ACCP Cardiology PRN Journal Club March 29 th , 2016 Announcements - - PowerPoint PPT Presentation

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

• We have created a PB Works Site that will house our recorded

calls, handouts, and Summary/Q&A documents. The link is https://accpcardsprnjournalclub.pbworks.com/

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

Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) Trial: Stopping vs. Continuing Aspirin before Coronary Artery Surgery

Zachary Noel, PharmD, BCPS PGY2 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

• f 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

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

• utcomes

Aspirin Use Perioperatively

Background: Current Guidelines on Aspirin Use Prior to Coronary Surgery

Guideline Year Recommendation Strength of Evidence Canadian Cardiovascular 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 Trials

Study Methods ASA Dose Results

Preoperative Aspirin Therapy Is Associated With Improved Postoperative Outcomes in CABG Retrospective cohort

• f patients receiving

ASA within 5 days of surgery 81-325mg Reduction in in-hospital mortality with no difference in bleeding Effect of Timing of Chronic Preoperative Aspirin Discontinuation in CABG Retrospective review

• f 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 and meta-analysis Systematic review and meta-analysis of pre-

• perative 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) Aspirin (ASA) +

• +

ASA TXA ASA Placebo

• Placebo

TXA 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 criteria
• 1. 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 50-100mg
• 2. Consider aprotinin
• 3. 5U platelet transfusion if platelets < 100,000/L
• 4. 5U fresh frozen plasma if INR >1.4 or fibrinogen

<150 g/L

• 5. Cryoprecipitate if fibrinogen <100 g/L
• 6. Recombinant factor VIIa 90ug/kg, aprotinin, or

desmopressin if above strategies ineffective

Endpoints

Endpoints Criteria Primary Composite all-cause mortality and major ischemic complications within 30 days

• f 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 (1047) +

• +

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) Placebo N=1053) Age (years) 66 66 Male (%) 872 (83) 858 (82) NYHA Classification (%) I II III IV 163 (16) 580 (55) 276 (26) 28 (3) 184 (17) 578 (55) 271 (26) 19 (2) EuroSCORE (% risk) 4.1 4.1 Comorbidities (%) Diabetes Hypertension Angina Heart failure MI within 90 days Previous 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-elective On-pump surgery Off-pump surgery Isolated CABG surgery Combined CABG-valve surgery 120 (12) 1013 (97) 34 (3) 775 (74) 233 (22) 111 (11) 1022 (97) 29 (3) 801 (76) 209 (20) Surgical Characteristics Median number of grafts Median cross clamp time (min.) Duration of surgery (hrs) 3 67 3.8 3 66 3.8 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 (%) Death MI Stroke Renal failure PE Bowel infarction 202 (19.3) 14 (1.3) 144 (13.8) 14 (1.3) 49 (4.7) 8 (0.8) 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

0.30 0.20 0.70 0.39 0.81 0.50

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 Intraoperatively Day 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 transfusion Intraoperatively Day 1 103 (9.8) 157 (15) 106 (10.1) 38 (13.1) 0.88 (0.76-1.26) 1.14 (0.93-1.41) 0.88 0.23 FFP transfusion Intraoperatively Day 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) 0.52 0.86 Red-cell transfusion Intraoperatively Day 1 Day 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) 0.76 0.81 0.08 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 prespecified

subgroups, including age, diabetes, history of MI, unstable angina, EuroSCORE, surgery type

• r 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
• r thrombotic events when ASA is administered

immediately preoperatively, contrary to other studies and meta-analyses

• These results do not suggest an increase in post-
• perative 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

• f 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.