July ACCP Cardiology PRN Journal Club 7/23/ PDF Free Download

July ACCP Cardiology PRN Journal Club 7/23/2018

Dr. Michael Plazak Dr. Michael Plazak is a PGY2 Cardiology Pharmacy Resident at the University of Maryland School of Pharmacy. He graduated from the University of North Carolina Eshelman School of Pharmacy and completed his PGY1 Pharmacy Residency at the University of Maryland Medical Center. His current practice interests include advanced heart failure, cardiac intensive care, mechanical circulatory support, and heart transplantation. After residency, Dr. Plazak plans to pursue a position as a clinical pharmacy specialist on either an advanced heart failure or cardiac surgery intensive care service.

Dr. Mallory Mouradjian Dr. Mallory Mouradjian is a PGY2 Cardiology Pharmacy Resident at the University of Maryland Medical Center. She graduated from MCPHS University in Boston, MA and completed her PGY1 Pharmacy Residency at the University of Maryland Medical Center as well. Her current practice interests include acute decompensated heart failure, heart transplantation, and precepting students. After residency, Dr. Mouradjian plans to obtain a position as a in-patient clinical specialist at an academic medical center working with patients with heart failure or heart transplants.

Dr. Rhonda Cooper-DeHoff Rhonda M. Cooper-DeHoff, Pharm.D., M.S., FCCP, FACC, FAHA, is an associate professor, Department of Pharmacotherapy and Translational Research; and associate director, Center for Pharmacogenomics, University of Florida, Gainesville, Florida. She received her Pharm.D. from the University of California, San Francisco, and completed a clinical residency at UCSF as well. Dr. Cooper-DeHoff has made many important contributions to the literature in the area of pharmacogenomics as well as hypertension and cardiovascular disease.

CYP2C19 Genotype-Guided Antiplatelet Therapy and Clinical Outcomes Data ACCP Journal Club July 23 rd, 2018 Presented by: Michael E. Plazak, PharmD PGY-2 Cardiology Pharmacy Resident, University of Maryland School of Pharmacy Mallory T. Mouradjian, PharmD PGY-2 Cardiology Pharmacy Resident, University of Maryland School of Pharmacy Mentor: Rhonda M. Cooper-DeHoff, PharmD, MS, FAHA, FACC, FCCP Associate Professor, University of Florida

Dr. Michael E. Plazak Disclosures No actual or potential conflicts of interest related to the content of this presentation to disclose Dr. Mallory T. Mouradjian No actual or potential conflicts of interest related to the content of this presentation to disclose Dr. Rhonda M. Cooper-DeHoff Discloses authorship on Cavallari, et al. JACC journal article and funding from the NIH Implementing Genomics in Practice (IGNITE) Research Network

Background STE and NSTE-ACS DAPT (ASA + P2Y 12 inhibitor) is standard of care Prasugrel and ticagrelor are more effective than clopidogrel However, associated with a greater risk of bleeding ACC/AHA provide weak recommendations (IIa, LOE B-R) to use prasugrel and ticagrelor first-line Clopidogrel is still used in 60-70% of patients Clopidogrel has variable response due to genetic polymorphisms CYP2C19 and ABCB1 STE-ACS or NSTE-ACS ST-Segment Elevation or Non-ST-Segment Elevation Acute Coronary Syndrome DAPT Dual Antiplatelet Therapy Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57. Yusuf S et al. N Engl J Med. 2001 Aug 16;345(7):494-502. Wiviott SD et al. N Engl J Med. 2007 Nov 15;357(20):2001-15. Fan W et al. Am J Cardiol. 2016;117:1439-43. Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-323. Mega JL, et al. Lancet. 2010;376(9749):1312-19. Levine GN et al. J Am Coll Cardiol. 2016;68:1082-11.

CYP2C19 Clopidogrel - pro-drug that requires two step activation CYP2C19 modulates metabolism of clopidogrel Genetic polymorphisms are common Wild-type/normal function allele *1 Decreased or no function alleles *2, *3, *4 - *8 Increased function allele *17 Su J, et al. PLoS One. 2012; 7(10): e46366. Accessed from: https://www.pharmgkb.org/pathway/pa154424674. Accessed on July 16, 2018.

Dosing Recommendations based on Metabolizer Status CYP2C19 Phenotype (Prevalence) Genotype Example Clopidogrel Effect CPIC Recommendation Ultra-rapid (~2-5%) Rapid (~2-30%) Normal (~30-50%) Intermediate (~18-45%) Poor (~1-15%) *17/*17 Greatest platelet inhibition *1/*17 *1/*1 *1/*2 *1/*3 *2/*17 *2/*2 *2/*3 *3/*3 Lowest platelet inhibition Use clopidogrel at labelrecommended dose (strong) Use alternative P2Y 12 inhibitor if no contraindication (prasugrel or ticagrelor) (IM moderate; PM strong) IM Intermediate metabolizer PM Poor metabolizer CPIC Clinical Pharmacogenetics Implementation Consortium Mega JL, et al. Lancet. 2010;376(9749):1312-19. Dean L. Medical Genetics Summaries [Internet}2018 Apr.18. Accessed 2018 Jul 12.

ABCB1 Encodes efflux transporter P-glycoprotein Mediates absorption of clopidogrel Single-nucleotide polymorphism: 3435 C = wildtype; T = mutant Meta-analysis showed increased odds of MACE in patients with ABCB1 polymorphism TT vs. CC OR 1.77 (95% CI, 1.19 to 2.63; p = 0.005) CC Homozygous wild-type TT Homozygous mutant MACE - Major Adverse Cardiovascular Event Su J, et al. PLoS One. 2012; 7(10): e46366. Accessed from: https://www.pharmgkb.org/pathway/pa154424674. Accessed on July 16, 2018.

Retrospective and Subgroup Data Mega et al. 2009 Mega et al. 2010 Wallentin et al. 2010 Sorich et al. 2014 Carriers from TRITON TIMI-38 cohort had a higher risk cardiovascular death, MI, or stroke (HR 1.53; 95% CI 1.07-2.19; p=0.01) and stent thrombosis (HR 3.09; 95% CI 1.19-8.00; p=0.02) Carriers of one reducedfunction CYP2C19 allele had an increased risk of cardiovascular death, MI, or stroke (HR 1.55; 95% CI 1.11-2.17; p=0.01) and stent thrombosis (HR 2.67; 95% CI 1.69-4.22; p<0.001). Cardiovascular death, MI, or stroke occurred less often with ticagrelor in those patients with any CYP2C19 LOF allele (HR 0.77; 95% CI 0.60-0.99; p=0.038) and high expression of ABCB1 (HR 0.71; 95% CI 0.55-0.92) Carriage of at least one CYP2C19 LOF allele while on clopidogrel was associated with a higher risk of major cardiovascular outcomes in Caucasians and Asians undergoing PCI PCI Percutaneous Coronary Intervention LOF Loss of Function MI Myocardial infarction Mega JL et al. N Engl J Med. 2009 Jan 22;360(4):354-62. Sorich MJ et al. Circ Cardiovasc Genet. 2014 Dec;7(6):895-902. Mega JL et al. JAMA. 2010 Oct 27;304(16):1821-30. Wallentin L et al. Lancet. 2010 Oct 16;376(9749):1320-8.

Observational and Prospective Data Xie et al. 2013 Shen et al. 2016 Deiman et al. 2016 Sanchez-Ramos et al. 2016 Composite of cardiovascular death, MI, stroke, or stent thrombosis was lower in the personalized group (2.66% vs. 9.03%, p<0.01) MACE was lower in the individualized therapy group. No difference in bleeding Cardiovascular death, MI, stent thrombosis, or stroke was significantly lower in prasugrel group (5% v. 31%, p=0.003) Genotype-guided prasugrel therapy was cost-effective Cardiovascular death, MI, or stroke was lower in the genotype-guided group (HR 0.63; 95% CI 0.41-0.97; p=0.037 No difference in minor or major bleeding between the groups LOF Loss of Function MI Myocardial infarction PCI Percutaneous Coronary Intervention MACE Major Adverse Cardiovascular Event Sanchez-Ramos J et al. Int J Cardiol. 2016 Dec 15;225:289-295. Deiman B et al. Neth Heart J. 2016 Oct; 24(10): 589 599. She D et al. J Cardiovasc Pharmacol. 2016 Mar;67(3):232-6. Xie X et al. Int J Cardiol. 2013 Oct 9;168(4):3736-40.

ADAPT-PCI Prospective, randomized trial Compared point-of-care CYP2C19 genotype-guided strategy (n=249) to usual care (n=255) following stent placement 28% of total population carried CYP2C19 LOF alleles and genotype-guided recommendations were followed in 71% of patients *1/*1 34% *1/*2 20% *2/*17 5% *2/*2 3% Outcomes CYP2C19 LOF carriers were more likely to be prescribed prasugrel or ticagrelor (53% vs. 22%) No difference in MACE and major bleeding LOF Loss of Function MACE Major Adverse Cardiovascular Event Presented by Dr. Sony Tuteja at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 10, 2018.

Cavallari LH et al. JACC Cardiovac Interv. 2018. 22;11(2):181-191

Objectives 1. Compare the risk of MACE between patients undergoing PCI with a CYP2C19 LOF allele prescribed clopidogrel and those with a CYP2C19 LOF allele prescribed alternative antiplatelet therapy 2. Compare the risk of MACE between those with a CYP2C19 LOF allele prescribed alternative therapy to those without a LOF allele treated with any P2Y 12 inhibitor LOF Loss of Function PCI Percutaneous Coronary Intervention MACE Major Adverse Cardiovascular Event Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Methods Trial Design Multicenter, pragmatic study of clinical CYP2C19 genotype-guided antiplatelet therapy post-pci in 7 US hospitals Genotype intervention was required at each institution, however, choice of P2Y12 inhibitor was at the discretion of the treating physician Followed for up to 12 months following index PCI CYP2C19 Genotype Ordered prior to or at the time of PCI All sites genotyped for LOF CYP2C19 * 2 and CYP2C19*3 alleles CYP2C19 Phenotype Intermediate metabolizer patients with one LOF allele Poor metabolizer patients with two LOF alleles Extensive metabolizer patients with no LOF alleles LOF Loss of Function PCI Percutaneous Coronary Intervention Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Methods Primary Outcome Composite outcome of MACE within 12 months of index PCI MI Stroke Death Secondary Outcomes Composite of MACE + stent thrombosis and UA Individual components of MACE UA Unstable Angina MI Myocardial Infarction MACE Major Adverse Cardiovascular Event Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Study Population Total Population n=1815 LOF allele n=572 Non-LOF allele n=1243 Clopidogrel 75 mg/day n=226 Alternative P2Y 12 n=346 Clopidogrel 75 mg/day n=1050 Alternative P2Y 12 n=193 LOF Loss of Function Cavallari LH et al. JACC Cardiovac Interv. 2018. 22;11(2):181-191

Statistical Analysis Basic Analysis Event rate = number of events/follow-up time (events per 100 patient-years) Student t-test, chi-square, or Fisher exact test used to compare baseline characteristics and PCI features Kaplan-Meier curves generated to estimate cumulative risk Propensity Scoring Used logistic regression to estimate the probability of receiving clopidogrel versus an alternative therapy using previously reported risk factors IPTWs were calculated using the estimated propensity score Primary and Secondary Analysis Constructed a cause-specific Cox proportional hazards model, weighted by IPTWS to compare primary and secondary outcomes Additional pre-specified analysis that assessed outcomes in patients with an ACS indication at time of index PCI Sample Size Sample of 1,815 patients required to achieve a power > 90% with an alpha level of 0.05 to detect a HR of 2.0 for the occurrence of MACE between the LOF-clopidogrel group and LOF-alternative group IPTW Inverse Probability of Treatment Weights ACS Acute Coronary Syndrome PCI Percutaneous Coronary Intervention Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Baseline Characteristics All (n=1,815) LOF-Alternative (n=346) LOF-Clopidogrel (n=226) Non-LOF (n=1,243) Age (years) 62.7 ± 11.8 61.4 ± 11.4 64.3 ± 11.7 62.8 ± 11.8 Male 67.4% 70.8% 66.4% 66.7% Caucasian 78.0% 77.2% 76.1% 78.6% BMI (kg/m 2 ) 30.0 ± 6.2 30.1 ± 7.0 30.0 ± 6.5 29.8 ± 5.9 ACS 66.7% 68.5% 64.2% 66.6% STEMI 19.3% 21.7% 14.6% 19.5% NSTEMI 28.3% 27.7% 31.8% 27.7% UA 19.1% 19.1% 17.7% 19.4% Stable CAD 30.5% 28.6% 31.0% 30.9% DES 83.6% 84.7% 80.5% 83.9% CAD Coronary Artery Disease DES Drug-eluting Stent ACS Acute Coronary Syndrome UA Unstable Angina NSTEMI Non-ST Segment Myocardial Infarction STEMI ST Segment Myocardial Infarction Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Baseline Characteristics Past Medical History All (n=1,815) LOF-Alternative (n=346) LOF-Clopidogrel (n=226) Non-LOF (n=1,243) Hypertension 79.8% 75.1% 81.0% 80.9% Discharge Medications Diabetes 38.1% 31.8% 41.2% 39.3% Prior MI 25.9% 24.9% 30.1% 25.4% Prior PCI 42.9% 39.6% 45.6% 43.4% Stroke/TIA 10.1% 6.9% 15.9% 9.9% Aspirin 98.2% 98.8% 97.4% 98.2% PPI 32.3% 31.8% 31.9% 32.5% Anticoagulant 8.4% 6.4% 11.5% 8.4% TIA Transient Ischemic Attack PCI Percutaneous Coronary Intervention MI Myocardial Infarction Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Results Time from index PCI to genotype result was a median of 1 day Alternative P2Y 12 agents were prescribed more often to patients with a LOF allele compared to patients without (60.5% vs. 15.5%, p<0.0001) 58% of intermediate metabolizers were prescribed an alternative P2Y 12 87% of poor metabolizers were prescribed an alternative P2Y 12 Among patients with a LOF allele, median time from genotype result to alternative P2Y 12 initiation was 1 day LOF Loss of Function PCI Percutaneous Coronary Intervention Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

LOF Loss of Function Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Clinical Outcomes LOF-Clopidogrel (n=226) LOF-Alternative (n=346) Adjusted HR (95% CI) % Event Rate % Event Rate MACE 7.96% 23.4 4.62% 8.7 2.26 (1.18-4.32) Death 3.54% 10.4 1.73% 3.3 3.76 (1.37-10.35) MI 4.87% 14.3 2.60% 4.9 1.85 (0.77-4.45) Stroke 1.33% 3.9 0.58% 1.1 2.81 (0.43-18.03) MACE + Ischemic Events 11.06% 32.5 8.09% 15.2 1.82 (1.07-3.12) Stent thrombosis 1.77% 5.2 1.16% 2.2 1.68 (0.37-7.53) UA 3.10% 9.1 3.47% 6.5 1.41 (0.55-3.64) UA Unstable Angina MACE Major Adverse Cardiovascular Event MI Myocardial Infarction Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Clinical Outcomes Non-LOF (n=1,243) LOF-Alternative (n=346) Adjusted HR (95% CI) % Event Rate % Event Rate MACE 5.95% 13.7 4.62% 8.7 1.14 (0.69-1.88) Death 2.90% 6.6 1.73% 3.3 1.56 (0.68-3.56) MI 3.06% 7.0 2.60% 4.9 1.00 (0.52-1.92) Stroke 1.05% 2.4 0.58% 1.1 2.52 (0.49-12.91) MACE + Ischemic Events 8.53% 19.6 8.09% 15.2 1.09 (0.72-1.63) Stent thrombosis 1.05% 2.4 1.16% 2.2 1.01 (0.32-3.15) UA 2.49% 5.7 3.47% 6.5 0.87 (0.44-1.70) UA Unstable Angina MACE Major Adverse Cardiovascular Event MI Myocardial Infarction Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Secondary Analysis Among patients with ACS at presentation, the LOF-clopidogrel group had a higher rate of MACE compared to the LOF-alternative group (HR 2.87; 95% CI 1.35-6.09, p=0.013) This held true for the MACE + UA + stent thrombosis outcome (HR 2.10; 95% CI 1.12-3.90, p=0.019) UA Unstable Angina PCI Percutaneous Coronary Intervention MACE Major Adverse Cardiovascular Event LOF Loss of Function ACS Acute Coronary Syndrome Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Author Conclusions Genotype-guided antiplatelet therapy following PCI is feasible with efficient return of genotype results Genotyping results in a high uptake of alternative P2Y1 12 agents Patients with CYP2C19 LOF alleles who are treated with clopidogrel have a higher risk of MACE compared to those who are treated with an alternative P2Y1 12 therapy Most events occurred in patients presenting with ACS at time of PCI LOF Loss of Function PCI Percutaneous Coronary Intervention MACE Major Adverse Cardiovascular Event ACS Acute Coronary Syndrome Cavallari LH et al. JACC Cardiovasc Interv. 2018. 22;11(2):181-191

Trial Critiques Strengths Weaknesses 1. High-risk patient population 1. Lack of safety outcomes 2. Propensity score matching and IPTW odds 2. Residual confounding 3. Real-world population with efficient application of genotypic results 4. Outcome measures were of clinical importance 5. Impact of CYP2C19 intermediate metabolizers on MACE 3. Rapid CYP2C19 genotypic testing is not widely available 4. No direct comparison of CYP2C19 normal or extensive metabolizers prescribed clopidogrel to those prescribed an alternative P2Y 12 inhibitor 5. Impact of genotypic testing prior to elective PCI remains unknown MACE Major Adverse Cardiovascular Event ACS Acute Coronary Syndrome PCI Percutaneous Coronary Intervention CAD Coronary artery disease LOF Loss of Function

Impact Validates the feasibility of incorporating CYP2C19 genotypic testing into clinical practice on a broader scale Adds to the existing evidence supporting the use of genotype-guided therapy in patients presenting for PCI following ACS to prevent MACE Highlights the importance of genotypic-guided therapy in intermediate metabolizers with a single LOF allele, stressing a need for more critical evaluation of these patients PCI Percutaneous Coronary Intervention ACS Acute Coronary Syndrome MACE Major Adverse Cardiovascular Event LOF Loss of Function CAD Coronary artery disease

JACC. 2018;71(17):1869-77.

PHARMCLO Study Objective To determine whether selecting antiplatelet therapy based on genetic information and a patient s clinical characteristics leads to better clinical outcomes compared with utilizing clinical characteristics alone

Trial Design Methods Multi-center, prospective, randomized, single-blind study Study Population Inclusion criteria Hospitalized for a STE-ACS or NSTE-ACS* European ancestry Exclusion criteria Contraindication to the use of P2Y12 inhibitor Life expectancy < 1 year Thrombolytic therapy within previous 24 hours Enrollment in another trial or observational registry Prior knowledge of patients genotype information *STE-ACS or NSTE-ACS = ST-segment elevation or non-st-segment elevation acute coronary syndrome

Intervention Randomized 1:1 to: Methods Genotyping-based P2Y12 inhibitor prescribing algorithm Prescribing based on clinical characteristics alone Primary endpoint Composite of cardiovascular death, non fatal MI, non fatal stroke, and BARC*-defined type 3 to 5 major bleeding events at 12 months Secondary endpoint Definite or probable stent thrombosis Statistical Analysis 1806 patients needed in each arm to achieve power of 95% Cox-proportional hazards model used for primary and secondary endpoints *BARC Bleeding Academic Research Consortium

Algorithm for P2Y12 Inhibitor Selection Genetic testing performed for: ABCB1 3435, CYP2C19*2 and CYP2C19*17 via ST Q3 system JACC. 2018;71(17):1869-77.

Baseline Characteristic Results Selected Baseline Characteristics (n=888) Pharmacogenomics Arm (n = 448) Standard-of-Care Arm (n = 440) Age (years) 71.1 ±12.3 70.7 ±12.1 Female n(%) 153 (34.2) 130 (29.6) STEMI n(%) 114 (25.5) 130 (29.5) Coronary angiography performed n(%) 433 (96.6) 422 (95.9) LAD occlusion n(%) 236 (54.5) 224 (53.1) PCI n(%) 268 (61.8) 264 (62.6) CABG n(%) 49 (11.3) 43 (10.1) STEMI ST segment elevation myocardial infarction LAD Left anterior descending artery PCI percutaneous coronary intervention CABG coronary artery bypass grafting JACC. 2018;71(17):1869-77.

Distribution of Genetic Variants ABCB1 3435 genotype Pharmacogenomics (n = 448) Standard-of-Care (n = 440) Heterozygous (C/T) n(%) 211 (47.1) NA Homozygous (T/T) n(%) 118 (26.4) NA CYP2C19*2 genotype Heterozygous (*1/*2) n(%) 131 (29.2) NA Homozygous (*2/*2) n(%) 19 (4.3) NA CYP2C19*17 genotype Heterozygous (*1/*17) n(%) 140 (31.3) NA Homozygous (*17/*17) n(%) 35 (7.8) NA P2Y12 Inhibitor Prescribed Clopidogrel n(%) 194 (43.3) 223 (50.7)* Prasugrel n(%) 34 (7.6) 37 (8.4) Ticagrelor n(%) 191 (42.6) 144 (32.7)* *p= 0.02 JACC. 2018;71(17):1869-77.

Outcomes at 12 Months Pharmacogenomics (n = 448) Standard-of-Care (n = 440) HR (95% CI, P-value) Primary Endpoint n(%) 71 (15.9) 114 (25.9) 0.58 (0.43 0.78, p<0.001) Ischemic Endpoints n(%) 58 (13) 94 (21.4) 0.57 (0.41 0.80, p<0.001) Bleeding Endpoints n(%) 19 (4.2) 30 (6.8) 0.62 (0.35 1.1, p=0.1) JACC. 2018;71(17):1869-77.

Critique Strengths ST Q3 Instrument allows for genotype results within 70 minutes Offer a protocol for implementing clinical decision-making Clinically meaningful endpoint examined Limitations Only 25% of pre-specified population enrolled ST Q3 instrument is not standard of care genotyping instrument Magnitude of benefit higher than would be expected Limited generalizability of patient population ( European descent )

Conclusions Point-of-care genotyping with protocolized decision making is feasible Combining genotype data along with patient specific clinical characteristics appears to be effective in improving outcomes Replication of results in other trials with reliable devices and more diverse patient population needed prior to wide acceptance of pointof-care genotyping in the setting of acute coronary syndrome

M&M s Take-Home Points* If readily available, it is reasonable to consider routine CYP2C19 genotyping in all patients presenting with acute coronary syndromes (Class IIa; LOE B) If readily available, routine CYP2C19 genotyping may be considered in all patients presenting for elective percutaneous coronary intervention with stenting (Class IIb; LOE B) In CYP2C19 poor metabolizers, prasugrel and ticagrelor should be considered as first line agents unless contraindications exist (Class I; LOE A) In CYP2C19 intermediate metabolizers, prasugrel and ticagrelor should be considered as first line agents unless contraindications exist (Class I; LOE A) If CYP2C19 genotyping is utilized, institution-specific protocols should be developed to guide P2Y 12 inhibitor selection (Class I; LOE C) *Disclaimer: these are the recommendations put forth by pharmacy residents with limited experience in the field.

Extra Slide

Genotyping Cost Taqman Clinical test is ~ $285 For a research test it s less than $1 Real-time PCR from whole blood Results same day or next day SpartanRx (Spartan Bioscience, Ottawa, Canada) Real-time PCR from buccal swab Results within 60 minutes Verigene System (Nanosphere, Northbrook, Illinois) Microarray-based assay using whole blood Results in 3 hours