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Wednesday, July 23, 2014

The debate rages (still): who should take cholesterol lowering drugs and why is the CTT bullying statin skeptics?

This morning 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 two 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 one 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 one 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 Healthcare
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.

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