ACCP Cardiology PRN Journal Club

Transcription

1 ACCP Cardiology PRN Journal Club

2 Dr. Lianjie Xiong Dr. Xiong is a PGY2 cardiology pharmacy resident at Vanderbilt University Medical Center in Nashville, TN. She went to Nova Southeastern University and completed her PGY1 Pharmacy Practice Residency at Palmetto Health Richland in Columbia, SC. Dr. Xiong s professional interests within cardiology include cardiac critical care, electrophysiology, anticoagulation, advanced heart failure, and academia.

3 Dr. Kristen Bova Campbell Dr. Campbell serves as the Residency Program Director for the PGY2 Cardiology Pharmacy Residency at Duke University Hospital. She graduated from the University of Virginia with a Bachelor of Arts degree in Environmental Sciences and obtained her PharmD from the UNC Eshelman School of Pharmacy. She completed an ASHP accredited Pharmacy Practice Residency and Cardiology Specialty Residency at the University of North Carolina Hospitals. Her current practice includes the care of Electrophysiology patients, precepting pharmacy students and residents, and clinical research.

4 Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation [RE-CIRCUIT] Lianjie Xiong, PharmD, MS, BCPS PGY-2 Cardiology Pharmacy Resident Vanderbilt University Medical Center Nashville, TN Kristen Bova Campbell, PharmD, BCPS (AQ-Cardiology), CPP, AACC Clinical Pharmacist & Senior Research Associate, Electrophysiology Director, PGY2 Cardiology Residency Duke University Hospital Durham, NC Calkins H, et al. N Eng J Med ; 376 (13):

5 Disclosures I have no financial interest or affiliation with the manufacturer of any marketed product discussed herein

6 Outline Review previous literature and therapeutic guidelines Discuss study design, statistics, and major findings of RE-CIRCUIT trial Explain application to practice

7 Shapira AR, et al. Am Fam Physician. 2009; 80: Catheter Ablation

8 AF Catheter Ablation Primary indication: Symptomatic paroxysmal AF refractory or intolerant to one Class 1 or 3 antiarrhythmic(s). (Class I, Level of Evidence: A) Other indications: Symptomatic persistent or long-standing (> 12 mo) AF refractory or intolerant to one Class 1 or 3 antiarrhythmic(s). (Class II, Level of Evidence: A) Recurrent symptomatic paroxysmal or symptomatic persistent AF; Initial rhythm control strategy. (Class II; Level of Evidence: B) Most important complications Peri-procedural stroke or TIA Cardiac tamponade Kirchhof P, et al. Eur Heart J. 2016; 37: January CT, et al. J Am Coll Cardiol. 2014; 64 (21): e1-e76 Calkins H, et al. Europace. 2012; 14:

9 Anticoagulation Guideline Before ablation During ablation After ablation 2012 HRS/EHRA/ECAS 2014 AHA/ACC/HRS - AF 48 hr or unknown, 3 weeks with warfarin (TEE if no anticoagulation) - AF <48 hr, TEE not mandatory - Heparin (ACT s) - Bridge with LMWH (decreased dose) or IV heparin if not therapeutically anticoagulated with warfarin at ablation - DTI or Factor Xa inhibitor alternatively - 2 months - No AF catheter ablation if patients cannot be treated with anticoagulant therapy during and after ablation 2016 ESC n/a - Continue VKAs/NOACs - Heparin (ACT>300 s) - 8 weeks Kirchhof P, et al. Eur Heart J. 2016; 37: January CT, et al. J Am Coll Cardiol. 2014; 64 (21): e1-e76 Calkins H, et al. Europace. 2012; 14:

10 Calkins H, et al. N Eng J Med. 2017; 376 (13): Zhao Y, et al. J Interv Card Eletrophysiol. 2017; 48: Cappato R, et al. Eur Heart J. 2015; 36(28): Wu S, et al. Am J Cardiol. 2016; 117: Di Biase L, et al. Circulation. 2014; 129: Blandino A, et al. J Interv Card Electrophysiol. 2016; 46: Medication Warfarin Trial/Study Population/ Intervention COMPARE (N=1584) - 30% paroxysmal, 20% persistent, 50% LSP - CHADS 2 score 1 (72% 2) - 1:1 to the off-warfarin or onwarfarin arm Major findings - Stroke/TIA combined in 48 hr after CA: 4.9% (off) vs 0.25% (on) (P value < 0.001) - No statistical differences for major bleeding/tamponade Dabigatran Rivaroxaban Apixaban Two Meta-analysis - Dabigatran appeared to be as safe and effective as uninterrupted warfarin for periprocedural anticoagulation in AF patients. VENTURE-AF (N=248) - 73% paroxysmal - Average CHA 2 DS 2 -VASc score 1.6-1:1 to rivaroxaban 20 mg daily or to a VKA - No significant difference in major bleeding (Primary end point) and TE (Secondary end point) after CA Meta-analysis (n=1691) - 1 randomized and 5 nonrandomized studies on apixaban and 1023 on warfarin - Patients on apixaban undergoing AF ablation: Low and similar rates of death, thromboembolic events, major/minor bleedings compared to warfarin

11 Background Limited systematic, prospective clinical data for non-vka oral anticoagulants in AF patients undergoing CA RE-CIRCUIT: To evaluate uninterrupted dabigatran compared with uninterrupted warfarin among patients undergoing catheter ablation for atrial fibrillation RE-LY: 150mg dabigatran less stroke/systemic embolism than warfarin, similar major bleeding in AF Calkins H, et al. N Eng J Med. 2017; 376 (13): Connolly SJ, et al. N Engl J Med. 2009; 361:

12 Study Design Randomized, open-label, multicenter, controlled trial in 678 nonvalvular AF patients undergoing ablation Collaboration Boehringer Ingelheim Funding for manuscript preparation Boehringer Ingelheim Calkins H, et al. N Eng J Med. 2017; 376 (13):

13 Inclusion Criteria Exclusion Criteria 18 yr Paroxysmal or persistent nonvalvular AF with planned ablation Documented AF within 24 months before screening Eligible for dabigatran 150 mg BID Permanent AF AF secondary to an obvious reversible cause Valvular AF Calkins H, et al. N Eng J Med. 2017; 376 (13):

14 Calkins H, et al. N Eng J Med. 2017; 376 (13): Study Design

15 Study Design N= 339 N= 339 Preablation Postablation Calkins H, et al. N Eng J Med. 2017; 376 (13):

16 Trial End Points Primary Incidence of major bleeding events as defined by International Society on Thrombosis and Hemostasis (ISTH) Secondary Adverse Effects A composite of stroke, systemic embolism, or TIA Minor bleeding events A composite of major bleeding events and thromboembolic events An adverse event = Any untoward medical occurrence A severe adverse event = An event that caused inability to work usual activities Collected from the time of signing informed consent Calkins H, et al. N Eng J Med. 2017; 376 (13):

17 Statistical Analysis Exploratory, noninferiority trial >2000 patients/group required (unfeasible) Study assumption: No difference in absolute rates of major bleeding events 290 patients/group Primary/Secondary end point analysis Based on ablation set Primary end point: Kaplan-Meier survival estimates by Cox proportional-hazards analysis Adverse events analysis Based on treated set Descriptively Calkins H, et al. N Eng J Med. 2017; 376 (13):

18 Calkins H, et al. N Eng J Med. 2017; 376 (13): Baseline Characteristics * Dabigatran (N=317) Warfarin (N=318) Age yr (SD) 59.1 (10.4) 59.3 (10.3) Male sex no. (%) 230 (72.6) 245 (77) Atrial fibrillation no. (%) Paroxysmal Persistent Long-standing persistent 213 (67.2) 86 (27.1) 18 (5.7) Mean CHA 2 DS 2 -VASc score Cardiovascular history no. (%) CHF LV dysfunction CAD PCI Previous MI Previous stroke HTN Bleeding history no. (%) Previous major bleeding or predisposition Previous GI bleeding or gastritis * Ablation set 31 (9.8) 25 (7.9) 32 (10.1) 16 (5.0) 10 (3.2) 10 (3.2) 166 (52.4) 3 (0.9) 24 (7.6) 219 (68.9) 81 (25.5) 18 (5.7) 34 (10.7) 23 (7.2) 48 (15.1) 19 (6.0) 15 (4.7) 9 (2.8) 177 (55.7) 4 (1.3) 21 (6.6)

19 Baseline Characteristic Medication use no. (%) VKA Dabigatran Rivaroxaban Apixaban Edoxaban NSAIDs PPIs Statins Beta-blockers Continued Dabigatran (N=317) 95 (28.1) 45 (13.3) 29 (8.6) 21 (6.2) 3 (0.9) 66 (19.5) 73 (21.6) 106 (31.4) 195 (57.7) Warfarin (N=318) 86 (25.4) 36 (10.7) 29 (8.6) 30 (8.9) 0 78 (23.1) 79 (23.4) 101 (29.9) 204 (60.4) Calkins H, et al. N Eng J Med. 2017; 376 (13):

20 Results Primary End Point Major bleeding during & up to 8 weeks after ablation - Dabigatran 1.6% vs Warfarin 6.9% * Absolute risk difference: - 5.3%, 95% CI (-8.4%, -2.2%); P<0.001 Calkins H, et al. N Eng J Med. 2017; 376 (13):

21 Calkins H, et al. N Eng J Med. 2017; 376 (13): Results Primary End Point Major Bleeding Events (n) Dabigatran, 150 mg BID (n=317) Warfarin (n=318) Pericardial Tamponade 1 6 Pericardial Effusion 1 0 Groin Bleed 2 2 Groin Hematoma 0 8 GI Bleed 1 2 Intracranial Bleed 0 2 Pseudoaneurysm 0 1 Hematoma 0 2 Total 5 23 * Major bleeding from the time of ablation to 7 days after ablation 4 17 * One patient had 2 ISTH major bleeding events.

22 Calkins H, et al. N Eng J Med. 2017; 376 (13): Subgroup Analyses

23 Results Secondary End Point Group Dabigatran, 150 mg BID (n=317) Warfarin (n=318) Thromboembolic Events * (TE, n) Minor Bleeding (n, %) 0 59 (18.6%) 5 (1.6%) 1 TIA 54 (17%) 23 (7.2%) Composite incidence of major bleeding and TE (n, %) * Stroke, transient ischemic attack, systemic embolism Calkins H, et al. N Eng J Med. 2017; 376 (13):

24 Results Adverse Events Event Dabigatran, 150 mg BID (N=338) Number (%) Warfarin (N=338) Number (%) Severe adverse event * 11 (3.3) 21 (6.2) Adverse event leading to treatment discontinuation 19 (5.6) 8 (2.4) Serious adverse event ** Fatal adverse event Immediately life-threatening event Event that resulted in clinically significant or persistent disability or incapacity Event that required hospitalization Event that prolonged hospitalization Other *Defined as an event that is incapacitating or causes an inability to work or perform usual activities ** Investigator-reported serious adverse event 63 (18.6) 0 1 (0.3) 0 26 (7.7) 13 (3.8) 29 (8.6) 75 (22.2) 0 2 (0.6) 1 (0.3) 34 (10.1) 22 (6.5) 27 (8.0) Calkins H, et al. N Eng J Med. 2017; 376 (13):

25 Author s Conclusion Dabigatran was associated with a significantly lower rate of major bleeding events than INRadjusted warfarin, and there were no differences in the incidence of stroke or systemic embolism in patients undergoing ablation of atrial fibrillation. Calkins H, et al. N Eng J Med. 2017; 376 (13):

26 Study Strengths Study Design Multicenter, randomized, prospective Sample size of 776 patients TTR 66%, compliance for dabigatran 98% Included patients with mean CHA 2 DS 2 -VASc score of ~ 2.0 Provided more evidence regarding procedural anticoagulation with non-vka in patients undergoing ablation of atrial fibrillation

27 Study Limitations Study Design Open-label design Excluded patients with renal impairment Prohibitive sample size for a noninferiority study Unspecified percentage of study participants in North America No baseline comparison for bleeding risk Potential financial conflict of interest

28 Conclusions RE-CIRCUIT supports the use of uninterrupted dabigatran over warfarin during catheter ablation for atrial fibrillation Less pericardial tamponade and groin hematoma in dabigatran group No differences in the incidence of stroke or systematic embolism Discontinuation of systemic anticoagulation therapy post ablation is NOT recommended in patients at high risk of stroke

29 Acknowledgements Kristen Bova Campbell, PharmD, BCPS (AQ Cardiology), CPP, AACC Daniel C Johnson, PharmD, BCPS (AQ-Cardiology) ACCP PRN Journal Club Coordinators Ted Berei, PharmD, MBA, BCPS Monique Conway, PharmD, BCPS Genevieve Hale, PharmD, BCPS Zachary Noel, PharmD, BCPS Thomas Szymanski, PharmD