Heart Protection Study

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Heart Protection Study Collaborative Group Writers. "MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial". The Lancet. 2002. 360(9326):7-22.
PubMedFull text

Clinical Question

In patients with high risk for CVD, does simvastatin reduce cardiovascular morbidity and mortality, as compared to placebo?

Bottom Line

In patients with high risk for CVD, simvastatin is safe and cholesterol lowering is associated with reduction in all-cause mortality and major vascular event risk, as compared to placebo. The benefit of cholesterol lowering was neither limited by a threshold LDL-C level nor dependent on the pre-treatment cholesterol level.

Major Points

HMG-CoA reductase inhibitors (statins) have been shown to reduce cardiovascular (CV) mortality and morbidity in certain high risk patient groups. For example, the 4S observed the benefit of simvastatin in patients with prior MI or angina and hyperlipidemia.[1] The LIPID study reported the benefit of Pravastatin in patients with coronary artery disease (CAD) and different cholesterol levels.[2] The AFCAPS showed that Lovastatin is effective in patients without atherosclerotic CAD with average total cholesterol, LDL-C, and below-average HDL-C levels.[3]

The Heart Protection Study studied the effect of cholesterol lowering with simvastatin in specific patient groups with increased CVD risk. This includes patients with diabetes, CAD, peripheral artery disease (PAD), cerebrovascular disease, and hypertension. The trial randomized 20,536 patients to receive simvastatin 40 mg daily or placebo. The primary outcome was all-cause mortality, fatal or non-fatal vascular events.

The trial reported that cholesterol lowering was associated with reduced all-cause mortality (12·9% vs. 14·7% in placebo [RR 0.87; 95% CI 0.81-0.94; P=0·0003]). In addition a significant benefit on coronary mortality and other vascular mortality was evident. Simvastatin also reduced the risk of major vascular events (19·8% vs. 25·2% in placebo [RR 0.76; 95% CI 0.72-0.81; P<0·0001]). There was no LDL-C threshold evident below which no benefit would be obtained. Additionally, the reduction in risk associated with cholesterol lowering did not differ according to pre-treatment cholesterol levels. Simvastatin demonstrated good safety profile.

The trial was included in a meta-analysis which concluded that intensive LDL-C lowering with statins is safe. Reduction by 1·0 mmol/L is associated with a reduction of major vascular events risk by 20% approximately without any evidence of a threshold level.[4] In addition, a Cochrane review concluded that statins are effective for the primary prevention of CVD.[5]

In a different paper, the trial also reported that antioxidant vitamin treatment did not reduce mortality or major vascular events.[6] Additionally, a subgroup analysis of diabetic patients in the trial was published.[7]

Guidelines

ACC/AHA Cholesterol Guidelines (2013, adapted)[8]

  • 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)[9]

  • 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

  • Double-blind, randomized, placebo-controlled, multicenter study
  • N=20,536
    • Simvastatin 40 mg daily: 10,269
    • Placebo: 10,267
  • Setting: 69 centers in the UK
  • Enrollment: 1994-1997
  • Mean follow-up: 5 years
  • Analysis: intention to treat
  • Primary outcome: all-cause mortality, fatal or non-fatal vascular events

Population

Inclusion Criteria

Described elsewhere[10]

  • Aged 40-80 years
  • Non-fasting total cholesterol ≥3·5 mmol/L (135 mg/dL)
  • One of the following:
    • Type 1 or type 2 diabetes mellitus
    • Coronary disease (MI, unstable or stable angina, CABG, or PCI)
    • Occlusive disease of non-coronary arteries (ischemic stroke which was non-disabling, TIA, PAD [eg, intermittent claudication], carotid endarterectomy, other arterial surgery or angioplasty)
    • Treated hypertension in males

Exclusion Criteria

  • clear indication or contraindication for statin therapy
  • MI, stroke, severe heart failure or hospital admission for angina within the prior 6 months
  • chronic liver disease or abnormal liver function (eg, ALT>67 lU/L [1·5xULN])
  • severe renal disease (creatinine >200 μmol/L)
  • inflammatory muscle disease or evidence of muscle problems (creatine kinase >750 IU/L [3XULN])
  • concurrent use of cyclosporin, fibrates, or high-dose niacin
  • child-bearing potential
  • life-threatening condition other than vascular disease or diabetes
  • conditions that might limit long-term compliance

Baseline Characteristics

From all patients

  • Demographics: 28.3% aged≥70 years; 75.3% males
  • Qualifying event specifics: diabetes 19.4%; MI 41%; other coronary disease 24%; cerebrovascular disease 16%; PAD 32.9% treated hypertension 41%
  • LDL-C: 3.4±0.8 mmol/L; total cholesterol 5.9±1.0 mmol/L; HDL-C 1·06±0·33 mmol/L; triglyceride 2.1±1.4 mmol/L; apolipoprotein A1 1·20±0·22 g/L, and apolipoprotein B 1·14±0·23 g/L

Interventions

  • Run-in period involved 4 weeks of placebo, followed by 4-6 weeks of simvastatin 40 mg fixed dose daily.
  • Patients were randomized to receive placebo or simvastatin 40 mg daily
  • Compliance was defined as having taken ≥80% of the study drug. The rate was 89% at the end of the first year of follow-up, and 82% at the end of the fifth year in the statin group.
  • Using a 2X2 factorial design, participants were also randomized to receive 600 mg vitamin E, 250 mg vitamin C, and 20 mg β-carotene daily or placebo. The outcomes are described in another paper.[6]

Outcomes

Comparisons are simvastatin vs. placebo

Primary Outcome

All-cause mortality
12·9% vs. 14·7% (RR 0.87; 95% CI 0.81-0.94; P=0·0003)
Cardiovascular mortality
7.6% vs. 9.1% (RR 0.83; 95% CI 0.75-0.91; P<·0001)
Coronary mortality
5·7% vs. 6·9% (P=0·0005)
Other vascular mortality
1·9% vs. 2·2% (P=0·07)
Non-vascular mortality
5·3% vs. 5·6% (RR 0.95; 95% CI 0.85-1.07; P=0·4)

Secondary Outcomes

Any major vascular event
19·8% vs. 25·2% patients (RR 0.76; 95% CI 0.72-0.81; P<0·0001)
Fatal or nonfatal coronary events
8·7% vs. 11·8% (RR 0.73; 95% CI 0.67-0.79; P<0·0001)
Fatal or nonfatal stroke
4·3% vs. 5·7% (RR 0.75; 95% CI 0.66-0.85; P<0·0001)
Coronary or non-coronary revascularisation
9·1% vs. 11·7% (RR 0.76; 95% CI 0.70-0.83; P<0·0001)

Additional Outcomes

LDL-C reduction
1.0±0.02 mmol/L (P value not reported)
Total cholesterol reduction
1.2±0.02 mmol/L (P value not reported)
HDL-C increase
0.03±0.01 mmol/L (P value not reported)
Triglyceride reduction
0.3±0.03 mmol/L (P value not reported)
Apo-A1 increase
0.01±0.007 mmol/L (P value not reported)
Apo-B reduction
0.28±0.01 mmol/L(P value not reported)

Subgroup analysis

No heterogeneity in the efficacy of simvastatin across major subgroups, including age, sex, treated hypertension, medication use at baseline, smoking status, pre-randomisation cholesterol levels or prior history of vascular disease.

Adverse Events

Discontinuation of treatment due to adverse events: 4.8% vs. 5.1% (P=NS)

ALT elevation >4xULN: 0·42% vs. 0·31% (P not given)

  • persistent elevation:0·09% vs. 0·04% (P=0.3)
  • leading to discontinuation: 0·5% vs. 0·3% (P=NS)

Myalgia: 32.9% vs. 33.2% (P=NS)

  • Myopathy without rhabdomyolysis: 0.05% vs. 0.01%
  • Myopathy with rhabdomyolysis: 0.05% vs. 0.03%
  • leading to discontinuation: 0·5% vs. 0·5% (P=NS)

New primary cancer (except non-melanoma skin cancer)

7.9% vs. 7.8% (RR 1; 95% CI 0.91-1.11; P-0.9)

non-melanoma skin cancer

2.4% vs. 2.0% (P=0.06)

Cognitive impairment: 23.7% vs. 24.2% (P=NS)

Fractures: 2.3% vs. 2.2% (P=NS)

Criticisms

  • Only 32% of all screened patients were randomized to receive simvastatin in the trial. It is important to take this into account when interpreting the low adverse event rate in the study and when applying the data to an unselected population.[11]

Funding

  • UK Medical Research Council, the British Heart Foundation
  • Merck & Co (manufacturers of simvastatin).
  • Roche Vitamins Ltd (manufacturers of the vitamins).

Further Reading

  1. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994. 344:1383-9.
  2. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N. Engl. J. Med. 1998. 339:1349-57.
  3. Downs JR et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998. 279:1615-22.
  4. Baigent C et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010. 376:1670-81.
  5. Taylor F, Huffman MD, Macedo AF, Moore THM, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.:CD004816. DOI:10.1002/14651858.CD004816.pub5.
  6. 6.0 6.1 Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,563 high-risk individuals: a randomised-controlled trial. Lancet 2002; 360: 23-33
  7. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: randomised placebo-controlled trial. Lancet 2003; 361:2005-16.
  8. Stone NJ et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2014. 63:2889-934.
  9. 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.
  10. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur. Heart J. 1999. 20:725-41.
  11. Hamilton-Craig I & The Heart Protection Study: implications for clinical practice. The benefits of statin therapy do not come without financial cost. Med. J. Aust. 2002. 177:407-8.