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MRC/BHF Heart Protection Study

 

The aim of the Heart Protection Study [1, 2, 3, 4] was to assess reliably the effects of cholesterol-lowering therapy and antioxidant vitamin supplementation on morbidity and mortality in patients with a wide range of different categories of high risk.


References

1. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002 360: 7-22.

2. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20 536 high-risk individuals: a randomised controlled trial. Lancet 2002 360: 23-33.

3. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003 361: 2005-2016.

4. www.hpsinfo.org


Background

Large randomised controlled trials have shown that treatment with a statin reduces coronary morbidity and mortality in certain groups of high-risk patients, but evidence for other groups, such as diabetics or the elderly, was limited. Observational studies have shown a continuous, positive relationship between coronary heart disease risk and blood total cholesterol levels, down to at least 3 mmol/L. There is no evidence of a threshold below which lower cholesterol levels are not associated with lower risk, suggesting that cholesterol reduction may be worthwhile for all at high risk of coronary heart disease, irrespective of baseline cholesterol level. In addition, epidemiological studies have shown an inverse relationship between both dietary intake and plasma levels of antioxidant vitamins and the incidence of coronary heart disease and cancer. These findings are plausible, but have not been supported unequivocally by clinical trials.

The study aimed to address these uncertainties by:

Patients

Patients were eligible for inclusion if they were aged 40 to 80 years, had non-fasting blood total cholesterol concentrations of at least 3.5 mmol/L, and were considered to have a substantial 5-year risk of death from coronary heart disease due to a history of:

Patients were ineligible if their own doctor considered that statin therapy was clearly indicated or contraindicated, or if they had:

Study

Potentially eligible patients entered a prerandomisation run-in period comprising four weeks of placebo followed by four to six weeks of 40 mg simvastatin daily. Those who remained eligible, were compliant, and did not have any serious problem during the run-in, were randomly allocated 40 mg simvastatin daily or matching placebo tablets, and antioxidant vitamins (600 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene daily) or matching placebo capsules, using a 2x2 factorial design. The aim of the run-in period was to allow general practitioners to review their patients' lipid profiles, and to limit randomisation to those thought likely to be compliant for at least five years. Patients were encouraged to start taking a non-study statin if their own doctor considered that it had become indicated.

Lipid profiles and medication compliance were assessed at follow-up visits, and information recorded on any vascular events or procedures, cancers, hospital admissions or other serious adverse events. Details were also obtained form general practitioner and hospital records where relevant. All the information was reviewed at the central coordinating centre by clinical staff, who were blinded to treatment allocation.

Outcomes

Primary outcomes were all-cause mortality, and fatal and non-fatal vascular events, and secondary outcomes were cancer and other major morbidity.

Results

20,536 patients were randomised, and the mean duration of follow-up was five years.

There was good balance between treatment groups for prerandomisation prognostic features.

Vitamin supplementation

For patients allocated vitamin supplement capsules the average plasma concentrations of vitamin E, vitamin C and b-carotene were increased by approximately 2-, 3- and 4-fold respectively. There were also small increases in plasma total cholesterol, LDL-cholesterol and triglycerides, but these were not clinically significant. There were no significant differences between those allocated vitamin supplements and those allocated placebo capsules for any outcome studied.

Simvastatin

On average 85% of simvastatin-allocated patients were compliant with treatment, and 17% of placebo-allocated patients took non-study statins, making a difference of about 67% in the percentage of patients actually taking a statin. The investigators estimate that the intention-to-treat comparisons reported assess the effects of about two-thirds of simvastatin-allocated patients actually taking 40 mg simvastatin daily, and that the real effect of treatment is 1.5x the apparent effect.

Patients allocated simvastatin had clinically significant changes in lipid profiles that were independent of baseline cholesterol levels. Mean (SE) reductions in total and LDL-cholesterol and triglycerides were 1.2 (0.02), 1.0 (0.02), and 0.3 (0.03) mmol/L respectively, and increase in HDL-cholesterol was 0.03 (0.01) mmol/L.

Primary outcomes: mortality

Mortality
simvastatin
placebo
RR
NNT
 
n=10,269
n=10267
(95% CI)
(95% CI)
all cause death
1328
1507
0.88 (0.82 to 0.94)
57 (37 to 124)
coronary death
587
707
0.83 (0.75 to 0.92)
85 (55 to 198)
other vascular death
194
230
0.84 (0.70 to 1.01)
cancer death
359
345
1.04 (0.90 to 1.20)
other non-vascular death
188
225
0.84 (0.69 to 1.02)

 

Primary outcomes: vascular events

Vascular events
simvastatin
placebo
RR
NNT
n=10,269
n=10267
(95% CI)
(95% CI)
any vascular event
2033
2585
0.79 (0.75 to 0.83)
19 (15 to 24)
major coronary event
898
1212
0.74 (0.68 to 0.80)
33 (26 to 45)
stroke
444
585
0.76 (0.67 to 0.86)
73 (51 to 129)
revascularisation
939
1205
0.78 (0.72 to 0.85)
39 (29 to 57)

 

Adverse events

No differences were found between treatment groups for the incidence of, or withdrawals due to, elevated levels of alanine aminotransferase or creatinine kinase, or for symptoms of muscle weakness, including rhabdomyolysis. The incidence of new primary cancers at any site, did not differ significantly between groups, nor was there any indication of an effect on neuropsychiatric disorders, respiratory disease, bone fractures or hospitalisations.

Comment

This study was large enough to allow sensible analyses to be performed on different subcategories of patients. These analyses demonstrated remarkably similar relative risk reductions of about one-quarter in men and women, older and younger patients, diabetics and non-diabetics, smokers and non-smokers, and in patients with or without prior coronary heart disease, taking other cardiovascular disease medications or not, and with high or low baseline cholesterol levels. Furthermore, patients taking statins who suffered a first event were at reduced risk of suffering a second event, compared to those taking placebo, and the benefits were additional to those of other treatments (eg aspirin. b-blockers).

The authors calculate that five years of statin treatment would typically prevent a major vascular event in:

The take-home message is that sustained reduction of LDL-cholesterol with simvastatin is safe and produces a substantial reduction in major vascular events in a wide range of high-risk individuals, irrespective of cholesterol levels at the start of treatment. This is particularly important for groups such as diabetics, who are at increased risk of vascular problems, but may have "normal" cholesterol levels. The relative risk reduction is remarkably constant, at about 25%, but the absolute benefit clearly depends on the individual's baseline risk. Supplements of antioxidant vitamins produced neither benefit not harm.