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


Although a few studies have demonstrated a beneficial effect on cardiovascular outcomes with high-dose statins versus low-dose statins in patients with acute coronary syndromes, there was also a higher incidence of adverse effects, including hepatic and musculoskeletal. Similarly, although observational studies seem to suggest a beneficial effect of homocysteine lowering with folic acid in patients with coronary artery disease, this has not borne out in prospective studies.

Accordingly, the SEARCH trial was a 2 x 2 trial designed to evaluate the safety and efficacy of aggressive statin therapy with 80 mg of simvastatin compared with 20 mg of simvastatin, as well as homocysteine reduction with folic acid 2 mg plus vitamin B12 1 mg, compared with placebo, in patients who had recently suffered a myocardial infarction (MI).


Simvastatin 80 mg and folic acid plus vitamin B12 would individually be associated with a reduction in cardiovascular events in patients who had recently suffered an MI, compared with simvastatin 20 mg, and placebo, respectively.

Study Design

Patients Screened: 83,237
Patients Enrolled: 12,064
Mean Follow Up: 6.7 years
Mean Patient Age: 64 years (median)
Female: 17%

Patient Populations:

  • History of MI
  • Current use of statin therapy, or clear indication for statin therapy
  • No clear indication for folic acid


  • MI, hospitalization for angina, coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty within the prior 3 months
  • Planned coronary revascularization within 3 months
  • Plasma cholesterol <135 mg/dl in patients on statin therapy, or <175 mg/dl in patients not on statin therapy
  • Chronic liver disease or abnormal liver function (ALT>1.5 times ULN)
  • Severe renal disease or renal impairment
  • Inflammatory muscle disease
  • Concurrent treatment with fibrates or >1 g/day of niacin
  • Concurrent treatment with cyclosporine, nefazodone, methotrexate, systemic azole antifungals, or systemic macrolide antibiotics
  • Women of child-bearing potential, not using contraceptive methods

Primary Endpoints:

  • Major vascular events, defined as nonfatal MI, coronary revascularization, coronary death, stroke, or noncoronary revascularization

Drug/Procedures Used:

Patients were randomized in a 2 x 2 factorial trial to either simvastatin 80 mg or 20 mg daily, and to folic acid 2 mg plus vitamin B12 1 mg daily, or placebo.

Concomitant Medications:

Aspirin (91%), beta-blockers (48%), angiotensin-converting enzyme inhibitors (38%), and angiotensin-receptor blockers (4%)

Principal Findings:

A total of 12,064 patients were randomized. In the first randomization, 6,033 received folic acid and vitamin B12 and 6,031 received placebo vitamins. In the next randomization, 6,031 received simvastatin 80 mg and 6,033 received simvastatin 20 mg. Baseline characteristics were fairly similar between the four groups. About 33% had a history of prior revascularization, 7% had a history of cerebrovascular disease, 11% had diabetes, and 42% had hypertension. The mean low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels were 97, 39, and 168 mg/dl, respectively. The mean baseline homocysteine level was 13.5 μmol/L.

High-dose versus low-dose simvastatin: Over the duration of the study, there was only a 14% (0.34 mmol/L) reduction in LDL cholesterol in the high-dose simvastatin arm, compared with the low-dose arm, secondary to many drop-ins in the low-dose arm. There was no difference between the high-dose and low-dose simvastatin arms in the incidence of major vascular events (24.5% vs. 25.7%, hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.88-1.01, p = 0.10). Similarly, there was no difference in the incidence of all-cause mortality (16.0% vs. 16.1%, p = 0.90), cardiac mortality (7.4% vs. 7.3%, p > 0.05), or strokes (4.2% vs. 4.6%, p > 0.05).

There was a significantly higher risk of myopathy in the high-dose simvastatin arm compared with the low-dose arm (0.9% vs. 0.0%, RR 26.6, 95% CI 6.5-109, p < 0.0001). Incipient myopathy was also significantly higher (1.4% vs. 0.2%). Confirmed rhabdomyolysis was noted in seven patients in the high-dose arm, and none in the low-dose arm, with an additional seven patients having creatine kinase values >40 times upper limit of normal (ULN) in the high-dose arm. Ten patients were hospitalized at the time of development of myopathy, and two died. Alanine aminotransferase (ALT) elevations were numerically higher in the high-dose arm, as compared with the low-dose arm.

Folic acid plus vitamin B12 versus placebo: Over the duration of the study, there was a mean 28% reduction in homocysteine levels in the folic acid and vitamin B12 arm. There was no difference between the folate + vitamin B12 groups and placebo in the incidence of major vascular events (25.5% vs. 24.8%, HR 1.04, 95% CI 0.97-1.12, p = 0.28). Similarly, there was no difference in the incidence of nonfatal MI (7.1% vs. 7.1%, p > 0.05), coronary revascularization (9.8% vs. 9.8%, p > 0.05), cardiac death (7.7% vs. 7.0%, p > 0.05), all-cause mortality (16.3% vs. 15.8%, p > 0.05), or stroke (4.5% vs. 4.4%, p > 0.05). There was also no difference between the two arms, when stratified by levels of baseline homocysteine.


The results of the SEARCH trial indicate that simvastatin 80 mg daily is not more efficacious than simvastatin 20 mg daily in the secondary prevention of adverse cardiovascular events in post-MI patients. High-dose statin therapy is also associated with a significantly higher incidence of myopathy, when compared with low-dose therapy. Further, homocysteine lowering with folic acid and vitamin B12 supplementation is also not associated with a reduction in cardiovascular events in this population.

The statin results are contrary to earlier published trials with high-dose statin in patients with known coronary artery disease, such as PROVE-IT/TIMI-22, TNT, and A to Z. One explanation for these findings is the low difference in LDL cholesterols between the two arms (14% at the end of follow-up). The homocysteine lowering results, however, are in sync with other trials such as WENBIT, NORVIT, and WAFACS, which did not demonstrate any cardiovascular benefit with folic acid and/or vitamin B12 supplementation. The totality of these results thus refutes data from observational studies that suggested a possible beneficial effect on cardiovascular outcomes with homocysteine lowering.


SEARCH Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 2010;376:1658-69

SEARCH Collaborative Group. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA 2010;303:2486-94.

Presented by Dr. Rory Collins at the American Heart Association Annual Scientific Sessions, New Orleans, November 2008.

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Stroke, Follow-Up Studies, Creatine Kinase, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Vitamin B 12, Rhabdomyolysis, Homocysteine, Trinitrotoluene, Folic Acid, Cholesterol, HDL, Confidence Intervals, Triglycerides, Hypertension, Diabetes Mellitus

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