ACCP Cardiology PRN Journal Club - PowerPoint Presentation

ACCP Cardiology PRN Journal Club 27 September 2019

Presenter Bio Dr. Maxwell Ditlevson is a PGY2 Cardiology Resident at the The Johns Hopkins Hospital. He completed his PGY1 Pharmacy Practice Residency at The Johns Hopkins Hospital too. Max received his PharmD from the University of Maryland School of Pharmacy.

Mentor Bio Dr. Farzad Daneshvar received his doctor of pharmacy degree from the University of Michigan in 2013. Post graduation, he completed a clinical residency training at Henry Ford Hospital in Detroit, followed by a specialty residency training with a focus on cardiovascular pharmacotherapy at Sharp Healthcare in San Diego, CA. Upon completion of his residency training, he practiced as a cardiology professor and a cardiology clinical pharmacist in Los Angeles, CA. He then moved back to MI to pursue a position as a cardiology clinical pharmacist specialist at Beaumont Dearborn. He currently rounds with an academic Cardiology Teaching Team in a Coronary Care Unit and has additional involvement is the Cardiac Cath Lab and Cardiothoracic Surgery. He was recently promoted as a non-physician faculty member for the Cardiology Fellowship Program at Beaumont Dearborn. He is a member of the Michigan Chapter and National American College of Cardiology (ACC) and has presented at both state-wide and national conferences.

Digoxin Discontinuation and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction Maxwell Ditlevson, PharmD PGY2 Cardiology Pharmacy Resident The Johns Hopkins Hospital, Baltimore, MD

Disclosures Maxwell Ditlevson and all other contributors have no relevant financial relationships to disclose

Background Cardiac glycoside isolated from the Digitalis (foxglove) genus Indications: Heart failure with reduced ejection fraction ( HFrEF ) Rate control in atrial fibrillation

Background PROVED (1993) RADIANCE (1993) Study Design Multicenter, randomized, placebo-controlled trial Population n = 88 NYHA II or III LVEF ≤35% Digoxin + diuretic for ≥1 month n = 178 NYHA II or IIILVEF ≤35%Digoxin + diuretic + ACEi for ≥3 monthsResults(Associated with Digoxin Discontinuation)Worsened maximal exercise performanceHigher rate of treatment failureShorter time to treatment failureWorsened maximal exercise performanceHigher rate of treatment failureShorter time to treatment failureWorsened NYHA class, quality of lifeLimitationsPatients not on contemporary GDMT (including beta-blockers, mineralocorticoid receptor antagonists (MRAs)) J Am Coll Cardiol . 1993;22:955-62 . New Engl J Med . 1993;329:1-7.

Background DIG trial (1997) Study Design Multicenter, double-blind, placebo-controlled RCT Population N = 6800 patients with chronic, NYHA class II or III HF, LVEF ≤45%, on diuretic + ACE inhibitor Study InterventionPatients randomized (1:1) to receive digoxin or placebo in addition to diuretic + ACE inhibitorResultsNo difference in all-cause mortality (34.8% vs. 34.1%; p=0.80)Lower incidence of HF hospitalizations (26.8% vs. 34.7%; p<0.001)ConclusionWhen added to diuretic and ACEi therapy in patients with HFrEF, digoxin reduces hospitalizations, but has no survival benefitNew Engl J Med. 1997;336:525-33.

Background 2013 ACCF/AHA HF Guidelines : “Digoxin can be beneficial in patients with HFrEF , unless contraindicated, to decrease hospitalizations for HF ” (Class IIa , LOE B) J Am Coll Cardiol. 2013;62:147-239.

Background 2015 Systematic Review of Digoxin-Associated Mortality ( Vamos et al.): 9 studies, 91,379 patients with HF Higher risk of all-cause mortality associated with patients on digoxin therapy: HR: 1.14, 95% CI: 1.06-1.22, P<0.01 Eur Heart J. 2015;36:1831-8. Study Cohort HR 95% CI p-Value

Objective To evaluate the relationship between discontinuation of pre-admission digoxin therapy and outcomes in a cohort of hospitalized patients with HFrEF receiving contemporary GDMT J Am Coll Cardiol . 2019;74:617-27.

Study Population OPTIMIZE-HF registry (2003-2004) linked with Medicare data HF with LVEF ≤45 % Receiving digoxin prior to admission Propensity score matching

Outcomes Examined at 30 days, 6 months, 1 year, and 4 years: Heart failure readmissions All-cause readmissions All-cause mortality Composite of HF readmissions or all-cause mortality J Am Coll Cardiol . 2019;74:617-27.

Statistical Analysis Propensity score matching Sensitivity cohort to account for AKI Sensitivity analysis to account for unmeasured confounders J Am Coll Cardiol . 2019;74:617-27.

Baseline Characteristics Before Propensity Matching After Propensity Matching Characteristic Digoxin Continued Digoxin Discontinued p Value Digoxin Continued Digoxin Discontinued p Value Age, yrs 75 +/- 11 76 +/- 11 0.047 76 +/- 11 76 +/- 11 0.827 Women, no. (%) 1086 (39) 290 (40) 0.58 287 (41) 279 (40) 0.663 LVEF, % 26 +/- 9 28 +/- 10 <0.001 28 +/- 9 28 +/- 10 0.973 Discharge medications, no. (%) ACEis or ARBs Beta-blockers Aldosterone antagonists Loop diuretic agentsNitrates2001 (72)2027 (73)559 (20)2354 (85)795 (29)436 (60)450 (62)106 (15)513 (71)170 (24)<0.001<0.0010.001<0.0010.007449 (64)457 (65)105 (15)507 (73)157 (22)429 (61)444 (64)106 (15)510 (73)170 (24)0.2680.4670.940.8570.411 J Am Coll Cardiol. 2019;74:617-27.

Outcomes at 30 days Outcomes Events by Digoxin Discontinuation at Discharge, n (%) HR Associated with Digoxin Discontinuation, (95% CI); p-value No Yes 30-day outcomes HF readmission All-cause readmission All-cause mortality HF readmission or all-cause mortality89 (13)195 (28)47 (7)131 (19)101 (14)193 (28)82 (12) 171 (24) 1.19 (0.90-1.59); 0.226 1.03 (0.84-1.26); 0.778 1.80 (1.26-2.57); 0.001 1.36 (1.09-1.71); 0.007 J Am Coll Cardiol . 2019;74:617-27.

Outcomes at 6 months, 1 year Outcomes Events by Digoxin Discontinuation at Discharge, n (%) HR Associated with Digoxin Discontinuation, (95% CI); p-value No Yes 6-month outcomes HF readmission All-cause readmission All-cause mortality HF readmission or all-cause mortality205 (29)377 (54)181 (26)321 (46)246 (35) 409 (59) 215 (31) 377 (54) 1.31 (1.08-1.57); 0.005 1.18 (1.03-1.36); 0.019 1.25 (1.02-1.52); 0.028 1.28 (1.10-1.48); 0.001 1-year outcomes HF readmission All-cause readmission All-cause mortality HF readmission or all-cause mortality 276 (40) 472 (68) 251 (36) 415 (59) 317 (45) 483 (69) 287 (41) 475 (68) 1.28 (1.09-1.51); 0.003 1.15 (1.02-1.31); 0.028 1.21 (1.02-1.43); 0.028 1.27 (1.11-1.45); <0.001 J Am Coll Cardiol. 2019;74:617-27.

Outcomes at 4 years All-cause readmissions: 1.16 (1.04-1.31); p = 0.01 All-cause mortality: 1.09 (0.97-1.24); p = 0.163 HF readmission or all-cause mortality: 1.20 (1.07-1.34); p = 0.002 J Am Coll Cardiol . 2019;74:617-27.

Combined Endpoint at 4 years Beta-Blocker at Discharge? Pre-admission Digoxin Discontinued? Combined Endpoint HR (95% CI) P Value No Yes Effect Interaction Yes No 397/457 (87%) 210/241 (87%) 393/444 (89%) 231/254 (91%) 1.11 (0.96-1.27) 1.38 (1.14-1.66) 0.161 0.001 0.044 J Am Coll Cardiol . 2019;74:617-27.

Findings from Sensitivity Cohort at 4 years Outcomes Events by Digoxin Discontinuation at Discharge, n (%) HR Associated with Digoxin Discontinuation, (95% CI); p-value No Yes 4 - year outcomes HF readmission All-cause readmission All-cause mortalityHF readmission or all-cause mortality336 (56)517 (86)438 (73)530 (88)355 (59)505 (84)449 (75) 543 (90) 1.26 (1.08-1.46); 0.003 1.15 (1.02-1.30); 0.026 1.12 (0.98-1.28); 0.098 1.22 (1.08-1.38); 0.001

Findings from Sensitivity Analysis 4-year associations of digoxin discontinuation with all-cause readmissions and the combined endpoint were insensitive to unmeasured confounders All-cause readmissions: Single unmeasured baseline characteristic would need to increase the odds of digoxin discontinuation by 3% to explain away this association HF readmissions or all-cause mortality: Single unmeasured baseline characteristic would need to increase the odds of digoxin discontinuation by 7% to explain away this association

Authors’ Conclusions Among hospitalized older patients with HFrEF receiving contemporary GDMT, discontinuation of pre-admission digoxin therapy was associated with poor outcomes It may be premature to abandon the use of digoxin in patients with HFrEF J Am Coll Cardiol . 2019;74:617-27.

Study Critique Limited generalizability “Contemporary” GDMT Lack of follow-up data Propensity score matching J Am Coll Cardiol . 2019;74:617-27.

Study Critique Limited generalizability “Contemporary” GDMT Lack of follow-up data Propensity score matching J Am Coll Cardiol . 2019;74:617-27.

Study Critique Limited generalizability “Contemporary” GDMT Lack of follow-up data Propensity score matching J Am Coll Cardiol . 2019;74:617-27.

Study Critique Limited generalizability “Contemporary” GDMT Lack of follow-up data Propensity score matching J Am Coll Cardiol . 2019;74:617-27.

Impact on Clinical Practice Discourages the routine discontinuation of pre-admission digoxin therapy in hospitalized older patients with HFrEF No impact on digoxin’s place in HFrEF therapy No impact regarding initiation of digoxin therapy J Am Coll Cardiol . 2019;74:617-27.

Digoxin Discontinuation and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction Maxwell Ditlevson, PharmD PGY2 Cardiology Pharmacy Resident The Johns Hopkins Hospital, Baltimore, MD

Presenter Bio Dr. Sara Ward is a PGY2 Cardiology Resident at the University of Kentucky. She completed her PGY1 Pharmacy Practice Residency at the Medical University of South Carolina. Sara received her PharmD from the University of Kentucky College of Pharmacy.

Presenter Bio Dr. Erica Sheridan is a PGY2 Cardiology Resident at the University of Kentucky. She completed her PGY1 Pharmacy Practice Residency at University of Pittsburgh Medical Center. Erica received her PharmD from the University of Toledo College of Pharmacy and Pharmaceutical Sciences.

Mentor Bio Dr. Craig Beavers is currently the Director of Cardiovascular Services at Baptist Health System in Paducah, Kentucky. He completed his PharmD , PGY1 Pharmacy Practice residency, and PGY2 Cardiology residency at the University of Kentucky.

Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes ISAR - REACT 5 Sara M. Ward, PharmD Erica A. Sheridan, PharmD , MBA PGY2 Cardiology Pharmacy ResidentsUniversity of Kentucky HealthCare

Disclosure We have no actual or potential conflicts of interest to disclose.

Background Dual-antiplatelet therapy is standard treatment for patients with acute coronary syndromes (ACS) Ticagrelor and prasugrel have a faster onset of action with more potent and consistent anti-platelet effects than clopidogrel Am Heart J 2007;153(1):66.e9-66 Circulation 2009;120:2577-2585

Previous Literature TRITON-TIMI (2007) Prasugrel vs. Clopidogrel Significant reduction in primary endpoint, driven by reduction in nonfatal MI Significant increase in the risk of major bleeding No significant difference in overall mortality PLATO (2009) Ticagrelor vs. Clopidogrel Significant reduction in MACE (not observed in N. American subgroup)Significant reduction in all-cause mortality No significant increase in major bleeding NEJM 2007;357:2001-2015NEJM 2009;361:1045-1057

Recap Schupke S, et al. NEJM 2019; Sept 1.

Antiplatelet Dosing Strategies NSTE - ACS STEMI PCI Coronary angiography Coronary angiography PCI Ticagrelor 180 mg ORPrasugrel 60 mg Ticagrelor 180 mg NSTE - ACS PCI Coronary angiography Prasugrel 60 mg STEMI: ST-segment elevation myocardial infarction, NSTE ACS: non-ST segment elevation acute coronary syndromes; PCI: percutaneous intervention

Methods Objective : Compare the efficacy and safety of two anti-platelet dosing strategies in patients with acute coronary syndromes Design: Investigator-initiated, phase 4, multicenter, randomized, open-label trial Schupke S, et al. NEJM 2019; Sept 1.

Study Population Inclusion Criteria Exclusion Criteria Adults > 18 y/o Hospitalization for: STEMI NSTEMI Unstable angina Planned invasive evaluation (i.e . coronary angiography)History of stroke or TIAHistory of ICHINR > 1.5 Dialysis OAC Known intolerance to study drugsPlatelets < 100,000/μLUse of fibrinolytics Moderate or severe hepatic dysfunctionConcomitant use of CYP3A inhibitorsy/o: years old; STEMI: ST-segment elevation myocardial infarction, NSTEMI: non-ST segment elevation myocardial infarction; TIA: transient ischemic attack; ICH: intracranial hemorrhage; INR: international normalized ratio; OAC: oral anticoagulantSchupke S, et al. NEJM 2019; Sept 1.

Randomization ACS: acute coronary syndrome; STEMI: ST-segment elevation myocardial infarction, NSTEMI: non-ST segment elevation myocardial infarction, LD: loading dose Hospitalization for ACS with planned invasive evaluation Ticagrelor or Prasugrel Ticagrelor STEMI or NSTE ACS Loading dose→ 180 mg X 1 Maintenance→ 90 mg BID Prasugrel STEMI or NSTE ACS*Loading dose→ 60 mg X 1 Maintenance→ 10 mg daily+*LD after coronary angiography if PCI+ 5 mg daily in patients > 75 y/o or < 60 kgSchupke S, et al. NEJM 2019; Sept 1.

Trial Endpoints Primary Outcome Composite of death, MI, or stroke at 1 year Secondary Outcomes Bleeding incidence at 1 year (BARC criteria) Individual components from primary endpoint Incidence of definite or probable stent thrombosis at 1 year MI: myocardial infarction; BARC: Bleeding Academic Research Consortium Schupke S, et al. NEJM 2019; Sept 1.

Statistical Analysis 1,895 patients in each group to achieve 80% power with significance defined < 0.05 Statistical analyses: Student’s t-test N on-parametric Wilcoxon rank-sum test Cox proportional hazard models Pre-specified subgroup analyses Primary endpoint→ intention-to-treat Safety endpoint→ modified intention-to-treat Schupke S, et al. NEJM 2019; Sept 1.

Characteristic Ticagrelor (N=2012) Prasugrel (N=2006) CV Risk Factors Diabetes 23.0% 21.4% Smoker 34.1% 33.4% Hypertension 71.3% 69.1%Hypercholesterolemia58.7%58.1%Diagnosis at AdmissionUnstable angina249 (12.4)261 (13.0)NSTEMI930 (46.2)925 (46.1) STEMI 833 (41.4) 820 (40.9) Treatment Strategy PCI 83.4% 84.8% CABG 2.3% 1.8% Medical management 14.2% 13.4% Schupke S, et al. NEJM 2019; Sept 1.

Population in Comparison with Previous T rials Schupke S, et al. NEJM 2019; Sept 1. TRITON , 2007 PLATO, 2009 ISAR React 5, 2019 PCI 99% 65% 84%Medical management0%25%14%CABG1%10%2%

Results Ticagrelor Prasugrel P Value Time to Load, median 6 min 61 min Receiving medication at discharge 81.1% 80.7% Discontinuation of drug at 1 yr follow-up15.2%12.5%P= 0.03Time to drug discontinuation, median84 days109 daysP= 0.01Schupke S, et al. NEJM 2019; Sept 1.

Clinical Efficacy Endpoints Schupke S, et al. NEJM 2019; Sept 1. Ticagrelor (N=2012) Prasugrel (N=2006) Hazard Ratio P Value Death, myocardial infarction, or stroke no. (%) 184 (9.3) 137 (6.9) 1.36 (1.09-1.70)0.006NNT =42Death no. (%)From any causeFrom CV causeFrom non CV cause90 (4.5)63 (3.2)27 (1.4)73 (3.7)59 (3.0)14 (0.7)1.23 (0.91-1.63)MI no. (%)96 (4.8)60 (3.0)1.63 (1.18-2.25)Stroke, any no. (%)22 (1.1)19 (1.0)1.17 (0.63-2.15)

Secondary Safety Endpoints Ticagrelor (N=2012) Prasugrel (N=2006) Hazard Ratio P Value BARC type 3,4, or 5 bleeding No. /total no. (%) 95/ 1989 (5.4) 80/1773 (4.8) 1.12 (0.83-1.51)0.46Schupke S, et al. NEJM 2019; Sept 1.

Subgroup Analyses Ticagrelor (N=2012) Prasugrel (N=2006) Hazard Ratio Age > 75 y/o < 75 y/o 74/490 (15.3) 110/1522 (7.3)66/492 (13.7)71/1514 (4.8)1.19 (0.85-1.66)1.55 (1.15-2.09)Weight < 60 kg > 60 kg 13/108 (12.2)171/1895 (10.2)10/94 (10.7)124/1894 (6.4)1.18 (0.52-2.71)1.40 (1.11-1.71)Clinical Presentation STEMI NSTEMI Unstable Angina83/833 (10.1)81/930 (8.8)20/249 (8.2)64/820 (7.9)60/925 (6.6)13/261 (5.1)1.31 (0.94-1.81)1.36 (0.97-1.90)1.62 (0.81-3.26)Treatment Strategy PCI Conservative CABG 162/1676 (9.8)17/285 (6.1)5/47 (10.6)120/1701 (7.1)12/268 (4.6)5/36 (13.9)1.41 (1.11-1.78)1.29 (0.62-2.70)0.66 (0.19-2.30) Schupke S, et al. NEJM 2019; Sept 1.

Author’s Conclusion Rate of death, myocardial infarction, or stroke is significantly lower in patients with ACS taking prasugrel as compared to ticagrelor There is no difference in major bleeding in patients with ACS taking prasugrel as compared to ticagrelor Schupke S, et al. NEJM 2019; Sept 1.

Strengths and Limitations Schupke S, et al. NEJM 2019; Sept 1.

Considerations

Recommendations

Thank you! Craig Beavers, PharmD , FACC, FAHA, BCCP, BCPS-AQ Cardiology, CACP Josh Jacobs, PharmD Jessie Dunne, PharmD, BCPS Ashley Schenk, PharmD, BCCP, BCPS Ayesha Ather, PharmD, BCCP, BCPS

Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes ISAR - REACT 5 Sara M. Ward, PharmD Erica A. Sheridan, PharmD , MBA PGY2 Cardiology Pharmacy ResidentsUniversity of Kentucky HealthCare