ACCP Cardiology PRN Journal Club. August 30 th 2018

Transcription

1 ACCP Cardiology PRN Journal Club August 30 th 2018

2 Disclosures No actual or potential conflicts of interest related to the content of this presentation to disclose

3 Mentor Dr. Kristen Bova Campbell is a Clinical Pharmacist at Duke University Hospital. She graduated from UNC School of Pharmacy and completed her PGY1 Pharmacy Residency her PGY2 Cardiology Pharmacy Residency at UNC Hospitals. Currently, Dr. Campbell is the Electrophysiology Pharmacist at Duke. She covers the inpatient service and manages an Antiarrhythmic Medication Clinic. She is the RPD for the PGY2 Cardiology Residency.

4 Dr. Lindsay Moreland Dr. Lindsay Moreland is a PGY2 Cardiology Pharmacy Resident at the UPMC Presbyterian Hospital. She graduated from Purdue University in West Lafayette, IN and completed her PGY1 Pharmacy Residency at the UPMC Presbyterian Hospital as well. Her current practice interests include advanced heart failure therapies, heart transplantation, and academia. After residency, Dr. Moreland plans to obtain a shared position as a in-patient clinical specialist focusing on advanced heart failure/transplant and a faculty member at a college/school of pharmacy.

5 Ranolazine in High-Risk Patients with Cardioverter-Defibrillators Lindsay Moreland, PharmD PGY2 Cardiology Pharmacy Resident UPMC Presbyterian Shadyside August 30, 2018

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7 Abbreviations VT: Ventricular tachycardia VF: Ventricular fibrillation ICD: Implantable Cardiac Defibrillator CRT-D: Cardiac Resynchronization Therapy with Defibrillator ACS: Acute Coronary Syndrome ICM: Ischemic Cardiomyopathy NICM: Nonischemic Cardiomyopathy NYHA: New York Heart Association ACEi: Angiotensin converting enzyme inhibitor ARB: Angiotensin II receptor blocker EF: Ejection Fraction ATP: Anti-tachycardia pacing HF: Heart failure AAD: Antiarrythmic drug

8 Ranolazine Imbalances of Oxygen Supply and Demand FDA-Approved Indication: Angina Increased I Na Blocks late sodium inward current preventing sodium overload Increased [Na]i Calcium Overload Ranolazine Electrical Instability Ranexa (ranolazine) [package insert] Mechanical Dysfunction Abnormal Contraction & Relaxation Increase Diastolic Tension

9 Prior Trials MERLIN RIVER-PCI Efficacy and safety of ranolazine during longterm treatment of patients with non-stelevation ACS Assess adjunctive anti-ischaemic therapy with ranolazine to improve the prognosis of patients with incomplete revascularization after percutaneous coronary intervention Did not decrease cardiovascular death, MI, or ischemia VT incidence: Ranolazine 30% vs. 38% (p<0.001) Did not reduce the composite rate of ischaemia-driven revascularization or hospitalisation without revascularization Morrow DA, et al. MERLIN-TIMI 36, JAMA ;297(16): Weisz G, et al. RIVER-PCI. Lancet :

10 Bunch, et al. Twelve patients were treated with ranolazine All patients were on a class III AAD (11 amiodarone, 1 sotalol) Over a follow-up of 6 ± 6 months, 11 (92%) patients had a significant reduction in VT and no ICD shocks were observed Two patients gastrointestinal side effects limited long-term use CONCLUSION: Ranolazine proved effective in reducing VT burden and ICD shocks in patients with AAD-refractory VT Bunch TJ, et al. Pacing Clin Electrophysiol. 2011;34(12):

11 RAID Trial Objective: To determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD Design: Double-blind, placebo controlled High-risk ICD patients with ICM or NICM Ranolazine 1,000 mg BID or placebo

12 Inclusion and Exclusion Criteria Inclusion: 21 years or older Stable pharmacologic therapy for the underlying condition High-risk patient: Secondary prevention after documented VT, VF, or cardiac arrest Primary prevention with an ejection fraction 35% Exclusion: QTc prolongation (>550 ms) Concomitant use of agents that prolong the QT interval Concomitant use of CYP3A4 inhibitors Chronic renal disease with creatinine > 2.5 mg/dl

13 Endpoints Primary Endpoint VT or VF requiring ICD therapy Death Secondary Endpoints ICD shock for VT, VF, death Recurrent VT or VF requiring ICD therapy First and recurrent inappropriate shocks Hospitalizations for cardiac causes Heart failure hospitalizations Repeated cardiovascular causes

14 Methods Follow-up clinic visits every 6 months in person Dispensing medication Gather clinical information ICD interrogations for data on arrhythmias Telephone calls in-between visits every 3 months ICD treatments Primary Prevention ICD Monitoring Zone: 170-<190 beats/min without ICD therapy VT Treatment: 190-<220 beats/min with duration of 5 seconds or equivalent number of beats 1 ATP followed by 1 shock as necessary VF Treatment: 220 beats/min with shock after 2.5 seconds or equivalent number of beats Secondary Prevention ICD* VT Treatment: beats below the rate of clinical VT 1 ATP followed by 1 shock as necessary

15 Statistical Analysis Intent-to-treat 80% power with two-sided significance level of 5% to detect a HR of 0.75 Estimated patients needed: 720 patients per arm Cumulative rate of primary endpoint of 19% in ranolazine group Cox proportional hazard

16 Patient Population Placebo (n=502) Ranolazine (n=510) Age, years 64.2 ± ± 10.3 Female 86 (17) 100 (20) NYHA Class II 240 (50) 228 (48) NYHA Class III 120 (25) 131 (28) Left Ventricular EF, % 31.0 ± ± 12.0 GFR, ml/min/1.73m ± ± 23.7 ICM 289 (58) 262 (51) NICM 213 (42) 248 (49)

17 Patient Population Placebo (n=502) Ranolazine (n=510) Beta Blocker 466 (93) 471 (93) ACEi/ARB 437 (87) 426 (84) Statin 384 (76) 356 (70) Digitalis 89 (18) 81 (91) Diuretic 362 (72) 376 (74) Mineralocorticoid Antagonist 189 (38) 180 (35) Antiarrhythmic 82 (16) 86 (17) Amiodarone 52 (10) 50 (10)

18 Results Placebo (n=502) Ranolazine (n=510) HR (95% CI) Primary Endpoint VT/VF requiring ICD therapy or death Secondary Endpoints Recurrent VT/VF requiring ATP or ICD shock Inappropriate ICD Shock Recurrent inappropriate shocks Cardiovascular hospitalization or death HF Hospitalizations or death 198 (39.4) 174 (34.1) (4.0) 16 (3.1) (44.2) 237 (46.5) 140 (27.9) 144 (28.2) 0.84 ( ) p= ( ) p= ( ) p= ( ) p= ( ) p= ( ) p=0.621

19 Study Drug Administration 872 (86%) received full dose ranolazine Drug discontinued 199 (39.6%) patients in placebo arm and 253 (49.6%) patients in ranolazine arm (p=0.001) Ranolazine discontinuation highest within the first 3 months: 9.3% patients in placebo arm and 20.5% patients in ranolazine arm Placebo (n=199) Ranolazine (n=253) p Value Unknown Reason 155 (79.1) 158 (64.2) Dizziness 8 (4.0) 30 (11.9) Constipation 12 (6.0) 37 (14.6) 0.004

20 Adverse Effects Placebo (n=502) Ranolazine (n=510) p Value Dizziness 11 (2) 39 (8) <0.001 Nausea 6 (1) 30 (6) <0.001 Constipation 3 (1) 18 (4) Vomiting 2 (0) 9 (2) Other side effects noted but not statistically significant: Palpitations, abdominal pain, dry mouth, headaches, cough, fatigue, indigestion, chest pain, shortness of breath, swelling of ankle

21 Trial Critique Strengths: Double-blind, placebo controlled Intent-to-treat analysis Follow-up schedule Limitations: Under powered risk for type 2 error Early termination of the study High number of patients discontinued study drugs

22 Clinical implications Ranolazine likely does not reduce VT, VF, or death Ranolazine may reduce recurrent VT or VF requiring ICD therapy without effect on mortality Ranolazine may be difficult for patients to tolerate Ranolazine currently has limited to no use to reduce VT, VF, or death in those with ICD therapy

23 References: 1. Ranexa (ranolazine) [package insert]. Foster City, CA: Gilead Sciences Inc; December Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-st-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA Apr 25;297(16): Weisz G, Genereux P, Iniguez A, et al. Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (RIVER-PCI): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;387: Bunch TJ, Mahapatra S, Murdock D, et al. Ranolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug-refractory ICD shocks. Pacing Clin Electrophysiol Dec;34(12):

24 Questions

25 Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial Julianne Fallon, PharmD PGY2 Cardiology Pharmacy Resident University of Virginia Health System August 30, 2018

26 Disclosures No actual or potential conflicts of interest related to the content of this presentation to disclose

27 Dr. Julianne Fallon Dr. Julianne Fallon is a PGY2 Cardiology Pharmacy Resident at the University of Virginia Health System. She graduated from Virginia Commonwealth University in Richmond, VA and completed her PGY1 Pharmacy Residency at the University of Virginia Health System. Her current practice interests include antithrombotic therapy, cardiac intensive care, acute decompensated heart failure, and precepting students. After residency, Dr. Fallon plans to pursue a position as a clinical pharmacy specialist on a heart failure or cardiac intensive care service.

28 Background Atrial fibrillation is one of the most frequently encountered cardiac arrhythmias Occurs in approximately 1% of the general population Major cause of stroke, heart failure, sudden death, and cardiovascular morbidity Cardioversion carries an inherent risk of stroke that is reduced with the use of anticoagulation ESC and ACC/AHA/ERS AF guidelines recommend: Start anticoagulation as soon as possible prior to cardioversion AF duration < 48 h: No imaging required prior to cardioversion AF duration > 48 h or unknown duration: At least 3 weeks of anticoagulation prior to cardioversion OR Imaging to rule out cardiac thrombus Continue anticoagulation for at least 4 weeks after cardioversion AF - Atrial fibrillation ESC Guidelines for the management of AF. Eur Heart J : AHA/ACC/HRS Guideline for the management of patients with AF. JACC. 2014: 63(21):

29 Prospective and Retrospective Data XTRA CLOT AF Rivaroxaban 20 mg (or 15 mg if CrCl ml/min) for 6 weeks Included primarily Eastern European (95%) patients with long-standing or persistent AF (76.6%) and average CHA2DS2-VASc of 4 Treatment for LA/LAA thrombus for 6 weeks resulted in a complete thrombus resolution rate of 41.5% (95% CI ) VKA +/- LMWH or UFH for 3-12 weeks Included Eastern and Western European patients with persistent or long-standing AF (56.4%) and average CHA2DS2-VASc of 3 Treatment for LA/LAA thrombus for 3-12 weeks resulted in a complete thrombus resolution rate of 62.5% (95% CI ) CRNM Clinically relevant non-major CV - Cardiovascular LA Left atrial LMWH Low molecular weight heparin LAA Left atrial appendage MI Myocardial infarction SEE Systemic embolic event UFH Unfractionated heparin VKA Vitamin K antagonist Lip G, et al. Am Heart J. 2016; 178:

30 Prospective Data X-VeRT Rivaroxaban 20 mg or 15 mg (if CrCl ml/min) vs. VKA (goal INR 2-3) for early (1-5 days) or delayed (3-8 weeks) cardioversion The cumulative risk of the composite endpoint of stroke, TIA, peripheral embolism, MI, and CV death was similar 0.51% vs. 1.02% (RR 0.5; 95% CI ) Major bleeding rates were similar (0.61% vs. 0.8%; RR 0.76; 95% CI ) Rivaroxaban was associated with a shorter time to delayed cardioversion (P<0.001) ENSURE-AF Edoxaban 60 mg or 30 mg (CrCl ml/min, <60 kg, or P-gp inhibitor use) vs. enoxaparin/warfarin The composite endpoint of SEE, MI, and CV death was similar (0.5% vs. 1% OR % CI ) The composite of major and CRNM bleeding events at 30 days were similar (1.5% vs. 1% OR 1.48, 95% CI ) CRNM Clinically relevant non-major CV - Cardiovascular LA Left atrial MI Myocardial infarction SEE Systemic embolic event TIA Transient ischemic attack VKA Vitamin K antagonist Cappato R, et al. Eur Heart J. 2014; 35: Goette A, et al. Lancet. 2016; 388:

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32 Objectives Assess the safety and efficacy of < 48 h of anticoagulation with either apixaban or a conventional heparin/vka regimen in patients with AF undergoing cardioversion Assess the safety of a loading dose of apixaban Assess the utility of image guidance to expedite cardioversion AF - Atrial fibrillation Ezekowitz M, et al. Eur Heart J : 1-13

33 Methods Multinational, randomized, active-controlled, open-label study in patients with recently diagnosed AF 134 centers in 12 countries Conducted between July 14, 2014 to February 8, 2017 Duration of follow up: Cardioverted patients: 30 ± 7 days Not cardioverted: 90 ± 7 days Trial Design Efficacy Endpoints Stroke Systemic embolism (SE) All-cause death Safety Endpoints Major bleeding Clinically relevant non-major (CRNM) bleeding AF - Atrial fibrillation Ezekowitz M, et al. Eur Heart J : 1-13

34 Intervention Randomized 1:1 to apixaban or Heparin/VKA Imaging Timing and type of cardioversion Anticoagulation in relation to cardioversion Apixaban Standard dose: 5 mg or 2.5 mg BID* LD: 10 mg or 5 mg* Performed at the discretion of the investigator Determined by local investigators Apixaban After 5 doses or 2 hours after LD Heparin/VKA Goal INR: 2-3 Heparin continued until INR > 2 If LA thrombus: cardioversion delayed until repeat imaging after 3 weeks Could be performed up to 90 days after randomization Heparin/VKA 2 hours after start of heparin BID - Twice daily INR - International normalized ratio LA - Left atrial LD - Loading dose VKA - Vitamin K antagonist *2.5 mg or 5 mg chosen if at least 2 of the following criteria were met: Age > 80 Weight < 60 kg SCr > 1.5 mg/dl Ezekowitz M, et al. Eur Heart J : 1-13

35 Methods Power Calculation Adequate power to assess for non-inferiority required 480 end points Due to follow up times and an estimated event rate of 1%, a total of 48,000 patients would need to be enrolled to test for non-inferiority Sample size Goal enrollment of 1,500 patients Analysis Efficacy endpoints studied in all randomized patients using an intention to treat analysis Safety endpoints studied in all patients who received at least 1 dose of study drug Efficacy and safety endpoint event rates were described using descriptive statistics Time to event displayed using Kaplan-Meier curves Time to cardioversion based on use of image guidance or use of apixaban loading dose in each treatment group was analyzed using a t-test AF - Atrial fibrillation Ezekowitz M, et al. Eur Heart J : 1-13

36 Baseline Characteristics Heparin/VKA (n=747) Apixaban (n=753) Age (years), mean ± SD 64.5 ± ± 12.2 Male gender 497 (66.5) 505 (67.1) Race* White Black Asian Other Hypertension* Yes No LVEF <40%* Yes No Diabetes* Yes No Values presented as n (%) unless otherwise specified * Remainder was not reported 648 (86.7) 20 (2.7) 76 (10.2) 3 (0.4) 481 (64.4) 263 (35.2) 54 (7.2) 690 (92.4) 140 (18.7) 604 (80.9) 654 (86.9) 21 (2.8) 78 (10.4) (65.9) 256 (34) 45 (6) 703 (93.4) 154 (20.5) 598 (79.4) LVEF Left ventricle ejection fraction SD Standard deviation Ezekowitz M, et al. Eur Heart J : 1-13

37 Baseline Characteristics First documentation of AF, n (%) New onset <3 months > 3 months Heparin/VKA (n=747) 504 (67.5) 82 (11) 157 (21) Apixaban (n=753) 505 (67.1) 81 (10.8) 165 (21.9) Heart rate (beats/min), mean ± SD 99.2 ± ± 25.4 CHA 2 DS 2 -VASc score, mean ± SD 2.4 ± ± 1.7 Antithrombotic treatment <48 h, n (%) Yes None AF - Atrial fibrillation SD Standard deviation 289 (38.7) 458 (61.3) 287 (38.1) 466 (61.9) Ezekowitz M, et al. Eur Heart J : 1-13

38 Ezekowitz M, et al. Eur Heart J : 1-13

39 Efficacy and Safety Outcomes Efficacy Heparin/VKA (n=747) Apixaban (n=753) Events Events RR (95% CI) P-value Stroke* 6 (0.8) 0 0 (0-0.64) SE All-cause death 1 (0.13)^ 2 (0.27)^^ 1.98 ( ) > Safety Heparin/VKA (n=721) Apixaban (n=735) Events Events RR (95% CI) P-value Major bleeding 6 (0.83) 3 (0.41) 0.49 ( ) CRNM bleeding 13 (1.8) 11 (1.5) 0.83 ( ) CI Confidence interval All events reported as n (%) CRNM Clinically relevant non-major bleeding RR Relative risk SE Systemic embolism * Ischemic: 5; Hemorrhagic: 1 ^ 1) Sudden death ^^1) Acute alcoholic hepatitis 2) Perforated colonic diverticulitis Ezekowitz M, et al. Eur Heart J : 1-13

40 Loading Dose and Imaging Outcomes Outcomes in patients receiving an apixaban LD Dose, 10 mg 5 mg LD (n=342) 331 (96.8) 11 (3.2) Stroke or SE 0 All-cause death 1 (0.3) Major bleeding 1 (0.3) CRNM bleeding 4 (1.2) All results reported as n (%) CRNM Clinically relevant non-major bleeding CT Computed tomography LA Left atrial LD Loading dose SE Systemic embolism TOE Tranesophageal echocardiogram Results of imaging and outcomes Imaging type: TOE CT Both Not specified Heparin/VKA (n=747) Apixaban (n=753) Underwent imaging (No LD) 250 (LD) Left atrial thrombus 31 (6.9) 30 (7.2) Repeat imaging 18 (58) 23 (77) Resolution of thrombus on repeat imaging Efficacy and safety events in patients with LA thrombus All results reported as n (%) 10 (56) 12 (52) 0 0 Ezekowitz M, et al. Eur Heart J : 1-13

41 Time From First Dose to Active Cardioversion Imaging Apixaban (LD) Apixaban (nold) Heparin/VKA No imaging Overall Imaging No imaging Overall Imaging No imaging n Mean, d Median, d Difference No difference in time to cardioversion with imaging (P=0.6214) Reduced time to cardioversion with imaging (P<0.0001) Reduced time to cardioversion with apixaban loading dose (P<0.0001) Overall Reduced time to cardioversion with imaging (P<0.0001) LD Loading dose VKA - Vitamin K antagonist Ezekowitz M, et al. Eur Heart J : 1-13

42 Author Conclusions Patients with predominantly new onset AF undergoing elective cardioversion receiving apixaban or heparin/vka experience low rates of: Stroke Systemic embolic events Death Bleeding events Justifies the use of apixaban in this patient population A loading dose of apixaban followed by imaging prior to cardioversion was associated with few outcome events Adds data to the use of non-vka in the setting of image-identified left atrial thrombus AF Atrial fibrillation VKA - Vitamin K antagonist Ezekowitz M, et al. Eur Heart J : 1-13

43 Strengths Trial Critique Weaknesses Study designed to reflect routine clinical practice Enrolled a large percentage of patients with new AF Similar event rates as other prospective trials of DOACs used for cardioversion Data on clinically relevant nonmajor bleeding Descriptive study with low event rates making it challenging to assess if results were due to chance Follow-up limited to 30 or 90 days Limited generalizability due to predominantly white patient population with a low prevalence of comorbidities AF Atrial fibrillation DOAC Direct oral anticoagulant

44 Impact on Clinical Practice Adds to the existing evidence for DOACs in cardioversion, particularly early cardioversion Validates the use of apixaban for cardioversion in new or early onset AF Supports the use of an apixaban loading dose to further reduce the time to cardioversion Confirms that imaging reduces the time to cardioversion AF Atrial fibrillation DOAC Direct oral anticoagulant

45 Questions