Medical Research Council/British Heart Foundation Heart Protection Study - HPS

Description:

Medical Research Council/British Heart Foundation Heart Protection Study.

Hypothesis:

Cholesterol-lowering therapy will benefit a much wider range of patients at high risk of coronary heart disease (CHD) death, who will also benefit from antioxidant vitamins.

Study Design

Patients Enrolled: 20,536
Mean Patient Age: 40-80 years
Female: 24

Patient Populations:

Men and women aged 40-80 years; increased risk of coronary heart disease (CHD) death due to prior disease: myocardial infarction (MI) or other CHD, occlusive disease of non-coronary arteries, or diabetes or treated hypertension; total cholesterol >3.5 mmol/L; statin or vitamins not considered clearly indicated or contraindicated by patient’s own doctors.

Primary Endpoints:

Total CHD (nonfatal myocardial infarction and CHD death); nonfatal and fatal strokes; and coronary and non-coronary revascularizations; major vascular events (total CHD, total stroke or revascularizations).

Drug/Procedures Used:

Simvastatin vs. placebo and antioxidant vitamins vs. placebo to determine benefit of cholesterol lowering and of antioxidants in little-studied groups.

Principal Findings:

Designed as a 2 x 2 factorial study to assess separately the effects of antioxidant vitamins and simvastatin in a high risk population.

With the vitamin cocktail employed, there was no benefit seen in terms of mortality: vitamin group 1443 (14.1%) vs 1388 (13.5%) placebo. No evidence found that the vitamins either reduced or increased the risk of a particular cause of death.

Additionally, no benefit was found from the vitamins in terms of major vascular outcomes: 2327 (22.7%) vs 2321 (22.6%).

Compliance over 6 years averaged 85% in the simvastatin group but 18% used non-study statin in the placebo group. Hence, three was an average difference in statin use between those allocated simvastatin and those allocated placebo of 67%.

This two-thirds difference for statin use produced an average reduction in LDL of nearly 1 mmol/L (40 mg/dL).

With a two-thirds compliance rate, simvastatin significantly reduced total mortality by 12% (12.9% vs 14.6%; p<0.001) and was even efficacious against vascular mortality with a 17% reduction rate (7.7% vs 9.2%; p<0.0002).

There was a nonsignificant but slightly favorable trend in reduction of nonvascular mortality, but no evidence of hazard on any particular nonvascular cause of death, including cancer.

Overall, patients experienced a 27% reduction in stroke risk (4.4% vs 6.0%; p<0.00001), most prominently in ischemic stroke, but no excess hemorrhagic stroke.

In terms of all major vascular events, researchers again found a significant 24% reduction in total CHD, total stroke, and revascularization (19.9% vs 25.4%; p<0.00001).

Over time the benefits of the statin therapy increase, suggesting that with more prolonged treatment than in such a 5-year trial, bigger absolute benefits would be expected.

All patient groups benefited from the simvastatin therapy, including patients with a previous MI (who were predominantly the elderly, women, and people with low LDL or total cholesterol for whom there was substantial uncertainty at the beginning), other coronary or vascular disease or diabetes.

This study is the largest study of cholesterol-lowering drug therapy in women (n=5,082) and provides direct evidence that women benefit from cholesterol-lowering therapy equally as men, and evidence of benefit in patients of ages over 75 at entry (n=5805).

HPS also substantially increases knowledge about diabetics; this trial included the largest number of diabetic patients ever randomized in a lipid-lowering trial. In diabetics with no history of CHD, there was a 28% reduction in major vascular events with simvastatin.

Looking at patients by baseline LDL cholesterol levels (split into 3 groups: <3.0 mmol/L; 3.0 to <3.5; and >3.5), there was a significant reduction in vascular events in all these groups, irrespective of their starting cholesterol level. Even in the lowest group, there was a 24% reduction in risk of major vascular events.

Simvastatin treatment was well tolerated, with only 0.8% of patients experiencing a liver enzyme elevation ALT 3x the upper limit of normal (compared with 0.6% of placebo-allocated patients) and only 0.09% experiencing muscle symptoms per creatinine kinase level (vs 0.05% placebo).

Investigators concluded that compliance with a regimen of 40 mg qd of simvastatin safely reduces the risk heart attack, stroke and revascularization by at least one-third in all study groups irrespective of starting cholesterol levels. In this population of high-risk patients, statin therapy prevented anywhere from 70 to 100 major vascular events per 1,000 treated for 5 years.

The researchers extrapolated that if an extra 10 million people were treated with a statin worldwide, there would be 50,000 lives saved annually and even larger numbers of nonfatal heart attacks and strokes prevented.

Interpretation:

Epidemiological and experimental evidence suggests that antioxidant vitamins would be beneficial, not only for the prevention of vascular disease outcomes, but also cancer. However, recent randomized trials of vitamins involving about 150,000 patients have shown that vitamins such as beta carotene and Vitamin E have been ineffective and not preventative of heart disease, at least in Western populations. It remains unclear whether antioxidant vitamins may prevent disease in nutritionally deficient populations or prevent cancer with prolonged treatment.

The benefits associated with simvastatin therapy were independent of initial lipid values, even in individuals with LDL <100 mg/dL, a group that all guidelines do not suggest receive treatment. Additionally, age is irrelevant to therapy, with patients >75 years receiving a resounding benefit. During the presentation at the AHA 2001 annual meeting, discussant Dr. Salim Yusuf noted that the impact on strokes was, to a certain extent, an expected finding from previous trials, but “in this trial one could say it was prospectively defined and confirms finding from the LIPID Study, the CARE Study, and several others.” Overall, simvastatin demonstrated an excellent safety profile, with no excess in any major side effect.

Dr. Yusuf congratulated the HPS investigators for a “superbly designed study with impressive results,” noting that the trial will “undoubtedly change both our practice of medicine as well as the guidelines that assist us.” The results imply that high-risk individuals should receive a statin regardless of their cholesterol levels. Furthermore, liver functions and enzyme levels may not need to be monitored as frequently as in the past, due to simvastatin’s excellent safety, although higher doses may not offer the same safety profile. Other statins also have shown favorable safety profiles.

The results of HPS may have implications for policy guidelines, especially for the U.S. National Cholesterol Education Program Guidelines. Dr. Yusuf said the data showing benefit even in individuals with LDL <100 mg/dL may suggest that physicians should initiate therapy in high-risk patients with low LDL levels – or even simplify therapy more by eliminating beginning and target levels. Certainly, the body of evidence shows that it is time to implement fully a complete therapy strategy for high-risk patients that includes aspirin, beta blockers, angiotensin-converting enzyme inhibitors and statins, as all these agents work independently irrespective of cholesterol or blood pressure levels. “If we use them collectively, we should reduce major vascular events by 75-80%. Now if you add to this blood pressure lowering with a diuretic in hypertensives, or smoking cessation in smokers, perhaps this number will increase to 85 or 90%,” he added.

References:

1. Efficacy and safety of simvastatin. Eur Heart J 1994;15:255-69.
2. WOSCOPS results. N Engl J Med 1995;333:1301-7.
3. Effects on haemostatic variables, lipoproteins, and free fatty acids. Eur Heart J 1997;18:235-41.
4. Safety and efficacy in HPS. Eur Heart J 1998;20:725-41.
5. Secondary prevention in the LIPID trial. N Engl J Med 1998;339:1349-57.
6. Vitamin E in CHD prevention. Arch Fam Med 1999;8:537-42.
7. Question from recent meta-analyses and subset analyses of lipid lowering. Circulation 1999;99:E1-7.
8. Need for evidence about LDL lowering in diabetics. Heart 2000;84:357-60.
9. Cost-effectiveness of treating hyperlipidemia in diabetics. Circulation 2000;102:722-7.
10. Statins not targeted to most appropriate patients. Clin Pharmacol Ther 2000;67:438-41.
11. Vitamin E in preventing CHD. Mayo Clin Proc 2001;76:1131-36.
12. Lipid-lowering and vitamin therapies for vasodilation. J Am Coll Cardiol 2001;38:1806-13.

Clinical Topics: Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Hypertension

Keywords: Myocardial Infarction, Stroke, Vitamin E, beta Carotene, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Diuretics, Creatinine, Simvastatin, Cholesterol, Cause of Death, Biomedical Research, Hypertension, Smoking Cessation, Diabetes Mellitus


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