Two controversial trials testing PFO closure with the Amplatzer PFO Occluder (St. Jude Medical) in patients with cryptogenic stroke, first presented last fall at the TCT meeting, have now been published in the New England Journal of Medicine. Both trials missed their primary endpoints but contained suggestions of possible benefit. The results appear unlikely to resolve the ongoing controversy over the value, or lack of value, of this procedure, but, as an accompanying editorial states, both advocates and critics of PFO closure will find source material for their arguments in these papers.
In the accompanying editorial, Steven Messé and David Kent write that both trials suffered from slow enrollment, “which was probably due to widespread off-label use of atrial septal closure devices.” They note that RESPECT and PC, like the only other randomized trial in the field, CLOSURE 1, did not show significant benefits in the main intention-to-treat analysis, but did present some evidence of possible benefit.
…we are left for the moment to make decisions under conditions of uncertainty. In such circumstances, evidentiary standards vary among decision makers — patients, clinicians, authors of practice guidelines, and regulatory authorities — depending not only on the interpretation of the results, but also on the potential consequences of their decisions. Some of them may interpret the data as supporting closure of a patent foramen ovale as a viable therapeutic option, even while conceding the failure of trials to show the superiority of closure over medical therapy. Yet given the prevalence of patent foramen ovale in the general population, the enormous potential for overuse of percutaneous closure of a patent foramen ovale, and the relatively low risk of stroke in patients who are treated medically, the routine use of this therapy seems unwise without a clearer view of who, if anyone, is likely to benefit…. Randomized studies of closure may come to an end, however, if the Amplatzer device is approved. Thus, all eyes will be on the regulatory agencies to see how they will interpret these results in light of their own evidentiary standards.
Click here to read the entire story on Forbes.
UPDATED–The already complicated story behind the PREVAIL trial, which was designed to confirm the safety and efficacy of the Watchman left atrial appendage closure device, just got even more complicated. This morning, after the trial’s sponsor, Boston Scientific, prematurely distributed to investors a press release summarizing the results of the trial, the ACC announced that the scheduled presentation of the results at the main opening session of the meeting would not take place.
By way of background, last week the trial’s sponsor, Boston Scientific, first announced that the principal investigator of the trial, David Holmes, would only “present the acute procedural safety results” from the trial. Then the company reversed itself two days later and announced that Holmes would present all three co-primary endpoints.
Holmes intended presentation this morning at the ACC in San Francisco makes clear why there was so much confusion. (The slides from his presentation have been made available to the media.) Although the trial results appear largely positive, the trial missed one of its three primary endpoints, and experts will likely spend a lot of time and energy trying to interpret the results.
Click here to read the full story on Forbes.
Don’t miss this very practical discussion about the new generation of anticoagulants over on CardioExchange. Here are a few excerpts.
Christian Thomas Ruff:
I believe the addition of the 3 currently approved novel anticoagulants (dabigatran, rivaroxaban, and apixaban) will eventually translate into a greater proportion of eligible patients being treated; it certainly has in my practice…
Although I think it is important to continue to develop reversal agents for the novel anticoagulants, I don’t think the lack of such an agent is sufficient reason to avoid using a novel anticoagulant.
I think that price is one of the most important factors that has hindered uptake of the novel agents. Although these drugs may well be “cost-effective” in complicated analyses that focused on the costs and benefits to society at large, it is the out of pocket expense for the drugs that really matters to patients…
Andrew E. Epstein:
It is highly unlikely that a direct comparison of the new anticoagulants will ever be done. Thus, we will have to choose between one or another based on pharmacokinetics, convenience, and perhaps formulary availability. Substudy analyses are also important…
I am concerned that although the elderly often have the most to gain from the new anticoagulants, they are also the patients at greatest risk for bleeding, especially if renal function is labile with drugs cleared by the kidneys. For such patients, warfarin should be considered.
You can choose from a myriad of metaphors– closing the book, sealing the deal, fixing a hole– but the story is simple: the publication of CLOSURE 1 in the New England Journal of Medicine is the final act of the long and sad melodrama of the CLOSURE 1 trial. As initially reported at the American Heart Association in 2010, Anthony Furlan and the CLOSURE I investigators randomized 909 patients with crytpogenic stroke to either medical therapy or PFO closure with the STARFlex Septal Closure System. There were no significant difference in the composite endpoint or its components(stroke or TIA in the first two years, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years):
Composite end point: 5.5% in the closure group versus 6.8% in the medical-therapy group (HR 0.78, CI 0.45 to 1.35, p=0.37)
- Stroke: 2.9% vs 3.1% (p=0.79)
- TIA: 3.1% vs 4.1% (p=0.44).
- Deaths at 30 days and deaths from neurological events at 2 years: zero in both groups
As expected there were more major vascular complications related to the procedure in the treatment group, as well as a higher incidence of atrial fibrillation:
- Major vascular procedural complicaton : 3.2% vs 0% (p<0.001)
- Atrial fibrillation: 5.7% vs 0.7% (p<0.001)
In an accompanying editorial, S. Claiborne Johnston discusses the troubling issues raised by the trial. Because of off-label use of closure devices, enrollment in the trial took 5 years and forced a reduction in the sample size of the trial. He continues:
During the 9 years it took for the results of this trial to be reported, approximately 80,000 patients have had a patent foramen ovale closed with the use of a device at an average cost of $10,000 per procedure. Even if only half these patients were treated by this method for the purpose of preventing stroke, it would suggest that during that period of time $400 million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved. By limiting the use of device closure to within the remaining clinical trials, such an expense could be curtailed and completion of these trials might be accelerated. In this setting, a strategy of withholding reimbursement for unproven device therapy unless such treatment is part of a randomized trial seems justified.