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Statin outcome trials update

 

Clinical bottom line

Across all large outcome studies, irrespective of baseline risk, statins have an NNT of 19 (17-23) for prevention of death or nonfatal heart attack of stroke. An updated analysis with an additional study makes little difference.


Bandolier first visited statins some time ago in issue 47 . Since than more large outcome studies have published, so now (June 2003) is a good time to revisit the subject.

Cardiovascular disease is a leading cause of morbidity and mortality in the industrialised world. Observational studies have demonstrated a clear link between elevated serum LDL cholesterol concentrations and coronary heart disease, making hyperlipidaemia a significant modifiable risk factor that can be targeted. Early attempts to modify lipid profiles using diet and drugs had limited success, and made little impact on clinical outcomes. Statins reduce cellular cholesterol synthesis and were introduced in 1987. They rapidly became popular because they cause larger and clinically significant reductions in cholesterol levels, with few serious adverse effects, and are well tolerated by patients.

Efficacy

Evidence for the efficacy of statins is dominated by relatively few large randomised controlled trials (4,000 to 20,000 patients).

Coronary heart disease (CHD)

Five of the big trials have been combined in a meta-analysis [1]. The trials were all randomised, placebo-controlled and double-blind, with mean intervention durations of more than four years and primary end points of clinical disease or death [2, 3, 4, 5, 6, 7]. A total of 30,817 patients were studied and the mean duration of treatment was 5.4 years with simvastatin, pravastatin or lovastatin. Three trials recruited patients with established coronary heart disease (secondary prevention) and two recruited patients with no history, signs or symptoms of coronary heart disease, but with at risk lipid profiles (primary prevention).

Lipid changes were similar across the trials (Table 1).

Table 1: Mean lipid changes

Lipid fraction
Reduction (%)
Increase (%)
Total cholesterol
20
Low-density lipoprotein cholesterol
28
High-density lipoprotein cholesterol
5
Triglycerides
13

There were no significant differences between primary and secondary prevention trials for all outcomes. Risk reduction and NNTs for various outcomes are shown in Table 2. There was no effect on non-cardiovascular mortality, and no difference in risk reduction between men and women or between those aged 65 years and more and less than 65 years.

Table 2: Major outcomes from meta-analysis [1]

Outcome

Relative risk (95% CI)

NNT (95% CI)

Major coronary event

0.73 (0.69-0.78)

28 (23-34)

Coronary death

0.73 (0.66-0.81)

75 (56-112)

Cardiovascular death

0.74 (0.67-0.82)

69 (52-103)

Data taken from meta-analysis of LaRosa 1999

Since then two reviews and one very large trial have been published that add detail to the evidence.

Stroke

The effects of cholesterol lowering on stroke have been less well studied and are more controversial. Observational studies have demonstrated an increased risk of ischaemic stroke at high cholesterol levels (more than 240 mg/dl, or 6.2 mmol/L) and an increased risk of haemorrhagic stroke at low cholesterol levels (less than 200 mg/dl; 5.2 mmol/L) [12, 13]. It is suggested that low cholesterol may predispose to haemorrhagic stroke by contributing to a weakening of the endothelium of small cerebral arteries. Many statin trials have focused on coronary events and total mortality, but others have prospectively collected data for stroke, and these have been subject to meta-analysis.

Warshafsky et al [14] analysed 13 trials involving 19,921 patients randomised to lovastatin, pravastatin or simvastatin. Baseline cholesterol levels varied from 200 to 272 mg/dl (5.2 to 7.0 mmol/L). Trial duration ranged from 0.5 to 5.4 years, with a weighted mean duration of 4.3 years. The total number of stroke events was low (404/19,921), and few trials showed a significant difference between statin and placebo. Pooled analysis showed a significant reduction for total stroke only in secondary prevention trials. Most studies did not report on the pathology of strokes.

The Pravastatin Pooling Project [8] (19,768 patients, 5 years or more) included two secondary prevention trials that were not included in the previous analysis [4, 6]. These trials again showed a reduction in total and non-fatal stroke, while the primary prevention trial showed a smaller non-significant reduction. The secondary prevention trials provided data on stroke pathology. There were 171 non-haemorrhagic, 19 haemorrhagic and 31 strokes of unknown type. Most of the effect of treatment was on nonfatal, non-haemorrhagic strokes, which comprised 70% of the total. There was no evidence for an effect on haemorrhagic strokes, but the numbers were small and on average cholesterol levels did not drop much below 200 mg/dl.

The MRC/BHF Heart Protection Study [11] (20,536 patients, simvastatin, 5 years, primary and secondary prevention) also demonstrated a significant reduction in non-fatal stroke, and a non-significant reduction in fatal stroke.

Combined outcomes

Most people are concerned with "all bad things happening", which combines death and non-fatal heart attacks and strokes. We have pulled together the large trials that provide data on fatal and non-fatal CHD and stroke in Table 3, together with results for different outcomes.

Table 3: Pooled results from large statin outcome trials

Event

Number of trials

Number of participants

Relative risk (95% CI)

NNT (95% CI)

All CHD

6

51353

0.73 (0.69-0.77)

30 (25-35)

Non-fatal CHD

6

51353

0.71 (0.66-0.76)

47 (39-58)

All stroke

5

44748

0.77 (0.70-0.84)

94 (70-143)

Non-fatal stroke

5

44748

0.74 (0.67-0.82)

95 (72-140)

All CHD and stroke

5

44748

0.75 (0.72-0.78)

23 (20-27)

All cause death

6

51353

0.85 (0.81-0.90)

59 (45-86)

All bad things

5

44748

0.78 (0.75-0.81)

19 (17-23)

[Note: 6 trials comprised SSSS [2], WOSCOPS [3], CARE [4, 5], AFCAPS/TexCAPS [6], LIPID [7], HPS [11] and 5 trials comprised 2, 3, 4, 5, 7, 11]

Figure 1: The outcome of "all bad things" in five RCTs

Comment

Our earlier assessment of the efficacy of statins to prevent death or non-fatal stroke or MI yielded NNTs for statins of 35 in primary prevention and 11 in secondary prevention, well in accord with the pooled outcome of 19 in Table 3. In Bandolier 47 our question was which patient to treat, and what statin to use.

Which patient is now usually defined as an individual having an absolute risk of coronary heart disease of 15% or more over 10 years (equivalent to a combined risk of CHD and stroke (cardiovascular risk) of over 20% over the same period. In reality the goal is usually to treat all patients whose 10-year CHD risk is 30%.

Which drug remains a question to be answered.

References

  1. JC LaRosa et al. Effects of statins on risk of coronary disease. A meta-analysis of randomized controlled trials. JAMA 1999 282: 2340-6.
  2. SSSS. Randomized controlled trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet 1994 344: 1383-9.
  3. J Shepherd et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. NEJM 1995 333:1301-7.
  4. FM Sacks et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. NEJM 1996 335:1001-9.
  5. SJ Lewis et al. Effect of pravastatin on cardiovascular events in women after myocardial infarction. J Am Coll Cardiol 1998 32: 140-6.
  6. JR Downs et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998 279: 1615-22.
  7. Long-term intervention with pravastatin in ischaemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. NEJM 1998 339:1349-57.
  8. FM Sacks et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors. Circulation 2000 102:1893-1900.
  9. M Pignone et al. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomized trials. BMJ 2000 321: 1-5.
  10. CD Furberg et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation 1994 90: 1679-87.
  11. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomized placebo-controlled trial. Lancet 2002 360: 7-22.
  12. H Iso et al. Serum cholesterol levels and six year mortality from stroke in 350 977 men screened for the multiple risk factor intervention trial (MRFIT). NEJM 1989 320:904-10.
  13. K Yano et al. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke 1989 20:1460-5.
  14. S Warshafsky et al. Efficacy of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for prevention of stroke. J Gen Intern Med 1999 14: 763-74.