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Perry T, editor. Therapeutics Letter. Vancouver (BC): Therapeutics Initiative; 1994-.
Therapeutics Letter 24 is based primarily on 2 published meta-analyses and an in-house systematic review and critical appraisal of the large double-blind randomized controlled trials (RCTs) examining the impacts of lipid lowering therapy. Conclusions: Lipid lowering dietary therapy can be effective and should be a component of all treatment regimens. In secondary prevention, in men age 35 to 70, the benefits from using statins are clear. The absolute benefits are greater the higher the cholesterol. Treatment with niacin is also effective, but is associated with a significant increase in problematic side effects. More secondary prevention data are needed for women and for all patients older than 70 years to be confident that the absolute benefit is the same in these groups. Primary prevention with lipid lowering therapy in high risk men age 45 to 64 causes a statistically significant reduction in MI and/or CV death, however large numbers of patients have to be treated for 5 years to prevent one event. Data are lacking for primary prevention for women and for all patients over age 65.
Trials involving patients with coronary artery disease (angina or previous MI) are designated secondary prevention. Trials involving patients with no evidence of coronary artery disease are designated primary prevention.
In the Rembold meta-analysis1 11 RCTs were identified in which various dietary therapies were compared to control. Four RCTs in which the cholesterol reduction was <4% were excluded. In the 7 RCTs (2431 patients) where dietary treatment was successful, dietary therapy was associated with a 12% reduction in total cholesterol. Diet was also associated with a significantly lower incidence of MI and/or CV death, 21.2%, as compared to the control, 27.8%, ARR = 6.6%, NNT(5 yrs) = 15.
Two well-designed and carefully conducted large RCTs have shown that patients with angina or MI benefit from statins: the 4S3 and CARE4 trials. The 4S trial studied simvastatin in 4444 men (82%) and women (18%) age 35 to 70, with stable angina or previous myocardial infarction and total cholesterol >5.5 mmol/L on a lipid-lowering diet. Simvastatin was associated with statistically significant reductions in total cholesterol (25%), non-fatal MI, CV and total mortality. Definite MI and/or CV death was 13.5% in patients taking simvastatin as compared to 21.5% in patients taking placebo (ARR = 8.0%, NNT(5 yrs) = 13).
A subgroup analysis in women found a statistically significant reduction in non-fatal MI (ARR=6.8%, NNT(5 yrs) = 15; p<0.05).5 However, women in the control and treatment groups differed at baseline; the baseline difference may explain some of the difference in non-fatal MI. Total mortality in women was similar in the simvastatin (6.9%) and placebo (6.0%) groups.
The CARE trial4 studied pravastatin in 4159 men (86%) and women (14%) age 21 to 75 (mean age of 59), with previous MI and total cholesterol <6.2 mmol/L. Pravastatin was associated with a statistically significant reduction in total cholesterol (20%), MI and/or CV death (ARR=2.7%, NNT(5 yrs) = 37). Total mortality was similar in the pravastatin (8.6%) and placebo (9.4%) groups. In a subgroup analysis there was a trend towards a greater reduction in major coronary events (non-fatal MI, death from CHD, CABG, and PTCA) in women as compared to men. Absolute reduction in major coronary events for patients age 60 to 75 (7%) was similar to patients <60 years (5%).
The Coronary Drug Project6 secondary prevention study compared niacin to placebo in men with CHD, age 30 to 64. Niacin reduced total cholesterol by 10% and was associated with a statistically significant reduction in the incidence of definite MI and/or CV death (ARR=5.0%, NNT(6 yrs) = 20). There were, however, statistically significant increases in side effects including flushing, cutaneous reactions, gastrointestinal problems, acute gout (Absolute Risk (AR)=2.1%, Number Needed to Harm (NNH)(6 yrs) = 48) and atrial fibrillation (AR=1.8%, NNH(6 yrs) = 56).
In the Coronary Drug Project6 RCT where niacin was found effective, clofibrate was not associated with any statistically significant reduction in MI and/or CV mortality. When one looks at all fibrate RCTs (both primary and secondary) non-fatal MI may be reduced, but total mortality is not.2 This is likely due to the fact that fibrates are associated with a statistically significant increase in non-CHD mortality; in our meta-analysis of all fibrate RCTs (22,300 patients), fibrates were associated with an absolute risk increase for non-CHD death of 0.5%, NNH(5 yrs) = 200, (p < 0.05).
These drugs have not been studied in any large secondary prevention trials.
The West of Scotland7 trial is the only published statin RCT for primary prevention. This trial of pravastatin recruited men from one of the populations with the highest incidence of ischemic heart disease (IHD) mortality in the world (IHD mortality rate in men of 6.9/1000 per year). This is 3 to 4 times higher than the Canadian IHD mortality rates of 2.1/1000 per year in men, and 1.1/1000 per year in women. The trial enrolled men age 45 to 64 with mean total cholesterol levels of 7.0 mmol/L. Up to 16% of the study participants were not necessarily asymptomatic, as they had established angina or ECG abnormalities at baseline. Pravastatin in this trial was associated with a statistically significant reduction in total cholesterol (20%), MI and/or CV death (ARR = 2.6%, NNT(5 yrs) = 38). Because of the lower IHD mortality rate in Canada, smaller ARRs and larger NNTs would be expected in most asymptomatic Canadians.
In a meta-analysis1 of the 7 main primary prevention studies (2 resins, 2 fibrates, 1 diet and 2 pravastatin) a mean reduction in total cholesterol of 13% was associated with a statistically significant reduction in MI and/or CV death, ARR = 1.4%, NNT (5 yrs) = 71. Total mortality was not significantly reduced. There are very little data on primary prevention for women or for patients over age 65.
The 6 statins available in Canada arranged from least to most potent are: fluvastatin, pravastatin, lovastatin, simvastatin, atorvastatin and cerivastatin. The drugs with a lower potency require a higher dose to achieve the same reduction in cholesterol. No RCTs have established the effectiveness of cerivastatin, lovastatin, fluvastatin or atorvastatin in reducing CHD morbidity and mortality. Fluvastatin and lovastatin have been shown to produce statistically significant reductions in angiographic progression of CHD. There have been no health outcomes trials comparing the effect of the different statins.
In the 3 large statin trials 3,4,7 the overall incidence of adverse events was similar in the statin group and the placebo group. The incidence of a large elevation in creatine kinase concentration in the 3 trials was 2.8/1000 in the statin group as compared to 1.1/1000 in the placebo group. Only one patient, a woman taking 20 mg of simvastatin, developed rhabdomyolysis; she recovered when the drug was stopped. It is important to note that long-term risks, beyond the duration of the trials, are largely unknown at the present time.
Adherence to dietary therapy outside of trials is poor unless there is high patient acceptance and incentive. A Saskatchewan analysis8 found that only 50% of patients take their lipid lowering drugs for more than 4 months; at one year, only 25% of patients were continuing their medications (mostly statins). In contrast, clinical trials have achieved adherence rates over 5 years of more than 94% in the CARE and 87% in the 4S trials. Comparable adherence rates are likely necessary to reproduce the trial benefits in the “real world”. The NNT evidence in this article can be used to provide incentive for patients to adhere to both dietary and drug therapy.
Patients are most likely to adhere and benefit from therapy if they have a good understanding of the rationale and evidence for the therapy. Those with the greatest risk (men with previous MI or angina) have the greatest likelihood of benefit, and should have the greatest incentive to adhere to treatment. For primary prevention the likelihood of benefit is considerably less than for secondary prevention. Likewise when treating patients post-MI, the benefits are greater in those with elevated cholesterol (4S study3) than in those with average cholesterol (CARE study4) (see Table 1).
NNT analysis of lipid lowering therapy in secondary and primary prevention trials.
| Drug | Trade Name | Daily Dose Range | Average Daily Cost ($)* |
|---|---|---|---|
| Fluvastatin | Lescol® | 20 – 80 mg | 0.80 – 2.25 |
| Pravastatin | Pravachol® | 20 – 80 mg | 1.85 – 4.46 |
| Lovastatin | Mevacor® | 20 – 80 mg | 1.73 – 6.37 |
| Simvastatin | Zocor® | 5 – 40 mg | 0.93 – 2.79 |
| Atorvastatin | Lipitor® | 5 – 80 mg | 0.85 – 4.59 |
| Cerivastatin | Baycol® | 0.2 – 0.3 mg | 1.20 – 1.45** |
| Niacin | Generic | 2000 – 3000 mg | 0.14 – 0.21 |
Based on average cost to Pharmacare for 1996 and 1997.
Based on manufacturer price and recommended daily dose.
There is evidence of a correlation between Relative Risk Reduction and percent cholesterol reduction.2 In addition, the magnitude of the ARR for patients with similar percent reduction in cholesterol is greater the higher the baseline cholesterol. How much lipid levels should be reduced is still unclear. The incidence of major coronary events in the CARE4 trial in patients with a low baseline LDL level of <3.2 mmol/L was unchanged by pravastatin, 22%, as compared to placebo, 21%. There is some controversy about whether the benefits are absent or simply diminished below an LDL of 3.2 mmol/L.9 However, in either case there is little rationale for attempting to reduce total cholesterol levels below 4.5 mmol/L or LDL levels below 3.2 mmol/L.
In a future Therapeutics Letter we plan to present an NNT analysis that will compare the benefits of other cardiovascular risk reducing therapies with that of lipid lowering therapy.
This Therapeutics Letter contains an assessment and synthesis of published (and whenever possible peer-reviewed) publications up to May 1,1998. We attempt to maintain the accuracy of the information contained in the Therapeutics Letter by extensive literature searches and verification by both the authors and the editorial board. In addition this Therapeutics Letter was submitted for review to 117 experts and primary care physicians in order to correct any identified shortcomings or inaccuracies and to ensure that the information is concise and relevant to clinicians. Newly published evidence on this topic will be presented as updates in future Therapeutics Letters.
All Therapeutics Letters are also available on our Web site:
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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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