by John D Abramson, Harriet G Rosenberg, and Nicholas Jewell, and James M WrightBritish Medical Journal. 2013 347:f6123.
…From a pharmacoeconomic perspective, expanding generic statin therapy to millions of low risk patients would add drug costs of up to $1/day or more per person for no net health benefit. Furthermore, if cholesterol lowering becomes established in low risk people, the indications for new, more expensive cholesterol lowering drugs such as the ApoB Antisence drugs and PCSK9 inhibitors currently being tested in clinical trials will probably expand as well.
The dominance of industry sponsored clinical trials of cardiovascular prevention has produced a body of scientific evidence that largely limits clinicians’ interventions to drug therapy. Rather than being compelled by guidelines to prescribe statin therapy for people at low risk of cardiovascular disease, doctors would provide a far greater service by explaining the magnitude of the benefits and uncertainty about the harms of statins together with discussion of the epidemiological evidence showing that behavioural risk factors—including tobacco use, lack of physical exercise, and unhealthy diet—are responsible for 80% of cardiovascular disease:What low risk patients need to know
- Lifestyle factors—including lack of exercise, tobacco use, and unhealthy diet—account for 80% of cardiovascular disease
- For people at low risk of cardiovascular disease [<10% risk over next five years], statins do not reduce the overall risk of death or serious illness
- In order to prevent one heart attack or stroke, 140 low risk people [< 10% five year risk] must receive statins for five years
- The side effects of statins—including muscle symptoms, increased risk of diabetes [especially in women], liver inflammation, cataracts, decreased energy, sexual dysfunction, and exertional fatigue—occur in about 20% of people treated with statins
by Fiona Godlee, editor BMJBritish Medical Journal. 2013 347:f6412
…There is a concern underlying their critique that will be familiar to BMJ readers. It is that all of the trials included in the CTT meta-analysis were funded by the manufacturer of the statin being studied. They list the various ways in which these trials might have exaggerated the benefits of statins and minimised the harms, and they summarise what low risk patients need to know. Top of the list is the benefit of lifestyle change, something that the dominance of industry sponsored clinical trials too often obscures.
None of this does much to bolster confidence in the published literature. Nor am I reassured by discussions at two recent meetings co-hosted by the European Federation of Pharmaceutical Industry Associations (EFPIA). Drug company AbbVie is suing the European Medicines Agency to stop summary reports of its clinical trials becoming publicly available [doi:10.1136/bmj.f1636]. AbbVie’s lawyer made clear that the company considers even the data on adverse events to be commercially confidential. Despite industry’s claims to be in favour of greater transparency, EFPIA and its American counterpart PhRMA are supporting Abbvie. The BMJ and BMA have joined forces to intervene on behalf of the EMA [doi:10.1136/bmj.f4728].As for a way forward, I can’t improve on the list of solutions proposed by Richard Lehman when emailing out his journal review blog this week [http://bit.ly/HcKvjy]: “All phase 3 trials to be designed and conducted independently of manufacturers, using the best available comparator. Research priorities to be determined by patients (James Lind Alliance). Value-based pricing. All data available from all trials, with meta-data: IPD [individual patient data] level for qualified independent centres. Big increase in comparative effectiveness research, much more research into non-pharmacological treatments.”
A Vignette: A friend down the road had been having a lot of muscle pain and stiffness and had been "sentenced" to Yoga Classes by his wife [which massively increased his symptoms]. On another day, he was talking about medication costs. He mentioned he’s taking a Statin that’s not yet generic. It costs a "mint," but his doctor says that it’s the "best one." Last night they were over and he mentioned he’d gotten back his most recent cholesterol count and said the number. His LDL [bad cholesterol] was "way down" [from normal to even more normal].
|The bottom line
Our calculations using data presented in the 2012 CTT patient level meta-analysis show that statin therapy prevents one serious cardiovascular event per 140 low risk people (five year risk <10%) treated for five years. Statin therapy in low risk people does not reduce all cause mortality or serious illness and has about an 18% risk of causing side effects that range from minor and reversible to serious and irreversible. Broadening the recommendations in cholesterol lowering guidelines to include statin therapy for low risk individuals will unnecessarily increase the incidence of adverse effects without providing overall health benefit…from Abramson et al [above]
After looking at all these psychoactive drug trials, I am learning more precise ways of thinking about all of this. For a drug to have a demonstrable statistical superiority over sugar is certainly of interest, but hardly justifies it being turned into a multi·billion dollar phenome – which is exactly what has happened repeatedly. There’s something else that can be said about such comparisons, the strength of effect being one. Just because a drug has antidepressant properties in a large cohort, doesn’t mean it will be a clinically meaningful effect in many depressed people. And those numbers are frequently omitted from articles – things like odds ratio, number needed to treat [NNT], effect size, etc. And then there are adverse effects [side effects] and serious adverse effects [SAEs]. They can be quantified as things like risk ratio, relative risk, or number needed to harm [NNT]. In the end, all of these things can be combined into a risk·benefit ratio, and while there are some ways to quantitate this, it’s usually discussed subjectively as in these articles.
I grew into doctor·hood when such things were more narrative than mathematical. Digitalis could be a life·saver or a poison, and I could say that in words to patients and explain why it was both. I thought of drugs categorically, as powerful or weak, as safe or dangerous, with not much in between on either axis. I thought of classes of drugs [the penicillins] more in terms of their similarities than their differences. Now, in the Age of Clinical Trials, we are bombarded with articles that are preoccuppied with small effects and small differences among members of a similar class. One frequently sees patients who have tried every known SSRI without success, but come seeking another new one. Rather than concluding the obvious, no chemical help in sight and likely there’s something wrong in their life. They think they just haven’t tried the right antidepressant [after all, they are anti·depressants].
So back to the Statins, this is a multi·billion dollar phenome extra·ordinaire, and in large measure is as big a much·ado·about·nothing as it was in 1971 when I found myself balking at all the guidelines that kept coming. To me, Statins are for high risk patients, side effects or not. The rest of us should drive carefully, and stick to the basics ["Lifestyle factors—including lack of exercise, tobacco use, and unhealthy diet—account for 80% of cardiovascular disease"]. Dr. David Healy’s book, Pharmageddon, makes this point more eloquently than I, but, in my words, we have become a culture of small differences – differences that don’t really matter [and they even fudge on that eg Paxil Study 329]. And the Pharmaceutical Industry and the proliferation of Clinical Trials have had a big part in making us that way – by design.