Qualifying and Outcome Strokes in the RESPECT PFO Trial: Additional Evidence of Treatment Effect JEFFREY L. SAVER, MD DAVID E. THALER, MD, PHD, RICHARD W. SMALLING, MD, PHD, JOHN D. CARROLL, MD, SCOTT BERRY, PHD, LEE A. MACDONALD, MD, DAVID S. MARKS, MD, MBA, DAVID L. TIRSCHWELL, MD, DIANE BOOK, MD, LARRY B. GOLDSTEIN, MD, BRIAN LARKIN, MD and THE RESPECT INVESTIGATORS
Disclosure Statement of Financial Interest Author J.L. Saver Disclosure Employment -University of California, which received clinical trial research funds and payments for consulting professional services from St. Jude Medical; Significant D. Thaler Research Grant; Modest; St. Jude Medical. Consultant/Advisory Board; Modest; St. Jude Medical R. Smalling Research Grant; Modest; St. Jude Medical. Consultant/Advisory Board; Modest; St. Jude Medical J. Carroll Research Grant; Modest; St. Jude Medical. Consultant/Advisory Board; Modest; St. Jude Medical S. Berry Consultant/Advisory Board; Modest; St. Jude Medical L. MacDonald Research Grant; Modest; St. Jude Medical. Consultant/Advisory Board; Modest; St. Jude Medical D. Marks Research Grant; Modest; St. Jude Medical. Consultant/Advisory Board; Modest; St. Jude Medical D. Tirschwell Research Grant; Modest; St. Jude Medical. Consultant/Advisory Board; Modest; St. Jude Medical D. Book Research Grant; Modest; St. Jude Medical. Consultant/Advisory Board; Modest; St. Jude Medical L.B. Goldstein Research Grant; Modest; St. Jude Medical. Consultant/Advisory Board; Modest; St. Jude Medical B. Larkin Consultant/Advisory Board; Modest; St. Jude Medical 2
Background: Cryptogenic Stroke and PFO Cryptogenic stroke remains a major challenge PFO-related strokes, i.e. due to paradoxical embolism, have been strongly implicated as a possible cause Patients age 20-54 are now a larger percentage of all stroke patients and among first ever strokes in the younger population there is growth in ischemic strokes 1 Cost of stroke is significant, with over $94B 2,3 spent each year in the US and EU alone cost implications with young patients are immense, based on the loss of productivity and long-term care The results of PFO closure trials have included positive observational studies and one neutral randomized trial The RESPECT trial was designed with a well-defined stroke population, a statistical design appropriate for expected low recurrent event rates, and used a device with an excellent safety record 1. Kissela, BM, Khoury, JC, Alwell, K,et al. Age at stroke Temporal trends in stroke incidence in a large, biracial population. Neurology 2012;79:1781-1787 2. Roger, V, Go, A, Lloyd-Jones, D, et. Al. Heart Disease and Stroke Statistics 2012 Update: A Report from the American Heart Association. Circulation. 2012; 125:e2-e220 3. Allender,S, Scarborough, P, Peto, V, et al European cardiovascular disease statistics 2008 3 *CAUTION: Investigational device in the United States. Limited by Federal (or U.S.) law to investigational use. Not available for sale in the U.S.
1. P-values ITT Raw Count are calculated using Fisher s Exact Test; all other P-values are calculated Log-Rank Test RESPECT Efficacy Analyses 46.6%-72.7% risk reduction of stroke in favor of device Totality of Evidence 46.6% - 72.7% risk reduction of stroke in favor of device Primary Endpoint Analyses ITT Cohort 50.8% risk reduction of stroke in favor of device Analysis Risk Reduction P-value 1 Intent to Treat Raw Count 46.6% 0.157 Intent to Treat KM 50.8% 0.083 Per Protocol KM 63.4% 0.032 As Treated KM 72.7% 0.007 Primary Endpoint Analyses PP Cohort 63.4% risk reduction of stroke in favor of device Primary Endpoint Analyses AT Cohort 72.7% risk reduction of stroke in favor of device 4
Objective To characterize the qualifying ischemic strokes in the RESPECT Trial To characterize the endpoint ischemic strokes in the RESPECT Trial 5
Methods: Trial Design Design Multicenter: 69 Sites (62 US, 7 Canada) Prospective, 1:1 Randomized stratified by site and atrial septal aneurysm Device Group (Test): Closure with the AMPLATZER TM PFO Occluder plus medical therapy Medical Group (Control): 5 Medical Treatment Regimens: Aspirin Clopidogrel Warfarin Aspirin with dipyridamole Aspirin with clopidogrel 1 Sample Size: Event-driven continued enrollment until 25 th endpoint Primary Analyses Trial Status Sponsor Four protocol-specified analyses with raw count primary analysis Trial was conducted under an Investigational Device Exemption (IDE) St. Jude Medical, St. Paul, MN *Study initiated under AGA Medical, Plymouth, MN 6 1. Aspirin with clopidogrel was removed from the protocol in 2006 based on changes to the AHA/ASA treatment guidelines
Study Governance and Organization Executive Steering Committee John D. Carroll, MD, University of Colorado/University of Colorado Hospital, Department of Medicine (Cardiology) Jeffrey L. Saver, MD, University of California, Los Angeles, Department of Neurology Richard W. Smalling, MD, PhD, University of Texas/Memorial Hermann Heart and Vascular Institute, Division of Cardiology David E. Thaler, MD, PhD, Tufts University/ Tufts Medical Center, Department of Neurology Independent Review Independent Clinical Events Committee (CEC) Independent Data Safety and Monitoring Board (DSMB) Independent Neurological Executive Committee Core Laboratories: Hematology (Quintiles) Echocardiography (CVR Consulting, PC) Statistical Oversight Independent Biostatistician: Berry Consultants 7
Inclusion/Exclusion Criteria Inclusion Criteria: Patients (ages 18 to 60) with PFO who have had a cryptogenic stroke within 270 days Stroke defined as acute focal neurological deficit, presumed to be due to focal ischemia, and either symptoms persisting 1) 24 hours, or 2) < 24 hours with MR or CT confirmed new, neuroanatomically relevant, cerebral infarct PFO defined as TEE visualization of micro-bubbles in the left atrium within 3 cardiac cycles of their appearance in the right atrium at rest and/or during Valsalva release Key Exclusion Criteria: Cerebral, cardiovascular, and systemic conditions that suggest other mechanisms for stroke. Examples: Carotid disease, atrial fibrillation, cardiomyopathy, etc. Arterial hypercoagulable states Contraindications: To aspirin or clopidogrel Uncontrolled diabetes mellitus or hypertension Other sources of right to left shunt Anatomical to device placement Any other reason to expect limited life expectancy, inability to attend follow-up visits, or inability to provide informed consent 8
RESPECT Entry Criteria Ischemic Stroke, not TIA Ischemic stroke: acute focal neurological deficit, presumed to be due to focal ischemia, and either: Symptoms persisting 24 hours or greater, or Symptoms persisting less than 24 hours but associated with MR or CT findings of a new, neuroanatomically relevant, cerebral infarct 9
RESPECT Entry Criteria Stroke Mechanism Inclusion criteria Age 18-60 Exclusion criteria Arteriopathy Atherosclerosis or other arteriopathy of intracranial or extracranial vessels >50% supplying the involved lesion Aortic arch plaque > 4 mm into the lumen Arterial dissection as qualifying event Cardioembolic source A fib/flutter chronic/intermittent; Intracardiac thrombus or tumor; MI within last 6 mos; LV aneurysm or akinesis; Mitral or aortic valve vegetation or prosthesis; LVEF < 35%; Endocarditis Arterial hypercoagulable state Antiphospholipid Abs, Homocysteinemia Lacunar infarct probably due to intrinsic small vessel disease 10
Key Exclusion - Lacunar Infarct Probably Due to Intrinsic Small Vessel Disease Ischemic stroke in the distribution of a single, small, deep penetrating vessel AND ANY of the following: HTN (except in 1 st week post stroke) DM Age 50 MRI or CT shows leukoaraiosis greater than symmetric, well-defined periventricular caps or bands (European Task Force on Age-Related White Matter Changes rating scale score > 0) 1 2 3 11 Wahlund LO et al, Stroke 2001
Etiologic Analysis: A-S-C-O-D Stroke Classification System* - Atherosclerosis - Other - Small Vessel Disease - Dissection - Cardiac Source --Amarenco et al, CVD 2009; Amerenco personal correspondence 2013, Delewi et al, Eur J Radiol 2012, Johari et al, Dis Mon 2012, Mathey et al, Circulation 2010 * Modified only in that presence of a PFO did not classify patients in a cardiac source category 0 Disease not detected 1 - Definitely a potential cause 2 - Present, causal link uncertain 3 - Present, unlikely a cause 9 - Testing not performed 12
Study Results Qualifying Strokes 13
Qualifying Ischemic Stroke Timing and Severity No difference between groups Device Group N=499 Medical Group N=481 All Subjects N=980 P- value Characteristic Days from stroke to 130 (70) 130 (69) 130 (70) 0.89 randomization a 100 100 NIHSS 0 (0 1) 0 (0 1) 0 (0 1) stroke deficit score b Barthel Index 100 (100 100) (100 100) (100 100) ADL score b mrs disability score b 1 (0 1) 1 (0 1) 1 (0 1) a. Data represented as mean (standard deviation) for months from randomization to event b. Data presented in terms of median (interquartile range) for NIHSS, Barthel and mrs. 14
Topography of Qualifying Ischemic Stroke Well balanced between groups Topography Device Group N=442 Medical Group N=448 All Subjects N=890 Superficial Only 53.8% 52.7% 53.3% Mixed Superf - Deep 9.5% 7.4% 8.4% Large Deep Only 4.1% 4.5% 4.3% Small Deep Only 12.9% 15.6% 14.3% Other 19.7% 19.9% 19.8% P- value a 0.64 a. P-values calculated using Chi-Squared Test 15
Lesion Size of Qualifying Ischemic Infarcts Larger lesions in almost 50% of subjects Lesion size Device Group N=443 Medical Group N=446 All Subjects N=889 Small (<0.5 cm) 17.6% 20.6% 19.1% Intermediate (0.5-1.5 cm) 33.0% 31.2% 32.1% Moderate (1.6-3.0 cm) 19.9% 28.5% 24.2% P-value 0.057 a Large (3.1-6.0 cm) 24.4% 16.6% 20.5% Massive (>6.0 cm) 5.2% 3.1% 4.2% Larger ( 1.5 cm) 49.4% 48.2% 48.8% 0.71 b a. P-values calculated using Mann-Whitney-Wilcoxon Test b. P-values calculated using Fisher s Exact test 16
Subpopulation Differential Treatment Effect P=0.17 17
Study Results Endpoint Strokes 18
Endpoint Ischemic Stroke Timing and Severity Characteristic Months from randomization to event Device Group n=9 16 (22.4) Medical Group n=16 17.9 (15.5) All Subjects n=25 17.2 (17.9) P-value a NIHSS 2 (2-3) 2 (0-4) 2 (0-4) 0.70 stroke deficit score b Barthel Index 100 (95-100) 100 (85-100) 100 (90-100) 0.59 ADL score b mrs 1 (1-3) 1 (0-2) 1 (0-3) 0.56 disability score b 0.38 a. P-values calculated using Mann-Whitney-Wilcoxon test b. Data presented in terms of median (interquartile range) for NIHSS, Barthel and mrs. Data represented as mean (standard deviation) for months from randomization to event 19
Topography of Endpoint Ischemic Strokes Superficial and other infarcts were more common in the Medical Group Topography Device Group n=7 Medical Group n=13 All Subjects n=20 Superficial Only 57.1% 61.5% 60% P-value a Mixed Superf - Deep 0.0% 15.4% 10% Large Deep Only 0.0% 0.0% 0.0% Small Deep Only 42.9% 0.0% 15% 0.04 Other 0.0% 23.1% 15% a. P-values calculated using Chi-Squared Test 20
Lesion Size of Endpoint Ischemic Strokes Recurrent larger infarcts were more frequent in the Medical Group at 69.2% vs. 14.3% in the Device Group Lesion size Device Group n=7 Medical Group n=13 All Subjects n=20 Small (<0.5 cm) 42.9% 23.1% 30% P-value Intermediate (0.5-1.5 cm) 42.9% 7.7% 20% Moderate (1.6-3.0 cm) 0.0% 30.8% 20% Large (3.1-6.0 cm) 14.3% 15.4% 15% 0.09 a Massive (>6.0 cm) 0.0% 23.1% 15% Larger ( 1.5 cm) 14.3% 69.2% 50% 0.06 b a. P-values calculated using Mann-Whitney-Wilcoxon Test b. P-values calculated using Fisher s Exact test 21
Number Lesion Size of Endpoint Ischemic Strokes Recurrent Medical Group infarcts overall were larger 4 3 2 1 Device Medical 0 Small Intermediate Moderate Large Massive Increasing Infarct Size --> 22
A-S-C-O-D Stroke Subtype Classification Cryptogenic stroke 9 in Medical Group vs. 4 in Device Group Mechanism Definite potential non-pfo Present, uncertain causality Cryptogenic, complete w/up Cryptogenic, incomplete w/up Device Group n=9 Medical Group n=16 n / (%) Details n / (%) Details Radiation arteriopathy - 1 Atrial fibrillation 3 2 (22%) 4 (25%) SLE + SVD - 1 SVD - 1 Dissection - 1 Atherothrombosis 2 3 (33%) 3 (19%) Atherothrombosis - 1 Post-ICH evacuation 1 SVD - 1 3 (33%) 6 (37%) 1 (11%) 3 (19%) 23
Stroke Mechanism Aspects of Endpoint Ischemic Strokes Device Arm 3 of the 9 device arm ischemic strokes occurred in patients without a device in place 1 after randomization but prior to PFO occluder implant 1 in patient who declined procedure and crossed to medical therapy 1 in patient who required a CABG after randomization but prior to study procedure and who underwent bovine pericardium patch PFO repair during the surgery instead of device closure Of the remaining 6 device arm ischemic strokes 2 had alternative causes evident (SLE, radiation) 2 were small, deep only infarcts 24
Discussion The RESPECT population was stringently selected to identify patients with cryptogenic ischemic stroke Frequency of recurrent strokes due to a defined mechanism other than PFO was low 6 over 2559 follow-up years - 0.2% per patient year The exclusion of small deep infarcts likely due to intrinsic small vessel disease was successful in limiting recurrent small deep infarcts as endpoint events The types of infarcts particularly averted in the device group were those associated with paradoxical embolic stroke mechanism Superficial vascular distribution Large infarct size In ITT analysis, event rate was low in medical arm (1.25% per patient-year) but even lower in device arm (0.61% per patient-year) 25
Limitations Subgroup interaction analysis with only 25 events is exploratory in nature Clinically, the atrial septal aneurysm, shunt size, and superficial topography findings are relevant and support mechanism of action Work-up of endpoint events incomplete in some cases Some occurred at non-study centers All occurred in patients who had already had a complete work up for qualifying infarcts 26
Conclusions Consideration of neurovascular aspects of the RESPECT trial reinforce the primary analysis With stringent patient selection to identify patients with a history of cryptogenic stroke and PFO, closure with the AMPLATZER PFO Occluder showed evidence of benefit over medical management alone Indications of magnified effect in averting superficial cerebral infarcts and larger cerebral infarcts provide additional evidence of a genuine biological effect of closure with the AMPLATZER PFO Occluder in preventing recurrent cerebral infarcts due to paradoxical emboli 27
Study Sites and Principal Investigators 28
Trial Sites Top 5 enrollers noted 29