SEARCH: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine

SEARCH was a large UK, randomised controlled trial of more intensive cholesterol-lowering with simvastatin 80mg daily versus a standard dose of simvastatin 20mg daily and of homocysteine-lowering with folic acid and vitamin B12 versus matching placebo. Between 1998 and 2001, 12,064 patients who had survived a heart attack were randomised in 88 hospital-based clinics around the UK. These patients were followed up for an average of about 7 years in the study clinics while they continued on their randomised treatment and follow-up is on-going for mortality and cancer via centralised electronic health records. 

SEARCH has shown that:

• The additional reduction in LDL-cholesterol with allocation to simvastatin 80mg daily versus 20mg daily reduced LDL-cholesterol by 0.35 mmol/L and major vascular events (MVEs ie heart attacks, strokes or coronary or non-coronary revascularisation) by 6% (95% CI 12% to +1%). This reduction was in line with expectations and contributed to the CTT meta-analysis showing that more intensive LDL-cholesterol lowering produces additional benefits.
• Supplementation with folic acid plus vitamin B12 significantly reduced homocysteine levels  and is safe, but does not reduce the risk of major vascular events or cancer
• Simvastatin 80mg daily was associated with an increased risk of myopathy (muscle symptoms with raised blood creatine kinase) with 53 vs 2 cases respectively among those allocated 80mg vs 20mg simvastatin daily  
• In a nested genetic case-control a genetic marker in the SLCO1B1 gene was shown to increase the risk of statin-induced myopathy

The SEARCH database continues to provide valuable information on other risk factors for myopathy. Data from SEARCH contributes to the CTT meta-analyses and the B Vitamin Treatment Trialists’ Collaboration (BVTTC) analyses. On-going investigations include looking at the long-term effects (over 10 years) of homocysteine-lowering on vascular and non-vascular deaths and cancers using data from electronic health records

The SEARCH trial was funded by Merck who also provided the packaged simvastatin and the packaged folic acid plus vitamin B12 combination tablet and matching placebos. The long-term follow-up is funded by core grants to CTSU from the Medical Research Council, British Heart Foundation and Cancer Research UK.

SEARCH: serious adverse events by MedRA classification