Re: Statins for the primary prevention of cardiovascular disease
We see that many discerning readers felt compelled to comment on Ebrahim et al’s recent therapeutic review “Statins for the primary prevention of cardiovascular disease”(1). It is confusing to us that the evidence for statins is often presented with such certainty and with an almost unwillingness to share the evidence gaps with patients, where it exists. Some of the gaps include but are not limited to:
1. The review(1)reports that statins reduce the risk of “major” vascular events in the primary prevention context. In our view, it would be quite useful for persons considering statin therapy if the authors could clarify whether or not statins reduce the risk of symptomatic (specifically) myocardial infarctions and disabling (specifically) strokes when prescribed in this setting. We have been unable to find data that clarifies whether or not statins reduce the risk of events that patients, rather than trialists, likely consider to be “major”. If not, we suggest the term “major” be abandoned. This data might prove to be useful as the “Tips for patients” portion of Ebrahim et al’s review suggests that patients be advised that “Statins have to be taken every day and for the foreseeable future”.
2. The authors state that “Lowering blood levels of LDL cholesterol, a major risk factor for cardiovascular disease, reduces the chances of having cardiovascular disease”(1). This is a common misrepresentation and cartoon-like oversimplification of LDL-C and of surrogate markers in general. It is understood that increasing LDL-C generally correlates with an increased risk of morbidity as the authors’ note, however, it is also understood that simply lowering LDL-C does not necessarily translate into a reduction in cardiovascular risk. LDL-C lowering interventions have proven LDL-C to be an inconsistent surrogate for morbidity risk reduction. Torcetrapib lowers LDL-C but increases the risk of mortality; ezetimibe lowers LDL-C but has never been shown on its own to reduce the risk of morbidity and mortality(2,3,4). This concept is critically important as statins are promoted based on their ability to lower LDL-C when the focus should obviously be on their impact on patient-centered outcomes. Thus, it occurs to us as irresponsible to continue to propagate this myth despite the available evidence. The review(1) also encourages consideration of the relationship between reductions in “major” vascular events and LDL-C lowering as described by the Cholesterol Treatment Trialists (CTT) Collaboration(5). It seems these post-randomization variable analyses have been sufficiently deconstructed(6,7). Further, the CTT meta-analysis seems to skip the critical and rigorous review processes such as those outlined by the Cochrane Review Group(8) but please do advise us if we are missing the risk of bias assessment of the RCTs the CTT performs their analyses on.
3. Ebrahim et al’s review reports that statins reduce the risk of combined fatal and non-fatal stroke(1). We note that in the recent Cochrane systematic review of statins for primary prevention(9), 65% of the weight of the analysis for this outcome is driven by two RCTs: JUPITER and WOSCOPS(10,11). By now numerous clinicians and researchers have outlined clearly for us why we should be suspect of analyses that are highly dependent on JUPITER (12,13,14,15). We wonder, is the WOSCOPS study still considered universally relevant? We ask because it is now decades old, enrolled only middle-aged men (mean age 55) from the West of Scotland district of whom 80% were current or ex-smokers. Likely not generalizable to women with an interest in reducing their risk of experiencing a disabling stroke.
4. The authors also contend that “Patients may expect not to be harmed in any way by prevention treatment with statins”(1). Does it seem appropriate to assure patients of this given four paragraphs earlier in the review they note that “unintended effects are not comprehensively reported in systematic reviews or trials”?. Also, is it currently possible to conclude that rhabdomyolysis is rare? We were not able to find a consistent event definition for rhabdomyolysis in statin RCTs and of course one statin RCT changed the event definition to one that was more exclusive but only after events were counted(16). Importantly, as has been recently discussed in this journal, considerable uncertainty remains of the effects of statins on total serious adverse events when prescribed in the primary prevention setting given the limited reporting of this net-benefit outcome(17,18).
5. Last, the reference made to ezetimibe and combination statin-fibrate therapy, as noted by others, was a surprise. We would suggest that the evidence is not “limited” as the authors describe but completely non-existent or entirely not supportive.
Given the less than complete picture of the net benefit of statins when prescribed for primary prevention we do hope clinicians will chose not to use the “Tips for patients” sheet to incompletely inform patients and that they will welcome tough questions raised when patients are advised that they must take a statin “every day and for the foreseeable future”(1).
Cait O’Sullivan (PharmD, BScPh, BA)
Clinical Pharmacist, Island Health, British Columbia, Canada
Aaron M Tejani (BSc(Pharm), PharmD)
Researcher, Therapeutics Initiative, University of British Columbia, Canada
1.Ebrahim S, Taylor F, Brindle P. Statins for the primary prevention of cardiovascular disease. BMJ 2014;348:g280.
2.Barter P, Caulfield M, Eriksson M, et al. Effects of torcetrapid in patients at high risk of for coronary events. N Engl J Med 2007;357:2109-22.
3.Taylor A, Villines T, Stanek E. Parodoxical progression of atherosclerosis related to low-density lipoprotein reduction and exposure to ezetimibe. Eur Heart J 2012;33:2939-45.
4.Krumholz H. Emphasizing the burden of proof. The American College of Cardiology 2008 expert panel comments on the ENHANCE trial. Circ Cardiovasc Qual Outcomes 2010;3:565-67.
5.Cholesterol Treatment Trialists (CTT Collaboration). The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;378:67-5.
6.Hayward R, Hofer Ti, Vijan S. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med 2006;145:520-30.
7.Hayward R, Krumholz H. Three reasons to abandon low-density lipoprotein targets. An open letter to the Adult Treatment Panel IV of the National Institutes of Health. Circ Cardiovasc Qual Outcomes 2012;5:2-5.
8.Higgens J, Green S (editors). Cochrane Handbook For Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.handbook.cochrane.org.
9.Taylor F, Huffman M, Macedo A, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Syst Rev 2013,1: CD004816.
10.Ridker P, Danielson E, Fonseca F, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.
11.Shepherd J, Cobbe S, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-7.
12.De Lorgeril M, Salen P, Abramson J, et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy. A critical appraisal. Arch Intern Med 2010;170:1032-36.
13.Morrissey R, Diamond G, Kaul S. The JUPITER trial: myth or reality. Curr Atheroscler Rep 2011;13:413-21.
14.Serebruany V. Extreme all-cause mortality in JUPITER requires reexamination of vital records. Cardiology 2011;120:84-88.
15.Lopez A, Wright J. Rosuvastatin and the JUPITER trial: critical appraisal of a lifeless planet in the galaxy of primary prevention. Int J Occup Health 2012;18:70-8.
16.Simvastatin. Division of Metabolism and Endocrinology (DMEP) Clinical Review. NDA 19-766 E001. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/019766s077.pdf.
17.Abramson J, Rosenberg H, Jewell N, Wright J. Should people at low risk of cardiovascular disease take a statin? BMJ 2013;357:f6123.
18.Abramson J, Rosenberg H, Jewell N, Wright J. Authors’ reply to the Cochrane Review Authors. www.bmj.com.ezproxy.library.ubc.ca/content/347/bmj.f6123/rr/678736.
Competing interests: No competing interests