Richard Lehman’s journal review – 25 June 2012

Richard LehmanJAMA 20 June 2012  Vol 307
2491   Most clinicians assume that the agencies which license new drugs—the Food and Drug Administration in the USA, or the European Medicines Agency over here—apply rigorous standards of effectiveness and safety before they let loose the latest products on the wider public. In fact they can only go by data from the few trials that have been conducted, invariably by the drug manufacturers, and then instruct the manufacturers to carry out phase 4 trials once the drug is in general use. This is a strangely lax system, and finally the US Institute of Medicine and the FDA are intending to do something about it and move towards a “lifecycle approach” in the evaluation of drugs, as Bruce Psaty explains in this article. But we need something much more rigorous and comprehensive, and soon.

2493   Do try and get a copy of this piece by Mary Tinetti and two colleagues: to me it seems the best summary of the real agenda of medicine for generalists in the coming decades. I make no apology for giving you great chunks of it. “Adults with multiple chronic conditions are the major users of health care services at all adult ages, and account for more than two-thirds of health care spending.” Does that sound familiar? “Quality measurement largely ignores the unintended consequences of applying the multiple interventions necessary to adhere to every applicable measure. Uncertain benefit and potential harm of numerous simultaneous treatments, worsening of a single disease by treatment of a coexisting one, and treatment burden arising from following several disease guidelines are the well-documented challenges of clinical decision making for patients with multiple chronic conditions.” Does that sound even more familiar? “Patient goal–oriented health care involves ascertaining a patient’s health outcome priorities and goals, identifying the diseases and other modifiable factors impeding these goals, calculating and communicating the likely effect of alternative treatments on these goals, and guiding shared decision making informed by this information.” So isn’t it time we abolished the Quality and Outcomes Framework and started learning the skills of patient goal-oriented health care? It won’t be easy. It will require a co-ordinator (is that you?) and a team (is that your practice team?). It will be a smarter, better kind of general practice, organized to meet the goals of patients as individuals. It will require new and better science about what works for individuals. “As this evidence becomes available, point-of-care risk calculators will be required to synthesize it to determine the best options for each patient.” Bring it on, say I: this is what I had hoped for ever since I came into general practice.

2499   The Emerging Risk Factors Collaboration must be getting despondent. Every time they publish a paper the conclusion is that whatever has emerged most recently makes little difference to risk scores derived from conventional factors. And happily the population risk for cardiovascular disease keeps going down. Here the Collaboration looked at the additive value of the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C. It’s a few per cent here and there.

NEJM  21 June 2012  Vol 366
2345    Avoid red meat; take daily aspirin; have a flexible sigmoidoscopy every 3-5 years. All these things will reduce your risk of dying from colorectal cancer. You will die of something else instead; so whether you adopt any of these practices should depend on how you rate dying from bowel cancer in your personal league table of nasty things to die from. That is my take-home message from this American trial which enrolled 154,900 people to be screened by flexible sigmoidoscopy either every 3 or 5 years or not at all. If there was any effect on total mortality, the authors fail to mention it, so I suspect there was not. After nearly 12 years of follow-up, there were 2.9 deaths from colorectal cancer per 10,000 person-years in the intervention group (252 deaths), as compared with 3.9 per 10,000 person-years in the usual-care group (341 deaths), which represents a 26% reduction. As with many screening decisions, this one is almost impossible to share with individuals in any meaningful way. It all depends on how you want to play the odds and what you might particularly wish not to die from. And of course if you particularly wish to avoid dying from bowel cancer, you need to have your whole bowel looked at, not just the final 35cm. The only problem is that the evidence for a mortality benefit from screening colonoscopy is actually weaker than for sigmoidoscopy: it is purely observational and not very strong.

2358   Nearly half of women who undergo repair operations for anterior vaginal prolapse have some degree of stress incontinence three months later: this randomized trial shows that you can halve that figure if you put in a urethral sling at the time of operation. And this was a blinded trial using sham incisions in the control group. There were no adverse events in the sham group but a small number in the sling group. So here is another nice little dilemma for shared decision making.

2397    Phew! We have just returned from a year in southern New England without contracting human babesiosis. This is a medical curiosity of the sort that regularly crops up in the Grand Rounds of the great New England teaching hospitals: so much easier and more fun to talk about than the confusing dilemmas of bowel cancer screening or proactive surgical procedures for female urinary incontinence. “Human babesiosis is an infectious disease caused by intraerythrocytic protozoa of the genus babesia. The disease is named after Victor Babes, the Hungarian pathologist and microbiologist who identified intraerythrocytic microorganisms as the cause of febrile hemoglobinuria in cattle in 1888.” Hurray, this is the stuff. All Americans love a didactic lecture. Sit back and enjoy. Next slide: a picture of Babeș, looking dapper with a fine moustache and gold-rimmed spectacles; actually Romanian, though born in the Austro-Hungarian Empire. Next slide: “The first identified case in an immunocompetent person, on Nantucket Island, off the coast of Massachusetts, in 1969. The causative agent was B. microti, and the vector was the Ixodes dammini tick (now referred to as I. scapularis.” Excellent. Time to check the Blackberry, send a surreptitious message or two, and doze awhile. “Treat with a combination of atovaquone and azithromycin”… Applause. Time to go back to work.

Lancet  23 June 2012  Vol 379
2352   Recombinant tissue plasminogen activator (rt-PA) for ischaemic stroke: a great therapeutic advance or a costly dead-end for health services? “Thrombolysis is of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4•5 h of onset. The third International Stroke Trial (IST-3) sought to determine whether a wider range of patients might benefit up to 6 h from stroke onset.” Those who got rt-PA in this trial died faster, though there was no difference in mortality at six months; and at that time there was also no significant difference in the combined end-point of survival plus independence. So among the 3035 patients randomized, a clearly negative result. But wait: we must heed the wisdom of our superiors on this matter. “Didier Leys has been an investigator in European Cooperative Acute Stroke Study (ECASS) 3 (Boehringer-Ingelheim) and participated in two symposia organised by Boehringer-Ingelheim; and is current president of the European Stroke Organisation, which received subventions from several companies including Boehringer-Ingelheim. Charlotte Cordonnier has been an investigator in ECASS 3.” These editorialists declare: “The key message of IST-3 and the updated meta-analysis is that many eligible patients from subgroups excluded by the European licence should now be given rt-PA.” And who is the leading manufacturer of rt-PA? Why, it is Boehringer-Ingelheim.

2364   The updated meta-analysis referred to here of rt-PA for ischaemic stroke is one conducted quite without industry influence, by pioneers of stroke research and leading proponents of open data access. And by combining the IST-3 data with those from 11 other trials, the authors do find some evidence of benefit in survival to independent living in all age groups treated within 3 hours: this is best seen in figure 3. The most striking feature is the small effect size. The industry-sponsored editorialists have only got two things wrong: the IST-3 trial shouldn’t appear in support of their declaration, and the words “be offered rt-PA within 3 hours if they are able to give informed consent” should take the place of “be given rt-PA.”

2373   Personally, the treatment I would most like to have if I suffer a substantial stroke over the age of 80 is a not rt-PA but a nice overdose of intravenous barbiturate, but I guess I will have to take my chances and maybe end my days with a PEG, a nappy, and a catheter, drooling helplessly while my surviving loved ones visit my smelly room in an expensive nursing home. Suicide when life is effectively over seems to me a humane option; but suicide in young people is always a tragedy. The figures from India are horrific: 40% of suicides in men and 56% in women occur between the ages of 15 and 29. Pesticides are a common means and restriction of their availability is a useful measure. Here in the UK, Keith Hawton has been a tireless investigator of self-harm and suicide in adolescents ever since he first taught me on the subject in 1973. “Prevention of self-harm and suicide needs both universal measures aimed at young people in general and targeted initiatives focused on high-risk groups. There is little evidence of effectiveness of either psychosocial or pharmacological treatment, with particular controversy surrounding the usefulness of antidepressants. Restriction of access to means for suicide is important.” The sober wisdom of 40 years: no magic wands.

BMJ  23 Jun 2012  Vol 344
When rosiglitazone was finally discredited as a treatment for type 2 diabetes, there was much rejoicing at Takeda Pharmaceuticals, since that left pioglitazone as the one agent of its class still on the market. But there is no convincing evidence that this thiazolidinedione improves any meaningful end-points in type 2 diabetes, and its association with heart failure is well known. To this we can add a probable doubling of the risk of bladder cancer, according to this case-control study from what was then called the UK General Practice Research Database (now Clinical Practice Research Datalink). No wonder the latest US guidelines leave a question mark over the choice of a second agent once control is lost with metformin alone. We simply know too little about any of the agents available; including metformin.

It’s great to be able to handle paper copy of the BMJ again, for all purposes except the truncated research section. Edwin Gale takes a hard look at the post-marketing studies of new insulins: a common characteristic is that they are “extravagantly powered,” and the vast numbers of patients who are recruited are usually from the countries which can least afford the cost of the new drug. An insider from industry confirms that such studies are simply meant to increase sales penetration with the support of opinion-leading local physicians. The net result is to make life-preserving treatment unaffordable in countries like India, where such practices are routine. John Yudkin challenges one company—NovoNordisk—to reclaim the moral high ground by helping such countries to avoid this blight of “catastrophic health expenditure” among helpless uninsured citizens.

I am looking forward to spending the remaining years of my active life exploring the challenges of shared decision making as the key element in many different kinds of medical encounter. The leading centre for this in the UK is Cardiff, though it has currently lost its greatest luminary, Glyn Elwyn, on secondment to Dartmouth College in the USA for a year. One of the greatest challenges of SDM is communicating risk and here some of Glyn’s Cardiff colleagues run through this complex topic with admirable clarity. It is high time that this was taught as a basic clinical skill at each stage of every medical career.

Ann Intern Med  19 June 2012  Vol 156
841   People with alcoholic liver cirrhosis have a high mortality, and hepatocellular carcinoma is supposed to be one reason. But this Danish study shows that the risk of liver cancer in alcoholic cirrhosis is actually very small, at 1% over five years—during which time nearly half the cohort had died of other causes.

861   A useful systematic review looks at drug treatments for female urinary incontinence. In case you hadn’t noticed, they aren’t very good. It’s a case of try this, then try something else. The trial literature abounds in uncertainties too, and there is no consistency about the end-points used, or the recording of harms. Oxybutynin may have more discontinuations for adverse effects than the rest, but the confidence intervals are all over the place. Try this, then try that.

Plant of the Week: Oenothera odorata

We arrived back from the States a couple of days ago and the garden was looking amazingly beautiful in a brief show of sunshine between rain and gales. All over the place were beautiful lamps of pale yellow from evening primroses that have sown themselves with wild generosity. They seem to go well with everything, from orange roses to blue geraniums—and more and more of their flowers appear as the evening draws in.

These are great plants for any garden, especially for beginners who need rapid abundance. You can always pull them up if you can bear to: they come away easily. Ironically, all the evening primroses are Americans by origin, even the ones that grow abundantly in the wild over here, as on the sand dunes of Devon. This particular one (often known as sulphureum) came over from South America in 1790.

The point of their beautiful pale colour and scent is of course to attract insects, especially moths. A certain prudishness forbids me to describe the scent exactly. Let the moths take their pleasure as they will.