TCT: Two PFO Closure Trials Miss Primary Endpoints

Two trials presented today at the TCT meeting in Miami testing the benefits of PFO closure in patients with cryptogenic stroke have failed to convincingly demonstrate any significant  benefit for the controversial procedure.

The RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial randomized 980 patients  to PFO closure with the Amplatzer PFO Occluder device or medical therapy. According to the lead investigator John Carroll, the rate of recurrent stroke was low in both arms of the trial: 1.6% in the closure group and 3% in the medical group.

This difference vetween the groups did not achieve significance in the intention-to-treat (ITT) analyses:

• ITT raw count: 46% risk reduction (p=0.157)
• ITT Kaplan Meier: 50.8% risk reduction, (p= 0.083

However, statistical significance was achieved in the per protocol and as treated analyses:

• Per protocol Kaplan Meier: 63.4 risk reduction (p=0.032)
• As treated Kaplan Meier: 72.7% (p=0.007)

The investigators reported that there were very few device- or procedure-related complications. There were a similar amount of serious adverse events in the two groups (23% in the device group and 21.6% in the control group).

The investigators concluded that “for carefully selected patients with history of cryptogenic stroke and PFO, the RESPECT Trial provides evidence of benefit in stroke risk reduction from closure with the AMPLATZER PFO Occluder over medical management alone.”

“The optimal secondary prevention strategy following a cryptogenic ischemic stroke in patients who are found to have a PFO has been unknown,” said Carroll, in a TCT press release. “This need to know is particularly intense for young stroke patients who have no or minimal traditional risk factors for ischemic stroke, yet face a risk of recurrent stroke for many decades. RESPECT makes progress in both removing the ‘unknown’ or cryptogenic cause of some strokes and providing high quality data from a large, long-term randomized trial.”

A similar pattern occurred in the smaller PC (Percutaneous Closure of Patent Foramen Ovale versus Medical Treatment in Patients with Cryptogenic Embolism) Trial, in which 414 patients were randomized to PFO closure or medical therapy. The primary endpoint, the composite of death, non-fatal stroke, TIA, and peripheral embolism, occurred in 3.4% of the treatment group compared to 5.2% of the control group (relative risk reduction: 37%, p=0.34). The incidence of stroke was 0.5% versus 2.4% (relative risk reduction 80%, p=0.14).

Study investigator Stephan Windecker said that because of a lower than expected rate of events after a mean followup of 4 years the trial ended up being underpowered to detect meaningful differences. He concluded that “the observed difference in stroke… may be clinically relevant if confirmed in further studies.”

We need a definitive trial of this approach if it’s going to be broadly used for PFO closure,” said Deepak Bhatt, in an interview with Bloomberg News. “Anecdotally, there are patients who seem to benefit. It’s unfortunate that none of the trials have been able to absolutely nail that down.”

Earning Respect?

As reported here over the summer, during an earnings call St. Jude CEO Dan Starks told investors that the results of RESPECT were “favorable.” As I wrote then, the danger of this sort of statement  is that the company’s initial evaluation of the results may clash with the eventual judgement of the medical community. Companies are simply in no position to be objective about their own products or trials. Caution in this case was particularly warranted because of the sorry history of negative trials in this area, as highlighted by the failed MIST trial of the STARFlex Septal Closure System. The results of the RESPECT and PC Trials demonstrate that the communication of medical information should not be left in the hands of industry. (St. Jude stock dropped 3.5% on the announcement of the trial results.)

Here are the TCT press releases for RESPECT and PC:

CLINICAL TRIAL SUGGESTS PFO CLOSURE WITH INVESTIGATIONAL DEVICE IS SAFE AND MAY IMPROVE CLINICAL OUTCOMES COMPARED TO MEDICAL MANAGEMENT IN THE PREVENTION OF CRYPTOGENIC STROKE

Results of the RESPECT Trial Presented at TCT 2012

MIAMI, FL – OCTOBER 25, 2012 – A clinical trial indicates that using an investigational medical device to close a PFO, or “hole in the heart,” may be superior to medical management alone in the prevention of a repeated stroke. Results of the RESPECT trial were presented today at the 24^th annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium. Sponsored by the Cardiovascular Research Foundation (CRF), TCT is the world’s premier educational meeting specializing in interventional cardiovascular medicine.

A PFO (patent foramen ovale) is a flap-like opening between the left and right upper chambers (atria) of the heart, which typically fuses shut after birth. In approximately one in four people, the opening does not fuse shut and in some cases, a blood clot may pass through the PFO and potentially travel to the brain causing an ischemic stroke. It is estimated that PFO rates are three times higher in the patient population with cryptogenic stroke, or stroke without an overt source. However, to date, no randomized clinical trial has demonstrated superiority of PFO closure over standard medical therapy for secondary stroke prevention, despite there being observational data suggesting a possible benefit.

RESPECT was a prospective, randomized (1:1), multi-center trial designed to evaluate whether PFO closure with the AMPLATZER PFO Occluder is superior to the current standard medical treatment in the prevention of recurrent stroke (a second stroke). Made of wire mesh, the investigational device is inserted into the PFO through a catheter to seal the passageway between the left and right atria.

A total of 980 patients were enrolled over eight years. Patients diagnosed with a cryptogenic stroke and PFO (age 18-60) were randomized to either the investigational device group or the medical therapy group within 270 days of the stroke. Forty-nine percent of the patients had a large stroke as the qualifying stroke event. The average age in the study was 46 and patients were otherwise generally healthy.

Statistics from the RESPECT trial:

• Two year events rates were low in both the device and medically treated groups
  • 1.6 percent vs. 3.0 percent respectively
  • All primary events were non-fatal, recurrent ischemic strokes
• The clinical risk reduction of stroke using the device ranged from 46.6 percent to 72.7 percent compared to medical management alone, depending on the analysis population being assessed
  • Among the intent-to-treat analysis population, this reduction achieved borderline statistical significance
  • In per-protocol and as-treated analyses, the reductions were statistically significant
• Serious adverse event (SAE) rates did not differ between the device and medical groups
  • 23.0 percent vs. 21.6 percent respectively
• Medical therapy included one of four regimens:
  • Warfarin (25.2 percent)
  • Aspirin (46.5 percent)
  • Clopidogrel (14.0 percent)
  • Aspirin combined with dipyridamole (8.1 percent)
  • Aspirin combined with clopidogrel (6.3 percent)
• The total incidence of atrial fibrillation was not significantly different between the device and medical group
  • 3.0 percent vs. 1.5 percent respectively
• No device related thrombus, erosion, or embolization was observed
• There were no study-related deaths

“In patients between 18 and 60 years old with cryptogenic ischemic stroke and PFO, the totality of evidence from RESPECT demonstrates that PFO closure with the AMPLATZER PFO Occluder provides evidence of benefit over medical management alone, with very low device and procedure-related risks,” said lead investigator John D. Carroll, MD. Dr. Carroll is Professor of Medicine, Co-Director of the Cardiac and Vascular Center, and Director of Interventional Cardiology at the University of Colorado.

“The optimal secondary prevention strategy following a cryptogenic ischemic stroke in patients who are found to have a PFO has been unknown. This need to know is particularly intense for young stroke patients who have no or minimal traditional risk factors for ischemic stroke, yet face a risk of recurrent stroke for many decades. RESPECT makes progress in both removing the “unknown” or cryptogenic cause of some strokes and providing high quality data from a large, long-term randomized trial.”

The results of the RESPECT trial will be presented on Thursday October 25 at 11:15 AM EDT in the Main Arena (Hall D) of the Miami Beach Convention Center.

The RESPECT clinical trial was sponsored by St. Jude Medical, Inc. who provided research support to the University of Colorado School of Medicine. Consulting fees for Dr. Carroll’s work on the RESPECT steering committee were paid to University Physician, Inc.

About CRF

The Cardiovascular Research Foundation (CRF) is an independent, academically focused nonprofit organization dedicated to improving the survival and quality of life for people with cardiovascular disease through research and education. Since its inception in 1991, CRF has played a major role in realizing dramatic improvements in the lives of countless numbers of patients by establishing the safe use of new technologies and therapies in interventional cardiovascular medicine.

Transcatheter Cardiovascular Therapeutics (TCT) is the annual scientific symposium of the Cardiovascular Research Foundation. TCT gathers leading medical researchers and clinicians from around the world to present and discuss the latest developments in the field.

For more information, visit www.crf.org.

###

CLINICAL TRIAL SHOWS THAT PFO CLOSURE WITH INVESTIGATIONAL DEVICE DOES NOT DECREASE ISCHEMIC AND BLEEDING EVENTS COMPARED TO MEDICAL THERAPY

Results of the PC Trial Presented at TCT 2012

MIAMI, FL – OCTOBER 25, 2012 – A clinical trial that compared catheter-based PFO closure using an investigational device found that there was no significant reduction in ischemic and bleeding events compared to standard medical therapy; stroke risk was non-significantly reduced with device therapy. The PC Trial was presented at the 24^th annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium. Sponsored by the Cardiovascular Research Foundation (CRF), TCT is the world’s premier educational meeting specializing in interventional cardiovascular medicine.

A PFO (patent foramen ovale) is a hole between the left and right upper chambers (atria) of the heart that fails to close just after birth. Approximately one in four people grow up with a PFO. In some cases a blood clot may pass through the PFO and can potentially travel to the brain causing an ischemic stroke. It is estimated that PFO rates are three times higher in the population of patients with cryptogenic stroke, or stroke without an overt source.

The PC Trial compared the efficacy of the percutaneous closure of a PFO using the Amplatzer PFO Occluder with medical treatment in patients with cryptogenic stroke with peripheral embolism. Made of wire mesh, the investigational device is inserted into the PFO through a catheter to seal the passageway between the left and right atria.

Patients were randomized in 29 centers in Europe, Brazil, Canada, and Australia. Enrollment of 414 patients was completed in February 2009. The primary endpoint of the trial was a composite of death from any cause, non-fatal stroke, transient ischemic attack (TIA), and peripheral embolism.

For the primary composite endpoint (death from any cause, non-fatal stroke, TIA, and peripheral embolism) researchers found a relative risk reduction of 37 percent when using the investigational device; this reduction was not statistically significant. Results also indicated no significant reduction in ischemic and bleeding events in patients who underwent PFO closure compared to those who received medical therapy (2.9 percent versus 5.7 percent, HR 0.49, 95 percent CI 0.19 – 1.32, P=0.16). The relative risk reduction of stroke through use of the device was 80 percent with a number needed to treat (NNN) of 40, but this reduction was also not statistically significant.

“Percutaneous PFO closure with the investigational Amplatzer PFO Occluder device for secondary prevention of thromboembolism showed no significant reduction in ischemic and bleeding events compared with medical treatment in this trial,“ said study investigator Stephan Windecker, MD. Dr. Windecker is a Professor and Head of Interventional Cardiology at the Swiss Cardiovascular Center in Bern.

“However, the observed difference in stroke may be clinically relevant if confirmed in further studies,“ Dr. Windecker said.

The results of The PC Trial will be presented on Thursday October 25 at 11:27 AM EST in the Main Arena (Hall D) of the Miami Beach Convention Center.

The trial was funded in part by an unrestricted grant provided by St. Jude Medical, Inc. Dr. Windecker reported  grant support from St. Jude Medical related to research in the field of optical coherence tomography.

About CRF

The Cardiovascular Research Foundation (CRF) is an independent, academically focused nonprofit organization dedicated to improving the survival and quality of life for people with cardiovascular disease through research and education. Since its inception in 1991, CRF has played a major role in realizing dramatic improvements in the lives of countless numbers of patients by establishing the safe use of new technologies and therapies in interventional cardiovascular medicine.

Transcatheter Cardiovascular Therapeutics (TCT) is the annual scientific symposium of the Cardiovascular Research Foundation. TCT gathers leading medical researchers and clinicians from around the world to present and discuss the latest developments in the field.

For more information, visit www.crf.org.

###