This is another instance in which the “Editor’s Capsule Summary” and my interpretation diverge significantly:
“This study provides some support that nitrates do not cause relevant hypotension and may be judiciously used in patients with aortic stenosis and pulmonary edema.”
Rather, as was the consensus last night at OHSU’s journal club, these data provide essentially no support.
These authors provide a retrospective regarding the incidence of “clinically relevant hypotension”, identifying three groups of patients presenting with acute pulmonary edema – severe, moderate, and no aortic stenosis. There were 65 patients in each cohort, and all patients received nitrates in either sublingual or intravenous form. Regarding their primary composite outcome, there was no difference between arms. Thus, the dogmantic avoidance of nitrates in aortic stenosis is challenged.
I am quite enthusiastic, as is Newman’s editorial, regarding the refutation of dogmatic (and erroneous) medical practice – he cites the example of the “dangers” of ketamine following head injury. However, these retrospective data are not of appropriately high quality to inform practice in the absence of stronger prospective or randomized, controlled trial data.
The retrospective selection of patients only with prior discharges from the enrolling hospitals, as well as the inclusion of multiple presentations of some patients, likely amplifies selection bias with the effect of overstating the apparent safety of the intervention. The study is powered to 80% to detect a 20% absolute difference between arms, which certainly exceeds the clinically relevant safety margin when comparing outcomes between cohorts. The primary composite outcome for “clinically relevant hypotension” was mostly comprised of outcomes for which nitroglycerin needed to be terminated. Termination of potentially helpful therapy is not a patient-oriented outcome or even a physiologic surrogate for one. Sustained hypotension for >30 minutes is a better physiologic outcome for judging potential adverse effects of nitrate use, and, finally, intubation or mortality are better clinical outcomes. The severe AS cohort had much higher incidence of these more serious outcomes, as opposed to the primary outcome in this study. Finally, as a catastrophic oversight, these authors fail to provide any sort of control group – there’s no way to compare these patients’ outcomes to any similar cohorts managed without nitrates.
If you place this study in context with Ioannidis’ “Why Most Published Research Findings Are False” it is easy to see, rigorously, why these data should have little impact. This study is underpowered, replete with bias, and the pre-study odds – for what “tradition” is worth – speak against the safety of nitrates in aortic stenosis. Now, importantly, I am not saying you should not use nitrates in aortic stenosis – only, rather, doing so requires acknowledging the profoundly limited clinical evidence guiding such a strategy.
“Complications Associated With Nitrate Use in Patients Presenting With Acute Pulmonary Edema and Concomitant Moderate or Severe Aortic Stenosis”
http://www.ncbi.nlm.nih.gov/pubmed/26002298
Thanks to Ran Ran, Ben Sun, Kavita Gandhi and the other OHSU residents for their excellent contributions to the discussion!