John R. Downs, MD; Patrick G. O'Malley, MD, MPH
This article was published online first at www.annals.org on 23 June 2015.
Disclaimer: The views expressed here are not to be construed as those of the U.S. Department of Veterans Affairs or the U.S. Department of Defense.
Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0840.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Requests for Single Reprints: John R. Downs, MD, South Texas Veterans Health Care System, Medicine Service (111), 7400 Merton Minter, San Antonio, TX 78229; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Downs: South Texas Veterans Health Care System, Medicine Service (111), 7400 Merton Minter, San Antonio, TX 78229.
Dr. O'Malley: Department of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814.
Author Contributions: Conception and design: J.R. Downs, P.G. O'Malley.
Analysis and interpretation of the data: J.R. Downs, P.G. O'Malley.
Drafting of the article: J.R. Downs, P.G. O'Malley.
Critical revision of the article for important intellectual content: J.R. Downs, P.G. O'Malley.
Final approval of the article: J.R. Downs, P.G. O'Malley.
Administrative, technical, or logistic support: J.R. Downs, P.G. O'Malley.
Collection and assembly of data: J.R. Downs, P.G. O'Malley.
Downs JR, O'Malley PG. 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. Ann Intern Med. 2015;163:291-297. doi: 10.7326/M15-0840
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Published: Ann Intern Med. 2015;163(4):291-297.
Appendix: VA/DoD Evidence-Based Practice Work Group
In December 2014, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline for the management of dyslipidemia for cardiovascular disease risk reduction in adults. This synopsis summarizes the major recommendations.
On 30 September 2013, the VA/DoD Evidence-Based Practice Work Group convened a joint VA/DoD guideline development effort that included clinical stakeholders and conformed to the Institute of Medicine's tenets for trustworthy clinical practice guidelines. The guideline panel developed key questions, systematically searched and evaluated the literature, developed a simple 1-page algorithm, and rated each of 26 recommendations by using the Grading of Recommendations Assessment, Development, and Evaluation system.
This synopsis summarizes key features of the guideline in 5 areas: elimination of treatment targets, additional tests for risk prediction, primary and secondary prevention, and laboratory testing.
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.
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 (3–5). (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-chairs—1 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 non–high-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 (7–9).
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.
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).
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, intima–media thickness, ankle–brachial 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
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 non–HDL-C levels as treatment targets. We did not identify any trials that showed the benefit of using LDL-C or non–HDL-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 90 056 patients in 2005 and 18 686 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.
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%) (15–17), 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.
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 calculators may overestimate risk (especially in lower risk cohorts, such as 10-year predicted risk <12%), which adds further uncertainty to this decision (22).
Although the absolute benefit of statin therapy depends on the patient's risk for CVD, the potential for harm is the same regardless of risk. Muscle-related symptoms were the most frequent adverse effects of statins seen in trials in 10% to 20% of patients (23–26), and the frequency is thought to be higher in community cohorts. These adverse effects are usually benign and resolve with treatment interruption but often lead to reluctance to resume statin treatment. Rhabdomyolysis is a more severe adverse effect related to statins, but it is relatively rare and generally limited to patients receiving high-dose statins or with factors that predispose them to muscle toxicity, such as drug–drug interactions, impaired hepatic or renal function, hypothyroidism, advanced age, rheumatic disorders, vitamin D deficiency, or alcohol misuse (10, 11, 27). Statins increase the risk for type 2 diabetes mellitus by 0.5%, and this risk seems to be higher in women and persons receiving high-dose statins (28, 29).
Although the decision to start statins should always be shared with patients, the VA/DoD guideline panel concluded that, for patients with a risk of 12% or greater, the benefits in CVD risk reduction substantially outweigh the risks. Thus, in such patients, the guideline strongly advocates offering treatment with a moderate-dose statin. In patients at intermediate risk (10-year CVD risk of 6% to 12%), the decision to initiate therapy should be based on an individual patient assessment and is nuanced; there is uncertainty about benefit because of the limited number of trials, the tendency for risk calculators to overestimate risk, and the more tenuous balance between benefit and risk.
The recommendation to initiate statin therapy at a moderate dose and titrate to a high dose (where appropriate; for example, ACS, recurrent atherosclerotic CVD events, or multiple uncontrolled risk factors) for secondary prevention is based on a high level of evidence from 3 meta-analyses from the Cholesterol Treatment Trialists' Collaboration (10, 11, 28). All dosing regimens in the secondary prevention trials included in these meta-analyses reduced all-cause mortality, nonfatal MI, coronary death, and nonfatal stroke compared with placebo. Statin doses were primarily fixed moderate doses (simvastatin, 20 to 40 mg; pravastatin, 40 to 80 mg; lovastatin, 20 to 80 mg; and atorvastatin, 10 mg).
The recommendation to consider a high-dose statin in patients with acute ACS and those with multiple uncontrolled risk factors or recurrent atherosclerotic CVD events is based on a low level of evidence from a 2010 meta-analysis of 10 trials (n = 41 778) comparing high-dose with low- to moderate-dose statins for secondary prevention (30). No significant difference was found in overall mortality (relative risk [RR], 0.92 [95% CI, 0.83 to 1.03]; P = 0.14) or CVD deaths (RR, 0.89 [CI, 0.78 to 1.01]; P = 0.07) between high-dose statins and lower doses. Significant differences in nonfatal MI (RR, 0.82 [CI, 0.76 to 0.89]; P < 0.001) and combined nonfatal and fatal stroke (RR, 0.86 [CI, 0.77 to 0.96]; P = 0.006) favored higher doses. The meta-analysis included a subgroup analysis of 3 trials in patients with ACS that found a statistically significant reduction in all-cause mortality and CVD death with higher statin doses. Limitations of this meta-analysis were that 5 of the 10 trials randomly assigned fewer than 1000 patients who were followed for less than 2 years, and some included surrogate end points, such as arteriosclerotic progression, as their primary end point.
A second meta-analysis included 5 studies of low- or moderate-dose versus high-dose statins and found that new-onset diabetes occurred more frequently in the high-dose group (odds ratio [OR], 1.12 [CI, 1.04 to 1.22]; number needed to harm, 498); there were an estimated 2 additional diabetes diagnoses per 1000 patients treated with high-dose statins for 5 years (31). Cardiovascular events (composite of all-cause mortality, cardiovascular death, nonfatal MI, nonfatal stroke, and coronary revascularization) occurred less often in the high-dose statin group (OR, 0.84 [CI, 0.75 to 0.94]), which translated into an estimated 6.5 fewer CVD events per 1000 patients treated with high-dose statins for 5 years (31). Another meta-analysis examined data from 4 of the trials comparing moderate- to high-dose statins and found that treatment with high-dose atorvastatin or simvastatin was associated with a higher risk for any adverse event (OR, 1.44 [CI, 1.33 to 1.55]; P < 0.001) and events leading to withdrawal of the statin (OR, 1.28 [CI, 1.18 to 1.39]) (32). High-dose regimens were also associated with more abnormalities in liver function tests and creatine kinase levels (32).
In summary, improvement in the primary outcome of major cardiovascular events was not consistently seen with a higher-dose statin compared with a moderate-dose statin because only 2 of the 5 original trials showed greater efficacy of the higher dose, and differences were limited to a reduction in nonfatal events. Although the risk for serious adverse events related to statins is low, other less severe adverse events, such as muscle symptoms (for example, myalgias), occur more often with higher-dose statins and may lead to decreased adherence and reluctance to continue statin therapy. None of the individual studies or meta-analyses addressed back titration from a high-dose to a low-dose statin or vice versa. On the basis of this evidence, the VA/DoD recommends that if high-dose statins are considered, clinicians and patients should carefully consider the known added harms and small additional benefits of such therapy and limit high-dose statins to patients at greatest risk for CVD.
A nonfasting lipid profile provides measures of total cholesterol and HDL-C levels that differ little from measures after a 9- to 12-hour fast (33). Compared with fasting measures, nonfasting LDL-C level may be 10% lower and triglyceride levels may be as much as 20% higher. Lipid measures are necessary to enable risk calculation based only on measures of total cholesterol and HDL-C levels, and the small variance in LDL-C level is unlikely to affect classification of risk or therapeutic decisions (34, 35). Thus, a nonfasting lipid profile provides acceptably accurate measures for risk calculation.
If triglyceride levels are greater than 4.52 mmol/L (>400 mg/dL), the Friedewald equation commonly used to calculate LDL-C levels may not be accurate. In this uncommon scenario, the nonfasting lipid profile may need to be remeasured after fasting. Fasting lipid measures are also indicated if the purpose is to measure or monitor triglyceride levels. Routine fasting lipid measures burdens patients and laboratories. Most patients do not come to clinic visits while fasting; thus, they are required to take time away from work or family and bear the expense and bother of a second visit after fasting. Some patients are unwilling to fast or to return and avoid lipid testing altogether. Laboratories can be burdened by the large number of patients who present early in the morning after an overnight fast. Thus, the small gain in accuracy of a fasting lipid profile over random measurement is outweighed by these burdens.
In addition, because the efficacy of statins is based on a target dose, not lipid levels, we do not recommend routine monitoring of lipids once a statin is initiated (36). If adherence is a concern, it may be reasonable to measure lipids to assess a patient's adherence. For patients receiving high-dose statins, it may also be reasonable to assess lipids because there are known adverse effects associated with very low LDL-C levels that can occur with high-dose therapy (37).
Measuring baseline creatine kinase levels and using liver function tests are clinically prudent to interpret potential future laboratory results or symptoms. All clinical trials that studied the efficacy of statins excluded patients with elevated levels of liver aminotransferases, and there is a concern that statins may exacerbate hepatotoxicity; therefore, the VA/DoD suggests assessing for evidence of liver damage before initiating statin therapy and avoiding statins in patients with evidence of worsening liver damage or fluctuating results on liver function tests. Once low- or moderate-dose statins have been initiated, the traditional recommendation is to do liver function tests on a regular basis to detect asymptomatic liver damage and measure creatine kinase levels if muscular symptoms occur. However, this practice is not based on studies specifically designed to test the effectiveness of frequent monitoring. No direct evidence shows that laboratory monitoring improves detection of myopathy or liver dysfunction (except at higher doses of statins). Further, in 2012, the U.S. Food and Drug Administration announced revisions in periodic liver monitoring in persons receiving statin therapy and concluded that serious liver injury with statins is rare and unpredictable in individual patients; also, routine periodic monitoring of liver enzyme levels does not seem to be effective in detecting or preventing this rare adverse effect (38).
The risk for serious liver injury while receiving moderate-dose statin therapy is extremely rare and did not differ from placebo in clinical trials. Patients with aspartate or alanine aminotransferase levels less than 3 times the normal levels do not warrant an immediate change in dose but should continue to follow up and consider repeated testing with their health care provider. Patients with aspartate and alanine aminotransferase levels greater than 3 times the normal levels should consult with their providers to evaluate the net benefit of continuing statin therapy versus adjusting or discontinuing medication (29, 39). Frequent laboratory testing has negative consequences from both patient (such as septic thrombophlebitis, cellulitis, pain at the blood draw site, and inconvenience) and provider (such as excess workload and opportunity costs) perspectives.
The VA/DoD guideline differs from the ACC/AHA guideline in several aspects. Although we agree with the ACC/AHA that the data support the elimination of targets, we extend the literature review through February 2014. Further, we support the use of risk calculators to estimate risk in primary prevention populations, call for a more nuanced shared-decision approach, and suggest the use of additional tests for risk prediction in a more conservative manner than the ACC/AHA advocates. Likewise, safety concerns influenced our pharmacologic treatment strategy that recommends starting with the more conservative and safer moderate-dose statin for both primary and secondary prevention, with upward titration in secondary prevention based on shared decision making. Laboratory testing is based on clinical need for monitoring the results of liver function tests and nonfasting lipid profiles. Lastly, our guideline group contained members with no conflict of interest.
Hayward and Krumholz (40) stated the following in 2012 about lipid targets: “Changing long-held beliefs is never easy, even when the need for change is based on strong evidence. Change is especially difficult when prior beliefs are firmly embedded in culture, accepted as dogma, and codified in books, articles, guidelines, public service announcements and performance measures.” This guideline will undoubtedly provoke criticism. However, as some have suggested (41), we hope to have brought some “order to the chaos” of clinical guidelines by providing a rigorous, simple, transparent, and high-quality guideline that providers can use to efficiently care for their patients and improve patient-centered clinical outcomes.
John R. Downs, MD (VA Co-Chair); Patrick G. O'Malley, MD, MPH (DoD Co-Chair); Ernest Degenhardt, MSN, FNP; Deborah Grady MD, MPH; Edward Hulten, MD, MPH; Cathy Kelley, PharmD; Azra Khan, PharmD; Amanda Logan, RD; Mark McConnell, MD; Michelle Pino, RD, LD; M. Eric Rodgers, PhD, FNP; James L. Sall, PhD, FNP; Robert Sylvester, MD; ECRI Institute; The Lewin Group; and Sigma Health Consulting.
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Jonathan A. Tobert MD PhD, Connie B. Newman MD FACP
Academic Visitor, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Department of Medicine, Division of Endocrinology and Metabolism, New York University School of Medicine
June 27, 2015
Conflict of Interest:
Dr Tobert reports having received consultant fees from Johnson & Johnson and Esperion and that, as a retired (2004) employee of Merck, he receives a fixed pension. Dr Newman reports no disclosures.
Statins and muscle symptoms
In their clinical guideline on the management of dyslipidemia (1) Downs and O’Malley state “Muscle-related symptoms were the most frequent adverse effects of statins seen in trials in 10% to 20% of patients (23-26).” Three of these 4 references are observational studies, not trials. Observational studies can measure the frequency of adverse events reported during a treatment, but are at risk of confounding, and compared to randomized double-blind placebo-controlled clinical trials are generally much less reliable for assessing causality. Without causality, an event is not an effect. The fourth citation is a meta-analysis that concluded “When the placebo-controlled trials of statins were pooled as a class in a pairwise meta-analysis including 43 531 participants, statins were not significantly different than control treatment (OR, 1.07; 95% CI, 0.89–1.29; I2, 22.1%) in terms of myalgia incidence.” (2) This is consistent with many other reports based on placebo-controlled clinical trials. In a 5-year trial in which over 20,000 patients were randomly allocated to simvastatin 40 mg daily or placebo and queried at every visit about muscle symptoms, about 6% in both groups reported them at each visit for a total incidence of 32.9% and 33.2% respectively over the course of the study (3). With the exception of rhabdomyolysis and muscle symptoms accompanied by an increase in creatine kinase above 10 times the upper limit of normal, which together occur in < 0.1% of patients, in clinical trials the incidence of less serious muscle symptoms has been consistently similar in the placebo and statin groups (4); consequently a causal relationship of statins with these muscle symptoms has never been demonstrated (2-5).1. Downs JR, O'Malley PG. 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 GuidelineVA/DoD 2014 Cholesterol Guidelines. Ann Int Med. 2015. doi:10.7326/M15-08402. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials. Circ Cardiovasc Qual Outcomes. 2013;6:390-9. [PMID: 23838105] 3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high risk individuals: a randomised placebo-controlled trial. The Lancet. 2002;360:7-22. [PMID 12114036] 4. Newman CB, Tobert JA. Statin intolerance: Reconciling clinical trials and clinical experience. JAMA. 2015;313(10):1011-2. [PMID 25756433]5. 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(25):2788-97. [PMID 17159064]
Bangladesh Institute of Family Medicine and Research
August 24, 2015
Once started, statin should be continued lifelong
Thanks to Dr. Downs and Dr. O’Malley for their elaborative descriptions covering 5 areas of the guideline. Statins are used for both secondary and primary prevention of cardiovascular morbidity and mortality. Once statin is started it should be continued lifelong because discontinuation of statin even LDL-C at goal as per ATP-III may result in sudden increase of C-reactive protein and LDL-C leading to higher risk of cardiovascular events  . ATP-III recommended treating LDL-C to target which means that once LDL-C goal is achieved, statin can be discontinued. It is very practical and effective change that recommended both in ATP-IV and VA/DoD guidelines that “elimination treatment targets”. “The lower the better” strategy may prevent cardiovascular mortality .Physicians should not be afraid of statin induced adverse effects because it happens very rare. According to FDA, myopathy is defined as CK ≥ 10 X ULN. As per FDA Adverse Effect Reporting System (AERS) we can notice that from 2002 to 2004 statin induced myopathy occurred only 0.74, 0.57 and 3.56 respectively per 1 million prescription. Most of the cases are dose related and reversible. Physicians should be vigilant for developing myopathy specifically in patients with some underlying conditions like hypothyroidism, concomitant drug, advanced age, alcoholism etc.Statin induced elevation of transaminases rarely associated with irreversible liver damage. A meta-analysis consisting of 164 statin trials published in 2003 showed no case of liver failure .Recently we have many studies about new onset of diabetes in statin users. One study published online in “Diabetologia” March 3, 2015  says that risk of new onset of diabetes among statin users is up to 46% due to statin induced reduction of insulin sensitivity and insulin secretion. Endothelial dysfunction occurs many years before diagnosis of overt type 2 diabetes. Protection of vasculature or in the other words cardiovascular events can well be prevented by the use of statin in patients progressing to overt diabetes. Cardiovascular benefit outweigh the risk of new onset of diabetes References:1. Van der Harst P. et al., Effect of withdrawal of pravastatin therapy on C-reactive protein and low-density lipoprotein cholesterol. Am J Cardiol. 2007 Nov 15;100(10):1548-512. Krumholz HM, Hayward RA. Shifting views on lipid lowering therapy. BMJ. 2010;341:c35313. Chinwong, Dujrudee et al. “Low-Density Lipoprotein Cholesterol of Less than 70 mg/dL Is Associated with Fewer Cardiovascular Events in Acute Coronary Syndrome Patients: A Real-Life Cohort in Thailand.” Therapeutics and Clinical Risk Management 11 (2015): 659–667. PMC. Web. 24 Aug. 2015.4. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003;326:1423.5. Henna Cederberg et al., Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia DOI 10.1007/s00125-015-3528-5 6. Waters DD, Ho JE, Boekholdt SM, et al. Cardiovascular Event Reduction Versus New-Onset Diabetes During Atorvastatin Therapy: Effect of Baseline Risk Factors for Diabetes. J Am Coll Cardiol. 2013;61:148-152
John R. Downs, MD, Patrick G. O'Malley, MD, MPH
South Texas VA Medical Center
October 8, 2015
We thank Drs. Tolbert and Newman for the opportunity to highlight some important strengths and limitations of available data to inform patient centered decisions. While randomized controlled trial (RCT) data is important, it is axiomatic that there cannot be an RCT to inform every aspect of every clinical decision, especially when it comes to discussing adverse effects. Data within a larger universe needs to be considered, synthesized, and clinically applied to individual patients. These data include observational trials.The typical published randomized trial design has important limitations. These include generalizability due to inclusion criteria that exclude common co-morbidities, relatively short duration of trials and follow up (when considering life-long therapy), run in periods, under appreciation of adverse effects due to dispersed reporting over numerous subcategories in the FDA Adverse Event Reporting System (1), and known suppression of data on adverse effects associated with industry-funded trials (2-3). As noted by Diamond and Ravnskov (1) a largely undiscussed feature of the British Heart Protection Study (BHS) (4) was the 26% of all eligible participants that withdrew during the run in period, inherently biasing the study against providing a representation of the actual rate of adverse events (i.e. likely to underestimate).Observational trials are subject to limitations due to potential confounding. However, they are currently the optimal way to identify adverse effects in free living, ‘real world’ patients that go undetected due to the limitations of relatively small RCTs (compared to the general population) of short duration(compared to life-long therapy). Because of confounding, observational data cannot confer causality. However the observational data on statin muscle related effects triangulates with clinician experience with patients stopping statins due to muscle related complaints. Providing some estimate of the incidence of those complaints is clinically useful information. Our guideline committee felt compelled to provide information relevant to the spectrum of what is available in the literature and what we know from active clinical practice. The challenge for providers will be to synthesize the evidence (with the inherent limitations) and apply it to individual patients in making patient centered decisions.1. Diamond DM, Ravnskov U. How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Expert Rev. Clin. Pharmacol. 2015 Mar; 8(2) 201-10. doi:10.1586/17512433.2015.1012494. [PMID 25672965]2. Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: a case study based on documents from rofecoxib litigation. JAMA. 2008 Apr 16;299(15):1813-7. doi:10.1001/jama.299.15.1813. [PMID 18413875]3. Brody H. (2007). Hooked. Lanham, Maryland: Rowman & Littlefield publishers. Chapter 6 Suppression of Research Data, pp 97-113.
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