March 25th, 2013
Selections from Richard Lehman’s Literature Review: March 25th
CardioExchange is pleased to reprint selections 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.
JAMA 20 Mar 2013 Vol 309
Effect of Aliskiren on Postdischarge Mortality and HF Readmissions Among Patients Hospitalized for HF (pg. 1125): Is aliskiren a good drug for heart failure? Despite the negative result of this Novartis-funded trial (ASTRONAUT), I think the answer is probably yes. First of all, let me remind you that aliskiren is a direct renin blocker. In other words, it acts right at the start of the renin-angiotensin- aldosterone cascade. But unfortunately for alis and her sister kirens, these renin blockers have come on the scene too late. We already have perfectly good RAAS inhibitors in the form of ACE inhibitors, ARBs, and aldosterone blockers, and between them they do all that it is possible to do via RAAS inhibition in heart failure: which, by the way, is not much, since typical NNTs lie over 30. Now imagine a world where renin blockers were first on the scene, and we selected patients for heart failure trials on the basis of BNP rather than ejection fraction; then this trial would probably have been a resounding success. Because the ASTRONAUT groups were not well matched: the patients put on aliskiren had a mean NT-BNP of 4239 pg/ml compared with 2718 pg/ml in the placebo group: in other words, they were experiencing considerably worse ventricular strain. Yet they still had better outcomes than the less ill controls, albeit not to the point of statistical significance. If you removed all the ACE inhibitors, ARBs, and the amazing amount of mineralocorticoid blockade (57%) from these patients, there would probably have been a very significant benefit in mortality and readmission from aliskiren. But life is unfair, and Novartis may just have to face the fact that Alice has come too late to lead them into Wonderland: though a trial in heart failure with preserved systolic ejection fraction, but without diabetes, might be interesting.
Long-term Mortality After Stroke Among Those Aged 18 to 50 Years (pg. 1136): Having a stroke when you are young (under 50) increases your risk of dying over the next 20 years by 3-4 times. Which is sad, but hardly unexpected.
NEJM 21 Mar 2013 Vol 368
Still No Closure on the Question of PFO Closure (pg. 1083): I love to read about medical progress, which makes me a sucker for giving innovative treatments the benefit of the doubt. About 15 years ago I was really intrigued to learn that quite a few ischaemic strokes were likely to be paradoxical—and that you could actually demonstrate shift of clot from the right to the left heart via a patent foramen ovale. In fact I was about a century late, because this mechanism had been proposed in the 1890s. But although in those days they were very good at performing autopsies, they didn’t have transoesophageal ultrasound to look for functional right-to-left shift. The excellent editorial “Still no Closure on the Question of PFO Closure” puts this into perspective: “In approximately 30% of young survivors of stroke, no clear cause is identified despite a thorough evaluation. Patent foramen ovale is found on transesophageal echocardiography in about half of these patients, as compared with approximately 25% of the general population. Clinicians, then, often assume that the patent foramen ovale was the cause of the stroke, although it may be incidental in some patients.”
Percutaneous Closure of PFO in Cryptogenic Embolism (pg. 1083): So there’s really no way to find out if PFO closure works better than standard medical therapy without doing a randomised trial, and even this won’t tell you whether any given individual will benefit. This first trial was designed 14 years ago to try out the Amplatzer PFO Occluder (St. Jude Medical) versus antiplatelet or anticoagulant treatment. After a mean patient follow-up of 4 years, the triallists conclude: “Closure of a patent foramen ovale for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy.” In fact they are quite harsh on themselves, because the device was observed to reduce strokes and TIAs by a third, but was inadequately powered to reach statistical significance.
PFO Closure vs. Medical Therapy after Cryptogenic Stroke (pg. 1092): And now, oddly enough, we get the results from another St Jude-funded trial of the same device in a similar but larger group of patients. Again, there were fewer events in the PFO closure group—this time fewer than half—but the authors seem reluctant to trumpet the fact. “In the primary intention-to-treat analysis, there was no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischemic stroke. However, closure was superior to medical therapy alone in the prespecified per-protocol and as-treated analyses, with a low rate of associated risks.” This is all very admirable, but it makes you wonder what is going on. Is this the NEJM responding to criticism that it lets industry get away with too much sales pitching in its abstracts? Or is this industry itself indulging in what you might call “reverse marketing”—being so modest in its claims that people will rally to the defence of the product? Either way, I’m sure it won’t affect NEJM sales of reprints to St Jude.
Ann Intern Med 19 Mar 2013 Vol 158
Chlorthalidone vs. Hydrochlorothiazide for the Treatment of Hypertension in Older Adults (pg. 447): I always bridle when I see articles describing “diuretics” as a treatment for hypertension. Say thiazides if you mean thiazides. And also specify your thiazide: if in the UK, you probably mean bendroflumethiazide, in Canada you probably mean hydrochlorthiazide, and in the USA and other countries you might perhaps mean chlortalidone. Are they all the same? Irfan Dhalla and colleagues seek to find out by looking at the records of people started on chlortalidone at age 66 and over and comparing them with people started on hydrochlorthiazide. In up to five years of follow-up there was no difference in cardiovascular outcomes, but more hypokalaemia in the chlortalidone group. As for good old standard British BFZ, I suspect we just don’t know.