RESPECT

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Carroll JD, et al. "Closure of patent foramen ovale versus medical therapy after cryptogenic stroke". The New England Journal of Medicine. 2013. 368(12):1092-1100.
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Clinical Question

Among patients with cryptogenic ischemic stroke, does closure of a PFO reduce recurrent stroke when compared to medical therapy alone?

Bottom Line

Among patients with cryptogenic ischemic stroke, PFO closure does not reduce nonfatal ischemic stroke, stroke mortality, and early all-cause mortality when compared to medical therapy alone.

Major Points

The large CLOSURE I trial (2012) demonstrated that routine PFO closure does not reduce rates of recurrent CVA among patients with cryptogenic ischemic stroke and PFO. However, CLOSURE I was criticized because a large proportion of its patients had several CV risk factors (diabetes, hypertension, etc.) and their qualifying "cryptogenic stroke" may have in fact been a result of atherosclerotic cerebrovascular disease. In addition, CLOSURE I used the STARFlex device for PFO closure, but extrapolation of data to other devices is difficult and the device manufacturer has since gone out of business. The PC Trial (2013)[1] and RESPECT, which began enrollment concurrently with CLOSURE I in 2003, studied a similar patient population using the Amplatzer PFO Occluder closure device.

The Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial randomized 980 patients with cryptogenic ischemic stroke and PFO to PFO closure or medical therapy. At 2.6 years, there was no difference in rates of the primary composite outcome of recurrent nonfatal ischemic stroke, stroke mortality, and early all-cause mortality. The primary outcome did, however, reach significance in as-treated and per-protocol analyses. The relevance of these results is unclear given the inherent bias in these analyses. Subgroup analysis suggested that PFO closure may best benefit those with substantial shunt, atrial aneurysm, or superficial location of infarcts. The article's accompanying editorial[2] notes that while RESPECT demonstrated that the Amplatzer device was associated with fewer atrial fibrillation episodes, it was associated with more atrial thrombi and pulmonary emboli compared to the STARFlex device. In addition, the editorial's authors note that even if we are to trust the per-protocol analysis which suggested an improvement with PFO closure, the trial had significant biases including its uneven dropout rates and unblinded adjudication of events.[2]

Guidelines

2011 AHA/ASA stroke guidelines[3]

  • For patients with an ischemic stroke or TIA and a PFO, antiplatelet therapy is reasonable (class IIa, level B).
  • There are insufficient data to establish whether anticoagulation is equivalent or superior to aspirin for secondary stroke prevention in patients with PFO (class IIb, level B).
  • There are insufficient data to make a recommendation regarding PFO closure in patients with stroke and PFO (class IIb, level C).

Design

  • Prospective, multicenter, open-label, randomized trial
  • N=980 patients with cryptogenic ischemic stroke
    • PFO closure (n=499)
    • Medical therapy (n=481)
  • Setting: 69 centers in the US and Canada
  • Enrollment: 2003-2011
  • Mean follow-up: 2.6 years
  • Analysis: Intention-to-treat
  • Primary outcome: Composite recurrent nonfatal ischemic stroke, stroke mortality, and early all-cause mortality

Population

Inclusion Criteria

  • Age 18-60 years
  • Cryptogenic ischemic stroke in previous 270 days
  • PFO demonstrated by TEE bubble study

Exclusion Criteria

Non-cryptogenic ischemic stroke (eg, large vessel disease, cardioembolic phenomenon, lacunar infarct, or arterial hypercoaguable states)

Baseline Characteristics

All patients

  • Age: 45.9 years
  • Male: 54.7%
  • PMH:
    • DM: 7.4%
    • HTN: 31.4%
    • Smoking status: 13.3% current, 28.3% former
    • HLD: 39.5%
    • CAD: 2.9%
    • MI: 0.7%
    • PVD: 0.6%
    • TIA: 12.1%
    • CVA: 10.6%, 24.9% with family history
    • Migraine: 38.8%
    • DVT: 3.6%
    • CHF: 0.3%
    • COPD: 1.1%
    • OCP or HRT use: 9.5%
  • Right-to-left shunt grade:
    • Grade 1 (1-9 bubbles): 22.7%
    • Grade 2 (10-20 bubbles): 26.4%
    • Grade 3 (≥20 bubbles): 48.8%
  • Atrial septal aneurysm: 35.6%

Interventions

  • Randomized to
    • PFO closure with the Amplatzer PFO Occluder; involved fluoroscopic closure within 21 days of randomization with discontinuation of antithrombotic regimen after device placement
      • After device placement, patients were continued on 1 month of combination aspirin/clopidogrel daily followed by five months of aspirin monotherapy
      • Subsequent medical therapy was performed at the discretion of the site investigator
    • Optimal medical therapy arm included treatment with aspirin, warfarin, clopidogrel, aspirin/clopidogrel, or aspirin/dipyridamole
      • Combination aspirin/clopidogrel was removed as an option in 2006 following publication of MATCH (2004) and updated AHA/ASA guidelines.

Outcomes

Comparisons are PFO closure vs. medical therapy. Analyses are intention-to-treat except where specified.

Primary Outcome

Composite recurrent nonfatal ischemic stroke, stroke motality, and early all-cause mortality
9 vs. 16 events (HR 0.49; 95% CI 0.22-1.11; P=0.08)
As-treated: 5 vs. 16 events (HR 0.27; 95% CI 0.10-0.75; P=0.007)
6 vs. 14 events (HR 0.37; 95% CI 0.14-0.96; P=0.03)

Secondary Outcomes

Composite recurrent symptomatic non-fatal ischemic stroke or CV mortality
Rates not given (HR 0.17; 95% CI 0.02-1.47; P=0.07)
TIA
Rates not given (HR 0.89; 95% CI 0.31-2.54; P=0.83)

Additional Analyses

Dropout
Rate: 9.2% vs. 17.2%
Follow-up observation: 1184 years vs. 1375 years (P=0.009)
Closure at 6 months, PFO group only
Complete: 72.7%
Effective: 93.5%
Defined as minimal or complete closure
Placement of the PFO closure device, PFO group only
93%

Subgroup Analysis

There were no differences in the primary outcome for age or sex. Non-significant interactions with significant subgroup analyses are presented below.

For the primary outcome

Shunt size
None, trace, or moderate: 2.8% vs. 2.5% (HR 1.03; 95% CI 0.35-3.08; P=0.95)
Substantial: 0.8% vs. 4.3% (HR 0.18; 95% CI 0.04-0.81; P=0.01)
Atrial septal aneurysm
Present: 1.1% vs. 5.3% (HR 0.19; 95% CI 0.04-0.87; P=0.02)
Absent: 2.2% vs. 2.2% (HR 0.89; 95% CI 0.31-2.54; P=0.83)
Site of index infarct
Superficial: 1.8% vs. 4.5% (HR 0.37; 95% CI 0.13-1.04; P=0.05)
Small deep: 3.5% vs. 1.4% (HR 1.76; 95% CI 0.16-19.93; P=0.64)
Other: 1.3% vs. 2.2% (HR 0.56; 95% CI 0.09-3.34; P=0.52)
Planned medical regimen
Anticoagulant: 3.0% vs. 2.5% (HR 1.14; 95% CI 0.26-5.10; P=0.86)
Antiplatelet: 1.4% vs. 3.6% (HR 0.34; 95% CI 0.12-0.94; P=0.03)

Adverse Events

Any serious
23.0% vs. 21.6% (P=0.65)
Atrial fibrillation
3.0% vs. 1.5% (P=0.13)
PE
1.2% vs. 0.2% (P=0.12)

Criticisms

  • No long-term follow-up
  • High and unequal rate of dropout[2]
  • High-risk patients were likely treated preferentially outside of the context of the trial
  • No significance for the primary outcome in the intention-to-treat analysis

Funding

St. Jude Medical, the makers of the Amplatzer PFO Occluder device

Further Reading

  1. Meier B, et al. "Percutaneous closure of patent foramen ovale in cryptogenic embolism." The New England Journal of Medicine. 2013;368:1083-1091.
  2. 2.0 2.1 2.2 Messé SR, Kent DM. "Still No Closure on the Question of PFO Closure." N Engl J Med. 2013;368:1152-1153
  3. Furie KL, et al. "Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack." Stroke. 2011;42(1):227-76.