Title: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH — Presented at AHA 2008)
Trial Sponsor: University of Oxford, UK, and Merck & Co, Inc.
Year Presented: 2008
Topic(s): General Cardiology, Prevention/Vascular
Summary Posted: 11/9/2008
Writer: Dharam J Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., F.A.C.C.
Author Disclosure: Research Grants: The Medicines Company, Significant (>= $10,000); Research Grants: Ethicon, Significant (>= $10,000); Research Grants: Bristol Myers Squibb, Significant (>= $10,000); Research Grants: Heartscape, Significant (>= $10,000); Research Grants: Eisai, Significant (>= $10,000); Research Grants: Sanofi Aventis, Significant (>= $10,000)

Related Resources
Related Trial: Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS)
Related Trial: Treating to New Targets Study (TNT)
Related Trial: Evaluation of early versus delayed initiation of simvastatin in patients who receive guideline based treatment for acute coronary syndrome (A to Z, Phase Z)
Related Trial: Western Norway B-Vitamin Intervention Trial (WENBIT)
Related Trial: Norwegian Vitamin Trial (NORVIT)
Related Trial: Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 (PROVE IT/TIMI 22—Lipid Lowering Results)

Description
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 plus vitamin B12, compared with placebo, in patients who had recently suffered a myocardial infarction (MI).
Hypothesis
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.
Drugs/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, 6,033 to folic acid and vitamin B12, 6,031 to placebo vitamins, 6,031 to simvastatin 80 mg, and 6,033 to 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% 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] 0.86, 95% confidence interval [CI] 0.68-1.09, p > 0.05). Similarly, there was no difference in the incidence of all-cause mortality (16.0% vs. 16.1%, p > 0.05), 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 (0.88% vs. 0.05%, p < 0.05). Patients taking amiodarone had a nearly 10-fold increase in myopathy in the high-dose arm. There was no difference in the incidence of cancer between the two arms (10.6% vs. 11.2%, p > 0.05).

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 0.95-1.14, p > 0.05). 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.
Interpretation
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.
Conditions
• Coronary heart disease

Therapies
• Lipid-lowering agent / HMG CoA Reductase Inhibitor / Simvastatin
• Antioxidant/folic acid

Study Design
Randomized. Blinded. Parallel. Factorial.

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

Primary Endpoints

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

Ages 18-80 years
History of MI
Current use of statin therapy, or clear indication for statin therapy
No clear indication for folic acid
Exclusions:

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 (alanine aminotransferase >1.5 x upper limit of normal)
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
References: Presented by Dr. Rory Collins at the American Heart Association Annual Scientific Sessions, New Orleans, November 2008.