Analysis

Should people at low risk of cardiovascular disease take a statin?

BMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f6123 (Published 22 October 2013) Cite this as: BMJ 2013;347:f6123

Re: Should people at low risk of cardiovascular disease take a statin?

We thank the Cochrane review authors for their thoughtful comments (excerpted in bold below), which provide the opportunity to clarify unresolved issues about the benefits and harms of statins in low risk people.

The timing of this Analysis predated by three weeks the publication of the 2013 American College of Cardiology/American Heart Association cholesterol treatment guidelines (November 12, 2013), but statements were made about “proposed standards” without full knowledge of these guidelines.

The “proposed 2013 standards” to which we referred in our Analysis[1] were not the as-yet-unpublished 2013 American College of Cardiology/American Heart Association cholesterol treatment guidelines,[2] but rather the 2013 update of the Cochrane review titled “Statins for the primary prevention of cardiovascular disease,”[3] which had incorporated the findings and recommendations of the 2012 CTT meta-analysis.[4]

The 2012 CTT meta-analysis reported that statin therapy provides a significant reduction in major vascular events in people “with 5-year risk of major vascular events lower than 10%.” It concluded that the then-current major guidelines – ATP-III in the U.S., the European Society of Cardiology task force, and the National Institute of Clinical Excellence in the U.K. – “might need to be reconsidered.”

The 2013 Cochrane Review stated: “….in light of new evidence derived from the CTT Collaboration on primary prevention, there is a need to update existing cost-effective analysis.”

We based our comments about “proposed standards” on these calls to update existing recommendations. Although we had no advanced knowledge of the contents of the forthcoming ACC/AHA cholesterol treatment guidelines, we anticipated that these findings and recommendations would be influential.

Abramson et al. state: "Under the proposed 2013 standards, however, no level of risk would preclude statin therapy…

The 2012 CTT meta-analysis published in the Lancet concluded: “The present report shows that statins are indeed both effective and safe for people with 5-year risk of major vascular events lower than 10% and, therefore, suggests that these guidelines might need to be reconsidered.” No lower limit of benefit is suggested in the CTT meta-analysis.

The 2013 Cochrane Review then stated, “Our previous conclusion urging caution in the use of statins in people at low risk of cardiovascular events is no longer tenable in light of the CTT Collaboration findings.” Again, a lower limit of risk for the benefit of statins was not specified.

…raising the question whether all people over the age of 50 should be treated.” Neither the Cochrane review nor the ACC/AHA cholesterol guidelines proposed treatment for everyone over the age of 50 years.

The 2012 CTT meta-analysis reported significant reduction in major vascular events for patients with less than 10% 5-year risk, averaging 2.6% 5-year risk for major coronary events.

Two editorials that accompanied publication of the 2012 CTT meta-analysis in the Lancet commented on the benefit of statin therapy in low risk people found in the 2012 CTT meta-analysis. One cautioned about the increased risk of new onset diabetes, but stated “a good case could be made for treatment of individuals with an absolute risk of a cardiovascular event of less than 5% during 5 years with statins.”[5]

The other editorial, titled “Statins for all by the age of 50 years?” discussed the translation of the CTT findings into practice: “Because most people older than 50 years are likely to be at greater than 10% 10-year risk of cardiovascular disease, it would be more pragmatic to use age as the only indicator for statin prescription…” Both authors of this editorial were members of the Cochrane Heart Group.[6]

The 2013 Cochrane Review to which we refer concluded: “The individual patient data meta-analyses now provide strong evidence to support [statin] use in people at low risk of cardiovascular disease.” No lower limit of benefit was indicated.

The ACC/AHA cholesterol guidelines, issued three weeks after our Analysis was published in BMJ, recommend statin therapy for people with ≥ 7.5% 10-year risk of cardiovascular disease, with the option of statin therapy for people whose 10-year risk is between 5 and 7.4%. This further strengthens the argument presented in the 2012 editorial that the decision to prescribe statins could more cost-effectively be made simply on the basis of age. A 50-year-old American man with all values entered into the AHA risk calculator[7] at the 50th percentile has a 6% 10-year risk of cardiovascular disease. A 55-year-old American man with risk factors at the 50th percentile has a 10% 10-year risk of cardiovascular disease.

The updating of the evidence base resulted in an expected narrowing of confidence intervals and the addition of JUPITER trial added important evidence on diabetes risk.

Narrowing of the confidence intervals is, obviously, expected with the addition of clinical trial data. However, the effect of statin therapy on cardiovascular risk did not change, and therefore did not provide a basis for the Cochrane Review to radically change its recommendation from 2011 to 2013. Furthermore, we question the validity of the JUPITER trial data given that the trial was prematurely stopped at a time when there was no difference in cardiovascular mortality or serious adverse events between the rosuvastatin and control groups, and the unrealistically low mortality rate (8.8%) associated with myocardial infarction in the control group, compared to a 29% case fatality rate in the rosuvastatin group, raised questions about bias in event ascertainment.[8]

The authors consider that statins should reduce total mortality if they are to have a place in primary prevention in people in lower CVD risk strata and estimate a relative risk of 0.95, 95% confidence interval 0.86 to 1.04. However, the authors included both individuals with and without prior vascular disease in this estimate.

The “Main results” of the 2013 Cochrane Review reported: “Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta-analysis indicate that these benefits are similar in people at lower (< 1% per year) risk of a major cardiovascular event.” The Table in our Analysis, titled “Comparative all cause mortality for low risk patients in statin studies included in Cholesterol Treatment Trialists’ meta-analysis” addresses this issue. As stated in our Analysis, statin therapy does not reduce over-all mortality significantly for the population of low-risk patients included in the clinical trials.

In considering the effect of statin therapy on the low-risk population, no clinical logic supports the removal of low risk patients diagnosed with cardiovascular disease from this calculation. Inclusion of these patients would be expected to increase rather than decrease the efficacy of statins. The discrepancy between the effects of treatment on the primary prevention population on the one hand and the low risk population as a whole on the other, exists because of a statistical quirk in the clinical trial data: low risk people (< 20% 10-year risk) with a history of vascular disease had no reduction in overall mortality (relative risk of overall mortality associated with statin therapy for < 5% risk = 1.04 and for ≥ 5% to < 10% = 1.00).[9] “Slicing and dicing” the data for overall mortality in the low risk group exploits the removal of these data to increase the estimated effect of statins.

Although the title of our Analysis addressing potential benefit of statin therapy in low risk people is correct, we agree that the précis beneath the title incorrectly points readers toward the effect of statin therapy in the primary prevention population rather than low risk population as a whole.

…the number of total deaths was small (1% of control group participants dying over 4 years) and non-CVD causes of death exceeded CVD deaths by more than 2:1… No strong evidence of benefit for total mortality was seen because other causes of death make up a greater proportion of total deaths, and it is unlikely that taking statins influences these non-CVD deaths.

We agree that, in the lower risk groups, by definition, cardiovascular causes of death will constitute a smaller proportion of total mortality. However, among low risk patients included in the CTT meta-analysis, statins failed to achieve a reduction in overall mortality and also failed to achieve a reduction in serious adverse events, and therefore no “net” or overall health benefit can be claimed.

We disagree with their statement that the “best indication of the net effect of a treatment on overall health is the total number of serious adverse events — which include deaths from all causes, hospital admissions, prolongations of admission, cancer, or permanent disability.”

We agree with this criticism. This sentence should read: “After overall mortality, the best indication of the net effect of a treatment on overall health…”

While criticizing the RCTs, they use low quality evidence from observational studies to support their statements about the hazards associated with statins despite likely high risk of bias.

We agree that observational studies provide a lower level of evidence than well-conducted RCT’s. Unfortunately none of the clinical trials included in the CTT meta-analysis compared drug therapy to lifestyle intervention in order to answer the question of how to most effectively and efficiently reduce the burden of cardiovascular disease on the low risk population. Thus, we relied upon the best available information.

A recently published metaepidemiological study included randomized controlled trials comparing the effectiveness of exercise and drug interventions in the reduction of mortality for secondary prevention of coronary heart disease, stroke, prediabetes, and congestive heart failure.[10] Results showed that exercise and statins were equally effective in patients with coronary heart disease, and exercise was 90% more effective than anticoagulants and antiplatelet drugs for stroke patients.

A publicly funded randomized controlled study comparing statin therapy, lifestyle intervention, and both for the prevention of cardiovascular disease in low risk patients would provide important comparative effectiveness information.

The authors also conflate muscle pain (myalgias), an important side effect of statins, with myopathy, a rare and more serious problem…

This is a semantic criticism, with which we disagree. From a practical point of view, statin-induced myopathy includes: myalgia (muscle symptoms without elevation in CK), myositis (elevated CK with or without muscle symptoms), and rhabdomyolysis (CK levels > 10 times the upper limit of normal).[11] Further, histopathologic findings of myopathy occur in patients with or without muscle symptoms and normal CK levels.[12] [13] [14]

The authors cite studies demonstrating adverse events associated with statin therapy but fail to cite systematic reviews which show no increased risk of psychological outcomes, fractures, acute renal failure, arthritis, or venous thromboembolism.

To narrow this concern, we did not comment on the relationship between statin therapy and the risk of fractures, arthritis, or venous embolism. In fact, an article we cited, based on 225,000 new users of statins in England and Wales, showed no significant association between statin therapy and these three adverse occurrences.[15] The same article did, however, show significant increased risk of acute renal failure associated with statin therapy. Because of under-ascertainment of adverse effects of statins in clinical trials, epidemiological data—like the data from general practices in England and Wales and the data addressing psychiatric adverse reaction from the New Zealand Center for Adverse Reactions Monitoring must be heeded as substantial warnings of potential adverse events.[16] The problem of under-ascertainment of adverse events in clinical trials is demonstrated by a 2006 meta-analysis of clinical trials involving statins that reported no increase in the risk of myalgia.[17] We agree that a more extensive review of the literature about each of these potential adverse reactions should include the full range of published articles.

Finally, Abramson et al. set up a false dichotomy, stating: “Rather than being compelled by guidelines to prescribe statin therapy for people at low risk of cardiovascular disease, doctors would provide a far greater service by explaining the magnitude of the benefits and uncertainty about the harms of statins together with discussion of the epidemiological evidence showing that behavioural risk factors—including tobacco use, lack of physical exercise, and unhealthy diet—are responsible for 80% of cardiovascular disease.” If they (and the BMJ editors) had awaited the publication of the 2013 ACC/AHA cholesterol guidelines, they would have been directed to the companion lifestyle guidelines, which aim to address these topics.

We agree that the 2013 ACC/AHA cholesterol guidelines include guidelines for positive lifestyle modification—as have the preceding guidelines. But once again, it is the expanded criteria for prescribing statins that is getting the attention, not the fundamental importance of lifestyle modification. The pro forma nature of the lifestyle recommendations is seen in an editorial written by a Vice Chair of the Expert Panel responsible for the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol: “Despite decades of exhortation for improvement, the high prevalence of poor lifestyle behaviors leading to elevated cardiovascular disease risk factors persists, with myocardial infarction and stroke remaining the leading causes of death in the United States. Clearly, many more adults could benefit from evidence-directed use of statins for primary prevention.”[18] Once again, doctors are implored to “get real”--stop hoping that efforts to assist their patients and communities in the adoption of healthy lifestyle habits will succeed, and start prescribing more statins. This is a self-fulfilling prophecy. Note that the author of these comments disclosed receipt of funding from 11 drug companies, at least 4 of which are producing or developing new classes of cholesterol lowering biologics[19] that are projected to achieve annual sales of up to $10 billion per year.[20]

Our response to the Cochrane Reviewers’ comments would not be complete without addressing the evidence upon which they have relied. The Cochrane review adhered to strict standards of data collection and analysis, reviewing data for risk of bias, examining heterogeneity, sensitivity analysis, etc. However, there is no evidence they were granted access to the fundamental clinical evidence that prevents bias: patient level data from the clinical trials. The References section of the 2013 Cochrane Review shows that the source of data for every study included in the review was “published data only.”[21] Unlike the Cochrane Review, the Cholesterol Treatment Trialists Collaboration has been granted access to and relies upon patient-level data for every study incorporated into its meta-analyses.

In 2009, when the Cochrane Reviewers of neuraminidase inhibitors for prevention and treatment of influenza in healthy adults were unable to gain access to primary data from the manufacturer’s clinical trials of oseltamivir (Tamiflu),[22] they withdrew previous reviews.[23] [24] Access to patient-level data is similarly necessary for Cochrane reviewers of statin therapy to perform a thorough and independent evaluation. At the very least, analyses of prespecified outcome measures could be performed independently and the question of whether statins reduce the incidence of serious adverse events across all trials could be addressed.

If the Cochrane Reviewers have requested and been denied access to the patient-level data from the statin studies, we believe they should do what the reviewers of oseltamivir have done: publicly declare their inability to perform a responsible evaluation and retract conclusions that are based on published data only. The entire world is relying upon third party representations of data that the manufacturers should make readily available to Cochrane Reviewers and other academic researchers.

References
1 Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013; 347:f6123. doi: 10.1136/bmj.f6123
2 Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum CB, McBride P, Eckel RH, Schwartz JS, Goldberg AC, Shero ST, Gordon D, Smith Jr SC, Levy D, Watson K, Wilson PWF, 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol 2013; in press. doi:10.1016/j.jacc.2013.11.002.
3 Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013; 1:CD004816. doi:10.1002/14651858.CD14004816.pub14651855
4 Cholesterol Treatment Trialists’ Collaborators. 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; 380:581-590. doi:10.1016/S0140-6736(12)60367-5
5 Watts GF, Ooi EM, Balancing the cardiometabolic benefits and risks of statins, Lancet, 2012;380:541-3
6 Ebrahim S, Casas JP, Statins for all but the age of 50 years? Lancet, 2012; 380:545-7.
7 American Heart Association Heart Attack Risk Assessment, https://www.heart.org/gglRisk/main_en_US.html Accessed December 14, 2013
8 De Lorgeril M, Salen P, Abramson J, et al, Cholesterol Lowering, Cardiovascular Diseases, and the Rosuvastatin-JUPITER Controversy, Arch Intern Med. 2010;170(12):1032-1036
9 Webfigure 9: Supplement to: Cholesterol Treatment Trialists’ (CTT) Collaborators. 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; published online May 17. DOI:10.1016/S0140-6736(12)60367-5.
10 Naci H, Ioannidis JPA, Comparative effectiveness of exercise and drug interventions on mortality outcomes:
metaepidemiological study, BMJ 2013;347:f5577 doi: 10.1136/bmj.f5577 (Published 1 October 2013)
11 Fernandez G, Spatz ES, Jablecki C, Phillips PS, Statin myopathy: A common dilemma not reflected in clinical trials, Cleveland Clinic Journal of Medicine, 2011;78:393-403
12 Draeger A, Monastyrskaya K, Mohaupt M, et al, Statin therapy induces ultrastructural damage in skeletal
muscle in patients without myalgia, Journal of Pathology, 2006; 210: 94–102
13 Association between statin-associated myopathy and skeletal muscle damage, Canadian Medical Association Journal, 2009;181(1-2):E11-E18
14 Phillips PS, Haas RH, Bannykh S, et al, Statin-Associated Myopathy with Normal Creatinine Kinase Levels, Annals of Internal Medicine, 2002;137:581-585
15 Hippisley-Cox J, Coupland C, Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database, BMJ 2010;340:c2197 doi:10.1136/bmj.c2197
16 Tatley M, Savage R. Psychiatric adverse reactions with statins, fibrates and ezetimibe. Implications for the use of lipid-lowering agents. Drug Safety 2007;30:195-201.
17 Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials, Circulation 2006;114:2788-97.
18 Robinson JG, Accumulating Evidence for Statins in Primary Prevention, Journal of the American Medical Association, 2012;310:2405-6
19 Hatsko MAR, Are These Drugs the Future of High-Cholesterol Treatment? The Motley Fool,
http://www.fool.com/investing/general/2013/08/20/are-these-drugs-the-fut... Accessed December 17, 2013
20 Garde D,Amgen's PCSK9 drug hits PhIII mark in the race for a new cardio blockbuster, Fierce Biiotech, http://www.fiercebiotech.com/story/amgens-pcsk9-drug-hits-phiii-mark-rac... Accessed December 17, 2013
21 2013 Cochrane Review, pp 15-19
22 Jefferson T, Doshi T, Thompson M, Heneghan C, Ensuring safe and effective drugs: who can do what it takes? BMJ, 2011;342:148-51
23 Doshi P, Jefferson T, Del Mar C (2012) The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience. PLoS Med 9(4): e1001201. doi:10.1371/journal.pmed.1001201
24 Jefferson T, Jones MA, Doshi P, Del Mar CB, Dooley L, Foxlee R. Neuraminidase inhibitors for preventing
and treating influenza in healthy adults. Cochrane Database of Systematic Reviews 2010, Issue 2. Art. No.: CD001265. DOI:10.1002/14651858.CD001265.pub3.

Competing interests: JDA and NJ serve as experts for plaintiffs’ attorneys in litigation involving the drug industry (including a statin). JDA has received payment for lectures from several universities, medical schools, and non-profit organisations. He was formerly executive director of health management for Wells Fargo Health Solutions.

20 December 2013
John D Abramson
lecturer
Harriet Rosenberg, Nicholas Jewell, James M Wright
Department of Health Care Policy
Harvard Medical School, 39 Spring Street, Ipswich, MA 01938, USA
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