Richard Lehman’s journal review – 3 January 2012

Richard LehmanJAMA  28 Dec 2011  Vol 306
2684    When I first became a GP in England well over 30 years ago, the early diagnosis of myocardial infarction was a matter of slight importance, since there was no intervention which made any difference to survival. You tried to reach patients in their homes quickly to relieve their pain with heroin, but only sent them to hospital if their pain was not controlled or they were going into shock: studies at the time indicated that patients with heart attacks survived better at home, where they were less likely to be killed with injections of lidocaine.

These days, by contrast, patients with chest pain are best to bypass primary care altogether and get transferred to a place offering percutaneous intervention as soon as possible: time equals myocardium. What we need most is a test to rule in myocardial infarction immediately. But what this German paper concentrates on is a test that can rule out myocardial infarction at three hours. And this test is nothing new at all: just conventional troponin 1, which proves just as discriminatory as the high-sensitivity troponin assay featured in the paper’s title. But then if you read the detail of this study of 1818 patients presenting with chest pain between 2007 and 2008, you discover that you can get nearly the same rule-out information three hours earlier if you measure either copeptin or sVEGFR-1/sFLT-1 together with high sensitivity troponin on arrival. The negative predictive value is 98.4% rather than 99.6%. Unfortunately the rule in characteristics are not so good, but I still think this is a discovery of major clinical importance, which you won’t even find mentioned in the abstract. It edges us closer to a diagnostic strategy where we could send many patients home at once with confidence, and should encourage us to develop new, more discriminatory tests to allow as many as possible of the remainder to benefit from immediate PCI.

2704    Over recent years, I’ve taken you laboriously through various studies of clopidogrel, in a personal quest to understand the importance of CYP2C19 genotype and the clinical effectiveness of this drug. To begin with, this looked like providing clear evidence of the dawn of genomic “personalized medicine,” the wondrous age in which anyone rich enough will be tested to find out if they are likely to respond to every drug their doctors prescribe for them. Because if you look at the aggregated studies of individuals with one or more CYP2C19 alleles associated with lower enzyme activity, you will find they have lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding, and a slightly higher risk of CVD events. But if you just look at the bigger, better studies, any clinical difference vanishes, as demonstrated in this painstaking systematic review. So we have come full circle; the long trail has taken us nowhere: pharmacogenomics may be about to dawn, but not just here. 

NEJM  29 Dec 2011  Vol 365
2463   Elastic stockings with graduated compression may not be the last word in sexy medicine, but they are very effective at preventing venous thromboembolism in acutely ill medical patients. So much so that adding enoxaparin prophylaxis to stockings makes no difference to mortality in such patients, while tending to increase their risk of bleeding. I am sure this cannot have been the result that Sanofi, manufacturers of enoxaparin, were hoping for when they funded this trial which recruited 8307 seriously ill patients in 193 hospitals situated in juicy potential market countries – China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia.

2473    Sometimes one almost feels sorry for drug manufacturers. Genentech developed the vascular endothelial growth factor antagonist bevacizumab which shows some action against advanced bowel cancer. Here they helped to support a trial in ovarian cancer, which typically presents at stages 3 and 4, too late for curative treatment. In a complex randomization process, some of the 1873 women recruited received placebo in addition to standard platinum-based chemotherapy, while others received one of two high-dose bevacizumab regimens. Calculating from British prices, the cost of the bevacizumab would have been about £40K per patient. The primary end-point was changed during the trial from overall survival to progression-free survival. Even with this dilution, the drug only achieved a 4 month difference, if continued beyond the duration of chemotherapy: and the Kaplan-Meyer charts in Figure 3 showing overall survival should dissuade all but the wealthiest funders from using this regimen.

2484   Another trial, this time British and partially funded by Roche, confirms the message: the incremental benefit of long-term bevacizumab on ovarian cancer is minimal. This trial included a wider group of women, some with early disease. Once again, the primary end-point was progression-free survival, and the mean difference was four months following prolonged treatment. The investigators deserve credit for stating that “Some will argue that final overall survival data are needed before the results can be fully interpreted.”

2507    We are surrounded by bioterrorists: they took over the world about 3 billion years ago and have been in charge ever since. Fortunately they have no particular interest in us, as we walk about carrying far more of them than there are cells in our bodies. Now and again, with or without human help, they turn nasty, and that is presumably why the gentle little state of Rhode Island houses a Center for Biodefense and Emerging Pathogens, source of this paper about proprotein convertases in health and disease. The New England Journal excels at telling us about these arcane and interesting subjects at the forefront of biomedical discovery: sometimes the accounts are even intelligible, as in this case. This group of enzymes does an awful lot of stuff in the body, from telling embryos to develop to helping cancer cells metastasise: but the bottom line here is that a lot of microbial pathogens hijack the proprotein convertases to produce their toxins. The family most involved are called furins, like something out of the prophetic works of William Blake: these children of the Fury of Los help to forge the toxins of germs as various as anthrax, influenza A and respiratory syncytial virus. Our protectors in Rhode Island comment,” Therapy targeted to proprotein convertases may therefore represent a universal countermeasure that could be deployed in tandem with other interventions, especially in cases of bioterrorism, in which a specific pathogen may not be immediately identified.”

For the second week running, The Lancet has failed to appear, but for those who are getting withdrawal symptoms (e.g. relief, happiness, clearing of the mind etc), there is a wealth of material backed up on the website stretching back to January 2011. One contribution I particularly commend was posted on 1 Dec and is a systematic review and meta-analysis of individual patient data from randomized trials of self-monitoring of oral anticoagulation. Conceptually, the age of anticoagulation using vitamin K antagonists is over: were cost no consideration, everyone would by now be taking a fixed dose of factor Xa or thrombin inhibitor. But as things stand, the need for INR measurement will remain with us for at least another decade, and this study should change practice during that time, especially among younger patients taking coumarins because they have mechanical heart valves. “We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0•51; 95% CI 0•31—0•85) but not for major haemorrhagic events (0•88, 0•74—1•06) or death (0•82, 0•62—1•09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0•33, 95% CI 0•17—0•66), as did participants with mechanical heart valve (0•52, 0•35—0•77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes.” Not only a clinically important paper but a nice example of individual patient data meta-analysis too.

The next BMJ will be a themed issue on data disclosure, about which my lips are sealed until Friday morning. But sneaked onto the website during the time warp between Christmas and New Year is an excellent piece called The Idolatry of Surrogates written by three friends – John Yudkin, Kasia Lipska and Victor Montori – using type 2 diabetes as an example.

My sole contribution was to suggest the word “idolatry” to John a good few months back. Obsessed with glycated haemoglobin and microalbuminuria, diabetologists are like the Children of Israel in the wilderness, worshipping the Golden Calf and ignoring the Voice from Mount Sinai, whose Great  Commandment is “First Do No Harm.” John went on to develop the full Ten Commandments, but was dissuaded from publishing them due to American religious sensitivities:

The New Therapeutics: Ten Commandments

  • Thou shalt treat according to level of risk rather than level of risk factor.
  • Thou shalt exercise caution when adding drugs to existing polypharmacy.
  • Thou shalt consider benefits of drugs as proven only by hard endpoint studies.
  • Thou shalt not bow down to surrogate endpoints, for these are but graven images.
  • Thou shalt not worship Treatment Targets, for these are but the creations of Committees.
  • Thou shalt apply a pinch of salt to Relative Risk Reductions, regardless of P values, for the population of their provenance may bear little relationship to thy daily clientele.
  • Thou shalt honour the Numbers Needed to Treat, for therein rest the clues to patient-relevant information and to treatment costs.
  • Thou shalt not see detailmen, nor covet an Educational Symposium in a luxury setting.
  • Thou shalt share decisions on treatment options with the patient in the light of estimates of the individual’s likely risks and benefits.
  • Honour the elderly patient, for although this is where the greatest levels of risk reside, so do the greatest hazards of many treatments.
  • I love Yudkin's “Ten Commandments.” I just posted a translation for patients with the help of the internist I'm sleeping with:

  • Re: NEJM article on TEDs v. enoxaparin–I am quite sure this is exactly the result that Sanofi wished for, since their Lovenox patent is about to expire. Expect a torrent of semuloparin-is-better-than-enoaxaparin articles in the coming years.

  • Nino Cartabellotta

    Thank you Richard for your commandments. I translate them in Italian for my blog

  • Janice Flahiff

    Thank you. I don't have access to BMJ…so you saved me long trip to nearby university library.  I included “the 10” in a blog posting also (… )

    Long time (30+ years) since I took a college statistic class, so I had to look up most of the terms.

    Much impressed with any patient who can empower themselves by keeping up with the literature concerning their disease(s)/condition(s) in order to have meaningful conversations with their doctors. The statistics alone can be a challenge.

  • Nappoantonio1977

    Thank you…Richard and Nino… I would like to create the 10 commandments for nursing care. I will get to workimmediately.

  • Mahesh

    A very interesting piece…Idolatry of the surrogate…..and what a word (Idolatry) to pick up…Bull's eye….Its high time people comprehended what they mean by Holistic and that its not a conglomeration of newly born surrogate parameters which needs focus.