January 19th, 2011
Review Raises Questions About Statins for Primary Prevention
Larry Husten, PHD
A Cochrane Review raises troubling questions about the evidence base supporting the use of statins for primary prevention. The Cochrane reviewers analyzed 14 randomized trials including 34,272 participants and found that statins were associated with significant reductions in overall mortality, fatal and nonfatal CV endpoints, and revascularization procedures. The reviewers found no evidence of harm.
However, the authors found “evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease.” They concluded that “only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.”
In an accompanying editorial, Carl Heneghan discusses the limitations of the trials under review, noting, among other limitations, that the power calculations in most of the trials were based on composite outcomes, that selective reporting of outcomes occurred in some trials, and that some trials reported no adverse outcomes at all. He concludes that “the most effective and cost-effective intervention for primary prevention in adults at low risk currently remains unclear” and argues that it is “unwise to use such studies to determine the overall benefits and harms to the population at risk and drive policy.”
10 Responses to “Review Raises Questions About Statins for Primary Prevention”
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The prudent, practical physician must treat his/her patients now, using the best evidence available, even if it is not ideal, rather than chose inaction, given the immense threat of a growing cardiovascular risk burden in our population.
This study adds another meta-analysis to those available concerning the effectiveness of statins in primary prevention. The imperfections in these trials are well known. In a recent issue of the Archives of Internal Medicine, Ray et al concluded that statins did not produce mortality benefits. In this Cochrane review, methodological problems are cited in such studies, even though benefits in hard end points were realized. One is left to doubt whether statins are worthwhile, thus favoring primordial prevention. However, in a related Cochrane review, the effects of counseling, education, and “programs” upon lifestyle behavior were also “dubious.” The seasoned cardiologist will not be surprised at either conclusion.
What is the prudent, practical physician to do in the interim, wait years to begin treatment while atherosclerosis disseminates? Should we not bother to talk about lifestyle change or risk factors while we also withhold statins, since both are “unclear “interventions?
The epidemiological and pathological evidence suggesting that the incubation period for CHD spans decades is strong and accepted. Tracking of risk factors in the Bogalusa Heart study, combined with additional data comparing worsening CIMT and CAC scores between youth and adulthood in proportion to the risk burden, clearly connect the dots. For several reasons, there will not be a study in the near future that definitively demonstrates statin treatment in a low-risk primary prevention population is an air-tight method of reducing hard end-points, including mortality, at a cost acceptable to everyone. Some models indicate it may do so under given conditions, but RCTs, no.
Rather than chose inaction, which would be disastrous in years to come, we should continue both methods—primordial prevention, and intensive evaluation followed by aggressive treatment in high-risk patients. The techniques used for each and cutoffs need continuous reevaluation and improvement, to be sure. The best evidence, while admittedly relying on logical inference, indicates statins should be used, since there are no equals. The safety of statins was not an issue in the first review, and in the second, the behavior change observed was simply insufficient. Assuming behavior change in humans is impossible has serious social implications. Acting on that assumption is irresponsible.
Extreme therapeutic nihilism based upon these reviews is unwarranted and potentially dangerous. Waiting for “clarification” involves far greater peril than beginning statins and intensifying primordial prevention efforts on a national scale. The evidence for primordial prevention is summarized at http://tak.sagepub.com/content/early/2010/12/21/1753944710391350.abstract
Richard Kones
Competing interests pertaining specifically to this post, comment, or both:
None
The problem with primary prevention is our poor sensitivity of predicting outcomes based upon conventional risk factors. It has been shown that 66% of women at highest risk for heat attack are classified as being at low risk by Framingham risk assessment. Over half of men with heart attacks would not qualify for prevention prior to their initial symptomatic event.
As this study celebrates our failures, we should reflect on opportunities to improve on practice dynamics.
Predicting coronary risk with coronary calcium imaging and stroke risk with carotid ultrasound imaging will identify and accurately stratify risk. Importantly, atherosclerosis imaging also identifies the 50% of the population that will not benefit from treatment. In addition, identification of increased coronary risk by coronary calcium imaging has been shown to be a strong motivator of behavioral change and medication compliance.
It is past time for the old guard to stop fighting against the use of atherosclerosis imaging.
Not only does the initial calcium score accurately predict risk, progression of the EBT calcium score over time is associated with inadequately treated risk while stability of serial EBT calcium scores have been shown to be consistent with dramatically reduced risk.
The recent study in JACC imaging showing a 3 fold difference in all cause mortality based upon progression vs stability of plaque with serial EBT imaging is further evidence that serial CAC imaging can provide significant evidence of adequacy of medical intervention.
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Using coronary calcium imaging, I have been able to reduce coronary events dramatically compared to what I could do prior to utilizing EBT technology. 750 patients, over half are age 65 and over, 0 heart attacks and 2 elective revascularizations for angina over the past 14 months.
While the Cochrane review highlights several important limitations of the primary prevention statin trials, it does little to advance clinicians’ ability to discuss these data with patients to make an informed decision of whether to initiate (or stop) statin therapy. I recently reviewed the major primary prevention statin trials, in an attempt to distill the risks and benefits of therapy.
Benefits:
The NNT ranges from 42 (WOSCOP) to 119 (MEGA). As the authors point out, these 2 study populations were very different – and thus may be relavent for different patients. In WOSCOP, a study of men, baseline LDL was >160 and many had vascular disease (16%) or signficant risk factors. MEGA, on the other hand, was in a relatively healthy population of Japanese patients(as evidenced by the very low event rate in both groups); baseline LDL was between 130-160. Of note, women did not derive any benefit in the MEGA study. In JUPITER, NNT=83 over 1.9 years (NNT=25 over 5 years), in addition to having an elevated CRP, over 40% had metabolic syndrome. While these results may be exaggerated given the early termination of the study, they give some indication of the benefit to be expected.
Risks:
We now know statins are safe, but the side effect most commonly experienced by patients – myopathy – is poorly, if at all, assessed. (Of note, the Cochrane review does not address this failure). While most trials report an incidence of 1-5%, clinical reports and observational data suggest that 1-2 out of every 10 patients will experience myopathy. Myopathy refers to any muscle complaint. While there are direct toxic effects to the muscle that may result in weakness or cramping, statin toxicity may also unmask or worsen an underlying arthritis or neuromuscular disease. Clinicians need to better recognize the symptoms of myopathy and the potential impact on patients’ quality of life.
When patients experience this often debilitating side-effect, the NNT data become ever more relavent. As one patient asked me the other day, “I can barely walk; can you tell me again, what are the benefits of me taking this medication?”
Is the agenda (not evidence) different in the UK and EU than in the US regarding lab and procedure utilization, indications, and priority, according to the weight of information gained vis-a-vis the action planned?
I think yes. Do the papers that eminate reflect it?
It is clear from the West of Scotland trial that men with a total cholesterol > 250 mg/dL benefitted significantly from a statin. The p value for mortality reduction at 5 years was 0.051. The data collected 6 months later showed a mortality reduction that became statistically significant. The AFCAPS/TexCAPS trial showed a very large decrease in cardiovascular events in subjects with multiple risk factors. In JUPITER, use of a potent statin in persons with a median age of 66 and an elevated CRP showed a statistically significant decrease in total mortality.
You don’t see a total mortality reduction in lower risk, younger adults, but you do in those with very high cholesterol or those in their 60’s with an elevated CRP and generally two or more components of the metabolic syndrome.
The authors of this recent Cochrane review would seem to side with Drs. Deborah Grady and Dr. Rita Redberg; in a recent issue of the Archives of Internal Medicine they wrote that lipid lowering in primary prevention is a therapy with no proven benefit and clear potential harms. This ridiculous statement is laughable and goes against everything in the NCEP guidelines. Do these very learned and accomplished individuals also believe that there is no reason to treat hypertension in the primary prevention setting since there are no mortality reductions within the next 2-5 years in most studies? Do they not presribe a bisphonate to women with osteoporosis and a family history of hip fracture since there is no mortality reduction in 2-5 years. If only 5-10% of cardiac events are fatal, one needs to prevent a lot of events to achieve a total mortality reduction in 2-5 years.
Cost-effective analysis in primary prevention using data from WOSCOPS and AFCAPS and JUPITER are reasonably favorable with brand-name prices. It is clear with generic statins that the ongoing cost-effectiveness analyses will be very cost-effective. If a person in San Francisco wants advice on comprehensive risk factor modification to lower their cardiac risk in the primary prevention setting, it would be best to seek it at Dr. Bill Grossman’s Preventive Cardiology Center at UCSF. Prudent use of lipid lowering therapy in primary prevention makes sense in those with multiple risk factors. We all agree that we want to emphasize comprehensive risk factor modification with better dietary and exercise habits in all adults.
Competing interests pertaining specifically to this post, comment, or both:
none
The JUPITER trial has been criticized by numerous well respected statisticians and cardiologists as a study with unreliable data from non-US enrollment sites all around the world.
Obviously primary prevention works in high risk groups, I practice in Cairo Egypt, and I have many diabetic smoking patients with LDL of above 130 and they are all on statins, as far as non diabetics, using risk scores is helpful, there are difficult issues let me ask you an anecdotal question, how would you treat a 30 year old obese woman with an LDL of 200 who failed to bring it down by life style modification over the last 24 months, I am not sure we have an solid scientific answer.
For those of us who had been practicing before the statin era, we respect all the trials and the data but we have seen with our own eyes the impact of lipid lowering on CV disease, this cochrane review is worth reading but should not change practice.
I agree with all of RB’s comments. I continue to risk being overly aggressive with statins. As far as myalgias…a reasonable percent may be a” nocebo” effect. Some of the placebo trials suggest no difference in myalgias. Is this because of the nocebo effect, initial” roll-in” phases, or a problem with reporting?
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nothing
When I was doing research, it was usually true that if you had to argue about the significance of the data, then the data was not very significant.
The relative risk reduction (of a vascular event) achieved by using a statin seems to be relatively constant across the spectrum of absolute risk (say 20% for older and lower dose statins, 30% for more potent and higher dose treatments). Not surprisingly, primary prevention trials can be diluted by a significant proportion of participants being at low or very low risk rather than there being a qualitative difference in effect. The following may seem simplistic but makes logical sense to me. Making a rough estimate of medium term (5 or 10 year) absolute risk for any given patient and then explaining what this would likely come down to with treatment would be the most honest approach and allow a patient to make an informed choice.
Competing interests pertaining specifically to this post, comment, or both:
None