PFO and hybrid defect a 2014 update

VHA Scientific Meeting, Danang 2014 Gianluca Rigatelli, MD, PhD, EBIR, FACP, FACC, FESC, FSCAI Section of Adult Congenital Heart Disease Cardiovascular Interventions Unit Rovigo General Hospital, Italy PFO and hybrid defect: a 2014 update PFO: Why trial in the past failed Anatomic entity with high prevalence in the general population Difficult pathophysiology External factors contributing to clinical manifestation Variable anatomy wiich impacts on outcomes Low clinical impact: A lot of factors and long time for manifestation Difficult to design trials; high risk of failure PFO: which are the evidences till now MIST I StarFlex Adverse events Residual shunt MIST II StarFlex Adverse events Residual shunt CLOSURE I StarFlex Adverse events Residual shunt PC Amplazter Safe Not effective RESPECT Amplazter Safe Effective Genesis of a failure Wrong device BIG FAILURE Unclear indications Too short Follow up Considerations on the past failed trials Low proportion of true ischemic stroke( 30% probably had a lacunar stroke) Low safety of the device used Inclusionon of patients with low risk of stroke Unclear medical therapy regimen in the medical arm? RANDOMIZED EVALUATION OF RECURRENT STROKE COMPARING PFO CLOSURE TO ESTABLISHED CURRENT STANDARD OF CARE TREATMENT RESPECT Trial Description Objective PFO closure with AMPLATZER PFO Occluder versus current SOC Medical Treatment Prospective Patients were first consented, enrolled in the trial and then followed according to defined protocol Randomized (1:1) Patients were enrolled in the study and hare an equal chance of being in either study group (receive a device or medical management only) The patients were nonblinded Multicenter Event-driven trial 69 centers from the US and Canada enrolled and tracked patients during the study The study ended patient enrollment when a certain number of pre-defined events occurred, also referred to as meeting a “stopping rule.” This is different than other prospective trials that follow enrolled patients for a specific time period or continue until a specific number of patients are enrolled Trial Design  The RESPECT trial had a very robust design and sought to recruit a pure cryptogenic patient population TIAs and lacunar strokes were not enrolled Inclusion Criteria Follow-up Patients (ages 18 to 60 – mean of 46) with PFO who have had a cryptogenic stroke within 270 days Up to years with mean approaching years Will continue until a ruling is made by the FDA for US device approval Composite of: Primary Endpoints Secondary Endpoints Primary Data Analysis Recurrence of nonfatal stroke Post-randomization death Fatal ischemic stroke Closure rate, absence of TIA, absence of recurrent cryptogenic (stroke of unknown cause) non-fatal stroke or CV death Four protocol-specified analysis with ITT raw count as primary endpoint analysis Subject Distribution Baseline Characteristics 10 Patient Cohorts    As directed by the trial’s Statistical Analysis Plan, the patient data would be divided into different cohorts – ITT, PP and AT ITT raw count data, would be analyzed to determine if the trial met its primary endpoint AT analysis would compare the outcomes of the patients that actually received treatment with the device or medical management alone 11 RESPECT Trial Results For patients with a history of cryptogenic stroke and PFO, the RESPECT Trial provides evidence that closure with the AMPLATZER PFO Occluder reduces stroke risk by 46.6 to 72.7% over medical management alone 12 RESPECT Trial Results The three remaining pre-specified analyses were deemed valid and demonstrated the following outcomes: • ITT-KM: 50.8% stroke risk reduction detecting a strong trend in favor of device • Per-Protocol & As-Treated KM: 63-73% stroke risk reduction that proved a statistically significant and clinically impactful benefit of PFO closure compared to medical management 13 Primary Endpoint Analysis – ITT Cohort 50.8% risk reduction of stroke in favor of device Note: 3/9 device group patients did not have a device at time of endpoint stroke, however, they must be included in the ITT 14 analysis Cox model used for analysis  Subpopulation Differential Treatment Effect 23 Number Needed to Treat  Using the Kaplan-Meier estimate for the ITT cohort, this analysis shows that 24 patients would need to be treated with the device in order to prevent stroke over a year period of time What’s new in the past year • Results of new metanalysis • New anatomical-pathophysiology studies • Concept of hybrid defect and atrial septum abnormalities continuum Metanalysis 2013-14 Percutaneous Closure versus Medical Therapy Alone for Cryptogenic Stroke Patients with a Patent Foramen Ovale: Meta-Analysis of Randomized Controlled Trials Tex Heart Inst J 2014 Aug 1;41(4):357-367 The use of the Amplatzer™ PFO Occluder resulted in significant stroke-prevention benefit over medical therapy alone: hazard ratio=0.44 (95% CI, 0.21-0.95; P=0.037) When compared with medical therapy alone, PFO closure with medical therapy showed a trend toward a decreased hazard of combined events, although the absolute event reduction was small and the number needed to treat was high Percutaneous closure of patent foramen ovale in patients with cryptogenic embolism: a network metaanalysis Eur Heart J 2014 Aug 11 pii: ehu292 The effectiveness of PFO closure depends on the device used PFO closure with AMPLATZER appears superior to medical therapy in preventing strokes in patients with cryptogenic embolism Transcatheter patent foramen ovale closure versus medical therapy for cryptogenic stroke: a metaanalysis of randomized clinical trials BMC Cardiovasc Disord 2013 Dec 11;13:116 In this meta-analysis, using intention-to-treat analysis, transcatheter device closure of PFO was not superior to standard medical therapy in the secondary prevention of cryptogenic stroke Transcatheter closure was superior using per-protocol analysis Device closure of patent foramen ovale versus medical therapy in cryptogenic stroke: a systematic review and meta-analysis.JACC Cardiovasc Interv 2013 Dec;6(12):131-23 PFO closure is beneficial as compared to medical therapy in the prevention of recurrent neurological events This meta-analysis helps to further strengthen the role of device closure in cryptogenic stroke Benefit exist depending on analyzed trials and device types used PFO anatomical variants correlate with stroke risk Long Channel +prominent eustachian valve ASA +/- Hyperthophic rims Most important independent predictor of recurrent cerebrovascular events Patent foramen ovale anatomical variants Hybrid defect DEFINITION: -OS ASD within the fossa ovalis associated to PFO and Atrial septal aneurysm -OS ASD with R-L shunt without associated PFO Peculiar anatomic and haemodynamic features Hybrid defect ANATOMIC FEATURES: - From ICE study, a flat ellyptical shape, more similar to a knife cut than to a circular hole - major axis of 7.6± 2.4 and minimal axis of 2.5±1.6 mm Hybrid defect CLINICAL/haemodynamic FEATURES: - Patients with HYBRID DEFECT had a higher frequency of deep venous thrombosis compared to PFO patients - In comparison to standard ASD, such patients had lower mean pulmonary pressure and smaller defects ATRIAl SEPTAL ABNORMALITIES CONTINUUM CONCLUSION 1.In the past few years, new trials and metanalysis had finally positive results in defining the role of PFO closure 2.New concept as the hybrid defects and the atrial septal abnormalities continuum have been suggested as an adjunction to the weel known field of ASD [...]... anatomical variants Hybrid defect DEFINITION: -OS ASD within the fossa ovalis associated to PFO and Atrial septal aneurysm -OS ASD with R-L shunt without associated PFO Peculiar anatomic and haemodynamic features Hybrid defect ANATOMIC FEATURES: - From ICE study, a flat ellyptical shape, more similar to a knife cut than to a circular hole - major axis of 7.6± 2.4 and minimal axis of 2.5±1.6 mm Hybrid defect. .. defect CLINICAL/haemodynamic FEATURES: - Patients with HYBRID DEFECT had a higher frequency of deep venous thrombosis compared to PFO patients - In comparison to standard ASD, such patients had lower mean pulmonary pressure and smaller defects ATRIAl SEPTAL ABNORMALITIES CONTINUUM CONCLUSION 1.In the past few years, new trials and metanalysis had finally positive results in defining the role of PFO closure...Patient Cohorts    As directed by the trial’s Statistical Analysis Plan, the patient data would be divided into 3 different cohorts – ITT, PP and AT ITT raw count data, would be analyzed to determine if the trial met its primary endpoint AT analysis would compare the outcomes of the patients that actually received treatment with the device or medical management alone 11 RESPECT Trial Results... used PFO closure with AMPLATZER appears superior to medical therapy in preventing strokes in patients with cryptogenic embolism Transcatheter patent foramen ovale closure versus medical therapy for cryptogenic stroke: a metaanalysis of randomized clinical trials BMC Cardiovasc Disord 2013 Dec 11;13:116 In this meta-analysis, using intention-to-treat analysis, transcatheter device closure of PFO was not... P=0.037) When compared with medical therapy alone, PFO closure with medical therapy showed a trend toward a decreased hazard of combined events, although the absolute event reduction was small and the number needed to treat was high Percutaneous closure of patent foramen ovale in patients with cryptogenic embolism: a network metaanalysis Eur Heart J 2014 Aug 11 pii: ehu292 The effectiveness of PFO closure... defect and atrial septum abnormalities continuum Metanalysis 2013-14 Percutaneous Closure versus Medical Therapy Alone for Cryptogenic Stroke Patients with a Patent Foramen Ovale: Meta-Analysis of Randomized Controlled Trials Tex Heart Inst J 2014 Aug 1;41(4):357-367 The use of the Amplatzer™ PFO Occluder resulted in significant stroke-prevention benefit over medical therapy alone: hazard ratio=0.44... was not superior to standard medical therapy in the secondary prevention of cryptogenic stroke Transcatheter closure was superior using per-protocol analysis Device closure of patent foramen ovale versus medical therapy in cryptogenic stroke: a systematic review and meta-analysis.JACC Cardiovasc Interv 2013 Dec;6(12):131-23 PFO closure is beneficial as compared to medical therapy in the prevention... neurological events This meta-analysis helps to further strengthen the role of device closure in cryptogenic stroke Benefit do exist depending on analyzed trials and device types used PFO anatomical variants correlate with stroke risk Long Channel +prominent eustachian valve ASA +/- Hyperthophic rims Most important independent predictor of recurrent cerebrovascular events Patent foramen ovale anatomical variants... for analysis  Subpopulation Differential Treatment Effect 23 Number Needed to Treat  Using the Kaplan-Meier estimate for the ITT cohort, this analysis shows that 24 patients would need to be treated with the device in order to prevent 1 stroke over a 5 year period of time What’s new in the past year • Results of new metanalysis • New anatomical-pathophysiology studies • Concept of hybrid defect and. .. Per-Protocol & As-Treated KM: 63-73% stroke risk reduction that proved a statistically significant and clinically impactful benefit of PFO closure compared to medical management 13 Primary Endpoint Analysis – ITT Cohort 50.8% risk reduction of stroke in favor of device Note: 3/9 device group patients did not have a device at time of endpoint stroke, however, they must be included in the ITT 14 analysis 1