Preliminary results of the PREVAIL trial have demonstrated the Watchman device (Boston Scientific / Atritech) is a safe alternative to oral anticoagulation therapy for stroke prevention in non-valvular atrial fibrillation patients. However, there are now questions towards Watchman’s efficacy. The device missed one out of its two efficacy endpoints, possibly, because of a low event rate of patients receiving warfarin.
The results of the PREVAIL (Prospective randomised evaluation of the Watchman Left Atrial Appendage (LAA) Closure device in patients with atrial fibrillation vs. long-term warfarin therapy) trial were expected to be presented at a late-breaking clinical trial session of the American College of Cardiology meeting (ACC, 9–11 March, San Francisco, USA). However, ACC cancelled the presentation due to an embargo break by Boston Scientific. Nevertheless, the results were available from TCTMD after cancellation.
Safety concerns raised in the PROTECT AF trial were the drivers for the design of the PREVAIL study. The Watchman device, which received CE mark in 2005, has not received FDA approval yet. In March 2010, the FDA decided not to approve the device due to safety issues related to a high initial rate of pericardial effusions and procedure-related strokes. There were also some concerns with regards to procedures performed by new operators.
Despite of the issues with safety, PROTECT AF demonstrated positive efficacy results showing non-inferiority of the device compared to warfarin. In order to provide additional information on the efficacy and to demonstrate improved safety of the device, Boston Scientific undertook the PREVAIL study in November 2010.
PREVAIL is a prospective trial which randomised 407 patients (2:1) to either LAA closure (269) or warfarin therapy (138) at 41 sites in the USA. The trial, lead by David Holmes, Mayo Clinic, Rochester, USA, and colleagues was also conducted to validate the safety of the implant procedure, including at least 25% of subjects treated by new operators.
With regards to patient characteristics, PREVAIL differs from PROTECT AF in that it included higher risk patients with CHADS2 or greater scores, the patients’ average age was 74 years, one-third (33.8%) of patients had diabetes and about one-quarter (27.5%) had a history of stroke.
PREVAIL preliminary results
According to preliminary results of PREVAIL, the trial met the pre-specified criteria of the first co-primary endpoint: occurrence of all-cause death, ischaemic stroke, systemic embolism, or device or procedure-related events requiring open cardiac surgery or major endovascular intervention (95% upper confidence bound < 2.67). There were six events (2.2%) through seven days post randomisation or hospital discharge.
PREVAIL showed that the Watchman device was implanted successfully referring to deployment and release of the device into the left atrial appendage in 95.1% of the cases. This study demonstrated a better implant success rate than previous studies (PROTECT AF 90.9% and CAP (Continued Access Protocol) trial 94.3%).
The trial included new centres and new operators to demonstrate if enhancements to the training programme were effective. The results showed a success rate of 93.2% with new operators.
Vascular complications in PREVAIL including: cardiac perforation, pericardial effusion with tamponade, ischaemic stroke and device embolization, were reduced by almost 50% (4.4%, n=12) compared to PROTECT AF (8.7% n=39). The results also showed that there were no procedure-related deaths reported in any of the trials. Additionally, new operators had only one occurrence (1.0%) of pericardial effusion requiring intervention with no device embolization, peri-procedural strokes or cardiac perforation.
One efficacy endpoint missed
The results of PREVAIL showed that the trial did not meet the pre-specified criteria for the second co-primary endpoint of the occurrence of all stroke (ischaemic or haemorrhagic), cardiovascular death and systemic embolism at 18 months. When Cardiac Rhythm News asked Holmes about this issue, he answered: “These data have shown preliminary results for all 407 enrolled PREVAIL patients, as well as the PROTECT AF patients included as a part of the Bayesian analysis. The follow-up is still ongoing and final validation is not yet complete.” While the second co-primary efficacy endpoint was not met, the device performed similar to warfarin with a rate ratio of 1.07.
The results also highlighted that in spite of the average CHADS2 score of 2.6 in the control group, the observed rate of stroke in the PREVAIL control group was lower (0.7 per 100 patient-years) than in other published warfarin studies.
Moreover, the PREVAIL trial met its pre-specified endpoint for the third co-primary endpoint of the composite of the occurrence of late ischaemic stroke and systemic embolism (eight days post randomisation and onward) at 18 months.
In conclusion, Holmes said: “Despite implantation in higher risk patients, the Watchman device can be safely implanted by new operators. Two of three primary endpoints were met even in the presence of an over performing control group.” He added, “The Watchman device is an alternative to oral anticoagulation therapy for thromboembolic prevention in patients with non-valvular atrial fibrillation.”
Martin B Leon, Columbia University Medical Center, Center for Interventional Vascular Therapy, Division of Cardiology, said in a webcast discussion from TCTMD: “The real issue for PREVAIL was related to safety. There were concerns with regards to get the device in enough patients, and as best as I read the data those concerns have been largely erased with this new study suggesting that the implant failure rate was cut in half and safety was significantly better even in new operators.” He added: “There are populations of patients out there that are ineligible for warfarin due to different comorbidities so we need to keep an eye on those patients and we need to make individualised decisions.”
Brian Whisenant, Intermountain Heart Institute, Murray, USA, also commented on the TCTMD webcast: “These trials (PARTNER AF and PREVAIL) have demonstrated equivalence if not superiority to drug but do we have enough statistical confidence to say that the Watchman is an alternative therapy? That actually comes to patient selection for most patients but not all. We need to trust physicians to make the best decisions for the patients.” He added, “If a patient is performing quite well with the drug I would not change it to the device because there is not statistical support just yet but maybe in the future we will have enough statistical data.”
To support device approval by the FDA, Boston Scientific has announced that it will use the data from the PREVAIL trial, complemented by the PROTECT AF four-year outcomes data, the Watchman Pilot study six-year data, the ASAP study and the CAP registry data update. Cardiac Rhythm News asked Holmes if the current data would be enough source of evidence for FDA approval of the device, he answered: “This analysis of the PREVAIL data is the last needed to complete the requirements of the clinical module. Once the analysis of the PREVAIL data is complete and validated, we will submit our entire clinical module to the FDA, including all of the updates you have listed as well as our OUS commercial experience. We believe this will represent the totality of the clinical evidence available to allow the agency to evaluate the safety and efficacy of the Watchman.”
See a full interview with Holmes in the May print issue of Cardiac Rhythm News.