The results of SEARCH trial have been published in the November issue of Lancet.(1) It was a double blind randomized trial involving 12 064 men and women aged 18—80 years with a history of myocardial infarction. Participants were either currently on or had clear indication for statin therapy, and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not.
The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularisation. Analysis was by intention to treat.
Aim was to establish reliably the balance of efficacy and safety of more intensive LDL-cholesterol-lowering therapy by comparing long-term treatment with 80 mg versus 20 mg simvastatin daily in a large population of patients at high risk of cardiovascular events.
Mean follow-up duration was 6·7 (SD 1·5) person-years: 40 129 person-years in those allocated 80 mg and 40 158 person-years in those allocated 20 mg simvastatin daily.
Compliance: Among participants allocated 80 mg simvastatin, 5275 (90%) were compliant after 12 months, and 2555 (77%) after 84 months. Compliance in patients on 20 mg simvastatin was similar after 12 months, but had dropped to 69% by 84 months, with an increasing proportion of patients having started a non-study statin. The main reason for discontinuation of study treatment in participants was medical advice, generally because of a perceived need for more intensive cholesterol-lowering therapy. By contrast, slightly more of the patients allocated 80 mg simvastatin were likely to stop because of raised liver or muscle enzyme concentrations or to have reported muscle pain or weakness.
At 2 months, LDL cholesterol was reduced by 0·51 (SE 0·06) mmol/L more in those allocated 80 mg simvastatin (as originally anticipated), but that difference had decreased to 0·34 (0·02) mmol/L by 84 months (mainly because of increasing non-compliance with the allocated treatment), yielding a weighted average difference during the study of 0·35 (0·01) mmol/L.
Major vascular events occurred during the scheduled treatment period in 1477 (24·5%) of the 6031 participants allocated 80 mg simvastatin versus 1553 (25·7%) of the 6033 allocated 20 mg simvastatin. This non-significant reduction in risk did not increase significantly with duration of treatment (p value for trend=0·7). Among participants in the low, middle, and high thirds of baseline LDL cholesterol, allocation to 80 mg simvastatin produced further average reductions in LDL cholesterol of 0·30 (SE 0·02), 0·37 (0·02), and 0·36 (0·02) mmol/L, respectively, but no significant difference between the major vascular event reductions.
The numbers of deaths attributed to vascular causes (565 [9·4%] vs 572 [9·5%]) or non-vascular causes (399 [6·6%] vs 398 [6·6%]) did not differ significantly between the treatment groups.
Persistent increases of alanine aminotransferase to four times the upper limit of normal were rare, and no significant difference was found between the treatment groups. Myopathy was confirmed in 53 (1%) participants and two participants in 80 mg simvastatin and 20 mg simvastatin groups respectively.
In the larger and longer SEARCH trial, LDL cholesterol was reduced from an average of 2·52 mmol/L to an average of 2·17 mmol/L for about 7 years and, again, there were similar numbers of non-vascular deaths in both groups (399 [6·6%] on 80 mg simvastatin vs 398 [6·6%] on 20 mg simvastatin), as well as similar numbers with incident cancer (640 [10·6%] vs 677 [11·2%]). The higher absolute rate of non-vascular mortality in SEARCH reflects both the older age of the participants and the longer study duration.
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