John R. Downs, MD; Patrick G. O'Malley, MD, MPH
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, email@example.com.
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.
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.
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
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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.
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. ;163:291–297. doi: 10.7326/M15-0840
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Published: Ann Intern Med. 2015;163(4):291-297.
Cardiology, Coronary Risk Factors, Dyslipidemia, Guidelines, High Value Care.
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