1、PROTECT AF研究：经皮闭合左心耳和华法林对房颤 预防脑卒中影响的前瞻性随机研究 PROTECT AF trials： Randomized Prospective Trial of Percutaneous LAA Closure vs Warfarin for Stroke Prevention in AF,David Holmes, MD;Vivek Reddy, MD; Zoltan Turi, MD，et al,Relevant Financial Relationship(s) Mayo receives research support from Atritech and
2、may receive royalties,PROTECT AF Trial,Sponsor: Atritech (Plymouth, MN) Principal Investigator: David Holmes Clinical Trials Indentifier: NCT00129545,Prospective, Multicenter Randomized Trial of Percutaneous Left Atrial Appendage Occlusion vs Long-term Warfarin Therapy in Patients with Non-Valvular
3、Atrial Fibrillation,Facts about Atrial Fibrillation (AF),AF is the most common cardiac arrhythmia Affects more than 3 million individuals in the US Projected to increase to 16 million by 2050 Patients with AF have a 5-fold higher risk of stroke Over 87% of strokes are thromboembolic Greater than 90%
4、 of thrombus accumulation originates in the Left Atrial Appendage (LAA) Stroke is the number one cause of long-term disability and the third leading cause of death in patients with AF,Non-Valvular Atrial Fibrillation Stroke Prevention Medical Rx,3000838-10,Cooper: Arch Int Med 166, 2006 Lip: Thromb
5、Res 118, 2006,Warfarin cornerstone of therapy Assuming 51 ischemic strokes/1000 pt-yr Adjusted standard dose warfarin prevented 28 strokes at expense of 11 fatal bleeds Aspirin prevented 16 strokes at expense of 6 fatal bleeds Warfarin 60-70% risk reduction vs no treatment 30-40% risk reduction vs a
6、spirin,Challenges in Treating AF,However warfarin is not always well-toleratedNarrow therapeutic range (INR between 2.0 3.0)Effectiveness is impacted by interactions with some foods and medicationsRequires frequent monitoring and dose adjustments Published reports indicate that less than 50% of pati
7、ents eligible are being treated with warfarin due to tolerance or non-compliance issues SPORTIF trials suggest only 60% of patients treated are within a therapeutic INR range, while 29% have INR levels below 2.0 and 15% have levels above 3.0,Watchman LAA Closure Technology,The WATCHMAN LAA Closure T
8、echnology is designed to prevent embolization of thrombi that may form in the LAA The WATCHMAN Left Atrial Appendage Closure Technology is intended as an alternative to warfarin therapy for patients with non-valvular atrial fibrillation,WATCHMAN LAA Closure Device in situ,3000838-18,PROTECT AF Clini
9、cal Trial Design,Prospective, randomized study of WATCHMAN LAA Device vs. Long-term Warfarin Therapy 2:1 allocation ratio device to control 800 Patients enrolled from Feb 2005 to Jun 2008 Device Group (463) Control Group (244) Roll-in Group (93) 59 Enrolling Centers (U.S. & Europe) Follow-up Require
10、ments TEE follow-up at 45 days, 6 months and 1 year Clinical follow-up biannually up to 5 years Regular INR monitoring while taking warfarin Enrollment continues in Continued Access Registry,Patient Study Timeline,Device subject takes warfarin,Preimplant interval,Day 0,Control subject takes warfarin
11、,Device subject gets implant,Device subject has ceased warfarin,Ongoing to 5 years,Randomize,Day 0,Day 45 postimplant,Day 2-14,Ongoing to 5 years,Device,Control,3000838-60,Warfarin Discontinuation,Reasons for remaining on warfarin therapy after 45-days: Observation of flow in the LAA (n = 30) Physic
12、ian Order (n = 13) Other (n = 9),87% of implanted subjects were able to cease warfarin at 45 days and the rate further increased at later time points,PROTECT AF Trial Endpoints,Primary Efficacy Endpoint All stroke: ischemic or hemorrhagic deficit with symptoms persisting more than 24 hours or sympto
13、ms less than 24 hours confirmed by CT or MRI Cardiovascular and unexplained death: includes sudden death, MI, CVA, cardiac arrhythmia and heart failure Systemic embolization Primary Safety Endpoint Device embolization requiring retrieval Pericardial effusion requiring intervention Cranial bleeds and
14、 gastrointestinal bleeds Any bleed that requires 2uPRBC NB: Primary effectiveness endpoint contains safety events,PROTECT AF Bayesian sequential design Accrue patient-yr up to possible maximum of 1,500 Analyze at specific time points; 600 patient-yr, then every 150 pt-yr thereafter Successful non-in
15、feriority based on first time success criterion met Success criterion defined on probability scale 97.5% probability that primary efficacy event rate for WATCHMAN is less than two times control 5% probability that primary efficacy event rate for WATCHMAN is less than control,PROTECT AF Statistical O
16、verview,3000838-45,Key Participation Criteria,Key Inclusion Criteria Age 18 years or older Documented non-valvular AF Eligible for long-term warfarin therapy, and no other conditions that would require long-term warfarin therapy Calculated CHADS2 score 1 Key Exclusion Criteria NYHA Class IV Congesti
17、ve Heart Failure ASD and/or atrial septal repair or closure device Planned ablation procedure within 30 days of potential WATCHMAN Device implant Symptomatic carotid disease LVEF 30% TEE Criteria: Suspected or known intracardiac thrombus (dense spontaneous echo contract),Patient Demographics,Patient
18、 Demographics,Events Total Rate Events Total Rate Rel. Risk Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) 900 pt-yr 48 554.2 8.7 13 312.0 4.2 2.08 (6.4, 11.3) (2.2, 6.7) (1.18, 4.13),Intent-to-Treat Primary Safety Results,3001664-1,Event-free probability,Days,Device,Control,244 143 51 11
19、463 261 87 19,WATCHMAN,Control,Randomization allocation (2 device : 1 control),Intent-to-Treat Primary Efficacy Results,3001664-2,Event-free probability,Days,Events Total Rate Events Total Rate Rel. Risk Non- Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority Superiority 900 pt-yr
20、 20 582.3 3.4 16 318.0 5.0 0.68 0.998 0.837 (2.1, 5.2) (2.8, 7.6) (0.37, 1.41),Device,Control,Posterior Probabilities,Randomization allocation (2 device : 1 control),ITT Cohort: Non-inferiority criteria met,244 147 52 12463 270 92 22,WATCHMAN,Control,PROTECT AF Trial What are the Analysis Issues,How
21、 do you deal with safety endpoints which are also primary efficacy endpoints? How do you deal with early procedural safety risks (seen with all invasive interventional procedures) vs late primary efficacy endpoints? How do you deal with a strategy of warfarin started immediately and indefinitely ver
22、sus an invasive approach that also requires 45 days of warfarin (?double jeopardy) How do you factor in procedural learning curve?,Potential Safety Endpoints Device,Procedural complications Pericardial effusion Stroke ischemic Bleeding during 45 days of Warfarin,Intent-to-Treat Primary Safety Result
23、s,3000838-61,Events Total Rate Events Total Rate RR Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) 600 pt-yr 45 386.4 11.6 9 220.4 4.1 2.85 (8.5, 15.3) (1.9, 7.2) (1.48, 6.43) 900 pt-yr 48 554.2 8.7 13 312.0 4.2 2.08 (6.4, 11.3) (2.2, 6.7) (1.18, 4.13),Device,Control,Pericardial effusions
24、 largest fraction of safety events in device group Stroke events most serious fraction of safety events in control group Bleeding events were also frequent,Pericardial Effusions by Experience,Pericardial effusions most common safety issue Throughout PROTECT AF Trial, procedural modifications and tra
25、ining enhancements were implemented Procedural events would be expected to decrease over time,No. % No. % Early patients (1-3) 13/154 8.4 10/154 6.5 Late patients (4) 27/388 7.0 17/388 4.4 Total 40/542 7.2 27/542 5.0,Site implant group,Any,Serious,3000838-70,Continued ACCESS Registry,No. % No. %1/88
26、 1.1 1/88 1.1,Any,Serious,Safety Events Stroke,Safety stroke events Also counted as efficacy events in efficacy analyses 5 events in device group classified as “ischemic stroke” All periprocedural: extended hospitalization by 7 days 3 were related to air embolism 1 hemorrhagic stroke in device group
27、 vs 6 in control group Device event occurred 15 days post implant while patient was on warfarin 4/6 stroke events in control group patients resulted in death,3000838-65,Intent-to-Treat All Stroke,ITT cohort: Non-inferiority criteria met,Event-free probability,Days,244,147,52,12,463,270,92,22,WATCHMA
28、N,Control,3000838-101,900 patient-year analysis,Events Total Rate Events Total Rate RR Non- Superiority Cohort eve pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority 600 14 409.3 3.4 8 223.6 3.6 0.96 0.927 0.488 pt-yr (1.9, 5.5) (1.5, 6.3) (0.43, 2.57) 900 15 582.9 2.6 11 318.1 3.5 0.74 0.998
29、0.731 pt-yr (1.5, 4.1) (1.7, 5.7) (0.36, 1.76),Device,Control,Posterior probabilities,Randomization allocation (2 device:1 control),Intent-to-Treat Hemorrhagic Stroke,ITT cohort: Superiority criteria met,Event-free probability,Days,244,147,53,12,463,275,95,23,WATCHMAN,Control,3000838-103,900 patient
30、-year analysis,Events Total Rate Events Total Rate RR Non- Superiority Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority 600 1 416.7 0.2 4 224.7 1.8 0.13 0.998 0.986 pt-yr (0.0, 0.9) (0.5, 3.9) (0.00, 0.80) 900 1 593.6 0.2 6 319.4 1.9 0.09 0.999 0.998 pt-yr (0.0, 0.6) (0.7, 3.7)
31、(0.00, 0.45),Device,Control,Posterior probabilities,Randomization allocation (2 device:1 control),Risk/Benefit Analysis,Intent-to-treat analysis Primary endpoint (intent to treat) achieved Other statistically significant endpoint findings Noninferiority for the primary efficacy event rate 32% lower
32、in device group Noninferiority for all strokes 26% lower in device group Superiority for hemorrhagic stroke 91% lower in device group Noninferiority for mortality rate 39% lower rate in device group Increased rate of primary safety events for the device group relative to the control group Most event
33、s in the device group were procedural effusions that decreased over the course of the study 87% of patients were able to discontinue warfarin at 45 days,3000838-120,Summary,Long-term warfarin treatment of patients with AF has been found effective, but presents difficulties and risk PROTECT AF trial
34、was a randomized, controlled, statistically valid study to evaluate the WATCHMAN device compared to warfarin In PROTECT AF, hemorrhagic stroke risk is significantly lower with the device. When hemorrhagic stroke occurred, risk of death was markedly increased In PROTECT AF, all cause stroke and all c
35、ause mortality risk are non-inferior to warfarin In PROTECT AF, there are early safety events, specifically pericardial effusion; these events have decreased over time,3000838-123,Conclusion,The WATCHMAN LAA Technology offers a safe and effective alternative to warfarin in patients with non-valvular atrial fibrillation at risk for stroke and who are eligible for warfarin therapy,3000838-124,
