Richard Lehman’s journal review—11 September 2017

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM  7 Sep 2017  Vol 377

Mucin & chronic bronchitis

In the 1970s I worked for two old Welsh chest physicians in a Derbyshire mining town. What poetry it was to hear them talk of chronic bronchitis, pink puff-ers, blue bloat-ers, emphys-ema, or (the very height of bliss) ten-acious mu-cus. I thought such language had gone out when COPD came in during the 1980s, but here it is back in a NEJM article called “Airway Mucin Concentration as a Marker of Chronic Bronchitis.” Mucin is what makes mucus sticky: it has a very ancient Proto-Indo-European pedigree in the root-word *meug—meaning slippery or slimy. Mucus is usually 98% water but gets its gel-like properties from high-molecular-weight (>107 Da) mucin polymers, predominantly MUC5B and MUC5AC. In days gone by “expectorants” were very popular drugs, and spitting was universal, but this is the first study of mucin and COPD that I can remember reading in the leading journals. It’s an exploratory observational study of the two leading mucins measured by mass spectroscopy in a cohort of 148 patients with COPD. Concentrations are highly related to past and present smoking and are a very plausible reason for infective exacerbationshence the use of “chronic bronchitis” in this paper. Eventually, as the two Welshmen would sadly conclude, these patients reach the point where they couldn’t blow the skin off a rice pud-ding.

Tezepelumab for adult asthma

Mucins certainly play a part in refractory adult asthma too, but why bother about sticky phlegm when you can target epithelial-cell-derived cytokine thymic stromal lymphopoietin (TSLP)? In a phase 2 randomised controlled trial, a human monoclonal antibody against TSLP, called tezepelumab, reduced asthma exacerbations by about two-thirds in adults who were getting on average 0.67 exacerbations per year on inhaled steroids and long-acting bronchodilators. It remains to be seen what this will mean in dollars per exacerbation not experienced, assuming the drug gets licensed.

Bivalirudin v heparin for MI

Heparin is a crude cellular extract developed one hundred years ago. And yet it remains good stuff: in the VALIDATE-SWEDEHEART trial it proved the equal of bivalirudin, which costs about a hundred times as much. This egregiously-named trial compared the two anticoagulants in 6006 patients undergoing emergency percutaneous intervention for myocardial infarction, with or without ST elevation.

Pyrrhus and anacetrapib

Anacetrapib was the last hope of a drug class once hyped as the new statins. A decade ago, the cholesterol ester transfer protein inhibitors (rapibs) carried high hopes of reducing cardiovascular disease by lowering LDL-cholesterol while raising HDL-cholesterol. But one by one, they flopped. The last remaining was anacetrapib, tested in the REVEAL trial against placebo in 30,449 people with atherosclerotic disease who were on intensive atorvastatin. At a median follow-up of 4.1 years, the primary outcome (coronary death, acute myocardial infarction, or coronary revascularization) occurred in 10.8% of the anacetrapib group and 11.8% of the placebo group, a statistically significant difference. So here’s a 1% difference in a composite outcome in a single industry-sponsored trial. What if the regulatory bodies decide to ask for a replication trial, which I think they should since this is a drug to be used long-term for secondary prevention? I suspect that in such a case Merck might find themselves in the position of King Pyrrhus of Epirus, whose victory in 279 left him growling, “If we are victorious in one more battle with the Romans, we shall be utterly ruined.”

JAMA 5 Sep 2017  Vol 318

Treading the marsh of useless information

After about ten years of reviewing the journals every week, I began to fear that medicine was entering a period of information overload. It’s only a slight consolation that in 1881, the great American surgeon John S Billings made the same complaint in the second volume of the British Medical Journal (Billings JS. An Address on our Medical Literature. British Medical Journal 1881. 2:262–268.) But now we really do have a new problem: the ability of modern sequencing techniques to generate genomic information on a scale that defies interpretation. We have to wander into this marshland without knowing if there is terra firma on the other side, with only flickers of marsh gas to guide us. Here’s a study of Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. Although guarded, I think the conclusion is still over-optimistic: “In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study.”

JAMA Intern Med Sep 2017  Vol 177

Sharing Medicine—a final call-out

As I try to explain in the opening piece, “Sharing Medicine” attempts a joined-up view of medicine based on simple questions about sharing. What is the use of shared decision making if we don’t have the skills and tools to underpin it? What is the use of open data if nobody is looking at it and sharing it? Why is the knowledge architecture of medicine so archaic and poorly designed for sharing information in real time? Do we really understand the basics of diagnosis well enough to share them among ourselves and patients? Are our communication skills properly adapted to a knowledge-rich environment? How do we learn from the sharing of narratives from patients and carers, including our own experiences? All these topics come together in the latest print issue of JAMA IM. And I hope you can think of many other topics, because “Sharing Medicine” is now a theme line for this journal, and I know they would welcome thoughtful, high-value submissions.

Lowering BP in chronic kidney disease

Here’s a meta-analysis of 18 trials which look at the mortality benefit of reducing blood pressure in people with Stage 3-5 chronic kidney disease. Baseline systolic BP averaged 148 mm Hg in both arms: an intensive arm which achieved a reduction of 16 mm and a less intensive arm which achieved 8mm. The basic ethics of sharing medicine demand that patients should make their own choices about long-term preventive treatment, while the basic principles of pharmacology tell us that not all BP-lowering drugs are likely to be equal in their effect on mortality in kidney disease. But brushing these considerations aside for the moment, we learn that more intensive vs less intensive BP control resulted in 14.0% lower risk of all-cause mortality (odds ratio, 0.86; 95% CI, 0.76-0.97; P = .01).

The Lancet 9 Sep 2017  Vol 390

Another good surgical trial

Little trials can have big effects. Bigger, longer trials often cancel these out. That is why underpowered trials are an abuse of human subjects and should be rejected by ethics committees. In surgery especially, they can lead to waves of enthusiasm and early adoption which later prove to be unwarranted or harmful. This article informs us that “short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy” for chronic pancreatitis. Read these reviews: you will learn something new each week. Anyway, this was a false signal: in a bigger, longer trial “No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting.”

Fooling the baroreflex to lower BP

The regulation of mammalian blood pressure is too important to be left to any single mechanism, but the carotid artery baroreceptors certainly play an important part, and sooner or later someone was bound to try tinkering with them. “Resistant hypertension” is a much fought-over concept which resembles no-man’s land in the Somme in November 1916: full of shell-holes, mud, corpses and unexploded munitions. Enter the new tank which can cope with all of this: a novel endovascular baroreceptor amplification device, MobiusHD (Vascular Dynamics, Mountain View, CA, USA). Sensitize the baroreceptors, and the War could be over by Christmas. It’s been tried in 30 patients, and worked in most, though four experienced serious adverse effects in the first six months (“an acceptable safety profile”). “Randomised, double-blind, sham-controlled trials are warranted to investigate the use of this treatment further.” Sorry folks, the troops won’t be home by Christmas.

The BMJ 9 Sep 2017  Vol 358

Who needs endocarditis prevention?

The first weeks of my clinical medical course seemed to be half taken up with what was then called SBE—subacute bacterial endocarditis. Rheumatic valvular disease was just dying out and modern valve replacement surgery was just coming in. The important thing was to make sure that any patient with valvular heart disease got antibiotics before dental procedures to prevent SBE due to the charmingly named Streptococcus viridans. We now know that there are in fact lots of streptococci in the mouth, some making blood agar plates green and some not. And in 2008, NICE decided that the risk of them floating onto a damaged valve was insufficient to warrant antibiotic prophylaxis at the time of dentistry. There is a long and well-illustrated article about this in this week’s print BMJ under the label “Uncertainties“. And just to muddy the waters a bit more, there is also an observational research article from France suggesting that oral streptococci do pose a risk to people with prosthetic heart valves after dental procedures, but with no proof that antibiotics reduce it.

Plant of the Week: late-flowering Alstroemeria 

Our alstroemerias flower a bit in July and then form a tangle of yellowing leaves. We are total failures and know nothing of late-flowering Peruvian lilies.

Others seem to achieve success effortlessly, and produce attractive flowers well into September. Readers must seek advice from such people, because these are lovely things with which to end the gardening season.