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Tuesday, August 26, 2014

Who should take statins and why are researchers demanding a retraction?

I received an invitation to sign a letter authored by the Lown Institute in support of an article published in the BMJ (formerly the British Medical Journal) questioning the wisdom of prescribing statin drugs to patients at low risk of cardiovascular disease such as heart attack or stroke. Statins such as Lipitor (atorvastatin) and Zocor (simvastatin) are drugs which reduce cholesterol levels by inhibiting an enzyme on cell membranes.

The article concludes that statin drugs are unlikely to be helpful to patients whose risk of heart disease or stroke is calculated to be less than 20% in 10 years. It was written by Dr. John Abramson, a lecturer at Harvard Medical School and the author of 2 books about inappropriate use of medications and tests; Harriet Rosenberg, a social scientist from Canada who has written about the lack of good scientific study of statins in women; Nicholas Jewell, a statistician from UC Berkeley; and Dr. James M. Wright, a professor at University of British Columbia who writes about appropriate use of prescription drugs for a publication called the Therapeutics Initiative. It is excellent, concise and well written, so please consider following the link above to read it.

The work of the CTT

One year before this article came out, a group of lipid researchers called the CTT (Cholesterol Treatment Trialists) published a meta-analysis of 27 trials on the effectiveness of lipid lowering drugs and concluded that even very low risk patients (essentially everyone over the age of 50 with a few exceptions) could benefit from taking statin drugs, and that evidence showed that statin drugs cause minimal harm. Dr. Abramson et al combed through these same studies and concluded that the harms associated with statin side effects had been grossly underestimated and that actual mortality was not improved in low risk patients when they took statin drugs.

Members of the CTT pointed out that Dr. Abramson and his coauthors may have misrepresented another study in describing the magnitude of statin side effects, so the article was changed to reflect this. Now the head of the CTT, Dr. Rory Collins of University of Oxford in the UK, is asking the BMJ to entirely retract the article, arguing that it misrepresents other information, it is unclear which, and might convince people who take statins to discontinue them. It appears, from the meta-analysis, that at least 140 people at low risk need to take statins for 5 years to prevent 1 major cardiovascular event (stroke or heart attack) and that there is no reduction in mortality at all for this group.

It is also true that the vast majority of patients prescribed statins stop taking them within 2 years without any knowledge of this debate or even realization that there is a debate. Bloomberg Business Week comments on the conflict here.

Roots of the disagreement

So it appears to me that some very intelligent doctors completely disagree on the subject of whether low risk patients ought to take statin medications. It comes down to differing values, I think. The doctors who favor giving statins to just about everybody over the age of 50 believe that it is no big thing at all to take a powerful medication daily so long as the side effects aren’t horrendous or the cost individually prohibitive. Avoiding 1 stroke or heart attack in 1 of 140 patients is worth having the rest take a medication which doesn’t clearly benefit them. The doctors questioning expanding statin use put a higher value on saving the 140 patients not destined for strokes or heart attacks from taking a useless medication with some obvious, though not universal, side effects.

Side effects

And what about these side effects? What are they and why is there such disagreement about how significant they are? The most common statin side effect is muscle pain. In early drug trials the first statin, or HMG CoA reductase inhibitor, was so toxic to muscles that it resulted in the deaths of some laboratory dogs on whom it was tested. Subsequent statins were less toxic and rarely cause serious muscle breakdown, though muscle pain and spasms are common. Many patients discontinue the medication due to this side effect, but may tolerate another drug in a similar class or the same drug if it is tried again. This is often cited as evidence that the muscle pain was never the fault of the statin in the first place, though it is just as likely that patients, on finding their doctors insist that they take the drug that caused muscle pain simply quit talking about it and took the prescribed medication.

Also common are complaints of weakness, foggy thinking and indigestion. More serious side effects include diabetes, which occurs more often in statin users (1 in 100 over 2 years) and severe and life threatening muscle breakdown. My personal experience of statin side effects when I practiced primary care medicine included professors who stopped taking statins because they couldn’t think straight, middle aged hikers who discontinued statins because of progressive muscle pains, weakness and intolerable night spasms, an ancient man who had thought he was going to die because his back had become weak and painful while taking a statin, and thanked me profusely for years after for curing him by stopping his statin, and a woman who nearly died from statin induced rhabdomyolysis (sudden muscle breakdown) due to a drug interaction between her statin and another medication.

I probably saw my share of statin induced diabetes, but was never on the lookout for it since that association was not known at the time. Many of my patients refused to ever take statins again due to muscle pain though they had been prescribed for perfectly good indications including after heart attacks or stent placements. For some patients there were no side effects of taking statins, but a sizable minority found these drugs very hard or impossible to tolerate.

Who are the CTT?

... and why do they think that these side effects are unimportant? According to the 2012 article, they are about 100 researchers who wrote diverse research papers about how effective statins were in reducing cardiovascular disease, most of which were supported by the pharmaceutical companies which produce statins. Many are academic cardiologists, and probably none are primary care physicians. They are mostly not in a position to actually prescribe these medications to real people and then see those people back on a frequent basis as they complain that they just don’t feel as well as they did before starting the statin. They are also heavily cognitively invested in the truth of the research they have been involved in, which was designed, with drug company support, to be most likely to show that statins improve health and have minimal side effects.

Primary vs. secondary prevention

It is well established that statins help reduce recurrent heart attacks in patients who have known coronary artery disease. This appears to be due to these drugs’ ability to reduce inflammation which is an important cause of arterial narrowing. This use of statins is called “secondary prevention” and is pretty well accepted as a good reason to take them. There is solid agreement among mainstream physicians that use of statins in secondary prevention is usually a good idea. Treating patients who have not had an event such as a heart attack is called “primary prevention” and potentially involves billions of people who are otherwise healthy in medication treatment. Primary prevention with statins for high risk patients, say diabetic, obese and sedentary smokers with high cholesterol levels, is probably a good idea and is not part of the present debate.

The successful industry of health care

Dr. Abramson et al make an excellent point at the end of their article that because the pharmaceutical industry funds so much of cardiovascular research most of this research is limited to drugs, creating a body of scientific evidence that drugs are the only route to good health. Less exhaustive but high quality research shows that lifestyle modifications, including a diet rich in fruits, vegetables and whole grains, exercise and avoidance of smoking, is very powerful in preventing cardiovascular disease and extending healthy life. If these things made any entity good money, we would be seeing a myriad of strategies to get patients to adopt healthy lifestyles. Instead, poor health and dependence on medications fuels an economically successful healthcare industry. Medicine as an industry thrives when people live longer but require many medications and many medical interventions, so expanded use of statins with associated significant side effects is a winning combination.

Drugs and money

Statin drugs were responsible for over $29 billion in sales last year. This was a reduction of 11% from the previous year, because many of the statins have become generic. Increasing the number of prescriptions for these drugs will increase the revenue related to them and will fuel demand for newer drugs in the class or related classes. Although physicians in the CTT may only have patients’ best interests in mind, drug companies sell statins in order to make money. The power of the pharmaceutical companies is likely an important factor in calls for retraction of article by Dr. Abramson et al, which questions the present recommendations to expand indications for statin therapy.

Janice Boughton, MD, ACP Member, practiced in the Seattle area for four years and in rural Idaho for 17 years before deciding to take a few years off to see more places, learn more about medicine and increase her knowledge base and perspective by practicing hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling. Disturbed by various aspects of the practice of medicine that make no sense and concerned about the cost of providing health care to every American, she blogs at Why is American Health Care So Expensive?, where this post originally appeared.

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3 Comments:

Anonymous Anonymous said...

I think you've missed a key issue in this debate - the nocebo effect. Have you see this paper?:
http://www.ncbi.nlm.nih.gov/pubmed?term=24623264
"What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice"

August 27, 2014 at 4:43 AM  
Blogger Janice Boughton said...

Hi Anonymous--The nocebo effect, that is an unpleasant reaction experienced by a patient when he or she receives a harmless substance because of negative expectations, is certainly responsible for some side effects of many medications. The physician author of the article you cite, Ben Goldacre of the UK, discusses (see link below) why the results of his paper do not have adequate data to evaluate the side effects of statins. Please look at the comments, as well, which are very astute. I hate to sound provincial and gullible, but as a primary care doctor who prescribes these, it is abundantly clear that they commonly cause muscle pain which resolves with discontinuation. Diabetes is also not a nocebo effect. HMG CoA is an enzyme that has far reaching physiological effects and blocking it is not trivial. Ben Goldacre's comment: Bhttp://www.badscience.net/2014/03/statins-have-no-side-effects-what-our-study-really-found-its-fixable-flaws-and-why-trials-transparency-matters-again/

August 27, 2014 at 4:39 PM  
Anonymous Anonymous said...

Ben Goldacre was speculating, and he also still writes that "I’m fairly certain that muscle ache on statins, for example, often is a product of the nocebo effect".

The knowledge that statins can cause a small increase in the risk of developing diabetes was gained from a meta-analysis of RCT data. So do you think the RCT data is reliable for diabetes, but unreliable for muscle pain? It seems a bit like cherry picking, and I just think your article would have benefited from being a little more balanced.

August 28, 2014 at 9:31 AM  

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Blog log

Members of the American College of Physicians contribute posts from their own sites to ACP Internistand ACP Hospitalist. Contributors include:

Albert Fuchs, MD
Albert Fuchs, MD, FACP, graduated from the University of California, Los Angeles School of Medicine, where he also did his internal medicine training. Certified by the American Board of Internal Medicine, Dr. Fuchs spent three years as a full-time faculty member at UCLA School of Medicine before opening his private practice in Beverly Hills in 2000.

And Thus, It Begins
Amanda Xi, ACP Medical Student Member, is a first-year medical student at the OUWB School of Medicine, charter class of 2015, in Rochester, Mich., from which she which chronicles her journey through medical training from day 1 of medical school.

Auscultation
Ira S. Nash, MD, FACP, is the senior vice president and executive director of the North Shore-LIJ Medical Group, and a professor of Cardiology and Population Health at Hofstra North Shore-LIJ School of Medicine. He is Board Certified in Internal Medicine and Cardiovascular Diseases and was in the private practice of cardiology before joining the full-time faculty of Massachusetts General Hospital.

Zackary Berger
Zackary Berger, MD, ACP Member, is a primary care doctor and general internist in the Division of General Internal Medicine at Johns Hopkins. His research interests include doctor-patient communication, bioethics, and systematic reviews.

Controversies in Hospital Infection Prevention
Run by three ACP Fellows, this blog ponders vexing issues in infection prevention and control, inside and outside the hospital. Daniel J Diekema, MD, FACP, practices infectious diseases, clinical microbiology, and hospital epidemiology in Iowa City, Iowa, splitting time between seeing patients with infectious diseases, diagnosing infections in the microbiology laboratory, and trying to prevent infections in the hospital. Michael B. Edmond, MD, FACP, is a hospital epidemiologist in Iowa City, IA, with a focus on understanding why infections occur in the hospital and ways to prevent these infections, and sees patients in the inpatient and outpatient settings. Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands).

db's Medical Rants
Robert M. Centor, MD, FACP, contributes short essays contemplating medicine and the health care system.

Suneel Dhand, MD, ACP Member
Suneel Dhand, MD, ACP Member, is a practicing physician in Massachusetts. He has published numerous articles in clinical medicine, covering a wide range of specialty areas including; pulmonology, cardiology, endocrinology, hematology, and infectious disease. He has also authored chapters in the prestigious "5-Minute Clinical Consult" medical textbook. His other clinical interests include quality improvement, hospital safety, hospital utilization, and the use of technology in health care.

DrDialogue
Juliet K. Mavromatis, MD, FACP, provides a conversation about health topics for patients and health professionals.

Dr. Mintz' Blog
Matthew Mintz, MD, FACP, has practiced internal medicine for more than a decade and is an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients.

Everything Health
Toni Brayer, MD, FACP, blogs about the rapid changes in science, medicine, health and healing in the 21st century.

FutureDocs
Vineet Arora, MD, FACP, is Associate Program Director for the Internal Medicine Residency and Assistant Dean of Scholarship & Discovery at the Pritzker School of Medicine for the University of Chicago. Her education and research focus is on resident duty hours, patient handoffs, medical professionalism, and quality of hospital care. She is also an academic hospitalist.

Glass Hospital
John H. Schumann, MD, FACP, provides transparency on the workings of medical practice and the complexities of hospital care, illuminates the emotional and cognitive aspects of caregiving and decision-making from the perspective of an active primary care physician, and offers behind-the-scenes portraits of hospital sanctums and the people who inhabit them.

Gut Check
Ryan Madanick, MD, ACP Member, is a gastroenterologist at the University of North Carolina School of Medicine, and the Program Director for the GI & Hepatology Fellowship Program. He specializes in diseases of the esophagus, with a strong interest in the diagnosis and treatment of patients who have difficult-to-manage esophageal problems such as refractory GERD, heartburn, and chest pain.

I'm dok
Mike Aref, MD, PhD, FACP, is an academic hospitalist with an interest in basic and clinical science and education, with interests in noninvasive monitoring and diagnostic testing using novel bedside imaging modalities, diagnostic reasoning, medical informatics, new medical education modalities, pre-code/code management, palliative care, patient-physician communication, quality improvement, and quantitative biomedical imaging.

Informatics Professor
William Hersh, MD, FACP, Professor and Chair, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, posts his thoughts on various topics related to biomedical and health informatics.

David Katz, MD
David L. Katz, MD, MPH, FACP, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care.

Just Oncology
Richard Just, MD, ACP Member, has 36 years in clinical practice of hematology and medical oncology. His blog is a joint publication with Gregg Masters, MPH.

KevinMD
Kevin Pho, MD, ACP Member, offers one of the Web's definitive sites for influential health commentary.

MD Whistleblower
Michael Kirsch, MD, FACP, addresses the joys and challenges of medical practice, including controversies in the doctor-patient relationship, medical ethics and measuring medical quality. When he's not writing, he's performing colonoscopies.

Medical Lessons
Elaine Schattner, MD, FACP, shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology, and as a patient who's had breast cancer.

Mired in MedEd
Alexander M. Djuricich, MD, FACP, is the Associate Dean for Continuing Medical Education (CME), and a Program Director in Medicine-Pediatrics at the Indiana University School of Medicine in Indianapolis, where he blogs about medical education.

More Musings
Rob Lamberts, MD, ACP Member, a med-peds and general practice internist, returns with "volume 2" of his personal musings about medicine, life, armadillos and Sasquatch at More Musings (of a Distractible Kind).

Prescriptions
David M. Sack, MD, FACP, practices general gastroenterology at a small community hospital in Connecticut. His blog is a series of musings on medicine, medical care, the health care system and medical ethics, in no particular order.

Reflections of a Grady Doctor
Kimberly Manning, MD, FACP, reflects on the personal side of being a doctor in a community hospital in Atlanta.

The Blog of Paul Sufka
Paul Sufka, MD, ACP Member, is a board certified rheumatologist in St. Paul, Minn. He was a chief resident in internal medicine with the University of Minnesota and then completed his fellowship training in rheumatology in June 2011 at the University of Minnesota Department of Rheumatology. His interests include the use of technology in medicine.

Technology in (Medical) Education
Neil Mehta, MBBS, MS, FACP, is interested in use of technology in education, social media and networking, practice management and evidence-based medicine tools, personal information and knowledge management.

Peter A. Lipson, MD
Peter A. Lipson, MD, ACP Member, is a practicing internist and teaching physician in Southeast Michigan. The blog, which has been around in various forms since 2007, offers musings on the intersection of science, medicine, and culture.

Why is American Health Care So Expensive?
Janice Boughton, MD, FACP, practiced internal medicine for 20 years before adopting a career in hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling.

World's Best Site
Daniel Ginsberg, MD, FACP, is an internal medicine physician who has avidly applied computers to medicine since 1986, when he first wrote medically oriented computer programs. He is in practice in Tacoma, Washington.

Other blogs of note:

American Journal of Medicine
Also known as the Green Journal, the American Journal of Medicine publishes original clinical articles of interest to physicians in internal medicine and its subspecialities, both in academia and community-based practice.

Clinical Correlations
A collaborative medical blog started by Neil Shapiro, MD, ACP Member, associate program director at New York University Medical Center's internal medicine residency program. Faculty, residents and students contribute case studies, mystery quizzes, news, commentary and more.

Interact MD
Michael Benjamin, MD, ACP member, doesn't accept industry money so he can create an independent, clinician-reviewed space on the Internet for physicians to report and comment on the medical news of the day.

PLoS Blog
The Public Library of Science's open access materials include a blog.

White Coat Rants
One of the most popular anonymous blogs written by an emergency room physician.

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