Mukul Sharma, MD, MSc; Mohammed T. Ansari, MBBS, MMedSc, MPhil; Ahmed M. Abou-Setta, MD, PhD; Karla Soares-Weiser, MD, PhD; Teik Chye Ooi, MBBS; Margaret Sears, PhD; Fatemeh Yazdi, MSc; Alexander Tsertsvadze, MD, MSc; David Moher, PhD
Acknowledgment: The authors thank Margaret Sampson, Chantelle Garritty, Heather Clark, Robert Côté, Nick Barrowman, Raymond Daniel, and Sophia Tsouros for their collective efforts.
Grant Support: By AHRQ, U.S. Department of Health and Human Services (contract 290-02-0021).
Potential Conflicts of Interest:Honoraria: M. Sharma (Merck & Co., Schering-Plough), T.C. Ooi (Oryx Pharmaceuticals, Fournier Pharma, AstraZeneca, Merck Frosst, Solvay Pharma, Schering-Plough).
Requests for Single Reprints: Mukul Sharma, MD, MSc, Canadian Stroke Network, Regional Stroke Program, The Ottawa Hospital, Civic Campus, C2, Room 2182, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada.
Current Author Addresses: Dr. Sharma: Canadian Stroke Network, Regional Stroke Program, The Ottawa Hospital, Civic Campus, C2, Room 2182, 1053 Carling Avenue, Ottawa, Ontario K1Y 4E9, Canada.
Drs. Ansari and Tsertsvadze and Ms. Yazdi: University of Ottawa Evidence-based Practice Center, CHEO-RI, 401 Smyth Road, Ottawa, Ontario K1H 8LI, Canada.
Dr. Abou-Setta: University of Alberta Evidence-based Practice Center, Alberta Research Centre for Health Evidence, Aberhart Centre One, Room 8412, 11402 University Avenue, Edmonton, Alberta T6G 2J3, Canada.
Dr. Soares-Weiser: Enhance Reviews, PO Box 137, Kfar-Saba, 44101, Israel.
Dr. Ooi: Division of Endocrinology and Metabolism, University of Ottawa, The Ottawa Hospital, Riverside Campus, 1967 Riverside Drive, Ottawa, Ontario K1H 7W9, Canada.
Dr. Sears: RR 1, Box 9012, Dunrobin, Ontario K0A 1T0, Canada.
Dr. Moher: University of Ottawa Evidence-based Practice Center, University of Ottawa, and Ottawa Methods Centre, Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, 6th Floor, Critical Care Wing, Room W6112, Ottawa, Ontario K1H 8L6, Canada.
Author Contributions: Conception and design: M. Sharma, M.T. Ansari, A.M. Abou-Setta, T.C. Ooi, A. Tsertsvadze, D. Moher.
Analysis and interpretation of the data: M. Sharma, M.T. Ansari, A.M. Abou-Setta, K. Soares-Weiser, T.C. Ooi, M. Sears, A. Tsertsvadze, D. Moher.
Drafting of the article: M. Sharma, M.T. Ansari, A.M. Abou-Setta, M. Sears, A. Tsertsvadze, D. Moher.
Critical revision of the article for important intellectual content: M. Sharma, M.T. Ansari, A.M. Abou-Setta, T.C. Ooi, M. Sears, A. Tsertsvadze, D. Moher.
Final approval of the article: M. Sharma, M.T. Ansari, A.M. Abou-Setta, K. Soares-Weiser, T.C. Ooi, M. Sears, D. Moher.
Provision of study materials or patients: F. Yazdi.
Statistical expertise: M.T. Ansari, A.M. Abou-Setta, D. Moher.
Obtaining of funding: D. Moher.
Administrative, technical, or logistic support: M.T. Ansari, A.M. Abou-Setta, M. Sears, F. Yazdi, D. Moher.
Collection and assembly of data: M. Sharma, M.T. Ansari, A.M. Abou-Setta, K. Soares-Weiser, T.C. Ooi, M. Sears, F. Yazdi, A. Tsertsvadze.
Statin therapy effectively prevents vascular disease, but treatment targets are often not achieved.
To compare the benefits and harms of high-dose statin monotherapy with those of combination therapy in adults at high risk for coronary disease.
English-language records from MEDLINE (1966 to 2009), EMBASE (1980 to 2009), and the Cochrane Library (third quarter of 2008).
A reviewer screened records, and a second reviewer verified selection of randomized, controlled trials in adult patients that compared combinations of statins and bile-acid sequestrants, fibrates, ezetimibe, niacin, or ω-3 fatty acids with statin monotherapy, as well as nonrandomized comparative studies that were longer than 24 weeks and reported clinical and harms outcomes.
Data were abstracted for studies by using standardized forms, and study quality was rated with a standardized scale and strength of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation approach.
102 studies met eligibility criteria. The main analysis compared combination therapy with high-dose statin monotherapy in high-risk patients. Very-low-strength evidence showed that statin–ezetimibe (2 trials; n = 439) and statin–fibrate (1 trial; n = 166) combinations did not reduce mortality more than high-dose statin monotherapy. No trials compared the effect of combination therapy versus high-dose statin monotherapy on the incidence of myocardial infarction, stroke, or revascularization procedures. Two statin–ezetimibe trials (n = 295) demonstrated higher low-density lipoprotein cholesterol goal attainment with combination therapy (odds ratio, 7.21 [95% CI, 4.30 to 12.08]). Trials in lower-risk patients did not show a difference in mortality.
Studies were generally short, focused on surrogate outcomes, and were heterogeneous in the sample's risk for coronary disease. Few studies examined treatment combinations other than statin–ezetimibe.
Limited evidence suggests that combinations of lipid-lowering agents do not improve clinical outcomes more than high-dose statin monotherapy. Very-low-quality evidence favors statin–ezetimibe treatment for attainment of low-density lipoprotein cholesterol goals.
Agency for Healthcare Research and Quality.
Although they are frequently used, whether combinations of lipid-lowering agents improve outcomes more than high-dose statin monotherapy in adults with dyslipidemia is not known.
This review of 102 studies found 2 trials that suggested lower target lipid levels were more often achieved with statin–ezetimibe combination therapy than with high-dose statin monotherapy. No firm trial evidence showed that combining a statin with another agent (bile-acid sequestrant, fibrate, ezetimibe, niacin, or ω-3 fatty acids) improved clinical outcomes (myocardial infarction, stroke, or mortality) more often than high-dose statin monotherapy.
Most trials were of short duration, focused on surrogate outcomes, and used similar doses of statins in the combination and monotherapy groups.
Appendix Table 1. Definitions of Low and High Doses of Statins
Literature search and selection.
FDA = U.S. Food and Drug Administration; NRS = nonrandomized study; RCT = randomized, controlled trial.
* Total does not sum to 48 because 1 study was excluded in 2 categories.
Appendix Table 2. Therapies Evaluated in Included Studies
Table. Strength of Evidence for Statin Combination Therapy Versus Monotherapy in Patients Requiring Intensive Treatment
Percentage of change in low-density lipoprotein cholesterol levels from baseline after low-dose statin combination therapy versus high-dose statin monotherapy in diverse populations.
BAS = bile-acid sequestrant.
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Mayada H. Issa
West Virginia University
November 17, 2009
Polypharmacy and risk of rhabdomyolysis
The study by Sharma et al highlights the fact that achieving treatment goals with fewer medications may prevent the risk of side effects and interactions from polypharmacy. However, caution is required when maximizing statin dose in some of our high risk aging population as more side effects may occur due to reduced plasma clearance (1). We recently admitted a 72 year old female with statin induced rhabdomyolysis. She had been on multiple chronic medications including simvastatin 10mg daily for hyperlipidemia and amiodarone and warfarin for atrial fibrillation without adverse reactions. Two months prior to her latest admission, she was hospitalized with a non ST elevation myocardial infarction and her simvastatin was increased to 80mg daily to comply with the current guidelines. Two weeks following the statin dose adjustment and the addition of the new medications, she started complaining of generalized weakness more so in the lower extremities but no myalgia. She was admitted to the hospital; however, the work up was negative including normal creatine kinase level, TSH and electromyogram and the patient was discharged with generalized weakness of unknown etiology. One month later she was admitted for myalgia and marked proximal muscle weakness in all four extremities. Her creatine kinase was 6791U/L, which raised up to 9213U/L the next day, with a positive urine myoglobin. Serum creatinine level was 2.18mg/dL, slightly higher than the baseline of 1.7mg/dL. She had a normal repeat electromyogram, which was in favor of statin-induced myopathy. Upon discontinuation of simvastatin and intravenous hydration, the creatine kinase returned to normal and she recovered her strength within two weeks with physical therapy. Statin induced myopathy is a concerning side effect but rhabdomyolysis is rare with an average incidence rate per 10000 persons-year of 0.44 (2). Among the available statins, simvastatin appears to have the most reported cases of myopathy. This may be due to the lipophilic nature allowing easy penetration of muscle membranes. Simvastatin is also metabolized by the enzyme CYP3A4 which metabolizes many other medications including warfarin and amiodarone, thereby carrying the risk for interaction(3,4). It is recommended that simvatatin dosage should not exceed 20mg daily when used in combination with amiodarone because of increased risk of myopathy. The current recommendation is to continue statins if the creatine kinase level is less than ten times the normal limit; however, clinical judgment is warranted as biopsy proven muscle damage has been found with lower levels of creatine kinase (5).
1. Carlos Escobar, Rocio Echarri, Vivencio Barrios. Relative safety profiles of high dose statin regimens. Vascular health and risk management 2008:4 (3) 525-533
2. D. J. Graham,J. A. Staffa; Deborah Shatin et al. Incidence of Hospitalized Rhabdomyolysis in Patients Treated With Lipid-Lowering Drugs JAMA. 2004;292:2585-2590
3. Molecular basis of statin-associated myopathy C. Vaklavas a, Y.S. Chatzizisis b, et al. Elsevier. Atherosclerosis 202 (2009) (18-28)
4. Miranda R. Andrus .Oral Anticoagulant Drug Interactions With Statins: Discussion. Pharmacotherapy. 2004;24(2)
5. Markus G., Mohaupt, R.H. Karas, E. B. Babiychuk et al . Association between statin-associated myopathy and skeletal muscle damage cmaj.081785 July 2009;181 (1-2)
Milind M Deshpande,Poornima M Deshpande
Goa Medical College;ESI,Goa
July 18, 2015
Risks and Benefits
Everything under the Sun including the Sun offers risks and benefits.Anti-hyperlipidemic drugs prescribed at the right hour offer benefits but their long term risks go unidentified since their adverse events manifest in such weird ways that the clinician may get carried away with newer diagnosis and also get swept away with newer shadows in the investigations!!! If only the clinician keeps an extremely low threshold to do away with these drugs he may find that the symptoms disappear within six weeks. Symptoms may range from “slow loss of memory,tinnitus,wry neck, carpal tunnel syndrome, sciatica” to “metatarsalgia,plantar fasciitis and peripheral ( glove and stocking) neuritis” !! We have withdrawn these drugs in over 3500 patients till date and what a relief my patients had! Relief from advices to decompresse the spinal canal stenosis,chronic carpal tunnel syndrome and steroid injections for tennis elbow !!!Its rewarding to stop these medications before surgical procedures and blood investigations to assess the thyroid .Ref: Anti-lipid drug menace, Published September 14, 2009, Ann Intern Med published ahead of print August 31, 2009, doi:10.1059/0003-4819-151-9-200911030-00144RegardsMilind M DeshpandePoornima M Deshpande
Goa Medical College,ESI,Goa,India
July 25, 2016
Growing Clinical Experience
SirThe number of patients in whom the anti-cholesterol drugs have been withdrawn from their drug box has now reached 5000!!!A 50 year old lady was being treated with omega -3-fatty acids and 2 capsules bd was her dosage for the last 5 years and it was prescribed by the dermatology fraternity for her perennial problem of developing multiple painful fissures on the pulps of her all ten fingers. She had presented to me with acute onset of anterior hip pain and I had offered her the most probable diagnosis of it being statin induced which got clinically proven when the hip pain disappeared after 3 weeks of statin withdrawal and off course the pulp fissures slowly stopped recurring after 10 weeks of statin ban. She has now withdrawn the omega too!!A 45 year old gentleman was advised L 4-5 diskectomy for his sciatica. He had episodes of unexplained itching all over the body on and off for which he consumed montelukast at least 15 days in a month for the last 3 years. I stopped his statins following which both sciatica and itching disappeared in 6 weeks!!RegardsMilind M DeshpandePoornima M Deshpande
Milind M Deshpande, Poornima M Deshpande
Goa Medical College,Goa,India
November 8, 2017
30 years back our teachers taught-----In India, place your bet on the diagnosis of Koch’s first than anything else and the simplest way to prove or disprove it is to give a therapeutic trial of anti tubercular therapy for 03 months.
Today, we would like to place our bet on statin induced pathy/statopathy.
We have now reached the 7000 mark, patients in whom we stopped statins.Our study is simply a clinical “Both eyes open” study rather than any blind one.
A 60 year old lady, non diabetic, non hypertensive developed a feeling of a marginally heavy and a sagging left cheek for about six months and was under investigation at other services. Her blood tests, CT and MRI brain, skin biopsy didn’t throw any light. The nerve conduction study revealed a diagnosis of paralysis of the buccal branch of the left facial nerve and it was labeled Idiopathic by the neurologist.
She was referred to me for neck pain and I happened to see all her above stated medical records. I quickly pulled out my favorite weapon from my armamentarium and asked her my leading question -----Are you on statins?? Yes was her reply. She was on statins for about a year for dyslipidemia.
After 12 weeks of stopping statins her cheek felt near normal to her and the smiley on her face felt more proportionate!!!!!
Drug Saf. 2014 Sep; 37(9):735-42. doi: 10.1007/s40264-014-0212-5.
Association between statin use and Bell's palsy: a population-based study.
Hung SH1, Wang LH, Lin HC, Chung SD.
Sharma M, Ansari MT, Abou-Setta AM, Soares-Weiser K, Ooi TC, Sears M, et al. Systematic Review: Comparative Effectiveness and Harms of Combination Therapy and Monotherapy for Dyslipidemia. Ann Intern Med. ;151:622–630. doi: 10.7326/0003-4819-151-9-200911030-00144
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Published: Ann Intern Med. 2009;151(9):622-630.
Cardiology, Coronary Risk Factors, Dyslipidemia.
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