Heart Protection Study Follow-up Confirms Consistent Benefit and Long-term Safety of Statin Treatment

Linda Brookes, MSc

Disclosures

June 12, 2007

Extended follow-up of patients who participated in the UK Heart Protection Study (HPS) has provided more evidence of the safety of statins and the persistence of their beneficial effects. The survival benefit associated with the prescribed simvastatin regimen over 5 years was maintained over 4 years after the study stopped. The results of the HPS posttrial follow-up study, which were presented at the 2007 ACC meeting by Richard Bulbulia, MD (Clinical Trial Service Unit, University of Oxford), also showed that simvastatin had no effects on the incidence of cancer or nonvascular mortality during this posttrial period.[1]

 

The original HPS, which was funded by the UK Medical Research Council, the British Heart Foundation, Merck, and Roche Vitamins, enrolled men and women aged 40-80 years with total cholesterol ≥ 3.5 mmol/L (≥ 135 mg/dL).[2] All HPS participants were considered to be at substantial 5-year risk of death from coronary heart disease (CHD) because of a medical history of coronary disease (myocardial infarction, unstable or stable angina, coronary artery bypass graft, or angioplasty), occlusive disease of noncoronary arteries, diabetes mellitus, or (in men aged ≥ 65 years only) treated hypertension. A total of 20,536 patients were randomly allocated to receive 40 mg simvastatin daily or matching placebo.

Over approximately 5 years, simvastatin was associated with an average 1.0-mmol/L (38 mg/dL) reduction in LDL cholesterol compared with placebo. This resulted in relative reductions in major vascular events of 24% and in all-cause mortality of 13%. During the first year of the study, the reduction in major vascular events did not differ significantly between the 2 groups, but subsequently it was highly significant, suggesting that more prolonged treatment with simvastatin might result in larger benefits. There were no adverse effects on nonvascular mortality or cancer during the study.

 

The 4-Year Follow-up

The posttrial 4-year follow-up was carried out for all 17,519 surviving HPS participants by means of mailed annual questionnaires (80% response rate) or via primary care physicians, supplemented with cause-specific mortality and site-specific cancer incidence noted from central registries. During this posttrial period, statin use was at the discretion of the managing physicians and was similar among patients previously allocated simvastatin or placebo in the main study, resulting in similar LDL cholesterol levels in both groups.

Over the 4-year posttrial period, there was no additional benefit associated with statin use. A total of 1810 major vascular events (20.4%) were recorded in the patients originally allocated simvastatin and 1858 (21.5%) in the patients originally allocated placebo ( Table 1 ). Rates of major coronary events and strokes did not differ significantly between the 2 groups, although a significant risk reduction was seen in revascularization.

During the first year of posttrial follow-up an additional small but significant benefit was seen in the group originally allocated simvastatin. In subsequent years, however, there was no evidence of this additional benefit.

During the original HPS treatment period, the beneficial effects of simvastatin on major vascular event was driven by an 18% reduction in vascular mortality among the patients originally allocated simvastatin. During posttrial follow-up there was no significant difference in vascular or nonvascular mortality between the 2 patient groups ( Table 2 ).

Over the study and posttrial periods combined, there was no evidence of an effect of simvastatin and cancer incidence (15.3% in the simvastatin group vs 15.0% in the placebo group). It is possible that an effect on cancer would not emerge during this time period, although if it existed it would probably have started to become apparent by the end of the posttrial follow-up, Dr. Bulbulia suggested.

 

Conclusion

These findings support the prompt initiation and continuation of statin therapy in individuals at increased vascular risk. These previous benefits persist during at least 4 years of posttrial follow-up, substantially increasing the cost-effectiveness of treatment.

The Original HPS

The original HPS, which was funded by the UK Medical Research Council, the British Heart Foundation, Merck, and Roche Vitamins, enrolled men and women aged 40-80 years with total cholesterol ≥ 3.5 mmol/L (≥ 135 mg/dL).[2] All HPS participants were considered to be at substantial 5-year risk of death from coronary heart disease (CHD) because of a medical history of coronary disease (myocardial infarction, unstable or stable angina, coronary artery bypass graft, or angioplasty), occlusive disease of noncoronary arteries, diabetes mellitus, or (in men aged ≥ 65 years only) treated hypertension. A total of 20,536 patients were randomly allocated to receive 40 mg simvastatin daily or matching placebo.

Over approximately 5 years, simvastatin was associated with an average 1.0-mmol/L (38 mg/dL) reduction in LDL cholesterol compared with placebo. This resulted in relative reductions in major vascular events of 24% and in all-cause mortality of 13%. During the first year of the study, the reduction in major vascular events did not differ significantly between the 2 groups, but subsequently it was highly significant, suggesting that more prolonged treatment with simvastatin might result in larger benefits. There were no adverse effects on nonvascular mortality or cancer during the study.

The 4-Year Follow-up

The posttrial 4-year follow-up was carried out for all 17,519 surviving HPS participants by means of mailed annual questionnaires (80% response rate) or via primary care physicians, supplemented with cause-specific mortality and site-specific cancer incidence noted from central registries. During this posttrial period, statin use was at the discretion of the managing physicians and was similar among patients previously allocated simvastatin or placebo in the main study, resulting in similar LDL cholesterol levels in both groups.

Over the 4-year posttrial period, there was no additional benefit associated with statin use. A total of 1810 major vascular events (20.4%) were recorded in the patients originally allocated simvastatin and 1858 (21.5%) in the patients originally allocated placebo ( Table 1 ). Rates of major coronary events and strokes did not differ significantly between the 2 groups, although a significant risk reduction was seen in revascularization.

During the first year of posttrial follow-up an additional small but significant benefit was seen in the group originally allocated simvastatin. In subsequent years, however, there was no evidence of this additional benefit.

During the original HPS treatment period, the beneficial effects of simvastatin on major vascular event was driven by an 18% reduction in vascular mortality among the patients originally allocated simvastatin. During posttrial follow-up there was no significant difference in vascular or nonvascular mortality between the 2 patient groups ( Table 2 ).

The posttrial 4-year follow-up was carried out for all 17,519 surviving HPS participants by means of mailed annual questionnaires (80% response rate) or via primary care physicians, supplemented with cause-specific mortality and site-specific cancer incidence noted from central registries. During this posttrial period, statin use was at the discretion of the managing physicians and was similar among patients previously allocated simvastatin or placebo in the main study, resulting in similar LDL cholesterol levels in both groups.

Conclusion

These findings support the prompt initiation and continuation of statin therapy in individuals at increased vascular risk. These previous benefits persist during at least 4 years of posttrial follow-up, substantially increasing the cost-effectiveness of treatment.

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