (9.3% vs. 10.4%; hazard ratio 0.89, 95% confidence interval [CI] 0.78-1.01; p = 0.07). Three of seven predefined secondary endpoints also remained unaffected: coronary deaths (3.9% vs. 4.0%; p = 0.90), overall mortality (8.2% vs. 8.4%; p = 0.81) and successful resuscitation (0.2% each). Nonfatal infarcts (6.0% vs. 7.2%; p = 0.02), the combination of coronary events or strokes (12.0% vs. 13.7%; p = 0.02), coronary events including coronary revascularisation and hospitalisation because of unstable angina (20.2% vs. 23.8%; p<0.001) along with cardiovascular events (26.5% vs. 30.8%; p<0.001) were less on atorvastatin.
More patients taking atorvastatin discontinued the study medication because of adverse events than with simvastatin (9.6% vs. 4.2%; p<0.001). E.g. rises in the transaminases and myalgia were more common with atorvastatin. Confirmed myopathy was not observed with either drug (1).
A serious methodological weakness of the study is the PROBE design, lacking blinding for investigators and patients. The results may be biased by the fact that the investigators carry out concomitant treatment and endpoint recording knowing the statin therapy in each case, as the authors themselves concede (1). According to a meta-analysis, an overestimation of the effect by an average of 14% in favour of the intervention can be found when blinding is absent in controlled studies (2). The positive results for some of the secondary endpoints cannot serve as proof of superiority of high-dose atorvastatin since no adjustment of the significance level was made despite multiple testing. Even an equivalence of 80 mg atorvastatin and 20 mg simvastatin was not confirmed by the study, as this hypothesis was not tested. Moreover, the IDEAL study did not compare 80 mg atorvastatin to the usual standard dose of simvastatin. The dosage schedule for simvastatin does resemble that of the 4S* study, in which 37% of the patients were finally treated with 40 mg/d simvastatin and in which for the first time a reduction in mortality was found due to simvastatin in chronic coronary heart disease (3). However, since publication of the HPS* study (a-t 2002; 33: 83-4) 40 mg simvastatin per day is regarded as the standard dose due to better data, if there is clinically manifest atherosclerosis (4).
The results of the IDEAL study, therefore, support the recent decision of the Berlin court at social right that atorvastatin cannot be granted a special status when determining the reference price system for statins (5).
|Proof of superiority of atorvastatin 80 mg daily (SORTIS) has failed compared to 20 mg to 40 mg of simvastatin (ZOCOR etc.) in patients with a past history of myocardial infarction, which the recently published IDEAL study was designed to adduce.
|Overall mortality and coronary mortality remain unchanged. Benefit of 80 mg atorvastatin daily in some mainly combined secondary endpoints does not proof preponderance.
|Equivalence of atorvastatin and simvastatin is also not proven by the study.
|More patients on atorvastatin than on simvastatin discontinued the medication because of side effects.
|40 mg simvastatin daily remain the agent of choice in patients with manifest atherosclerosis such as coronary heart disease.