September 8th, 2014
Selections from Richard Lehman’s Literature Review: September 8th
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 4 Sep 2014 Vol 371
Sham Controls in Medical Device Trials (pg. 892): A terrific piece by Rita Redberg discusses sham controls in medical device trials. Whenever sham procedures are used in the control arms of such trials (or in surgical trials generally) they reveal a huge placebo effect. For example, renal denervation therapy produced huge sustained falls in recorded blood pressure in unblinded, uncontrolled trials in people with “resistant hypertension”. But when it was tested in a properly blinded trial using a sham control, it failed to detect enough difference to satisfy its primary end-point. She goes on to point out that percutaneous coronary intervention has never been tested against sham PCI. I’ve just learnt to my amazement that Darrel Francis at Imperial College is planning a trial to do just this in people with angina and single-vessel disease, and it’s still open to extra UK investigators on http://clinicaltrials.gov/ct2/show/NCT02062593.
Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure (OL): And now, alas, to the much-vaunted PARADIGM-HF trial. This has been hyped as the biggest breakthrough in heart failure for at least 20 years. A fixed dose of enalapril was compared with a substance called LCZ696. This turns out to have been a mixture of valsartan and sacubitril, a neutral endopeptidase inhibitor, and most participants ended up receiving a daily dose of 320mg of valsartan, versus 20mg of enalapril. A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died after a median follow-up of 27 months, at which point the trial was stopped prematurely. So just what are we looking at here? How can we distinguish the effect of the sacubitril from the effect of the high dose of valsartan? Well, we can’t. And this trial is a perfect example of everything that is wrong with heart failure trials. The mean age of the 8442 patients was 63.8, nearly 80% were male, and they were selected by reduced ejection fraction in 1043 centres across 47 countries. A logistic nightmare, but a great way for Novartis to spread influence. And Novartis then collected, managed and analyzed all the data itself. As I have said, a submaximal dose of one drug was compared with a maximal dose of another plus an extra ingredient. There was a run-in period, in which patients who were intolerant to the new treatment (12%) dropped out. Adding bias to bias, the trial was terminated prematurely. One of the primary end-points was hospitalization, which was ably demolished in a JAMA article I pointed out last week. And yes, there was a mortality benefit, but the number-needed-to-treat was about 35 to prevent one death in 2 and half years, in a population far removed from the elderly co-morbid patients we see in real life. As I draw to the end of a clinical career in which I’ve tried to help people with heart failure, I stand bemused. This is just how things have been done for the last 30 years, and it’s not good enough. At the very least, Novartis must make its full data set available for independent analysis. And before sacubitril is licensed, we need a properly designed trial, say between valsartan 160mg b.d. alone and valsartan plus sacubitril, in a typical population with heart failure. It will be very interesting to see what the FDA, the EMA and NICE decide.
JAMA 3 Sep 2014 Vol 312
Comparison of Weight Loss Among Named Diet Programs in Overweight and Obese Adults (pg. 923): Never mind the diet: just consume less. Boring as this is, it’s always the message where weight loss is concerned. The best diet for you is the one you can stick to, says this meta-analysis of named diet programmes for overweight and obese adults. For most people, this seems to be a low-carbohydrate diet. It usually carries the name of Atkins, though plenty of others got there before him.
JAMA Intern Med Sep 2014
Hypoglycemia After Antimicrobial Drug Prescription for Older Patients Using Sulfonylureas (OL): Hypoglycaemia has overtaken hyperglycaemia as a cause for admission in people with diabetes, and sulfonylureas are the commonest oral agents responsible. What we often forget in the hurly-burly of clinical practice is that certain antibiotics are known to potentiate the glucose-lowering effect of sulfonylureas. According to this survey of Medicare claims in Texas, the antibiotic most likely to do this is clarithromycin, with a number needed to harm of 71, followed by levofloxacin, sulfamethoxazole-trimethoprim, metronidazole and ciprofloxacin. Not particularly common then, especially as the first three antibiotics are not usually first-line choices in the UK. There is an excellent commentary by Kasia Lipska on the wider issues.
Lancet 6 Sep 2014 Vol 384
Efficacy of β Blockers in Patients with HF plus AF (OL): The trials which established the role of beta-blockers in systolic heart failure came up with some surprising subgroup results, one of which was that the mortality benefit of ß-blockade did not seem to extend to patients with atrial fibrillation and reduced systolic ejection fraction. On the face of it, you would expect them to benefit most. I have already hinted at the deficiencies of these trials, which were dominated by younger male patients without major comorbidity, but we’ll let that go and congratulate the authors of this paper for coming together and performing an individual patient data meta-analysis based on the randomized trials. A clear message emerges: people with AF do not experience the benefits which people in sinus rhythm derive from taking ß-blockers for heart failure. I hope this message filters out to heart failure nurses as well as cardiologists.
BMJ 6 Sep 2014 Vol 349
Perioperative β Blockade: Guidelines Do Not Reflect the Problems with the Evidence from the DECREASE Trials: In a superb analysis by Graham Cole and Darrel Francis, we’re taken through the sorry story of how perioperative beta-blockade for high risk patients became accepted practice due to the DECREASE trials, which have since been shown to contain internal inconsistencies and unverifiable data. If you meta-analyze all the other trials they show convincing evidence of harm. Now the specialist cardiology societies of Europe and the USA have come up with a shared August 2014 guideline in which they claim to have excluded the DECREASE data, but still come up with a positive recommendation. In fact they have been misled by including meta-analyses which still included the DECREASE results. It’s a story that certainly decreases one’s confidence in the credibility of specialist society guidelines. As Larry Husten has said, guidelines should follow the same rules as declarations of war: only to be issued when there is absolute agreement and an urgent need.