ACCP Cardiology PRN Journal Club

ACCP Cardiology PRNJournal Club

November 18, 2019

Moderator: Josh Jacobs, PharmD

Mentor Bio

• Dr. Tracy Macaulay is a Clinical Associate Professor at the University of Kentucky College of Pharmacy. She completed her PharmD at University of South Carolina, PGY1 at Mayo Clinic and PGY2 training at The Ohio State University. She currently practices as a Cardiology Specialist in Ambulatory Care with the Gill Heart Institute.

Presenter Bio

• Dr. Tong Young Huang is a PGY2 cardiology pharmacy resident at UMass Memorial Medical Center in Worcester, Massachusetts. He graduated from University of Colorado Skaggs School of Pharmacy and completed his PGY1 training at Riverside University Health System.

Presenter Bio

• Dr. Annaliese Clancy is a PGY2 cardiology pharmacy resident at UMass Memorial Medical Center in Worcester, Massachusetts. She graduated from the University of Rhode Island College of Pharmacy and completed her PGY1 training at UMass Memorial Medical Center.

Presenter Bio

• Dr. Kristina Gill is a PGY2 cardiology pharmacy resident at UMass Memorial Medical Center in Worcester, Massachusetts. She graduated from Auburn University Harrison School of Pharmacy and went on to complete her PGY-1 Pharmacy training at North Florida Regional Medical Center.

Ticagrelor with or without Aspirin in High-Risk Patients after PCI

TWILIGHT

Tong Young Huang, PharmD

Annaliese Clancy, PharmD

Kristina Gill, PharmD

PGY2 Cardiology Pharmacy Residents

UMass Memorial Medical Center, Worcester, MA

Background

Dual Antiplatelet Therapy (DAPT) Duration Trials

SMART-CHOICE 2019

STOPDAPT-2 2019

TWILIGHT 2019

• Aspirin decreases incidence of myocardial infarction (MI), stroke and mortality

• Antiplatelet therapy prevents stent thrombosis in patients undergoing percutaneous coronary intervention (PCI)

• Aspirin + P2Y12 = increased bleeding (i.e. gastrointestinal bleeding)

• Type of stent (bare metal vs drug-eluting) correlates with risk of thrombosis

• Does taking away aspirin decrease bleeding events? Does it increase thrombotic events?

Background – Clopidogrel Trials

CURE (2001) PCI-CURE (2001)

Study Design RCT, Double-blind, placebo-controlled in ACS Post hoc analysis

PopulationN = 12,562Unstable Angina 74.9%NSTEMI 26.1%

N = 2,658NSTEMI 42.4%

Intervention Clopidogrel 300 mg load, then 75 mg daily or placebo plus aspirin for 3-12 months

Results Composite death from CV cause, nonfatal MI, or stroke9.3% vs 11.4%, RR 0.80, 95% CI 0.72 – 0.90

Composite death from CV cause, MI, or urgent target-vessel revascularization12.1% vs 15.4%, RR 0.76, 95% CI 0.62-0.93

Limitations Primarily medically managed Subgroup analysis from the larger CURE trial

Clinical Implication

Twelve month duration of therapy utilized in these trials have become standard of care.

ACS = acute coronary syndromesNSTEMI = Non-ST elevation myocardial infarctionCV = cardiovascular

Cleve Clin J Med. 2002 May;69(5):377-8.Lancet. 2001 Aug 18;358(9281):527-33.

Background – Ticagrelor Trials

PLATO (2009) PEGASUS-TIMI 54 (2015)

Population

N = 18,624STEMI 38%; NSTEMI 43%; unstable angina 17%PCI 61%46% received clopidogrel load in both arms

N = 21,162Patients with a history of MI (1-3 years prior) on aspirin therapySTEMI 53%; NSTEMI 41%; PCI 83%

Intervention

1) Ticagrelor 180 mg then 90 mg BID2) Clopidogrel 300 mg then 75 mg dailyDuration: Plus aspirin for 12 months

1) Ticagrelor 90 mg BID + aspirin2) Ticagrelor 60 mg BID + aspirin3) Placebo + aspirinDuration: 12 months

Results

Composite of death from vascular causes, MI, or strokeTicagrelor vs clopidogrel 10.2% vs. 12.3%, HR 0.84, 95% CI 0.77-0.92

Composite CV Death, MI or Stroke1) 7.8% HR vs placebo 0.85, p = 0.0082) 7.8% HR vs placebo 0.84, p = 0.043) 9.0%

Safety

Major bleeding (study criteria)Ticagrelor vs clopidogrel 11.6% vs 11.2% (p =0.43)

TIMI Major bleeding1) 2.6% (P<0.001)2) 2.3% (P<0.001)3) 1.1%

N Engl J Med. 2009 Sep 10;361(11):1045-57.J Am Coll Cardiol. 2017 Sep 12;70(11):1368-1375.

Background – DAPT Trials 1996-2017

Eur Heart J. 2018 Jan 14;39(3):213-260.

Background – DAPT Trials 2016-2020

Circulation. 2016 Sep 6;134(10):e192-4.

Background – Shorter Duration of DAPT

SMART-CHOICE (2019) STOPDAPT-2 (2019) GLASSY (2019)

Study Design Randomized, open-label, noninferiority Randomized, open-label Randomized in a 1:1 ratio

Population

N = 2,993Unstable angina 31%; NSTEMI 16%; STEMI 11%

N = 3,045Unstable angina 13%; NSTEMI 5%; STEMI 20%

N = 7,585 (20 largest recruiting centers of the GLOBAL LEADERS study)Unstable angina 13%; NSTEMI 20%; STEMI 18%

Intervention

1) Ticagrelor + aspirin 3 months then ticagrelor monotherapy2) DAPT Duration: 12 months

1) 1- month DAPT (clopidogrel or prasugrel), then clopidogrel monotherapy2) 12 months DAPT (clopidogrel), then aspirinDuration: 5 years

1) 1-month DAPT (ticagrelor), then 23 months of ticagrelor monotherapy2) 24 months of DAPT (ticagrelor)

Results

Composite all cause death, MI, Stroke 2.9% vs 2.5%, 95% CI -∞% to 1.3%; p = 0.007

Composite of CV death, MI, Stroke, stent thrombosis, TIMI major or minor bleeding2.36% vs 3.70%; HR 0.64; 95% CI -2.57% to -0.11%

Composite death, MI, stroke, or urgent target vessel revascularization7.14% vs 8.41%, 95% CI 0.72-0.99; p = 0.047

Safety

Stent thrombosis0.2% vs 0.1%, p = 0.65BARC type 2-52.0% vs 3.4%, 95% CI 0.36- 0.92, p = 0.02

Stent thrombosis0.13% vs 0.07%; p = 0.57TIMI Major bleeding0.20% vs 1.07%; p = 0.01

Stent thrombosis0.71% vs 1.00%, p = 0.173BARC 3 or 5 bleeding events2.48% vs 2.48%, p = 0.986

JAMA. 2019 Jun 25;321(24):2428-2437.JAMA. 2019 Jun 25;321(24):2414-2427.BMJ Open. 2019 Mar 9;9(3):e026053.

2016 ACC/AHA Focused Update On DAPT

Caveat: High-risk patients can

receive up to 6 months of DAPT therapy (IIb,

LOE C)

Circulation. 2016 Sep 6;134(10):e192-4.

DAPT Risk Stratification

PRECISE-DAPT score DAPT score PARIS score

Time of useAt the time of coronary

stentingAfter 12 months of uneventful

DAPTAt time of coronary stenting

DAPT Duration strategy

• Short = 3-6 months• Standard/long = 12-24

months

• Standard = 12 months • Long = 30 months

• Predicts events associated with DAPT use up to 24 months

Score Range 0 to 100 points -2 to 10 pointsThrombosis

(0 to 10)Bleed

(0 to 14)

Interpretation• Score ≥ 25 = short DAPT• Score < 25 = standard/

long DAPT

• Score ≥ 2 = long DAPT• Score < 2 = standard DAPT

• Low 0 - 2 • Mod 3 - 4• High ≥ 5

• Low 0 - 3• Mod 4 - 7• High ≥ 8

Circulation. 2016 Sep 6;134(10):e192-4.J Am Coll Cardiol. 2016 May 17;67(19):2224-2234.

Trial Design / Purpose

• Prospective, international, randomized, double-blind, placebo-controlled trial

• Evaluate the safety and efficacy of ticagrelor monotherapy after 3 months of DAPT in patients at high risk for ischemic or hemorrhagic complications

Am Heart J. 2016 Dec;182:125-134.

Methods – Key Inclusion / Exclusion Criteria

Exclusion

• STEMI patients, cardiogenic shock, treatment with anticoagulant, active bleeding or extreme risk for major bleeding

Inclusion

• One clinical and one angiographic feature associated with high risk of ischemic or bleeding events

STEMI = ST elevation myocardial infarction

Methods – Features of High Ischemic or Bleeding Risk

Clinical

• Age 65+ years

• Female sex

• Troponin-positive ACS

• Established vascular disease

• Diabetes on medications

• CKD

Angiographic

• Multivessel CAD

• Total stent length > 30 mm

• Bifurcation lesion with two stents

• Obstructive LM or proximal LAD

• Calcified target lesion treated with atherectomy

CKD = chronic kidney diseaseCAD = coronary artery disease

LM = left mainLAD = left anterior descending

Methods – Endpoints

• BARC type 2, 3, or 5 bleedingPrimary (bleeding)

• Death from any cause, nonfatal MI, or nonfatal strokeSecondary

(ischemic)

• BARC, TIMI, GUSTO, and ISTH bleeding

• Death from CV cause, MI, stroke, and definite or probable stent thrombosis

Secondary (other)

BARC = Bleeding Academic Research ConsortiumTIMI = Thrombolysis in Myocardial Infarction

GUSTO = Global Use of Strategies to Open Occluded ArteriesISTH = International Society on Thrombosis and Haemostasis

BARC Bleeding Chart

Type Description

Type 0 No bleeding

Type 1 Non-actionable bleeding

Type 2 Actionable, clinically overt sign of hemorrhageRequires hospitalization or treatment by healthcare professional

Type 3aType 3b

Type 3c

Overt bleeding plus Hgb drop of 3 to < 5 g/dL; transfusion with overt bleedingOvert bleeding plus Hgb drop < 5 g/dL; cardiac tamponade; requires surgical intervention, requires vasopressorsIntracranial hemorrhage; intraocular bleed

Type 4 Coronary artery bypass grafting (CABG)-related bleeding

Type 5 Probable or definite fatal bleeding

J Am Coll Cardiol. 2016 May 10;67(18):2135-2144.

Methods – Statistical Analysis

• Superiority assumption for the primary endpoint of bleeding events• Intention-to-treat population

• Non-inferiority assumption for the key secondary endpoint of ischemic events• Per-protocol population

• Sample size of 8200 for 80% power with an alpha of 0.05

• Time-to-event data: Kaplan-Meier and Cox proportional-hazards

Baseline Characteristics

CharacteristicTicagrelor plus Placebo

(N = 3555)Ticagrelor plus Aspirin

(N = 3564)

Age – yr 65.2 ± 10.3 65.1 ± 10.4

Female (%) 23.8 23.9

Past Medical History (%)

Diabetes mellitus 37.1 36.5

CKD 16.8 16.7

Anemia 19.8 23.1

Current smoker 20.4 23.1

Hypertension 72.6 72.2

Previous myocardial infarction 27.8 28.6

Previous PCI 42.3 42

Multivessel coronary artery disease 63.9 61.6

Previous major bleeding event 0.9 0.9

Baseline Characteristics continued

Indication for PCITicagrelor plus Placebo


(N = 3563)

NSTE-ACS• NSTEMI• Unstable angina

64% 66%

SIHD• Asymptomatic• Stable angina

36% 34%

NSTE-ACS = non-ST elevation acute coronary syndromeSIHD = stable ischemic heart disease

Results: Primary Endpoint

EndpointsTicagrelor plus Placebo


(N = 3564)Hazard Ratio

(95% CI)P Value

No. of patients (%)

Bleeding: BARC type 2, 3, or 5

141 (4.0) 250 (7.1)0.56

(0.45-0.68)<0.001

(Superiority)

Ischemic (secondary): Death from any cause, nonfatal MI, or nonfatal stroke

135 (3.9) 137 (3.9)0.99

(0.78-1.25)

<0.001(Non-

inferiority)

Number Needed to Treat: 3232 patients treated with ticagrelor monotherapy versus DAPT to prevent one additional bleed (BARC type 2, 3, or 5)

Results: Secondary Endpoints



(N = 3564)Hazard Ratio

(95% CI)

Bleeding endpoints (%)

BARC type 3 or 5 1 2 0.49 (0.33-0.74)

TIMI minor or major 4 7.1 0.56 (0.45-0.68)

GUSTO moderate or severe 0.7 1.4 0.53 (0.33-0.85)

ISTH major 1.1 2.1 0.54 (0.37-0.80)

Ischemic endpoints (%)

Death from CV causes, nonfatal MI, or nonfatal ischemic stroke

3.6 3.7 0.97 (0.76-1.24)

Death from any cause 1 1.3 0.75 (0.48-1.18)

Death from CV causes 0.8 1.1 0.7 (0.43-1.16)

MI 2.7 2.7 1.00 (0.75-1.33)

Ischemic stroke 0.5 0.2 2.00 (0.86-4.67)

Stent thrombosis, definite or probable 0.4 0.6 0.74 (0.37-1.47)

Landmark Analysis Between 15 to 18 Months



(N = 3454)Hazard ratio (95% CI)

Placebo vs. Aspirin

No. of patients (%)

BARC 2, 3, or 5 Bleeding 20 (0.7%) 16 (0.5%) 1.24 (0.64-2.40)

Death, MI, or Stroke 28 (0.9%) 33 (1.1%) 0.84 (0.51-1.40)

Key Subgroup Analysis – Bleeding Endpoint

SubgroupNo. of

PatientsTicagrelor plus

PlaceboTicagrelor plus

AspirinHR (95% CI)

No. of events

Sex• Male• Female

54211698

9942

17872

0.55 (0.43-0.7)0.57 (0.39-0.83)

CKD• No• Yes

56901145

11325

18850

0.6 (0.47-0.75)0.48 (0.3-0.78)

Total stent length (mm)• <30• >30

30364082

6477

93157

0.7 (0.51-0.97)0.47 (0.36-0.61)

Multivessel Disease• No• Yes

24224697

4794

94156

0.53 (0.37-0.75)0.57 (0.44-0.74)

J Am Coll Cardiol 2015;66:1036-45Lancet 2017;389:1025-34

Key Subgroup Analysis – Ischemic Endpoint

Subgroup No. of Patients Ticagrelor plus Placebo Ticagrelor plus Aspirin HR (95% CI)

No. of events

Age (years)• <65• >65

33623677

5679

6077

0.94 (0.65-1.35)1.02 (0.75-1.4)

Prior MI• No• Yes

50202019

7758

8156

0.95 (0.7-1.3)1.03 (0.72-1.49)

JAMA 2016;315:1735-49

Author’s Conclusions

In high-risk patients with stable ischemic heart disease or NSTE-ACS who undergo PCI and complete 3 months of DAPT with ticagrelor and aspirin

without major events

Continuation with ticagrelor monotherapy versus DAPT leads to:

Substantially less bleeding No increase in risk of death, MI, or stroke

Study Critique

Strengths

• Multicenter, randomized, double-blind, placebo-controlled

• Required high-risk angiographic criteria

• Appropriate endpoints

Limitations

• Limited generalizability:• STEMI excluded

• Underpowered to detect a difference in stent thrombosis and stroke

• Lower than expected composite end point of death, MI, or stroke

• Concomitant medications unknown (i.e. proton pump inhibitors)

Clinical Implications

Duration of DAPT?

• SMART-CHOICE (2019)

• No difference in major bleeding with 3 months versus 12 months of DAPT

• STOPDAPT-2 (2019)

• Significant reduction in composite outcome of cardiovascular and bleeding events with 1 month versus 12 months of DAPT

Optimal antiplatelet regimen?

• ISAR-REACT 5 (2019)

• Prasugrel significantly reduced death, MI, stroke with no significant difference of major bleeding compared to ticagrelor

JAMA. 2019 Jun 25;321(24):2428-2437.JAMA. 2019 Jun 25;321(24):2414-2427 N Engl J Med. 2019 Oct 17;381(16):1524-1534.

Conclusions

• There is growing evidence that up to 3 months of DAPT therapy is noninferior to 12 months in patients with NSTE-ACS

• This trial may be inappropriately extrapolated to include STEMI patients in practice

• It may be justified to stop DAPT earlier in patients at high bleed risk

Impact on clinical practice remains unknown

Ticagrelor with or without Aspirin in High-Risk Patients after PCI

TWILIGHT

Tong Young Huang, PharmD

Annaliese Clancy, PharmD

Kristina Gill, PharmD

PGY2 Cardiology Pharmacy Residents

UMass Memorial Medical Center, Worcester, MA

Presenter Bio

• Dr. Bailey Colvin is a PGY2 cardiology pharmacy resident at the University of Pittsburgh Medical Center. She graduated from the Philadelphia College of Pharmacy at the University of the Sciences and completed her PGY1 training at UPMC as well.

Ticagrelor in Patients with Stable Coronary Disease and Diabetes

THEMIS

Bailey Colvin, PharmD

PGY2 Cardiology Pharmacy Resident

UPMC Presbyterian, Pittsburgh, PA

Background

• In all patients with stable CAD low-dose aspirin daily is recommended (Class I, LOE A)• In patients with high risk for ischemic events and without bleeding risk, a

second antithrombotic drug can be considered for long-term secondary prevention (Class II, LOE A)

• Diabetes is an independent risk factor for vascular disease• Increases risk ~2x

• Current risk-lowering strategies in diabetes focus on reducing lipid levels and blood pressure

Knuuti J, et al. Eur Heart J 2019; Aug 31. Sarwar N, et al. Lancet 2010; Jun 26.CAD: coronary artery disease

Outcomes in Patients with DM in Major Secondary Prevention

TrialPatients

(DM/Overall)Setting Treatment Arm Primary Efficacy Outcomes in DM

Bleeding Risks in DM

CAPRIE 3,866/19,185Recent MI,

stroke, established PADClopidogrel v ASA

Vascular death, MI, ischemic stroke

15.6% v 17.7% 1.8% v 2.8%

CURE 2,840/12,562 NSTE-ACSASA + clopidogrel v

ASA + placeboCV death, nonfatal

MI, stroke14.2% v 16.7% NA

CHARISMA 6,556/15,603Multiple risk

factors, CAD, CVD, or symptomatic PAD

ASA + clopidogrel v ASA + placebo

CV death, MI, stroke

Not provided, no interaction with overall results

3.0% v 4.1%

TRITON-TIMI 38

3,146/13,608 ACS undergoing PCIASA + prasugrel

v ASA + clopidogrel

CVdeath, nonfatal, no

nfatal stroke12.2% v 17.0% 2.6% v 2.5%

PLATO 4,662/18,624 ACSASA + ticagrelor v ASA + clopidogrel

Vascular death, MI, stroke

14.1% v 16.2% 14.1% v 14.8%

TRA 2P-TIMI 50

6,274/26,449History of MI, ischemic

stroke, or PADAPT + vorapaxar v

APT + placeboCV death, MI,

stroke14.6% v 16.3% 4.4% v 2.6%

ATLAS ACS-TIMI 51

4,964/15,526 ACSAPT + rivaroxaban v

APT + placeboCV death, MI,

stroke7.1% v 7.5% 1.2% v 0.2%

Park Y, et al. Circ J 2016; Mar 16.DM: diabetes mellitus; ACS: acute coronary syndrome; PCI: percutaneous intervention; PAD: peripheral artery disease: ASA: aspirin; APT: antiplatelet; MI: myocardial infarction; CV: cardiovascular

THEMIS Objective

• To compare the efficacy and safety of ticagrelor and aspirin with aspirin alone in patients with stable coronary artery disease and diabetes without a history of stroke or myocardial infarction

Steg PG, et al. N Engl J Med 2019; Sep 1.

Patient Population

• ≥50 years of age

• Type 2 diabetes• Antiglycemic therapy ≥6 months

• Stable coronary artery disease• History of PCI

• History of CABG

• Angiographic documentation of ≥50% stenosis of ≥1 coronary artery

• Excluded: Known history of stroke or myocardial infarction

CABG: coronary artery bypass grafting Steg PG, et al. N Engl J Med 2019; Sep 1.

TreatmentStable CAD + T2DM

Ticagrelor + Aspirin Aspirin + Placebo

Ticagrelor 90 mg BID


PEGASUS-TIMI 54 (2015)


T2DM: type 2 diabetes mellitus Steg PG, et al. N Engl J Med 2019; Sep 1.

Outcomes

Primary Efficacy Composite

Cardiovascular death

Myocardial infarction

Stroke

Secondary Efficacy

Cardiovascular death

Myocardial infarction

Ischemic stroke

Death from any cause

Primary Safety

TIMI Major Bleeding criteria

Net Irreversible Harm: Death from any cause, myocardial infarction, stroke, fatal bleeding, intracranial hemorrhage

TIMI: thrombolysis in myocardial infarction Steg PG, et al. N Engl J Med 2019; Sep 1.

Statistical Analysis

• 19,000 patients required to achieve 90% power • 2.5% placebo event rate

• 16% lower risk in intervention arm

• Efficacy outcomes: Intention-to-treat

• Safety outcomes: Modified intention-to-treat for on-treatment period

• Time-to-event: Cox proportional-hazards model


Baseline CharacteristicsCharacteristic Ticagrelor (N=9619) Placebo (N=9601)

Age, yr (IQR) 66.0 (61.0-72.0) 66.0 (61.0-72.0)

Female sex, no (%) 3043 (31.6) 2988 (31.1)

Revascularization history, no (%)

Any 7679 (79.8) 7667 (79.9)

PCI 5558 (57.8) 5596 (58.3)

CABG 2120 (22.0) 2071 (21.6)

PCI and CABG 676 (7.0) 670 (7.0)

Neither 1941 (20.2) 1934 (20.1)

Diabetes history

Median duration (IQR), yr 10 (5-16) 10 (5-16)

Complications, no (%) 2480 (25.8) 2430 (25.3)

Median glycated hemoglobin (IQR), % 7.1 (6.4-8.1) 7.1 (6.4-8.1)Steg PG, et al. N Engl J Med 2019; Sep 1.

Results

Outcome Ticagrelor (N=9619) Placebo (N=9601) Hazard Ratio (95% CI)

Primary Efficacy

CV death, MI, stroke 736 (7.7) 818 (8.5) 0.90 (0.81-0.99), p=0.04

Secondary Efficacy

Cardiovascular death 364 (3.8) 357 (3.7) 1.02 (0.88-1.18), p=0.79

Myocardial infarction 274 (2.8) 328 (3.4) 0.84 (0.71-0.98)

Ischemic stroke 152 (1.6) 191 (2.0) 0.80 (0.64-0.99)

Death from any cause 579 (6.0) 592 (6.2) 0.98 (0.87-1.10)


Results

Outcome Ticagrelor (N=9562) Placebo (N=9531) Hazard Ratio (95% CI)

Adjudicated Adverse Events

TIMI major bleeding 206 (2.2) 100 (1.0) 2.32 (1.82-2.94), p<0.001

TIMI major or minor bleeding 285 (3.0) 129 (1.4) 2.49 (2.02-3.07), p<0.001

BARC bleeding score

3, 4, or 5 341 (3.6) 163 (1.7) 2.36 (1.96-2.84), p<0.001

5 17 (0.2) 10 (0.1) 1.90 (0.87-4.15), p=0.11

Intracranial hemorrhage 70 (0.7) 46 (0.5) 1.71 (1.18-2.48), p=0.005

Any adverse event of interest 2562 (26.8) 1302 (13.7) 2.30 (2.15-2.46), p<0.001

Dyspnea leading to discontinuation 661 (6.9) 75 (0.8) 9.27 (7.30-11.77), p<0.001

BARC: Bleeding Academic Research Consortium Steg PG, et al. N Engl J Med 2019; Sep 1.

Time-to-Event Analysis

Primary Composite Efficacy Outcome

Primary Safety Outcome


NNT = 125 patients

NNH = 83 patients

Author’s Conclusions

• Patients with stable coronary artery disease and type 2 diabetes without history of myocardial infarction or stroke treated ticagrelor in addition to aspirin experienced a lower incidence of ischemic events compared to patients on aspirin alone

• However, treatment with ticagrelor plus aspirin was associated with a higher incidence of major bleeding

• Net irreversible harm was not significantly lower in the ticagrelor plus aspirin group


Findings from the PCI-specific cohort

PCI Group No PCI Group Overall THEMIS Population

Primary Efficacy 7.3% v 8.6%, HR 0.85 (0.74-0.97), p=0.013 8.2% v 8.4%, HR 0.98 (0.84-1.14), p=0.76 7.7% v 8.5% 0.90, HR (0.81-0.99), p=0.04

TIMI Major Bleeding 2.0% v 1.1%, HR 2.03 (1.48-2.76), p<0.0001 2.4% v 1.0%, HR 2.79 (1.91-4.06), p<0.0001 2.2% v 1.0%, HR 2.32 (1.82-2.94), p<0.001

Net Irreversible Harm 9.3% v 11.0%, HR 0.85 (0.75-0.95), p=0.005 11.1% v 10.5% HR 1.06 (0.93-1.21), p=0.39 HR 0.93 (0.86-1.02)

Ticagrelor + aspirin associated with reduced rates of the primary composite outcome and overall net clinical benefit in patients with a history of PCI

Bhatt DL, et al. Lancet 2019; Sep 28.

Study Critique

• Large, robust patient population• Generalizable

• Ticagrelor dosing strategy

• Diabetes definition

• Concomitant medications at goal• High intensity statins

• Metformin

• High-risk patients?

• Ticagrelor as single agent?

Impact on Clinical Practice

PEGASUS TIMI 54 GLOBAL LEADERS TWILIGHT THEMIS

PopulationMI 1-3 years prior + high-

risk featurePost-PCI in stable CAD

or post-MIPost-PCI with DES +

high-risk featureStable CAD + DM with

no MI or stroke

InterventionsTicagrelor 90 mg BIDTicagrelor 60 mg BID

Placebo

1 month DAPT then Ticagrelor 90 mg BID x

23 months

12 months DAPT then aspirin therapy

3 months DAPT thenTicagrelor 90 mg BID

+ ASA or placebo

Ticagrelor + ASAPlacebo + ASA

Results

Both 90 and 60 mg ↓ischemic events

60 mg had less bleeding than 90 mg

Ticagrelor therapynonsignficantly ↓ primary endpoint

Bleedingnonsignificantly ↓

Ticagrelor alone ↓ bleeding events

Ischemic events were ≈

Ticagrelor 60 mg BID ↓ ischemic events

Bleeding events were ↑, resulting in no net

clinical benefit

Bonaca MP, et al. Circulation 2016; Jun 14.Vranckx P, et al. Lancet 2018; Aug 27.Mehran R, et al. NEJM 2019; Sep 26.


Impact on Clinical Practice

• The majority of patients with diabetes who have stable CAD without prior myocardial infarction or stroke should be on aspirin as a single antiplatelet regimen

• There is a subset of this population that may benefit from DAPT with ticagrelor 60 mg BID plus aspirin• PCI, especially <1 year prior

• Other high-risk patients?

Ticagrelor in Patients with Stable Coronary Disease and Diabetes

THEMIS

Bailey Colvin, PharmD

PGY2 Cardiology Pharmacy Resident

UPMC Presbyterian, Pittsburgh, PA

We will be back in December!

• Date/Time to be determined

• Happy Holidays!

ACCP Cardiology PRN Journal Club

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