ACCP Cardiology PRN August Journal Club

STOPDAPT-2

AUGUSTUS

8/29/2019

Mentor Bio

Dr. Danielle Blais is a Cardiology Specialty Pharmacist at OSUWMC in Columbus, OH. She completed her PharmD at SUNY Buffalo, PGY1 SUNY Upstate Medical Center in Syracuse, NY and PGY2 in Cardiology at OSUWMC in Columbus, OH. Some of her current practice interests include treatment of acute coronary syndromes and pulmonary embolism, and safe and effective use of anticoagulation/antiplatelet therapy. She oversees services for the ACS Service/CICU/Cardiac Catheterization Lab.

Presenter Bio

Dr. Nick Orvin is a PGY2 Cardiology Pharmacy Resident at WakeMed Health & Hospitals in Raleigh, NC. He graduated from the South Carolina College of Pharmacy at MUSC in Charleston, SC and completed his PGY1 Pharmacy Residency at WakeMed. His current practice interests include anticoagulation, heart failure and cardiothoracic surgery.

Effect of 1-month dual antiplatelet therapy (DAPT) followed by clopidogrel vs 12-month DAPT on cardiovascular and bleeding events

in patients receiving PCI: STOPDAPT-2

Nick Orvin, PharmD

PGY2 Cardiology Pharmacy Resident

WakeMed Health & Hospitals, Raleigh, NC

Disclosures

• Nick Orvin and all other contributors have no relevant financial relationships to disclose

Background

• 2016 ACC/AHA Guidelines recommend 12 months of DAPT after drug-eluting stent (DES) placement in patients with acute coronary syndromes (ACS)

– 6 months may be reasonable if high bleeding risk

• Patients with stable CAD receiving a DES, at least 6 months are recommended

– 3 months may be reasonable if high bleeding risk

Circulation 2001;345:494-502.CAD – Coronary artery disease

Previous Literature

StudyDAPT

DurationDAPT

RegimenAcute Coronary

SyndromeStents

UtilizedPrimary OutcomeRR or HR (95% CI)

CURE(1998-2001)

8 months*

Clopidogrel+ ASA

USA 75%NSTEMI 25%

17%(N/A)

Ischemia^: 0.80 (0.72-0.90)Bleeding: 1.38 (1.13-1.67)

TRITON-TIMI 38(2004-2007)

14 months*

Prasugrel+ ASA

USA/NSTEMI 74%STEMI 26%

DES 47%BMS 48%

Ischemia^: 0.81 (0.73-0.90)Bleeding: 1.32 (1.09-2.08)

PLATO(2001-2005)

9 months*

Ticagrelor + ASA

USA 17%NSTEMI 43%STEMI 38%

DES 19%BMS 42%

Ischemia#: 0.84 (0.77-0.92)Bleeding: 1.03 (0.93-1.15)

*Mean or median duration of follow-up^Composite of cardiovascular mortality, non-fatal MI or non-fatal stroke#Composite of vascular death (CV or stroke or unknown), MI, stroke NEJM 2001;345:494-502.

NEJM 2007;357:2001-2015.NEJM 2009;361:1045-1057.

Evolution of the DES

• Cobalt-chromium everolimus-eluting stent (CoCr-EES)

Lancet 2012;379:1393-1402

Potential Risk with Longer DAPT

BMJ 2015;350:h1618.Eur Heart J 2017:1034-1043.BMJ 2019;365:I2222

Meta-analysisDAPT

DurationDAPT

RegimenDES type used CAD

Overall Outcomes with Shorter DAPT

Navarese et al(2015)

≤6 vs 12ASA +

clopidogrel1st Gen 57%2nd Gen 43%

ACS 50%Stable CAD 50%

↔ MI or ST↓ Major Bleeding

Palmerini et al(2017)

≤6 vs ≥12ASA +

Clopidogrel1st Gen 13%2nd Gen 87%

ACS 44%Stable CAD 56%

↔ MI or ST↓ Major Bleeding

3 vs 12ASA +

Clopidogrel1st Gen 14%2nd Gen 86%

ACS 44%Stable CAD 56%

↔ MI or ST↔ Major Bleeding

≤6 vs 12ASA +

Clopidogrel- All ACS Subgroup

↔ MI or ST↔ Bleeding

3 vs 12ASA +

Clopidogrel- All ACS Subgroup

↑ MI or ST↔ Bleeding

Yin et al(2019)

≤6 vs 12ASA +

Clopidogrel1st Gen 54%2nd Gen 46%

ACS 53%Stable CAD 47%

↔ MI or ST↔ Bleeding

≤6 vs 12ASA +

Clopidogrel- ACS Subgroup

↔ MI or ST↔ Bleeding

ST – Stent thrombosisMI – Myocardial infarction

STOPDAPT-2: Objective

• To evaluate the efficacy of 1 month of DAPT compared with 12 months after CoCr-EES implantation.

JAMA 2019;321:2414-2427.

Study Population

Inclusion Exclusion

• PCI with CoCr-EES• No major post-PCI complications• Eligible to receive ASA + clopidogrel

• Requiring oral anticoagulation• Non-aspirin or P2Y12 antiplatelets • Known intolerance to clopidogrel• History of intracranial bleeding

CoCr-EES – Cobalt chromium everolimus-eluting stentPCI – Percutaneous coronary interventionASA – Aspirin P2Y12- Adenosine diphosphate receptor antagonists JAMA 2019;321:2414-2427.

Methods• Multicenter, open-label, randomized clinical trial in Japan

JAMA 2019;321:2414-2427.*DAPT for 1st month– Aspirin 81-200 mg/day + clopidogrel 75 mg/day or prasugrel 3.75 mg/day

3,045 patients included

Randomized 1:1

DAPT* x 1 month DAPT* x 1 month

Clopidogrel 75 mg x 11 months ASA + Clopidogrel x 11 month

Endpoints

• Primary efficacy endpoint

– Composite: CV death, MI, definite ST, stroke, TIMI major or minor bleeding

• Key secondary endpoint

– CV Composite: CV death, MI, definite ST, or stroke

• Key safety endpoint

– TIMI major/minor bleeding

JAMA 2019;321:2414-2427.TIMI – Thrombolysis in myocardial infarction

Statistical Analysis

• Intention-to-treat

• 2,980 patients would be needed for 85% power to exclude non-inferiority (ꭤ=0.025)

• Pre-specified subgroup analyses

• Time-to-event methods & hazard ratios with 95% CI

JAMA 2019;321:2414-2427.

Baseline Characteristics

HFrEF – Heart failure with reduced ejection fractionCABG – Coronary artery bypass graft JAMA 2019;321:2414-2427.

Characteristic 1-Month DAPT (n=1500) 12-Month DAPT (n=1509)

Age – years 68 ± 10.9 69.1 ± 10.4

Male– no. (%) 1183 (78.9) 1154 (76.5)

Past Medical History – no. (%)

Hypertension 1105 (73.7) 1116 (74.0)

Hyperlipidemia 1116 (74.4) 1128 (74.8)

Diabetes 585 (39.0) 574 (38.0)

Severe chronic kidney disease 82 (5.5) 84 (5.6)

Congestive heart failure 115 (7.7) 107 (7.1)

Prior myocardial infarction 207 (13.8) 199 (13.2)

Prior CABG 17 (1.1) 42 (2.8)

Prior PCI 503 (33.5) 529 (35.1)

Prior bleeding events 19 (1.3) 28 (1.9)

Baseline Characteristics

JAMA 2019;321:2414-2427.

Characteristic 1-Month DAPT (n=1500) 12-Month DAPT (n=1509)

Indication for PCI, no. (%)

Stable coronary artery disease 935 (62.3) 926 (61.4)

Acute coronary syndrome 565 (37.7) 583 (38.6)

STEMI 291 (19.4) 270 (17.9)

NSTEMI 81 (19.4) 99 (6.6)

Unstable Angina 193 (12.9) 214 (14.2)

Procedural characteristics

Number of target lesions, mean±SD 1.1 ± 0.4 1.1 ± 0.4

Left main coronary artery, no. (%) 43 (2.9) 37 (2.5)

Discharge medications, no. (%)

Clopidogrel 903 (60.2) 949 (62.9)

Prasugrel 594 (39.6) 557 (37.0)

Statins 1318 (87.9) 1318 (87.3)

Beta blockers 672 (44.8) 643 (42.6)

ACEi/ARB 934 (62.3) 939 (62.2)

ACEi/ARB–Ace inhibitor/Angiotensin-receptor blocker

Primary EndpointEndpoint

1-Month DAPT(n=1500)

12-Month DAPT(n=1509)

HR (95% CI)

Primary Composite, no. (%) 35 (2.36) 55 (3.70) 0.64 (0.42-0.98)

CV death 9 (0.61) 11 (0.74) 0.83 (0.34-1.99)

MI 13 (0.88) 11 (0.75) 1.19 (0.54-2.67)

Definite ST 2 (0.13) 1 (0.07) 2.02 (0.18-22.26)

Ischemic or hemorrhagic stroke 8 (0.54) 16 (1.09) 0.50 (0.22-1.18)

TIMI major/minor bleeding 6 (0.41) 23 (1.54) 0.26 (0.11-0.64)

JAMA 2019;321:2414-2427.

Secondary Endpoints

• Cardiovascular efficacy composite endpoint

JAMA 2019;321:2414-2427.

Key Subgroup Analyses

JAMA 2019;321:2414-2427.

Conclusions

• 1 month of DAPT therapy led to a significant reduction in the composite outcome of cardiovascular and bleeding events

– This was driven by less major and minor bleeding in the extra short DAPT group

• Further studies are required to substantiate these findings

JAMA 2019;321:2414-2427.

Study Critique

• Selection bias

• Underpowered for thrombotic outcomes

• Low ACS population

• Antiplatelet regimens

• Only DES was CoCr-EES

• Open label design

• Exclusive Japanese population

JAMA 2019;321:2414-2427.

Clinical Implications

• Impact on clinical practice is unknown

– GLOBAL LEADERS (2018)

• No reduction in major bleeding with 1 month of DAPT

– SMART-CHOICE (2019)

• No reduction in major bleeding with 3 months of DAPT

• Larger studies are needed in higher risk patient populations

JAMA 2019;321:2414-2427.

Effect of 1-month dual antiplatelet therapy (DAPT) followed by clopidogrel vs 12-month DAPT on cardiovascular and bleeding events

in patients receiving PCI: STOPDAPT-2

Nick Orvin, PharmD

PGY2 Cardiology Pharmacy Resident

WakeMed Health & Hospitals, Raleigh, NC

Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation

(AUGUSTUS)

Melissa Chinn, PharmDPGY2 Cardiology Resident

University of Virginia Health SystemCharlottesville, VA

Presenter Bio

Dr. Melissa Chinn is a PGY2 Cardiology Pharmacy Resident at the University of Virginia. She graduated from Lipscomb University College of Pharmacy and completed her PGY1 Pharmacy Residency at Baptist Memorial Hospital in Memphis, Tennessee.

Disclosure Statement

Melissa Chinn has no conflicts of interest to disclose.

Background

Atrial Fibrillation (AF)

Acute Coronary Syndrome (ACS)

Curr Emerg Hosp Med Rep. 2016;4(3):107-118.

Background

Pioneer AF-PCI

Rivaroxaban 15mg daily or 2.5mg twice daily

12 months

Lower clinically significant bleeding vs. warfarin

No difference in major CV events

Re-Dual PCI

Dabigatran 150mg twice daily or 110mg twice daily

12 months

Lower major or clinically relevant non-major bleeding vs. warfarin

No difference in major CV events

NEJM 2016;375(25):2423-2434.

NEJM 2017;377(16):1513-1524.

Study Objective

Assess the safety and efficacy of standard-dose apixaban as compared with a vitamin K antagonist

(VKA) and of low-dose aspirin as compared to placebo in patients with AF and recent ACS or PCI.

NEJM 2019;380(16):1509-1524.

Study Population

Inclusion Criteria Exclusion Criteria

- 18 years of age or older- Previous, persistent, permanent, or

paroxysmal AF and planned long-term use of an oral anticoagulant

- Recent ACS or PCI- Planned use of a P2Y12 inhibitor for

at least 6 months

- Use of anticoagulation for other conditions (e.g. prosthetic valves, venous thromboembolism, mitral stenosis)

- Severe renal insufficiency (SCr > 2.5 or CrCl < 30mL/min)

- History of intracranial hemorrhage- Recent or planned coronary artery

bypass graft surgery- Coagulopathy- Ongoing bleeding- Contraindication to a VKA, apixaban,

all P2Y12 inhibitors, or aspirin

NEJM 2019;380(16):1509-1524.

Study Design• Prospective, multicenter, 2x2 factorial, randomized clinical trial

• Randomization• Study Groups

• Stratification• ACS vs. PCI at enrollment

• Patients received concomitant P2Y12 inhibitor during the trial

P2Y12 Inhibitor Total

Clopidogrel 4165 (92.6)

Prasugrel 51 (1.1)

Ticagrelor 280 (6.2)

NEJM 2019;380(16):1509-1524.

Aspirin No Aspirin

N (%)

Apixaban 1153 (25) 1153 (25)

Warfarin 1154 (25) 1154 (25)

Outcomes

• Major or clinically relevant non-major bleedingPrimary Outcome

• Apixaban would be non-inferior or superior to VKA

• P2Y12 inhibitor as single agent would be superior to DAPT

Hypotheses

• Composite: death or hospitalization

• Composite: death or ischemic eventsSecondary Outcomes

NEJM 2019;380(16):1509-1524.

Statistics & Enrollment

Statistics

• 4,600 patients (357 events) required to detect non-inferiority margin of 1.2 77% power

• Intention to treat analysis

Enrollment

• Sept 2015 – April 2018

• N = 4,614

• 492 sites in 33 countries

• Median time from index event = 6 days (IQR 3-10)

NEJM 2019;380(16):1509-1524.

Baseline Characteristics

Age 70.7 years (median)

29% women

92% Caucasian

37.3% ACS with PCI

38.8% elective PCI

23.9% medically managed ACS

13.8% history of CVA/TIA

CHA2DS2-VASc median score 4 (IQR 3-5)

HAS-BLED median score 3 (IQR 2-3)

49% previous use of an anticoagulant

8.4% with SCr ≥ 1.5mg/dL

10% received apixaban 2.5mg twice daily

NEJM 2019;380(16):1509-1524.

Outcomes

NEJM 2019;380(16):1509-1524.

Outcomes

Outcomes

Outcomes

NEJM 2019;380(16):1509-1524.

Outcomes

NEJM 2019;380(16):1509-1524.

Individual Efficacy OutcomesOutcome Anticoagulation Regimen Antiplatelet Regimen

ApixabanVitamin K

AntagonistHazard Ratio

(95% CI)Aspirin Placebo

Hazard Ratio (95% CI)

Hospitalization 518 (22.5) 607 (26.3) 0.83 (0.74-0.93) 585 (25.4) 540 (23.4) 1.10 (0.98-1.24)

Death 77 (3.3) 74 (3.2) 1.03 (0.75-1.42) 72 (3.1) 79 (3.4) 0.91 (0.66-1.26)

Death from CV causes 57 (2.5) 54 (2.3) 1.05 (0.72-1.52) 53 (2.3) 58 (2.5) 0.92 (0.63-1.33)

Stroke 13 (0.6) 26 (1.1) 0.50 (0.26-0.97) 20 (0.9) 19 (0.8) 1.06 (0.56-1.98)

Myocardial infarction 72 (3.1) 80 (3.5) 0.89 (0.65-1.23) 68 (2.9) 84 (3.6) 0.81 (0.59-1.12)

ARC definite or probable stent thrombosis

14 (0.6) 18 (0.8) 0.77 (0.38-1.56) 11 (0.5) 21 (0.9) 0.52 (0.25-1.08)

Urgent revascularization

40 (1.7) 44 (1.9) 0.90 (0.59-1.38) 37 (1.6) 47 (2.0) 0.79 (0.51-1.21)

NEJM 2019;380(16):1509-1524.

Individual Safety OutcomesOutcome Anticoagulant Regimen Antiplatelet Regimen

ApixabanVitamin K

AntagonistHazard Ratio

(95% CI)Aspirin Placebo

Hazard Ratio (95% CI)

ISTH major bleeding

69 (3.0) 104 (4.6) 0.64 (0.47-0.86) 108 (4.7) 65 (2.9) 1.70 (1.25-2.31)

Clinically relevant nonmajor bleeding

180 (7.9) 246 (10.9) 0.69 (0.57-0.84) 275 (12.1) 148 (6.5) 1.93 (1.58-2.36)

Intracranial hemorrhage

5 (0.2) 13 (0.6) 0.39 (0.14-1.12) 8 (0.4) 10 (0.4) 0.82 (0.32-2.07)

GUSTO severe or moderate bleeding

41 (1.8) 68 (3.0) 0.58 (0.39-0.86) 68 (3.0) 40 (1.8) 1.72 (1.17-2.55)

TIMI major or minor bleeding

96 (4.2) 132 (5.8) 0.70 (0.54-0.91) 146 (6.4) 80 (3.5) 1.88 (1.43-2.47)

NEJM 2019;380(16):1509-1524.

Author’s Conclusions

In patients with AF and a recent ACS or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted

in less bleeding and fewer hospitalizations

NEJM 2019;380(16):1509-1524.

Study Critique

Strengths

• Included ACS with PCI, medical management, and elective PCI patients

• Appropriate AF dosing of apixaban

• On concomitant P2Y12 inhibitor

• Superiority of primary and secondary outcomes

Limitations

• Time in therapeutic range with VKA lower than previous AF trials

• ACS with PCI indication not differentiated into STEMI vs. NSTEMI

• Not powered to detect differences in individual ischemic outcomes

Impact on Clinical Practice

• Increased use of apixaban with P2Y12 inhibitor in patients with AF and recent ACS or PCI?• Necessity of DAPT after PCI vs. aspirin omission

• Future studies• Differentiate STEMI and NSTEMI patients

• Larger population of women

Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation

(AUGUSTUS)

Melissa Chinn, PharmDPGY2 Cardiology Resident

University of Virginia Health SystemCharlottesville, VA

Next Journal Club

• See you in September!• Date/Time to be determined