ACCP Cardiology PRN Journal Club

March 29th, 2016

Announcements

• Thank you attending the ACCP Cardiology PRN Journal Club– Thank you if you attended before or have been attending

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Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS)

Trial: Stopping vs. Continuing Aspirin before Coronary Artery Surgery

Zachary Noel, PharmD, BCPSPGY2 Cardiology Resident

University of Kentucky Healthcare

Danielle Blais, PharmD, BCPS Cardiology Specialty Pharmacist

Ohio State University Medical Center

Background: Effect of Aspirin on Platelets

• Average platelet lifespan 7-10 days

• Aspirin (ASA) prevents formation of thromboxane A2 via cyclooxygenase (COX) inhibition– Single 100mg dose provides maximal COX

inhibition in 60 minutes

– Effect persists for lifespan of platelet

• Discontinuation of aspirin for ~3-5 days restores 50% of the active platelet pool

Aspirin. Circulation. 2000;101:1206-1218

Background: Aspirin Use in Coronary Artery Disease• Aspirin is one of the cornerstone therapies for

secondary prevention of coronary artery disease (CAD)

• Interventional therapies for CAD include percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)

• Optimal perioperative ASA dose and timing prior to CABG is not known– Risk of thrombotic events with discontinuation vs. risk

of bleeding complications with continuation is not well defined

Perioperative Use of Aspirin in Coronary Artery Surgery

-5 +2 Discontinuing likely associated with greater thrombotic risk

-4 0

Unknown whether continuing aspirin during this period reduces thrombotic events, but may be associated with modest increases in blood loss

Restarting ASA within 24-48 hours post-op associated with improved graft patency, fewer ischemic events, and mortality benefit

Delayed ASA initiation associated with worse outcomes

Aspirin Use Perioperatively

Background: Current Guidelines on Aspirin Use Prior to Coronary Surgery

Guideline Year Recommendation Strength of Evidence

CanadianCardiovascular Society Guidelines

2011 Patients who are receiving ASA and require CABG should continue ASA up to the time of surgery

IB

ACCF/AHA Guidelines 2011 Aspirin should be administered preoperatively IB

Society of Thoracic Surgeons Guidelines

2012 The interval between discontinuation of antiplatelet drugs and operation is uncertain and depends on multiple factors related to patient drug responsiveness and thrombotic risk

IIA

American College of Chest Physicians Guidelines

2012 Continue ASA around the time of surgery instead of stopping ASA 7 to 10 days before surgery

2C

The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines. Can J Cardiol. 2011; 27.2011 ACCF/AHA guideline for coronary artery bypass graft surgery: executive summary. J Thorac Cardiovasc Surg. 2012; 143: 4-34.Antiplatelet Drugs in Cardiac and Noncardiac Operations. Ann Thorac Surg. 2012;94:1761–81.Douketis JD, et al. The perioperative management of antithrombotic therapy: Chest 2012; 133: Suppl: 299S-339S.

Background TrialsStudy Methods ASA Dose Results

Preoperative Aspirin Therapy Is Associated With ImprovedPostoperative Outcomes in CABG

Retrospective cohort of patients receiving ASA within 5 days of surgery

81-325mg Reduction in in-hospital mortalitywith no difference in bleeding

Effect of Timing of Chronic Preoperative Aspirin Discontinuation in CABG

Retrospective review of those taking ASA >6 days or ≤5 days before CABG

Unknown No difference in mortality or thrombotic events but more transfusions in the late use group

Aspirin and coronary artery surgery: a systematic review andmeta-analysis

Systematic review and meta-analysis of pre-operative ASA use prior to CABG

81-325mg Lower incidence of MI but higher blood loss and surgical re-exploration in those taking ASA before surgery

Circulation. 2005;112 [suppl I]:I-286–I-292.Circulation. 2011;123:577-583.British Journal of Anaesthesia. 2015, 376–85

ATACAS Trial

• Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) Trial

• Designed to evaluate patients at risk for thrombotic complications undergoing elective CABG to determine whether:

1. ASA should be continued up until the day of CABG

2. TXA should be routinely used in CABG

Trial Design

Tranexamic Acid (TXA)

Asp

irin

(A

SA) + -

+ ASATXA

ASAPlacebo

- PlaceboTXA

Placebo Placebo

• Randomized, double-blind, multicenter, placebo-controlled trial

• 2 x 2 factorial design with patient allocated in a 1:1:1:1 fashion

Methods

• Inclusion criteria1. Elective CABG (on- or off-pump)

AND

2. Identified as elevated risk for major complications:• Age ≥ 70 years old

• Left ventricular (LV) impairment

• Concomitant valvular or aortic surgery

• Chronic obstructive pulmonary disease

• Repeat cardiac surgery

• Renal impairment (SCr >2.0 mg/dl; CrCl<45 ml/min.)

• BMI >25 kg/m2

• Mean pulmonary arterial pressure >25 mm Hg

• Peripheral vascular disease

Methods

• Exclusion Criteria– ASA use within 5 days of surgery– Warfarin or clopidogrel use within 7 days of surgery– Glycoprotein IIb/IIIa antagonists within 24 hours of surgery– History of bleeding disorder– Thrombocytopenia– Severe renal impairment (serum creatinine >3.3 mg/dl;

creatinine clearance <25 ml/min.)– Poor English language comprehension– Clinician preference towards antifibrinolytic therapy– Thromboembolic disease– Urgent CABG – Allergy of contraindication to ASA or TXA– Pregnancy

Procedures

• Randomized in a 1:1 fashion to:

– ASA 100mg 1-2 hours preoperatively

OR

- Placebo

- Postoperative antiplatelet therapy was administered in accordance with local practices

- Patients followed for 30 days

Standardization

• Standardized protocols for heparinization, ACT goal, protamine reversal, and red blood cell transfusions were employed

• Stepwise algorithm for excessive bleeding:1. Protamine 50-100mg2. Consider aprotinin3. 5U platelet transfusion if platelets < 100,000/L4. 5U fresh frozen plasma if INR >1.4 or fibrinogen

<150 g/L5. Cryoprecipitate if fibrinogen <100 g/L6. Recombinant factor VIIa 90ug/kg, aprotinin, or

desmopressin if above strategies ineffective

EndpointsEndpoints Criteria

Primary

Composite all-cause mortality and major ischemic complications within 30 days of operation

Major ischemic complications defined as:• MI, stroke, PE, renal failure, bowel

infarction

Secondary

All-cause mortality

Ischemic complications Defined as:• MI, stroke, PE, renal failure, bowel

infarction

Bleeding complications and blood transfusions

Bleeding complications defined as:• Major hemorrhage requiring

reoperation for bleeding• Cardiac tamponade

MI – myocardial infarction; PE – pulmonary embolism

Prespecified Subgroup Populations

• Age • Sex• Diabetes• Prior MI• Unstable angina• European System for Cardiac Operative Risk

Evaluation (EuroSCORE)• LV function• Bleeding risk during surgery• On-pump/off-pump procedure• Aortic total ischemic time

Statistical Analysis

• Intent-to-treat analysis

• Power calculations

– 4484 patients needed to detect a 30% difference in the primary outcome (alpha 0.05; beta 0.1)

– Prespecified goal to enroll 4600 patients

Results

• Over 11,000 were screened but only 5700 were eligible

• 2127 patients were enrolled between 2006 to 2013

TXA (1053)

ASA

(1

04

7) + -

+ 517 523

- 525 524

Myles PS et al. N Engl J Med 2016;374:728-737

Results

• Due to lower than expected enrollment rates but higher than anticipated primary outcome rates, the trial was stopped in July 2013

• Revised power analysis based on enrollment at that time could detect with 96% power a 30% relative risk reduction

– Minimal between group difference that could be detected with 80% power was 24% lower relative risk

Baseline Characteristics

Characteristic ASA(N=1047)

PlaceboN=1053)

Age (years) 66 66

Male (%) 872 (83) 858 (82)

NYHA Classification (%)IIIIIIIV

163 (16)580 (55)276 (26)

28 (3)

184 (17)578 (55)271 (26)

19 (2)

EuroSCORE (% risk) 4.1 4.1

Comorbidities (%)DiabetesHypertensionAnginaHeart failureMI within 90 daysPrevious cardiac surgery

347 (33)847 (80)744 (71)136 (13)

75 (7)17 (2)

368 (35)845 (80)756 (72)133 (13)

83 (8)14 (1)

Baseline Characteristics (cont.)Characteristic ASA

(N=1047)Placebo

(N=1053)

Surgery Status (%)Non-electiveOn-pump surgeryOff-pump surgeryIsolated CABG surgeryCombined CABG-valve surgery

120 (12)1013 (97)

34 (3)775 (74)233 (22)

111 (11)1022 (97)

29 (3)801 (76)209 (20)

Surgical CharacteristicsMedian number of graftsMedian cross clamp time (min.)Duration of surgery (hrs)

3673.8

3663.8

Postoperative ASA use within 24 hours (%) 819 (78) 799 (76)

Primary Outcome

Outcome ASA (N=1047)

Placebo(N=1053)

Risk Ratio (95% CI)

P Value

Primary outcome (%)

DeathMIStrokeRenal failurePEBowel infarction

202 (19.3)

14 (1.3)144 (13.8)

14 (1.3)49 (4.7)8 (0.8)

0

215 (20.4)

9 (0.9)166 (15.8)

12 (1.1)41 (3.9)10 (1.0)2 (0.2)

0.94 (0.80-1.12)

1.56 (0.68-3.60)0.87 (0.71-1.07)1.17 (0.55-2.52)1.20 (0.80-1.80)0.81 (0.32-2.03)

--

0.55

0.300.200.700.390.810.50

Bleeding Outcomes

Outcome ASA (N=1047)

Placebo(N=1053)

Risk Ratio (95% CI)

P Value

Reoperation for hemorrhage 19 (1.8) 22 (2.1) 0.87 (0.47-1.60) 0.75

Cardiac tamponade 11 (1.1) 4 (0.4) 2.77 (0.88-8.66) 0.08

Recombinant factor VII administration

IntraoperativelyDay 1

3 (0.3)3 (0.3)

2 (0.2)2 (0.2)

1.51 (0.25-9.01)1.21 (0.37-3.94)

0.69>0.99

Platelet transfusionIntraoperativelyDay 1

103 (9.8)157 (15)

106 (10.1)38 (13.1)

0.88 (0.76-1.26)1.14 (0.93-1.41)

0.880.23

FFP transfusionIntraoperativelyDay 1

59 (5.6)182 (17.4)

67 (6.4)187 (17.8)

0.89 (0.63-1.24)0.98 (0.81-1.18)

0.520.86

Red-cell transfusionIntraoperativelyDay 1Day 2 to discharge

152 (14.5)303 (28.9)199 (18.8)

147 (14.0)299 (28.4)169 (16.1)

1.04 (0.84-1.28)1.02 (0.89-1.17)1.19 (0.98-1.43)

0.760.810.08

Blood transfusion within 24 hours of surgery

460 (43.9) 449 (42.6) 1.03 (0.93-1.14) 0.57

Subgroup Analyses

• No significant difference in the prespecifiedsubgroups, including age, diabetes, history of MI, unstable angina, EuroSCORE, surgery type or cross clamp time

• Statistically significant increase in 30 day mortality among males in the aspirin group (RR 2.94; 95% CI 1.11-13.9; p value 0.046)

Study Limitations

• Change in practice guidelines during study

• Selection bias

• Institution specific protocols

• Postoperative MI detection

Trial Conclusions

• There was no association between ASA use immediately prior to CABG and risk of death, thrombotic complications, or bleeding complications

Clinical Implications

• Results confirm that what most institutions already do - continue ASA before surgery - is not harmful

• These results do not suggest a decrease in death or thrombotic events when ASA is administered immediately preoperatively, contrary to other studies and meta-analyses

• These results do not suggest an increase in post-operative bleeding when ASA is administered immediately preoperatively, contrary to other studies and meta-analyses

Conclusion

• Because the majority of patients undergoing CABG are on ASA for CAD and there does not appear to be an increased risk of bleeding complications postoperatively in those taking ASA, combined with the well-established benefits of starting ASA within 24-48 hours postoperatively, continuing ASA before CABG is practical and safe; however, it does not appear to have clinical benefit in reducing death and thrombotic complications

Thank You

• Danielle Blais, PharmD, BCPS

• Craig Beavers, PharmD, FAHA, AACC, BCPS (AQ-Cardiology), CACP

• Carrie Oliphant, PharmD, FCCP, BCPS-AQ Cardiology

• Ted Berei, PharmD, MBA

Questions?

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

Join us next month when we hear the EMPA-REG Trial from

Dr. Michelle Lew, PharmD, BCPS PGY-2 Cardiology resident at

USC with Dr. Craig Beavers, PharmD, FAHA, AACC, BCPS (AQ-

Cardiology), CACP as her mentor.