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

SEARCH was a large UK, randomised controlled trial of cholesterol-lowering with simvastatin 80mg daily (high intensity) versus a standard dose of simvastatin 20mg daily (standard dose) 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.

Results were reported in 2008 and 2010 with SEARCH showing 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 i.e. 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. See the ‘Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom’ paper in our Selected Publications list. Data from SEARCH contributes to the CTT meta-analyses and the B Vitamin Treatment Trialists’ Collaboration (BVTTC) analyses.

The SEARCH trial was initially funded by MSD who also provided the packaged simvastatin and the packaged folic acid plus vitamin B12 combination tablet and matching placebos. The trial was conducted, analysed and published independently by the investigators at CTSU.  The long-term follow-up has been funded by core grants to CTSU from the Medical Research Council, British Heart Foundation and Cancer Research UK. Ongoing funding comes from the HDR UK, and the University of Oxford.

SEARCH: serious adverse events by MedDRA classification

LONG-TERM FOLLOW-UP

Participants stopped taking study treatment in 2008. We will continue to collect information on health outcomes by obtaining routinely collected data via NHS Data Custodians (e.g. NHS England, Public Health Scotland, and SAIL and DHCW – in Wales) until 2035. On-going investigations include looking at the very long-term effects of homocysteine-lowering on vascular and non-vascular deaths and cancers using data from electronic health records. 

See our SEARCH Legacy Study Protocol for more information about this long-term follow-up, and our Privacy Notice for information on how we use participant data.

We have several similar studies (REVEAL, HPS, THRIVE, and SEARCH) with common aims. Due to the similarities between the studies and the participant cohorts, where any one study does not have enough data to be able to give a clear answer for a specific research question, we will perform meta-analyses. This means that we will combine data from all the studies and then analyse it to answer a common research question. All research will be in-line with the original study protocols, and will include methodology work.

PATIENT AND PUBLIC INVOLVEMENT AND ENGAGEMENT (PPIE)

If you were a participant in the REVEAL trial and would like to join the Oxford Population Health PPIE group we would love to hear from you. PPIE is very important for learning about the lived experience of our trial participants and providing feedback about new and ongoing research projects. The Oxford Population Health website gives more information on what this group does and how to get in touch.