June 9th, 2014

Selections from Richard Lehman’s Literature Review: June 9th

CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.

NEJM 5 Jun 2014 Vol 370

Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome (pg. 2191): It was once the same with statins: while they could earn big money, new ones kept appearing. And I don’t mind that, because often there are useful differences within drug classes, as you can see from the latest Cochrane review of thiazides for blood pressure lowering. From the start, about 30 years ago, statins have had their fans and their detractors. It became obvious from an early stage that they had actions well beyond lipid lowering, and that these so-called “pleiotropic” effects included reduction of inflammation. This week’s NEJM tests this in two groups of patients with respiratory disease. In acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life threatening organ failure. A randomised trial aimed to recruit 1000 patients with ARDS and give them either rosuvastatin or placebo. It was stopped early for futility. In fact, the statin may have contributed to hepatic and renal organ dysfunction.

Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD (pg. 2201): There is a strong suggestion, based on retrospective observational evidence, that statins can decrease the rate and severity of exacerbations, the rate of hospitalisation, and mortality in chronic obstructive pulmonary disease (COPD). What’s not to like? Unfortunately, however, this large prospective randomised controlled trial, conducted at 45 sites across North America, shows that simvastatin 40mg daily does not decrease the rate and severity of exacerbations, the rate of hospitalisation, and mortality in high risk COPD patients. Another good teaching paper showing why RCTs are necessary.

JAMA 4 Jun 2014 Vol 311

Kidney Function After Off-Pump or On-Pump CABG Surgery (pg. 2191): For a while, coronary artery bypass grafting was the commonest surgical procedure in parts of the developed world. Surgeons argued hotly about whether to do it on or off a cardiopulmonary bypass pump. Off-pump surgery was a badge of technical skill, and was supposed to produce less cognitive impairment in the post-op period. And as for the brain, so for the kidney. This massive multicentre CORONARY trial randomised 4752 patients to on- or off-pump CABG, and followed renal function in 2932 of these. There was less acute postoperative kidney injury in the off-pump group, but no difference in renal function at one year.

Association of Azithromycin With Mortality and CV Events Among Older Patients Hospitalized With Pneumonia (pg. 2199): Hmm. I’ve just told you that you can’t depend on retrospective observational evidence; but sometimes it’s all you can get. I suppose you could prospectively randomise thousands of older patients in Veterans’ hospitals to receive azithromycin-containing versus other drug regimens for pneumonia, and compare cardiovascular outcomes in the two groups. But this has not been done. Instead these investigators go through a complex process of propensity matching in 73 690 actual VA patients and conclude that: “Among older patients hospitalized with pneumonia, treatment that included azithromycin compared with other antibiotics was associated with a lower risk of 90-day mortality and a smaller increased risk of myocardial infarction.” Goddam it, this is a good mycin.

Lancet 7 Jun 2014 Vol 383

Diabetes as a Risk Factor for Stroke in Women Compared with Men (pg. 1973): Life is unfair. Men get a lot more cardiovascular disease than women. But once fasting blood glucose rises above about 6mmol/l, the reverse applies. The sugar effect may not be causal, but it’s a marker for something that is. Once it gets a bit higher, we call it diabetes, though I find this a perplexing term. Three authors have crunched through an immense amount of data from 64 cohort studies to discover what is known about the risk of stroke in women and men with diabetes. Women have a risk ratio of 2.28 for stroke if they are labelled diabetic, while for men the figure is 1.83. Not that this actually tells you anything about the risk of the person coming to see you: “we were unable to assess whether the excess risk of stroke in women with diabetes varied with different indices of glycaemic control or duration of diabetes because of insufficient data for these variables.”

Prevention and Management of Type 2 Diabetes: Dietary Components and Nutritional Strategies (pg. 1999): And everything conspires to make people enjoying peace and prosperity get fat in the first place. A review called “Prevention and management of type 2 diabetes: dietary components and nutritional strategies” whistles bravely in the dark. We don’t really know what works, but in the meantime we are told to stick to a diet rich in wholegrains, fruits, vegetables, legumes, and nuts; moderate in alcohol consumption; and lower in refined grains, red or processed meats, and sugar sweetened beverages. Has a familiar ring.

Cardiovascular Outcome Trials of Glucose-Lowering Drugs or Strategies in Type 2 Diabetes (pg. 2008): I may be older and fatter than I would like, but on the whole I am optimistic. I keep meeting brilliant young people who are brighter and kinder than most of my generation. The world has little need of me: it will be safe in their hands. And another pleasure is watching eminent authority figures changing their tune in line with evidence. Here is a review of cardiovascular outcome trials of glucose lowering drugs or strategies in type 2 diabetes. I was first author on two Editorials for The BMJ on this topic, and in 2010 the first one was not welcomed by the British diabetes establishment because it criticised the notion that HbA1c lowering below 7 was a worthwhile target in established T2DM. You can still see this idea going through its death pangs in the introduction to this article: “No trial results have shown unequivocal cardiovascular risk reduction with glucose lowering. However, results of the post-trial follow-up of the UK Prospective Diabetes Study, and of a meta-analysis of the four glucose-lowering outcome trials completed to date, suggest about a 15% cardiovascular relative risk reduction per 1% decrement in HbA1c.” I would lay a fair bet that the first bit of that came from Robert Califf and the “However” bit from Rury Holman. I don’t buy his suggestions of course, but I rejoice that almost all the rest of the piece is bang on, especially the conclusion calling for longer, better trials designed with patients.

The BMJ 7 Jun 2014 Vol 348

Effect of Fixed Dose Combination Treatment on Adherence and Risk Factor Control Among Patients at High Risk of CVD: A very recent Cochrane review of fixed dose combination pills for reducing cardiovascular risk concluded that: “Compared with placebo, single drug active component, or usual care, the effects of fixed-dose combination therapy on all-cause mortality or CVD events are uncertain; only few trials report these outcomes and the included trials were primarily designed to observe changes in CVD risk factor levels rather than clinical events.” So we don’t know what “polypills” of various similar kinds really do to real outcomes. And I don’t think the Cochrane reviewers would change their mind in the light of the latest trial, which comes from New Zealand. To be sure, many more people take their medicines if they are all rolled into one pill; they also get more adverse effects, and frequently discontinue them. It’s a shame that people are not more like sheep, who will follow each other into a pasture, feed on the same grass, and die at an appointed time. “Among this well treated primary care population, fixed dose combination treatment improved adherence to the combination of all recommended drugs but improvements in clinical risk factors were small and did not reach statistical significance. Acceptability was high for both general practitioners and patients, although the discontinuation rate was high.”

Time to Treatment with rtPA and Outcome of Stroke in Clinical Practice: A study of outcomes after administration of thrombolysis for stroke, in a population of 4 million Germans, concludes that treatment with recombinant tissue plasminogen activator within the first 1.5 hours after onset is highly effective, with a NNT of 4.5. The inconsistencies within this study are neatly explored in two rapid responses. Thrombolysis is a treatment of zero or marginal benefit for the great majority of stroke patients.



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