Management of Dyslipidemia for Cardiovascular Disease Risk Reduction: Synopsis of the 2014 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in the United States and globally (1). Addressing CVD is a priority for the U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DoD). In December 2014, the VA/DoD approved an evidence-based clinical practice guideline about the management of dyslipidemia for CVD risk reduction (www.healthquality.va.gov/guidelines/CD/lipids). This synopsis summarizes the guideline, which largely concerns the overall risk for CVD over a short-term (10-year) horizon. Guideline Development Process To develop these recommendations, the VA/DoD followed methods developed by the VA/DoD Evidence-Based Practice Working Group (EBPWG) (2) that adhere to the standards described for trustworthy guidelines (35). (For a list of EBPWG members, see the Appendix) The guideline project team completed conflict-of-interest disclosures for relationships in the prior 2 years and affirmed the disclosures verbally during the project. Web-based surveillance (for example, ProPublica) was used to screen for potential conflicts of interest among project team members, and action was taken to mitigate identified conflicts. The EBPWG selected 2 guideline panel co-chairs1 each from the VA and DoD. The co-chairs then selected a multidisciplinary panel of practicing clinician stakeholders, including primary care physicians (family and internal medicine), cardiologists, medical nutritionists, pharmacists, nurse practitioners, and physician assistants. The VA/DoD contracted with The Lewin Group, a third party with expertise in clinical practice guideline development, to facilitate meetings and develop key questions (KQs) using the population, intervention, comparison, outcome, time, and setting (PICOTS) format. The guideline panel developed 7 KQs. Three were identical to questions that the American College of Cardiology and American Heart Association (ACC/AHA) used in developing their guideline on cholesterol treatment (6) and concerned evidence supporting low-density lipoprotein cholesterol (LDL-C) and nonhigh-density lipoprotein cholesterol (HDL-C) levels as targets of treatment, treatment effectiveness in reducing clinically important CVD events (fatal and nonfatal myocardial infarctions [MIs], strokes, and total mortality), and adverse effects of each drug class. The 4 additional KQs dealt with cost-effectiveness of cholesterol-modifying drugs, additional risk-stratifying tests, frequency of laboratory testing, and effects of dietary intervention on CVD outcomes. A systematic search of the peer-reviewed literature through February 2014 was conducted to find evidence relevant to the KQs that focused on randomized trials and systematic reviews and meta-analyses of fair or better quality. The search methods and results are detailed in the full guideline (www.healthquality.va.gov/guidelines/CD/lipids). The guideline panel rated recommendations using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method (79). The draft guideline was sent to more than 20 expert reviewers inside and outside the federal sector. Comments were considered and incorporated according to panel consensus into the final guideline, which the VA/DoD EBPWG approved on 1 December 2014 and released on 7 January 2015. Recommendations The guideline focuses on CVD risk reduction through the management of lipids among adults who are most likely to benefit. The guideline panel developed a simple 1-page algorithm (Figure), and the Appendix Table summarizes all 26 recommendations. Here we highlight 5 areas of most relevance to general practice. The full guideline report provides complete recommendations, rationale, and supporting evidence (www.healthquality.va.gov/guidelines/CD/lipids). Figure. VA/DoD clinical practice guideline algorithm for managing dyslipidemia for cardiovascular risk reduction. AAA = abdominal aortic aneurysm; ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CABG = coronary artery bypass graft; CAD = coronary artery disease; CHF = congestive heart failure; CVA = cerebral vascular accident; CVD = cardiovascular disease; DM = diabetes mellitus; DoD = U.S. Department of Defense; EF = ejection fraction; ESRD = end-stage renal disease; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; N = no; NYHA = New York Heart Association; PCI = percutaneous coronary intervention; PVD = peripheral vascular disease; TIA = transient ischemic attack; VA = U.S. Department of Veteran Affairs; Y = yes. * Does not include asymptomatic atherosclerosis (coronary artery calcium, exercise test, intimamedia thickness, anklebrachial index, or brachial reactivity). For patients unable to tolerate the appropriate moderate- or high-dose statin, the highest tolerable statin dose is an option according to their risk. 80 mg once a day or 40 mg twice a day. Appendix Table. 2014 VA/DoD Cholesterol Recommendations and Their Strength, Grouped by Clinical Management Category 1. Elimination of Treatment Targets Our literature review updated the 2013 ACC/AHA review (6) which concluded that the available evidence does not support the use of LDL-C or nonHDL-C levels as treatment targets. We did not identify any trials that showed the benefit of using LDL-C or nonHDL-C targets. Although some use the 2010 Cholesterol Treatment Trialists' Collaboration to justify treatment goals, this meta-analysis included statin trials that were not designed as treat-to-target studies (10). Analyses about treatment goals were post hoc and should be regarded as hypothesis-generating and not proof of benefit. Further, these analyses included the soft end point of revascularization in the composite primary end point. This fundamentally changed the results of the individual trials in patients with the acute coronary syndrome (ACS) and stable coronary artery disease and was a different primary end point than the original Cholesterol Treatment Trialists' Collaboration analyses of 90056 patients in 2005 and 18686 diabetic patients in 2008 (11, 12). These issues raise serious concerns about the validity of inferences about treatment targets based on these data (13). Because of the lack of direct evidence about target cholesterol goals, which can lead to physicians prescribing escalating doses of statins and combinations of drugs with higher rates of adverse effects without known benefit in outcomes, the VA/DoD recommends against the use of cholesterol levels as treatment targets. However, clear evidence shows that moderate fixed-dose statin monotherapy improves total mortality and results in fewer CVD events. 2. Use of Additional Tests to Refine Risk Prediction Although there has been strong interest in new genetic, serologic, physiologic, anatomical, and psychosocial risk markers to improve CVD risk prediction in populations in which there is relative indifference to treatment (such as adults at intermediate risk [10-year CVD risk of 6% to 12%]), only C-reactive protein and coronary artery calcium testing have shown minimal additive predictive risk beyond conventional risk factors. High-sensitivity C-reactive protein adds marginal additive strength to prediction models (increase in area under the curve of 0.004 and improved net reclassification of 1.5%) (14). Coronary artery calcium adds more to risk prediction (increase in area under the curve of 0.05 and improved net reclassification of 5% to 16%) (1517), but this is generally considered to be a small effect. Both factors tend to add more predictive power among men, smokers, and adults at intermediate risk. No randomized trial has shown that incorporating such testing into practice improves CVD outcomes. The VA/DoD concluded that evidence is insufficient to recommend for or against either of these tests in patients at any level of risk for CVD. In theory, these tests might be used in intermediate-risk patients for whom there is uncertainty about treatment benefit or indifference about treatment. A negative test result could decrease the probability across a threshold of no treatment, and a positive test result could increase the probability across a treat threshold. However, such testing should be a shared decision with the patient, and the rationale for the test should be clear before it is used. Routine use of these tests is not recommended because of the lack of evidence that testing improves patient outcomes, the costs of testing, and exposure to potentially harmful radiation during coronary artery calcium testing. 3. Primary Prevention: More Nuanced Once a patient's 10-year risk has been calculated, the VA/DoD recommends shared decision making to decide whether the potential benefits of medications outweigh the potential harms for each patient. This tradeoff varies by the level of 10-year risk for CVD largely because of the varying level of evidence of benefit weighed against a constant risk for adverse events: less than 6% (no evidence of benefit), 6% to 12% (limited evidence), and greater than 12% (convincing evidence). For patients with a 10-year risk greater than 12%, clinical trials indicate that CVD risk can be decreased by 20% to 30% with use of a moderate-dose statin for 5 years. The rationale for a 12% risk threshold is that it most closely resembles the populations in the clinical trials for which the benefits clearly outweighed the risks (18, 19). A similar rationale is used for the threshold of 6%; no clinical trials specifically address patients in this category. The mean 10-year risk from the very few primary prevention trials that included patients in an intermediate-risk group (6% to 12%) was approximately 8%, but these trials had idiosyncratic inclusion criteria (20, 21). The thresholds represent rationally defined inflection points of increasing risk and increasing congruency with the populations included in clinical trials that showed benefit from statin therapy. Current risk