ACCP Cardiology PRN Journal Club - PowerPoint Presentation

Slide1

ACCP Cardiology PRN Journal ClubSlide2

Announcements

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link is https://

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/

If there are any suggestions, please let us know. Slide3

The Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction (PEGASUS-TIMI 54)

Sheena Mathew,

Pharm.D

.

May 29, 2015Slide4

Disclosure Statement:

Presenters have no conflicts to report related to financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation Slide5

Background

Patients with myocardial infarction (MI) have higher risk for recurrent ischemic events

Activated platelets responsible for cardiovascular (CV) ischemic risk

Use of dual-antiplatelet therapy (DAPT) with aspirin and a P2Y

12

inhibitor can help reduce the risk of ischemic events in the first year after acute coronary syndrome (ACS)

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide6

Background: PLATO Trial

Multi-center randomized double-blind trial

Compared clopidogrel (loading dose 300-600 mg, maintenance dose 75 mg daily) to ticagrelor (loading dose 180 mg, maintenance dose 90 mg twice daily)

In addition to aspirin 75-325 mg

Patient Population: All ACS patients, with or without ST-segment elevation with an onset of symptoms in the previous 24 hours

Primary endpoint: composite of death from vascular causes, MI, or stroke

Wallent

L, et al. NEJM. 2009; 361 (11):1045-1057.Slide7

Background: PLATO Trial

Outcome

Ticagrelor

vs. Clopidogrel,

Hazard Ratio (95% CI)

P-Value

Primary

outcome:

9.8 % vs 11.7,

0.84 (0.77-0.92)

<0.001

Secondary

Endpoints:

Death from

any cause, MI, or stroke

10.2% vs. 12.3%, 085 (0.77-0.92)<0.001Death from vascular causes, MI, stroke, severe recurrent ischemia, TIA or other arterial thrombotic event14.6% vs. 16.7%, 0.88 (0.81-0.95)<0.001MI5.8% vs. 6.9%, 0.84 (0.75-0.95)0.005Death from any cause4.5% vs. 5.9%, 0.78 (0.69-0.89)<0.001Stent thrombosis-definite1.3% vs. 1.9%, 0.67 (0.50-0.91)0.009Adverse EventsTIMI Major Non-CABG Bleeding2.8% vs. 2.2%, 1.25 (1.03-1.43)0.03PLATO Major Non-CABG Bleeding4.5% vs. 3.8%, 1.19 (1.02-1.38)0.03Dyspnea-Any13.8% v.s 7.8%, 1.84 (1.68-2.02)<0.001

Wallent

L, et al. NEJM. 2009; 361 (11):1045-1057.Slide8

Background

Trial

Outcomes

DAPT Trial

Compared continued

thienopyridine

vs aspirin alone for 30 months

Statistically significant difference in the decrease of the primary outcome in the continued

thienopyridine

group:

Stent-thrombosis

MACCE: Death, MI

Statistically significant increase in bleeding in the continued

thienopyridine

group (based on the GUSTO criteria and the BARC criteria)

Trilogy-ACS Trial Compared the use of 30 months of DAPT with prasugrel vs. clopidogrel for 30 months in patients with unstable angina or MI without ST-segment elevation and did not undergo revascularization Prasugrel did not significantly reduce the primary endpoint of death from CV causes, MI, or strokeThe incidence of bleeding occurred with similar frequency in both groups (based on the GUSTO criteria) in both age <75 years and overall populationSlight increase in the prasugrel group in the TIMI criteria for major or minor bleed in patients <75 years of ageTreatment with DAPT Beyond 12 Months Maur L, et al. NEJM. 2014; 371(23):2155-2166.Roe mT, et al. NEJM. 2012; 367 (14): 1297-1309.Slide9

Background

Treatment with DAPT Beyond 12 Months

Trial

Outcomes

CHARISMA

Trial

DAPT with

clopidogrel + low-dose aspirin vs. aspirin alone in patients with high-risk

atherthrombotic

events

There was no difference between the two groups in the primary efficacy end point of first occurrence of MI, stroke, or death from CV causes

Statistically significant increase in moderate bleeding based on the GUSTO definition in the

clopidogrel

group vs. the placebo group

Bhatt DL, et al. NEJM. 354(16):1706-1717.Slide10

Background

Minimum Duration of DAPT

Levine G, et al.

Circulation

. 2011; 124(23): e574-e651

Windecker S, et al.

Eur Heart J

. 2014;

35:2541-619Slide11

Background & Purpose

Randomized, Double-Blind, placebo-controlled clinical trial

Purpose:

To test whether long-term therapy with ticagrelor added to low-dose aspirin reduces the risk of major CV events among stable patients with a history of MI.

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide12

Study-Design

Inclusion

Criteria

Exclusion Criteria

Spontaneous

MI 1-3 years before enrollment

Age

≥ 50 years

One of the following additional high-risk features:

Age of 65 years or older

Diabetes mellitus requiring medications

A second prior spontaneous MI

Multivessel

CAD

Chronic renal dysfunction (CrCl<60 ml/min)

Planned use of a P2Y12 receptor antagonist, dipyridamole, cilostazol, or anticoagulant therapy during the study period Bleeding disorder historyHistory of ischemic strokeHistory of intracranial bleed Central nervous system tumor Intravascular abnormalityGastrointestinal (GI) bleed within the previous 6 months Major surgery within the previous 30 days Renal failure requiring dialysis Concomitant use of potent inducer/inhibitor/substrate of CYP3A4Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.Slide13

Study-Design

Treatment Arms: Study Duration-3 years

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide14

Statistical Analysis

Power:

90-mg dose vs. placebo for the primary endpoint: 1360 events for 90% power to detect a 20% reduction

60-mg dose vs. placebo for the primary endpoint:1360 events to provide 83% power to detect a 19% reduction

Event probabilities:

Kaplan-Meier estimates of cumulative incidence at 36 months

Hazard ratios:

Generated using Cox proportional hazard model

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide15

Study-Design

Primary Endpoint

Composite of CV death, MI, or stroke

Secondary Endpoint

CV death and death from any cause

Composite

endpoint

of death from coronary heart disease, MI, or stroke

Individual components of the composite endpoints

Urgent coronary revascularization

Hospitalization for unstable angina

Transient ischemic attack (TIA)

Safety Endpoint

Major

Bleeding based on the thrombolysis of myocardial infarction (TIMI) definition

Intracranial hemorrhage Fatal bleeding Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.Slide16

Patient Demographics

Characteristic

Ticagrelor, 90 mg (N=7050)

Ticagrelor,

60 mg (N=7045)

Placebo (N=7067)

Age

65.4±8.4

65.2±8.4

65.4±8.3

Multivessel

CAD

1-

no/total no. (%)

4155/7049

(58.9)4190/7042 (59.5)4213/7067 (59.6) History of PCI-no. /total no. (%)5852/7049 (83.0)5879/7044 (83.5)5837/7066 (82.6) >1 Prior MI –no. (%)1143 (16.2)1168 (16.6)1188 (16.8)Years since MI-Median (IQR)1.7 (1.7-2.3)1.7 (1.2-2.3)1.7 (1.2-2.3)Type of MI-no. (%) STEMI3753/7043 (53.4)3757/7035 (53.4)3809/7057 (54.0)NSTEMI2898/7043 (41.1)2842/7035 (40.4)2843/7057 (40.3)Unknown 382/7043 (5.4)436/7035 (6.2)405/7057 (5.7) Aspirin at any dose-no. (%) 7039 (99.8)7036 (99.9)7057 (99.9

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide17

Results

Endpoint

Ticagrelor 90

mg vs. Placebo; % (HR, 95% CI; P-value)

Ticagrelor 60 mg. vs.

Placebo; % (HR, 95% CI; P-value)

C

V Death, MI, or Stroke

7.85 vs.

9.04 (0.85, 0.75-0.96, p=0.008)

7.77 vs. 9.04 (0.84, 0.74-0.95, p=0.004)

Death from CHD

1

, MI,

or stroke

6.99 vs. 8.33 (0.82, 0.72-0.93, p=0.002)7.09 vs. 8.33 (0.83, 0.73-0.94, p=0.003)CV death or MI6.79 vs. 7.81 (0.85, 0.75-0.97, p=0.01)6.77 vs. 7.81 (0.85, 0.74-0.96, p=0.01)Death from CHD, or MI5.59 vs. 6.68 (0.81, 0.71-0.94, p=0.004)5.75 vs. 6.68 (0.84, 0.73-0.96, p=0.01)CV death2.94 vs. 3.39 (0.87, 0.71-1.06, p=0.15)2.86 vs. 3.39 (0.83, 0.68-1.01, p=0.07)1Coronary heart diseaseBonaca MP., et al. NEJM. 2015;372(19):1791-1800.Slide18

Results

Outcome

Ticagrelor 90

mg vs. Placebo; % (HR, 95% CI; P-value)

Ticagrelor 60 mg. vs.

Placebo; % (HR, 95% CI; P-value)

Death from CHD

1.53

vs. 2.08 (0.73, 0.56-0.95, p=0.02)

1.72 vs. 2.08 (0.80, 0.62-1.04, 0.09)

MI

4.40

vs. 5.25 (0.81, 0.69-0.95, p=0.01)

4.53 vs. 5.25 (0.84, 0.72-0.98, p=0.03)

Stroke-

Any1.61 vs. 1.94 (0.82, 0.63-1.07, 0.14)1.47 vs. 1.94 (0.75, 0.57-0.98, p=0.03)Death from any cause 5.15 vs. 5.16 (1.00, 0.86-1.16, p=0.99)4.69 vs. 5.16 (0.89, 0.76-1.04, p=0.14) Bonaca MP., et al. NEJM. 2015;372(19):1791-1800.Slide19

Results

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide20

Results

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide21

Results

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide22

Author’s Conclusion

Addition of ticagrelor at a dose of 90-mg twice daily or 60-mg twice daily, to low-dose aspirin reduced the risk of CV death, MI, or stroke and increased the risk of TIMI major bleeding among patients who had an MI 1-3 years later

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide23

Discussion

Use of ticagrelor with low-dose aspirin in patients 1-3 years after MI significantly reduced the risk of CV death, MI, or stroke

Rates of discontinuation due to dyspnea of ticagrelor in the 90-mg group vs. the 60-mg was higher

displaying a more attractive benefit-risk profile in the 60-mg group

Longer duration of

ticagrelor

treatment was associated with an increased risk of bleeding

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide24

Discussion

PEGASUS-TIMI 54 compared to other long-term studies DAPT, Trilogy-ACS, and CHARISMA

varying data on extended-use of DAPT

mixed patient population

Vorapaxar

has been recently approved:

Reduction of thrombotic events in MI and peripheral arterial disease

Possible benefit for extended-use of DAPT

Usage of these agents will come with risk of bleed

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.

Morrow DA., et al. NEJM. 2012;366:1404-1413.Slide25

Discussion

Bonaca

MP., et al. NEJM. 2015;372(19):1791-1800.Slide26

Critique

Strengths

Study Design

Studied a lower-dose of ticagrelor (i.e. 60 mg twice daily)

Endpoints appropriately powered

Limitations

Excluded other antiplatelet agents and anticoagulants

Rates of discontinuation due to bleeding and dyspnea down-played

Did not disclose patient population bleeding history Slide27

Practical Implications

Displays the benefit and effect of DAPT with

ticagrelor

and aspirin in patients who had an MI in the previous 1-3 years

Must assess the risk of bleed vs. the benefit in utilization of extended use of dual antiplatelet therapy

NNT: 90

mg:

84, 60

mg:

79

NNH: 90

mg: 64, 60 mg: 8160 mg tablet strength not available

FDA recently accepted priority review of ticagrelor 60 mg tablet

If approved potential benefit of using 60-mg twice daily dose instead of the 90-mg twice daily doseSlide28

Acknowledgements

Journal Club Mentor:

Carrie Oliphant,

Pharm.D

., BCPS-AQ Cardiology

Program Directors:

ACCP Cardiology PRN Journal Club Coordinator:

Craig Beavers,

Pharm.D

.,

FAHA, AACC, BCPS-AQ Cardiology, CACP

Elizabeth McNeely, Pharm.D., BCPS-AQ CardiologySlide29

The Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction (PEGASUS-TIMI 54)

Sheena Mathew,

Pharm.D

.

May 29, 2015Slide30

Thank you for attending!

If you would like to have your resident present, would like to be a mentor, or have questions or comments please e-mail the journal club at

accpcardsprnjournalclub@gmail.com

or

craig.beaverspharmd@gmail.com