4S

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Pedersen TR, et al. "Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)". The Lancet. 1994. 344(8934):1383-1389.
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Clinical Question

Among patients with prior MI or angina with hyperlipidemia, does addition of simvastatin reduce all-cause mortality when compared to placebo?

Bottom Line

In patients with prior MI or angina and hyperlipidemia, Simvastatin reduces all-cause mortality as well as CAD-related mortality.

Major Points

Hyperlipidemia was first identified as a risk factor for CAD in a publication from the Framingham Study group (1961).[1] Early trials with cholesterol modifying agents had modest success. LRC-CPPT (1984)[2] demonstrated a significant 1.6% absolute reduction in fatal or non-fatal MI at 7 years with use of the bile acid sequestrant cholestyramine in patients with type II hyperlipoproteinemia. The Helsinki Heart Study (1987)[3] demonstrated a similar reduction in the incidence of CAD with the fibrate gemfibrozil men hyperlipidemia. Neither trial demonstrated a mortality benefit. A new class of cholesterol-lowering medications called "statins" lowered cholesterol by reducing endogenous production through inhibition of HMG-CoA reductase. Their role in patients with CAD resultant to their hyperlipidemia, was unclear.

Published in 1994, the Scandinavian Simvastatin Survival Study (4S) randomized 4,444 patients with CAD (defined by prior MI or angina) and hyperlipidemia to simvastatin or placebo. At only 5.4 years of median follow up, the trial was stopped early because of a 3.3% absolute risk reduction in all-cause mortality with simvastatin (11.5% vs. 8.2%; P=0.0003; NNT 30). The trial also demonstrated reductions in multiple other endpoints including major coronary event (NNT 15), CV mortality (NNT 31), and coronary interventions (NNT 17). The medication was overall well-tolerated. Of note, a post-hoc analysis included by the authors demonstrated a reduction in incidence of cerebrovascular disease, a finding that was later confirmed in SPARCL (2006).

Multiple other trials confirmed the efficacy of statins in the role of primary and secondary prevention of CAD. These medications have now become standard of care in the treatment of multiple diseases, including hyperlipidemia and CAD.[4]

Guidelines

ACC/AHA Cholesterol treatment to reduce ASCVD risk (2013, adapted)[5]

  • Secondary prevention with high-intensity statin therapy for patients ≤75 years in age with clinical ASCVD (i.e. stable CAD) unless contraindicated (grade A, class I, level A)
  • Moderate-intensity therapy for above group if contraindication to high-intensity statin therapy or risk for statin-associated adverse events (grade A, class I, level A)
  • For patients ≥75 years with clinical ASCVD, evaluate risks and benefits when initiating high- or moderate-intensity statin therapy (grade E, class IIa, level B)
  • No recommendation for specific targets for LDL- and non-HDL-cholesterol for primary or secondary prevention of ASCVD.
  • Definition of intensity of statin therapy as:
    • High-intensity (LDL reduction ≥50%): Atorvastatin 40-80 mg, rosuvastatin 20-40 mg
    • Moderate-intensity (LDL reduction 30-<50%): Atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, pravastatin 40-80 mg, lovastatin 40 mg, fluvastatin XL 80 mg, fluvastatin 40 mg BID, pitavastatin 2-4 mg
    • Lower-intensity (LDL reduction <30%): Simvastatin 10 mg, pravastatin 10-20 mg, lovastatin 20 mg, fluvastatin 20-40 mg, pitavastatin 1 mg

ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Stable Ischemic Heart Disease (2012)[4]

  • Recommend physical activity and weight management for all patients with stable ischemic heart disease (class I level B)
  • Recommend moderate or high dose of a statin should be prescribed for patients with stable ischemic heart disease unless contraindicated (class I level A)

Design

  • Multicenter, randomized, placebo-controlled trial
  • N=4,444
    • Placebo (n=2,223)
    • Simvastatin (n=2,221)
  • Setting: 94 centers in Scandinavia
  • Enrollment: 1988-1989
  • Median follow-up: 5.4 years (stopped after interim analysis)
  • Analysis: Not specified
  • Primary outcome: All-cause mortality

Population

Inclusion Criteria

Adults aged 35-70 years with angina pectoris or MI >6 months prior

Exclusion Criteria

  • Tchol <5.5 or >8.0 mmol/L (<212 or >309 mg/dL); TG >2.5 mmol/L (>221 mg/dL)
  • Women of childbearing potential
  • Secondary hypercholesterolemia
  • Tendon xanthomata
  • Planned coronary intervention
  • Current UA or MI in prior 6 months
  • Antiarrhythmic medications
  • HF requiring digoxin
  • Persistent AF
  • Cardiomegally
  • Hemodynamically significant valvular heart disease
  • Stroke
  • Liver disease
  • Partial ileal bypass
  • Abuse of drugs or alcohol
  • "Poor mental function"
  • "Other serious disease"
  • Treatment with another trial medication
  • Statin hypersensitivity

Baseline Characteristics

From the simvastatin group.

  • Demographics: Male 82%, male age 58.2 years, female age 60.5 years
  • Baseline health data: BMI 26.0 kg/m2, BP 138/83 mmHg, LDL 4.87 mmol/L (188 mg/dL), HDL 1.18 mmol/L (45.5 mg/dL), TG 1.49 mmol/L (132 mg/dL), Tchol 6.74 mmol/L (260 mg/dL)
  • Eligibility diagnosis: Angina 21%, infarction 63%, both 16%
  • Time since eligibility diagnosis: <1 year 27%, 1-5 years 42%, ≥5 years 31%
  • Q-wave on EKG: 33%
  • Other PMH: HTN 26%, claudication 6%, DM 5%, smokers 25% (former 50%)
  • PSH: CABG or PTCA 9%
  • Medications: ASA 37%, beta blocker 57%, CCB 32%, ISDN 31%, thiazide 7%, warfarin 1%, fish oil 13%

Interventions

  • Potentially eligible patients were given dietary advice followed by a two week placebo run-in with subsequent enrollment if they were compliant with the therapy
  • Randomization to simvastatin 20 mg by mouth before dinner daily or placebo
  • Follow-up laboratory monitoring with centrally-controlled dose adjustments to 40 mg or 10 mg when lipids went out of range

Outcomes

Presented as placebo vs. simvastatin. Statistics omitted when not reported by the authors.

Primary Outcome

All-cause mortality
11.5% vs. 8.2% (RR 0.70; 95% CI 0.58-0.85; P=0.0003; NNT 30)

Secondary Outcome

Major coronary event
22.6% vs. 15.9% (RR 0.66; 95% CI 0.59-0.75; P<0.00001; NNT 15)
Definite MI: 12.1% vs. 7.4%
Probable MI: 18.8% vs. 12.6%
Silent MI: 4.9% vs. 4.0%

Additional Analyses

CV mortality
9.3% vs. 6.1% (RR 0.65; 95% CI 0.52-0.80; NNT 31)
Coronary mortality: 8.5% vs. 5.0% (RR 0.58; 95% CI 0.46-0.73; NNT 42)
All-cause mortality or any atherosclerotic CV event
47.0% vs. 37.1% (RR 0.74; 95% CI 0.67-0.81; P<0.00001; NNT 10)
Non-CV mortality
2.2% vs. 2.1% (NS)
Non-MI coronary heart disease
14.9% vs. 13.3% (NS)
Non-coronary cardiac event
4.9% vs. 4.9% (NS)
Cerebrovascular event

A post-hoc analysis

4.3% vs. 2.7% (RR 0.70; 95% CI 0.52-0.96; P=0.024; NNT 63)
Coronary intervention
17.2% vs. 11.3% (RR 0.63; 95% CI 0.54-0.74; P<0.00001; NNT 17)
Dose modification of those receiving simvastatin in the first 6 months
Increase to 40 mg daily: 37%
Continued 20 mg daily: 63%
Reduce to 10 mg daily: <1%
Cessation of taking study medication or placebo
13% vs. 10%
Because of adverse events: 5.8% vs. 5.7%
Change in lipids in the simvastatin group at 6 weeks

The authors note that other than a slight increase in the triglycerides, no significant change in cholesterol was noted in the placebo group.

Tchol: -28% (-25% at 1 year)
LDL: -38% (-35% at 1 year)
HDL: +8% (+8% at 1 year)
Triglycerides: -15% (-10% at 1 year)
Tchol <5.2 mmol/L (201 mg/dL) in the simvastatin group at 1 year
72%

Subgroup Analysis

All cause mortality
Women: 6.0% vs. 6.6% (RR 1.12; 95% CI 0.65-1.93)
Men: 12.8% vs. 8.5% (RR 0.66; 95% CI 0.53-0.80)
Age <60 years: 8.1% vs. 5.2% (RR 0.63; 95% CI 0.45-0.88)
Age ≥60 years: 14.8% vs. 11.0% (RR 0.73; 95% CI 0.58-0.92)
Major coronary event
Women: 21.7% vs. 14.5% (RR 0.65; 95% CI 0.47-0.91)
Men: 29.4% vs. 20.5% (RR 0.66; 95% CI 0.58-0.76)
Age <60 years: 27.6% vs. 17.6% (RR 0.61; 95% CI 0.51-0.73)
Age ≥60 years: 28.3% vs. 21.0% (RR 0.71; 95% CI 0.60-0.86)

Adverse Events

Similar in both groups.

Criticisms

  • This was only one positive trial in one statin at the time of the study, it was suggested that further trials are necessary in order to change practice[6]
  • Unclear if there was a different effect in those enrolled because of MI versus those with chronic angina[6]
  • Low rate of aspirin use[6]
  • Unclear cost/benefit ratio with this expensive brand name medication[6]

Funding

Merck, the makers of Zocor, the brand name of simvastatin.

Further Reading

  1. Kannel WB et al. "Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study." Annals of Internal Medicine. 1961;55(1):33-50.
  2. Lipid Research Clinics Writing group. "The Lipid Research Clinics Coronary Primary Prevention Trial Results." JAMA 1984;251:351-364.
  3. Frick MH, et al. "Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease." The New England Journal of Medicine. 1987;317(20):1237-1245.
  4. 4.0 4.1 FIHN SD, et al. "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease." Journal of the American College of Cardiology. 2012;60(24):e44-e164.
  5. Stone NJ, et al. "2013 ACC/AHA guideline on the treatment of blood cholesterol o reduce atherosclerotic cadiovascular risk in adults." Journal of the Amercan College of Cardiology. 2014;63(25 Pt B):2889-2934.
  6. 6.0 6.1 6.2 6.3 Multiple authors. "Correspondence: Scandinavian Simvastatin Study (4S)." The Lancet. 1994;344:1765-8.