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Therapeutics Letter, issue 24, April - May 1998

LIPID LOWERING THERAPY


This Letter is based primarily on 2 published meta-analyses1,2 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. Unpublished trials are not included. The data are presented as absolute risk reduction (ARR) and number needed to treat (NNT), these being judged the best estimates of the health benefit. The NNT(year) is defined as the number of people that needs to be treated (for a specified number of years) to prevent one event. Whenever possible we have used a standard combined measure of benefit: definite myocardial infarction (MI) and/or cardiovascular (CV) death. This measure was used in the one meta-analysis1; it captures most of the benefit (ARRs are near maximal), and it allows direct benefit comparisons between treatments and trials.

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.

What are the benefits of dietary therapy for secondary 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.

What are the benefits of drug therapy for secondary prevention?

HMG-CoA reductase inhibitors (statins):

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 in men. 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%).

Niacin:

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).

Fibrates (clofibrate, gemfibrozil, bezafibrate, and fenofibrate):

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).

Resins:

These drugs have not been studied in any large secondary prevention trials.

What are the benefits of drug therapy for primary prevention?

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.

Choosing a statin

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.

What are the major adverse effects of 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 therapy

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.

Who will benefit most from 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).

By how much should you reduce LDL levels?

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.

Summary

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.

Table 1. NNT analysis of lipid lowering therapy in secondary and primary prevention trials.

Secondary
Prevention

Drug

MI and/or CV death
Event incidence
Control | Active

ARR (%)

NNT

Average Duration
(yrs)

Meta-analysis1 23 trials, diet and various drugs

24.8%

18.4%

6.4

16

4.9

Coronary Drug Project6 Niacin

36.5%

31.5%

5.0

20

6.2

4S3 Simvastatin

21.5%

13.5%

8.0

13

5.4

8 statin trials except CARE1 Simvastatin
Lovastatin
Pravastatin

19.9%

13.3%

6.3

16

4.1

CARE4 Pravastatin

13.7%

11.0%

2.7

37

5.0

Primary Prevention

           
Meta-analysis1 7 trials, diet and various drugs

5.4%

4.0%

1.4

71

4.9

West of Scotland7 Pravastatin

8.4%

5.8%

2.6

38

4.9

Table 2: Drugs, dose range and cost comparisons for statins and niacin

Drug

Trade Name

Daily Dose Range

Average Daily Cost ($)*

Fluvastatin

Lescol ®

20 - 80 mg

0.80 - 2.25

Pravastatin

Pravachol ®

10 - 40 mg

0.93 - 2.23

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.


References:

  1. Rembold CM. Number-needed-to treat analysis of the prevention of myocardial infarction and death by antidyslipidemic therapy. J Fam Pract 1996;42:577-586.
  2. Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction yields clinical benefit. Impact of statin trials. Circulation 1998;97:946-52.
  3. The Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.
  4. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-9.
  5. Miettinen TA, Pyörälä K, Olsson AG, Musliner TA, Cook TJ, Faergeman O et al. Cholesterol lowering therapy in women and elderly patients with myocardial infarction or angina pectoris. Findings from the Scandinavian Simvastatin Survival Study (4S). Circulation 1997;96:4211-8.
  6. The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. J Amer Med Assoc. 1975;231:360-381.
  7. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-7.
  8. Health Services Utilization and Research Commission. Adherence to cholesterol-lowering drugs in Saskatchewan. Summary report No.9. September 1997.
  9. Grundy SM. Statin trials and goals of cholesterol-lowering therapy. Circulation 1998;97:1436-1439.

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