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Should Statin Therapy Be Guided by Cardiovascular Risk Models?

  • Robert DuBroff
    Correspondence
    Requests for reprints should be addressed to Robert DuBroff, MD, Division of Cardiology, University of New Mexico, 1 University of New Mexico, MSC10-5550, Albuquerque, NM 87131-0001.
    Affiliations
    Division of Cardiology, University of New Mexico, Albuquerque
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Published:November 06, 2015DOI:https://doi.org/10.1016/j.amjmed.2015.10.021
      Cholesterol-lowering statin drugs have become the mainstay of many cholesterol guidelines and are intended to reduce the risk of atherosclerotic cardiovascular disease and death. In general, the use of statins after a cardiovascular event is well established, whereas the recommendation for primary prevention statin therapy is often based upon a risk calculation. If a patient's estimated 10-year atherosclerotic cardiovascular disease risk exceeds 7.5%, then statin therapy is recommended because higher-risk patients are believed to benefit most from statin therapy.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      Tremendous effort has been expended to find the best risk calculator, but rather than debate which risk calculator is best, it may be more productive to examine the fundamental assumption that statin therapy guided by an atherosclerotic cardiovascular disease risk calculation actually saves lives, reduces atherosclerotic cardiovascular disease, and avoids unnecessary treatment in low-risk individuals.

      High-risk Populations Don't Consistently Benefit From Statin Therapy

      While many randomized controlled trials (RCTs) of statin therapy in high-risk populations have reported benefit, it may be instructive to review some that did not. For example, coronary artery calcium scores have consistently been shown to identify high-risk patients. The St. Francis Heart Study was an RCT of atorvastatin in 1005 asymptomatic patients with coronary artery calcium scores >80th percentile for age and gender. Remarkably, no significant reduction in atherosclerotic cardiovascular events was observed after 6 years. Patients with chronic kidney disease are also considered to be at very high risk of atherosclerotic cardiovascular disease. No significant mortality benefit was observed in the 3 RCTs of statin therapy that specifically targeted chronic kidney disease (German Diabetes and Dialysis Study [4D], A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events [AURORA], and Study of Heart and Renal Protection [SHARP]). However, SHARP did report a modest 17% reduction in major atherosclerotic events, while 4D and AURORA reported no significant reduction in major cardiovascular events. In contrast, a Cochrane meta-analysis of statins in patients with chronic kidney disease concluded there was a significant mortality and clinical benefit, but this analysis relied heavily on post hoc subgroup analyses.
      • Palmer S.C.
      • Navaneethan S.D.
      • Craig J.C.
      • et al.
      HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis.
      While subgroup analysis can provide valuable information, the conclusions of such an analysis can be misleading and should not supersede the results of well-conducted RCTs.
      • Wang R.
      • Lagakos S.W.
      • Ware J.H.
      • Hunter D.J.
      • Drazen J.M.
      Statistics in medicine—reporting of subgroup analyses in clinical trials.
      Patients who have undergone coronary artery bypass surgery are also at high risk, yet the Post Coronary Artery Bypass Graft (Post-CABG) trial showed no significant reduction in cardiovascular events in patients randomized to statin therapy. The elderly represent another high-risk population, but only one RCT specifically designed to assess the effect of statins in this population has been reported. The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study randomized 5804 patients ages 70-82 years to pravastatin or placebo and observed a significant reduction in combined cardiovascular events, but no significant mortality benefit. Notably, PROSPER patients without prior vascular disease (primary prevention) showed no significant reduction in cardiovascular events or mortality. Similarly, rosuvastatin did not reduce cardiovascular events or mortality in older individuals with ischemic, systolic heart failure in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Diabetic patients are considered to have a coronary artery disease risk equivalent, and 3 RCTs of statin therapy specifically in diabetics have been reported (Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus [ASPEN], 4D, Collaborative Atorvastatin Diabetes Study [CARDS]). Only one showed a significant reduction in cardiovascular events (CARDS), while all 3 failed to demonstrate a significant mortality benefit. These findings are discordant with the Cholesterol Treatment Trialists (CTT) meta-analysis of statin use in diabetes, which did conclude that statins were beneficial.
      Cholesterol Treatment Trialists' (CTT) Collaborators
      Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
      However, the CTT meta-analysis relied heavily on subgroup analysis and only one of the 14 studies analyzed was specifically designed and powered for diabetes (CARDS). Finally, patients with peripheral vascular disease represent an additional high-risk population. Although there have been no long-term RCTs specifically designed and powered to assess statin therapy in these patients, a Cochrane meta-analysis of 18 cholesterol-lowering trials (some with statins) in patients with peripheral vascular disease concluded there was no significant reduction in total mortality or cardiovascular events.
      • Aung P.P.
      • Maxwell H.G.
      • Jepson R.G.
      • Price J.F.
      • Leng G.C.
      Lipid-lowering for peripheral arterial disease of the lower limb.

      Higher Baseline Risk Does Not Lead to Greater Statin Benefit

      One doesn't have to estimate the baseline risk of atherosclerotic cardiovascular events in placebo-controlled RCTs of statins for primary prevention because the actual event rates are reflected in the control (placebo) group. If the risk-driven model were correct, one would expect a gradation of benefit based upon underlying risk. A recent Cochrane meta-analysis of statins for primary prevention provides the data for such an assessment.
      • Taylor F.
      • Huffman M.D.
      • Macedo A.F.
      • et al.
      Statins for the primary prevention of cardiovascular disease.
      This meta-analysis identified 9 primary prevention RCTs that reported total cardiovascular event outcomes. The Figure illustrates the relationship of the risk ratio to the cardiovascular event rate in the control groups and suggests that there is no correlation between the baseline risk and the degree of statin benefit.
      Figure thumbnail gr1
      FigureCardiovascular disease (CVD) risk ratio compared with baseline CVD event rates in primary prevention statin trials from the Cochrane meta-analysis.
      • Taylor F.
      • Huffman M.D.
      • Macedo A.F.
      • et al.
      Statins for the primary prevention of cardiovascular disease.

      Cardiovascular Risk Models Perform Poorly in the Real World

      Ideally, the risk-guided model should help us identify both patients who should be treated with statin therapy to prevent a myocardial infarction and patients who will not benefit from statin therapy. The modified Framingham risk model was tested in a retrospective analysis of 222 relatively young patients without a history of coronary disease or coronary disease equivalent who sustained a myocardial infarction.
      • Akosah K.O.
      • Schaper A.
      • Cogbill C.
      • Schoenfeld P.
      Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform?.
      When their risk score was calculated and applied to the then-current National Cholesterol Education Program Adult Treatment Panel III (NCEP III) guidelines, only 25% of these patients would have qualified for statin therapy. Conversely, the recently published Multi-Ethnic Study of Atherosclerosis (MESA) study demonstrated that 57% of study participants who would have been eligible for statin therapy based upon the 2013 American Heart Association/American College of Cardiology guidelines had no detectable coronary artery calcium on computed tomography scan.
      • Nasir K.
      • Bittencourt M.S.
      • Blaha M.J.
      • et al.
      Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association Cholesterol Management Guidelines: MESA (Multi-Ethnic Study of Atherosclerosis).
      These patients would be unlikely to benefit from statin therapy because their atherosclerotic cardiovascular disease risk is extremely low based upon their zero calcium scores.
      Millions of patients are currently being treated with statin drugs for primary prevention based upon the risk-driven model. While the concept of recommending statin therapy based upon risk seems both intuitive and logical, proof of concept is lacking and statin drugs are not without risk. Underappreciated is the recent report that statin therapy was associated with a 363% increased risk of diabetes after 15-20 years of statin exposure.
      • Macedo A.F.
      • Douglas I.
      • Smeeth L.
      • Forbes H.
      • Ebrahim S.
      Statins and the risk of type 2 diabetes mellitus: cohort study using the UK clinical practice research datalink.
      Multiple RCTs of statin therapy for primary prevention in high-risk populations have failed to demonstrate a consistent clinical benefit or a gradation of benefit based upon risk. We must also acknowledge that the risk-driven model fails to accurately identify patients who would benefit from statin therapy and also those who would not. At issue is not whether statins are effective, but rather, how best to identify appropriate individuals for primary prevention.

      References

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        • et al.
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        Statistics in medicine—reporting of subgroup analyses in clinical trials.
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        Lipid-lowering for peripheral arterial disease of the lower limb.
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        Statins for the primary prevention of cardiovascular disease.
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