Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment - RESPECT

Contribution To Literature:

The RESPECT trial showed that PFO closure with the Amplatzer PFO Occluder was superior to medical management in reducing recurrent ischemic strokes on long-term follow-up in patients with true cryptogenic stroke and evidence of a PFO.

Description:

Numerous observational studies have suggested a beneficial effect of patent foramen ovale (PFO) closure on recurrent stroke in patients with cryptogenic stroke and PFO. However, the only randomized controlled trial on this topic, CLOSURE I, failed to show a benefit with PFO closure using the STARFlex device over routine medical management with anticoagulant/antiplatelet agents. The RESPECT trial sought to compare outcomes after PFO closure with the Amplatzer PFO Occluder over medical therapy in patients with cryptogenic stroke and evidence of a PFO.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Patients ages 18-60 years
  • Documented PFO
  • Cyptogenic stroke within 270 days

    Number of enrollees: 980
    Duration of follow-up: 5 years (median)
    Mean patient age: 46 years
    Percentage female: 45%

Exclusions:

  • Cerebral, cardiovascular, and systemic conditions that suggest other mechanisms for stroke
  • Contraindications to antiplatelet therapy
  • Anatomical contraindications to device placement
  • Any other reason to expect limited life expectancy, inability to attend follow-up visits, or inability to provide informed consent

Primary Endpoints:

  • Recurrence of a nonfatal ischemic stroke or fatal ischemic stroke or early post-randomization death (defined as all-cause mortality: device group–within 30 days after implant or 45 days after randomization; medical group–within 45 days after randomization)

Secondary Endpoints:

  • Complete closure of the defect demonstrated by transesophageal echocardiography and bubble study at the 6-month follow-up (Device Group)
  • Absence of recurrent symptomatic cryptogenic nonfatal stroke or cardiovascular death
  • Absence of transient ischemic attack

Drug/Procedures Used:

Patients with a documented PFO and evidence of cryptogenic stroke were randomized to either percutaneous closure with the Amplatzer PFO Occluder or medical management (aspirin 46.5%, warfarin 25.2%, clopidogrel 14%, aspirin + dipyridamole 8.1%, aspirin + clopidogrel 6.2%). Patients with PFO closure received aspirin 81-325 mg for 6 months and clopidogrel for 1 month.

Principal Findings:

This was an event-driven trial, and the trial was stopped when the total number of events was met. At this time, a total of 980 patients had been randomized at 69 centers in North America, 499 to PFO closure and 481 to medical management. Baseline characteristics were fairly similar between the two arms. Approximately 7% had diabetes, 13% were current smokers, 3% had evidence of coronary artery disease, and 23% had experienced another cerebrovascular accident event. Procedural success was achieved in 96.1% of the device-treated patients, with effective closure in 93.5% of the patients. Dropout rates were significantly higher in the medical therapy arm (18.7% vs. 9.6%).

Over a median duration of follow-up of 2.1 years, the primary endpoint (all recurrent strokes) was similar between the PFO closure and medical therapy arms (0.66/100 patient-years [PY] vs. 1.38/100 PY; hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.22-1.11, p = 0.08). Event rates were nonsymmetric: 1.3% vs. 1.7% at 1 year, 1.6% vs. 3.0% at 2 years, and 2.2% vs. 6.4% at 5 years. On per-protocol analysis, there was a benefit favoring PFO closure (0.46/100 PY vs. 1.30/100 PY; HR 0.37, 95% CI 0.14-0.96, p = 0.03). On subgroup analysis, there were trends toward a benefit in patients with large shunts (p = 0.07), atrial septal aneurysms (p = 0.10), and those on concomitant antiplatelet medications (p = 0.19).

Atrial fibrillation was noted in 0.6% of patients in both arms. Other procedural complications were rare, including major bleeding (1.6%), major vascular complications (0.8%), and cardiac thrombus formation (0.4%). There were no device embolizations.

Longer-term follow-up: No difference was noted in all-cause strokes between PFO and medical management arms on extended follow-up (mean ~5 years) (p = 0.16). A blinded assessment was performed of the recurrent strokes, and one third of them were noted to be noncryptogenic (i.e., due to other mechanisms such as small-vessel disease, atrial fibrillation, atherosclerosis, etc.). There was a significant benefit in favor of PFO closure among patients with a recurrent cryptogenic stroke (HR 0.46, p = 0.042), in patients aged <60 years (HR 0.48, p = 0.035), and in those with an atrial septal aneurysm (HR 0.25, p = 0.007). All-cause mortality was 0.22% vs. 0.42%/100 PY.

On further long-term follow-up (mean 5.9 years), there was a significant reduction in recurrent ischemic strokes in favor of PFO closure (0.58 vs. 1.07/100 PY; HR 0.55, 95% CI 0.31-1.0, p = 0.046). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (HR 0.38, 95% CI 0.18-0.79, p = 0.007). No device embolizations or erosions were reported. Atrial fibrillation rates between PFO closure and medical management were 0.25/100 PY vs. 0.15/100 PY, p = 0.37.

Interpretation:

The results of the RESPECT trial indicate that PFO closure with the Amplatzer PFO Occluder is superior to medical management in reducing recurrent strokes in patients with presumed cryptogenic stroke and evidence of a PFO on long-term follow-up (>5 years). On more intermediate-term follow-up, trends for benefits were noted earlier, such as among patients with large shunts and with atrial septal aneuryms. An interesting observation was that nearly one third of strokes thought to be cryptogenic likely had another underlying mechanism. This is a landmark trial and will likely change practice paradigms for the management of cryptogenic stroke.

Based on the extended follow-up, the US Food and Drug Administration (FDA) approved the use of the Amplatzer PFO occluder in patients between ages 18 and 60 years old with a cryptogenic stroke. A strong collaboration between neurologists and cardiologists to exclude other causes of strokes also was emphasized in the FDA statement.

These results are similar to those noted in the REDUCE and CLOSE trials.

References:

Saver JL, Carroll JD, Thaler DE, et al., on behalf of the RESPECT Investigators. Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy After Stroke. N Engl J Med 2017;377:1022-32.

Editorial: Ropper AH. Tipping Point for Patent Foramen Ovale Closure. N Engl J Med 2017;377:1093-5.

Presented by Dr. David E. Thaler the Transcatheter Cardiovascular Therapeutics meeting (TCT 2016), Washington, DC, November 1, 2016.

Presented by Dr. John Carroll at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2015), San Francisco, CA, October 15, 2015.

Carroll JD, Saver JL, Thaler DE, et al., on behalf of the RESPECT Investigators. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013;368:1092-100.

Presented by Dr. John Carroll at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2012), Miami, FL, October 25, 2012.


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