Richard Lehman’s journal review – 10 April 2012

Richard LehmanJAMA  4 Apr 2012  Vol 307
1394    A special dread settles on me this week as I know I am going to have to write about breast cancer screening. But let’s leave the dread question of whole-population mammography for later, and consider the add-on benefit of annual ultrasound or single-screening MRI in selected high-risk women. While the war over breast screening rages unchecked in the letters and a book review in this week’s Lancet, let’s take refuge in this little corner of the battlefield, where at least the fog of war is not too thick and we can count a few weapons and estimate a few casualties. The volunteer combatants are women with dense breasts and at least one factor that increases their risk of breast cancer. The ultimate proof of victory, as in all screening studies, will be a reduction in total mortality. The casualty list should include every woman undergoing biopsy or surgery, because nobody comes away from these things altogether unscathed, be it mentally or physically. This study gives us a casualty list, including the number of enemy killed (breast cancers detected and operated on), but cannot give us any idea of the extent or the cost of victory, because it was run over a three-year period only. Our brave lasses certainly saw their share of action: 2725 over the age of 25 (!) went through annual mammography and ultrasound, and 612 ended up having MRI. During that time 110 had 111 breast cancer events: 33 detected by mammography only, 32 by ultrasound only, 26 by both, and 9 by MRI after mammography plus ultrasound; 11 were not detected by any imaging screen. Enough. We can tell from these figures that the three imaging modalities will pick up most cancers; but the true cost—mentally, physically, and financially—can only be hinted at in a study like this. Only very long-term follow-up will give us a true estimate of overdiagnosis and the degree to which such screening detects cancers which would never progress. But in just these three years, a total of 1272 biopsies were performed—more than ten for each cancer detected. So this high risk group may well see a small reduction in all-cause mortality over the course of their “screening lives,” but it will be purchased at a high cost in medical procedures and anxiety. In fact any woman undergoing this cycle of procedures would be extremely lucky to get away with a single fine-needle biopsy during her life—two or three would be more likely.

1414  Oral fluoroquinolones are cheap and ubiquitous these days, and lots of doctors take them abroad in case of traveller’s diarrhoea. But beware: this case-control study confirms that they may carry a more than fourfold risk of retinal detachment. OK, still not a huge absolute risk, and usually fixable; but it may not be what you want to happen to you while you are cruising down the Nile, admiring Cambodian temple complexes, or trekking to Machu Picchu.

NEJM  5 Apr 2012  Vol 366
1287   The successful EINSTEIN-PE trial of rivoroxaban has been talked about for a while, and you don’t have to be Einstein to work out that this is very good news for Bayer HealthCare and Janssen Pharmaceuticals, who co-funded the trial. It was an open-label trial, pitting the new oral fixed-dose factor Xa inhibitor against an adjusted-dose vitamin K antagonist (in the States, they use dicoumarol as well as warfarin) for 3, 6, or 12 months after symptomatic pulmonary embolism. As far as I can tell (and you know I am far from infallible) the stuff did what the manufacturers put on the can: rivaroxaban was as good at preventing recurrences, and less likely to cause major bleeds than a coumarol/INR regime.

1298   This trial comparing two artesunate-based antimalarial regimens in patients with uncomplicated falciparum malaria is principally a fairly routine affair of showing that pyronaridine–artesunate was noninferior to mefloquine plus artesunate for the primary outcome. This is useful knowledge for those in the field, across Asia and Africa. But the study has rapidly become more famous for the unwelcome confirmation it brings of artemesinin resistant malaria in Cambodia. This is suggested by increased parasite clearance times in a subset of patients from the region which first produced strains resistant to previous antimalarial drugs. Those lethal little zoites may be on the verge of outwitting us yet again in the jungles of IndoChina: a sickening thought, after so many decades of effort, never quite sufficiently carried through.

1310   Here’s a really thought-provoking study from Sweden showing that in the week after receiving a cancer diagnosis, the relative risk of suicide goes up by 12.6 and the RR for cardiovascular death by 5.6. Taken over the first year, the risk ratios are slightly over 3 for both. The immediate cardiovascular effects of a shocking diagnosis could hardly be more dramatically demonstrated, while the continuing physical effect could be partly explained by prothrombotic and inflammatory effects from the cancer itself. But the suicide figures once again raise the question of what is an “appropriate” response to a cancer diagnosis. Palliative care specialists, at least in the UK, share a religious predisposition to expect all cancer patients, at whatever stage, to bear their sufferings to the end, encouraged by promises (which may be undeliverable) of complete relief. To me personally, this interpretation of the will of God seems neither rational or generous, nor even always honest. The original Zarathustrian religion of good thoughts, good words, and good deeds seems to me a better guide: it acknowledges that God (or good, or whatever you want to call it) can only act through man in the physical world. Suicide in the first week of diagnosis is likely to be an immediate distress reaction, almost certain to cause a lot of distress in others: it is not irrational, but is usually best averted if possible. But well-planned suicide in the face of impending suffering and death does not seem to me either irrational or ignoble, provided it is done with full consideration to others.

1319   The ancient Good Religion of Zarathustra dominated Iran for at least a thousand years, before the Arab conquest gradually led to the imposition of Islam from the mid-seventh century onwards. The Muslim tradition in Persia contains elements of both, as shown by the linguistic parentage of the name Faramarz Ismail-Beigi. How nice it would be to dwell on the history of this wonderful part of the world a little longer, but unfortunately we must move on to the topic of glycaemic management of type 2 diabetes mellitus, upon which the distinguished Dr Ismail-Beigi writes in this week’s NEJM. You may perhaps be expecting some harsh words from me on this subject, but I must honour the Iranian tradition of intelligence, charm, and moderation as best I can on this occasion. Professor I-B acknowledges that there is a lot we do not understand about the disordered metabolic state that we please to call “type 2 diabetes,” on the grounds that it is characterised by high levels of blood glucose and gradual depletion of beta-cell function. He goes through the evidence and finds that it is insufficient to guide any choice of agents beyond diet and metformin in the first instance. Pretty well everything we know about long-term effects—whether driven by treatment or disease processes – is derived from a single study designed in the 1970s, the UKPDS. Survivors of this group who were treated intensively at the outset with sulfonylureas and insulin show a “legacy effect” according to levels of blood sugar control, which the investigators attribute to the treatment—though not to the extent of suggesting we use these interventions as first-line treatment in 2012. Rather we should look at the subgroup of fatter patients who were given metformin, and extrapolate from them, since they had somewhat better outcomes. We should hope that these newly diagnosed patients maintain a glycated haemoglobin level of around 6-6.5%, as people who managed to stay at these levels did best in the long term. We can’t tell whether this was due to treatment or because they had a more favourable disease process. This may not be the pinnacle of evidence-based medicine, but it is what specialists agree on when they meet in High Council to discuss what we should do with tens of millions of people with this condition around the world, basing their judgements on what happened to a few hundred British diabetics from the time of Mrs Thatcher. For more modern sugar-lowering interventions, we have no long-term data on harms or benefits, since no-one has thought it necessary to require them. About all this, Faramarz Ismail-Beigi is quite candid, calm, and polite: so in the best tradition of Persian courtesy, I shall stay the same towards the whole profession of diabetology. Salaam, Khoda hafez.

Lancet  7 Apr 2012  Vol 379
1310   This cluster-randomised trial from British general practice compared computer-generated reminders about medication dangers with something they grippingly called PINCER—“a pharmacist-led information technology intervention, composed of feedback, educational outreach, and dedicated support.” You can choose which you hate most—this description or the acronym. The end-points were: non-selective non-steroidal anti-inflammatory drugs (NSAIDs) prescribed to those with a history of peptic ulcer without co-prescription of a proton-pump inhibitor; β blockers prescribed to those with a history of asthma; long-term prescription of angiotensin converting enzyme (ACE) inhibitor or loop diuretics to those 75 years or older without assessment of urea and electrolytes in the preceding 15 months. Fair enough, I suppose (though I suspect some surprises when someone eventually looks at the end-points in “asthma” patients given very low-dose β blockers versus those given β agonists): and of course the PINCERed practices did better. So what should you commissioning guys invest in? More paid-for interference—sorry, I mean outreach and dedicated support—by community pharmacists, or punchier, clearer computer reminders?

1331   “Knee-replacement surgery is frequently done and highly successful.” I can vouch for that—not because I’ve had it, but because a lot of my patients had it done by the first author of this review, and they have fared well. During my GP career, I’ve seen this procedure grow up from a last-resort, almost experimental operation to a routine procedure for painful osteoarthritis. The technology seems to have improved steadily over that time, though with the present pitiful standard of device regulation, there is nothing to stop some new prosthesis winning most of the knee surgery market before it turns out to be a disaster. I refer of course to the metal-on-metal hip scandal; but I’ve seen it happen with some other kinds of innovative knee surgery, like the carbon ligaments once favoured by another local surgeon. The international epidemiology of TKR is fascinating for its insights into the variability of preference-sensitive surgery in different health systems. In the UK, demand for TKR may actually have peaked—or is it just being rationed more effectively?

BMJ  7 Apr 2012  Vol 344
Ah, a plate of plain white rice. How like the research pages of the BMJ this week: bland, unappetizing, and badly in need of some original additions. Maybe that’s why the journal let through this terrible study which traces the links between white rice consumption and diabetes, by a series of population survey methods which have BEWARE OBVIOUS CONFOUNDERS written all over them: perhaps they just wanted newspaper coverage and rapid responses. They certainly got plenty of the latter, and I will let them do their work unhindered by any further comment from me.

Well, maybe this is interesting, if it is confirmed in other studies: women who have had surgical treatment for treatment for human papillomavirus-associated vulval or cervical disease are less likely to experience recurrence if they have had previous vaccination with quadrivalent HPV vaccine. This is based on retrospective pooled data from interventional trials.

Anns Intern Med  3 Apr 2012  Vol 152
491   And now, as I warned you, we must return to the battlefield of breast cancer screening. I defy anyone to reach clarity on this subject: the nature of the data just doesn’t allow it. So we are on the horns of a real dilemma here. We need women to make up their own minds on whether to go for this kind of screening, but we cannot inform their choice in a way which is either easily comprehensible or free from our own value judgements. By saying this, I’ll probably draw fire from both sides in this debate—the screening enthusiasts who will say there is clear evidence of benefit and women shouldn’t worry their pretty little heads about the matter but just go along and have their breasts X-rayed; and the sceptics, led by the redoubtable Peter Gøtzsche, who will say that the benefits are dubious or non-existent and the harms are all too real. Each side will then go through a selection of mainly observational studies to try and prove their point. At this point I tend to find some excuse to slip out of the room, glad that I am a man, and that I no longer have to give my advice to anyone: muffled cries of anger pass me by as I make my escape. But for your sakes, dear readers, let’s take a passing look at this latest observational study from Norway. Leave aside the costs, the anxiety, and the needle biopsies and concentrate on how many detected cancers can be considered as overdiagnosed. “The number of cases of breast cancer found in screened women was compared with that in matched unscreened women. Investigators estimated that 15% to 25% of cases of breast cancer detected represented overdiagnosis.” OK guys, you be downloading the paper and discussing the methods, and the meaning of “overdiagnosis.” I’m just nipping out to get some coffee…

Plant of the Week: Ribes x gordonianum

The flowering currants are classic spring bushes to be looked forward to with special pleasure. As forsythias scream their yellow at the spring winds, hard by battered expanses of browning magnolia flower, and cherry trees filled with blowsy pink, it’s a relief to look down at or below head height and see the intriguing brick and pinkish yellow flowers of this unassuming but essential little shrub.

It is a quintessentially British plant, discovered as a chance hybrid in Ipswich in 1837. It carries the reds of Ribes sanguineum subtly blended with the yellows of Ribes odoratum, in open clusters of small bell-shaped flowers with bright yellow and red stamens. I keep trying to detect the spicy fragrance of odoratum but the feral rankness of currant-bush tends to predominate. Nonetheless, this tousled, prickly, loveable scamp should be in every garden to welcome the spring.