Long-term results from statin trials: answers but more unresolved questions.

The benefits of statin treatment in both primary and secondary prevention of cardiovascular disease (CVD) have been well established in multiple randomized controlled trials (RCTs). In general the safety profile of statins is good. However, most of the statin trials have an average duration that is fairly short to study the long-term effects and safety of drugs that should be taken lifelong. Therefore, longer follow-up of participants from statin trials is advocated. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is a multicentre trial involving two treatment comparisons in a factorial design. Two antihypertensive regimens [ASCOT blood pressurelowering arm (ASCOT BPLA)] are compared and in the lipid-lowering arm (ASCOT-LLA) the effects of atorvastatin 10 mg/day are examined using a double-blind placebo-controlled design; the ASCOT-LLA trial involved 10 305 patients with arterial hypertension, a cholesterol level of ≤6.5 mmol/L, and at least three other cardiovascular (CV) risk factors. The ASCOT-LLA trial was stopped prematurely by the Data Safety Monitoring Board (DSMB) after a mean follow-up of 3.3 years due to a significantly lower incidence of the primary endpoint (non-fatal acute myocardial infarction and fatal coronary heart disease) in the atorvastatin group. The relative risk reduction (RRR) was –35% [95% confidence interval (CI) –17 to –49%, P 1⁄4 0.0006]. This premature discontinuation has led to some unresolved issues due to reduced power in secondary endpoints and in prespecified subgroup analyses. After the ASCOT-LLA was discontinued, trial physicians were invited to offer atorvastatin 10 mg/day to all LLA patients until the end of ASCOT-BPLA, which was also stopped by the DSMB in early 2005, 2.2 years after the discontinuation of ASCOT-LLA. At the time of the discontinuation of ASCOT-LLA, 13% of the patients originally assigned to placebo were on any statin, but this had increased to 63% at 5.5 years; their total cholesterol level was reduced, reaching 4.36 mmol/L; it was predicted that this should have accounted for an RRR in primary endpoint of 19% from the end of ASCOT-LLA to the end of ASCOT-BPLA; the observed RRR was 37%. Among those originally assigned to atorvastatin, 84% of the patients were still taking any statin at 3 years, but this was reduced to 67% at 5.5 years; the total cholesterol level had risen slightly to 4.31 mmol/L. If in this group there was no carry-over benefit from atorvastatin in those who had stopped active treatment at the end of ASCOT-LLA one might have expected a modest rise in event rates. In reality event rates continued to decline, suggesting an important carry-over effect. At the end of ASCOT-BPLA, the RRR in the primary endpoint among those originally assigned to atorvastatin remained unchanged at 36%; all-cause mortality (showing a non-significant –13% difference at the premature termination of ASCOT-LLA) showed a significant 15% reduction after the extension. These results are consistent with post-trial follow-up observations over short-term periods of up to 2 years from the Scandinavian Simvastatin Survival Study (4S), the LIPID study, and the ALERT trial. During these short-term periods they all observed ongoing benefits in terms of reduced deaths from coronary heart disease (CHD) in the group originally assigned to statin therapy. However, it might be predicted that in long-term follow-up, and assuming treatment rates equalize in those originally assigned placebo and statin, that CV event rates would converge. Results from long-term follow-up have been reported by the 4S and by the West of Scotland coronary prevention study (WOSCOPS), an RCT in middle-aged men without a history of myocardial infarction. At the 5 years completion of the trial, the combined outcome of coronary death or non-fatal myocardial infarction was significantly reduced in the pravastatin group. An extended follow-up was organized covering 10 years of observations after the end of the trial. The percentages of participants being treated with a statin among those assigned to the original pravastatin and placebo groups were 38.7% and 35.2%, respectively, at 5 years after the end of the trial. There was evidence of