1 / 24

The PLATO trial was funded by AstraZeneca

Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO trial. The PLATO trial was funded by AstraZeneca

talen
Download Presentation

The PLATO trial was funded by AstraZeneca

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO trial The PLATO trial was funded by AstraZeneca Dr. Held discloses research grants/support from the following companies: AstraZeneca, GlaxoSmithKline, Schering-Plough, Sanofi-Aventis, Pfizer, Bristol-Myers Squibb

  2. PLATO background • In NSTEMI and STEMI ACS, current guidelines recommend 12 months’ treatment with aspirin and clopidogrel • Clopidogrel has been studied extensively and used to treat millions of ACS patients successfully, but its efficacy is hampered by • slow and variable transformation to the active metabolite • modest and variable platelet inhibition • risk of stent thrombosis and MI in poor responders • irreversible effect – and increased risk of bleeding if urgent CABG is required • In patients with an urgent need for CABG, clopidogrel is recommended to be withdrawn 5 days prior to surgery • Clinical reality often require surgery earlier and a rapid offset of the antiplatelet therapy is preferred PLATO = PLATelet inhibition and patient Outcomes; NSTEMI = non-ST segment elevation; STEMI = ST segment elevation; ACS = acute coronary syndromes; MI = myocardial infarction; CABG = coronary artery bypass graft

  3. Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP) • Direct acting • Not a pro-drug; does not require metabolic activation • Rapid onset of inhibitory effect on the P2Y12 receptor • Greater inhibition of platelet aggregation than clopidogrel • Reversibly bound • Degree of inhibition reflects plasma concentration • Faster offset of effect than clopidogrel • Functional recovery of circulating platelets within ~48 hours

  4. PLATO study design NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624) Clopidogrel-treated or -naive; randomized <24 hours of index event After randomization, 1,261 patients underwent CABG and were on study drug treatment for ≤7 days prior to surgery Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre-PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) 6–12 months treatment Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding Recommendations for patients undergoing CABG:Study drugs withheld prior to surgery – 5 days for clopidogrel and 24–72 hours for ticagrelor. Study drug be restarted as soon as possible after surgery and prior to discharge PCI = percutaneous coronary interventionCV = cardiovascular

  5. PLATO main endpoints* Primary safety endpoint Primary efficacy endpoint 13 15 12 11.7 Clopidogrel 11 Ticagrelor 10 11.58 9.8 11.20 9 10 Clopidogrel Ticagrelor 8 7 K-M estimated rate (%) K-M estimated rate (%) 6 5 5 4 3 2 HR 0.84 (95% CI 0.77–0.92), p=0.0003 1 HR 1.04 (95% CI 0.95–1.13), p=0.434 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Months from randomization Months from randomization No. at risk 9,235 7,246 6,826 6,545 5,129 3,783 3,433 Ticagrelor 9,333 8,460 4,147 8,628 8,219 6,743 5,161 9,186 7,305 6,930 6,670 5,209 3,841 3,479 Clopidogrel 9,291 8,362 4,047 8,521 8,124 6,743 5,096 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval * Wallentin, L et al., New Eng J Med. 2009;361:1045–1057

  6. Objectives • Antiplatelet therapy currently recommended in ACS is clopidogrel and aspirin • Recovery of platelet function occurs after 5–7 days following irreversible platelet inhibition by aspirin and clopidogrel • This can increase the risk of complications in patients urgently needing major surgery such as CABG • However, the reversible P2Y12 inhibition provided by ticagrelor could shorten this interval to 2–3 days • The objective of this pre-defined PLATO analysis was to evaluate the efficacy and safety after CABG (in patients with last intake of study drug within 7 days of surgery)

  7. Patient disposition 18,758 patients enrolled in PLATO 134 patients not randomized 18,624 patients randomized Non-CABG: 16,725 patients CABG: 1,899 patients Last intake of study drug ≤7 days prior to surgery: 1,261 patients 629 patients treated with clopidogrel 632 patients treated with ticagrelor

  8. Baseline characteristics of patients undergoing CABG with last intake of study drug within 7 days of surgery

  9. Baseline CV risk and history

  10. Evaluations and invasive procedures bpm = beats per minute; LBBB = left bundle branch block; TIMI = thrombolysis in myocardial infarction

  11. Study medication OL = open-label; IP = investigational product

  12. Study medication pre- and post-CABG *Percentages calculated based on number of patients with available data

  13. Co-medication (at study start) ACE = angiotensin II-converting enzyme; ARB = angiotensin II receptor blocker

  14. Time to first CABG surgery by treatment(total PLATO population) 12 10 8 6 4 2 0 Clopidogrel 11.4 10.9 Ticagrelor K-M estimated rate (%) HR: 0.96 (95% CI = 0.87–1.05), p=0.36 0 1 2 3 4 5 6 7 8 9 10 11 12 Months from randomization No. at risk Ticagrelor Clopidogrel 9,235 7,289 6,862 6,570 5,144 3,775 3,414 9,186 7,320 6,936 6,657 5,209 3,843 3,470

  15. Primary endpoint: CV death, MI or stroke 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Clopidogrel 13.1 10.6 Ticagrelor K-M estimated rate (%) HR: 0.84 (95% CI = 0.60–1.16), p=0.29 0 1 2 3 4 5 6 7 8 9 10 11 12 Months from CABG procedure No. at risk Ticagrelor 629 543 519 458 386 268 108 Clopidogrel 629 541 516 448 386 255 125

  16. Primary and secondary efficacy endpoints post-CABG Ticagrelor(n=631) Clopidogrel(n=629) Hazard Ratio (95% CI) Characteristic p-value Primary endpoint 0.84 (0.60, 1.16) 10.5 12.6 0.29 CV death + MI + stroke Secondary endpoints 1.06 (0.66, 1.68) 5.9 5.6 0.82 MI 0.52 (0.32, 0.85) 4.0 7.5 0.009 CV death 1.17 (0.53, 2.62) 1.7 0.70 2.1 Stroke 1.29 (0.57, 2.95) Non-hemorrhagic/unknown stroke 2.1 1.6 0.54 0.0 0.2 Hemorrhagic stroke 0.49 (0.32, 0.77) 4.6 9.2 0.002 All-cause mortality 0.35 (0.11, 1.11) 0.07 0.6 1.7 Non-CV death 0.2 0.5 1.0 2.0 Ticagrelor better Clopidogrel better Patients could have had more than one type of endpoint. Event rate is number of events divided by n

  17. CV death post-CABG Clopidogrel 8 7 6 5 4 3 2 1 0 7.9 4.1 K-M estimated rate (%) Ticagrelor HR: 0.52 (95% CI = 0.32–0.85), p=0.009 0 1 2 3 4 5 6 7 8 9 10 11 12 Months from CABG procedure No. at risk Ticagrelor 629 583 557 491 415 291 119 Clopidogrel 629 565 539 472 404 269 130

  18. All cause mortality post-CABG Clopidogrel 10 9 8 7 6 5 4 3 2 1 0 9.7 K-M estimated rate (%) 4.7 Ticagrelor HR: 0.49 (95% CI 0.32–0.77), p<0.01 0 1 2 3 4 5 6 7 8 9 10 11 12 Months No. at risk Ticagrelor Clopidogrel 629 583 557 491 415 291 119 629 565 539 472 404 269 130

  19. Safety: bleeding post-CABG Characteristic Ticagrelor(n=631) Clopidogrel(n=629) Odds Ratio (95% CI) p-value CABG-related bleeding Major bleeding 81.2 80.1 0.67 1.07 (0.80, 1.43) Life-threatening/fatal bleeding 0.73 43.7 42.6 1.04 (0.83, 1.31) 0.83 (0.20, 3.28) 0.77 Fatal bleeding 0.8 1.0 1.01 (0.06, 16.09) All intracranial bleeding post-CABG* 1.00 0.2 0.2 0.53 1.08 (0.85, 1.36) TIMI major bleeding 59.3 57.6 0.84 0.97 (0.73, 1.28) TIMI minor bleeding 21.0 21.6 GUSTO severe bleeding 0.38 10.6 12.2 0.85 (0.59, 1.22) 0.2 0.5 1.0 2.0 Ticagrelor better Clopidogrel better All event rates are number of events divided by n *Hazard ratio Kaplan-Meier estimates. Both CABG-related and non-related

  20. Safety: bleeding post-CABG (cont’d) Characteristic p value Ticagrelor(n=631) Clopidogrel(n=629) Hazard/Odds Ratio (95% CI) Hemoglobin decrease* >50 g/L 38.1 36.2 0.52 1.08 (0.86, 1.37) 0.40 >30 g/L 69.9 67.6 1.12 (0.87, 1.43) Major/life-threatening CABG-related bleeding resulting in death within 7 days of CABG† 0.44 (0.19, 1.01) 0.05 1.3 2.9 1.19 (0.63, 2.27) Re-operation due to bleeding* 4.0 3.3 0.65 0.2 0.5 1.0 2.0 Ticagrelor better Clopidogrel better *Odds ratio and p-value from Fisher’s exact test †Hazard ratio Event rate is number of events divided by n

  21. Treatment safety: transfusions post-CABG 0.2 0.5 1.0 2.0 Ticagrelor better Clopidogrel better p value Ticagrelor(n=631) Clopidogrel(n=629) Hazard/Odds Ratio (95% CI) Characteristic Transfusions within 7 days post-CABG 0.98 (0.85, 1.14) Any transfusion 55.2 55.8 0.83 1.03 (0.88, 1.20) PRBC or whole blood* 52.7 51.2 0.69 0.88 (0.67, 1.16) 15.3 17.3 Platelets 0.37 Fresh frozen plasma 1.05 (0.84, 1.31) 25.2 24.0 0.67 Transfusions post CABG-related bleeding† 1.12 (0.83, 1.53) >4 units blood 17.9 16.2 0.45 1.25 (0.70, 2.23) >5 units whole blood/PRBC (2 days) 0.49 4.9 4.0 1.24 (0.61, 2.52) Chest tube output >2L (24 hours)† 3.3 2.7 0.62 *Median (range) units transfused within 7 days post-CABG: tic 3.0 (2.0–4.0) vs. clop 3.0 (2.0–4.0); p=0.86†Odds ratio and p-value from Fisher’s exact test

  22. CABG-related bleeding Ticagrelor Clopidogrel 100 NS 90 81.2 80.1 80 NS 70 59.3 57.6 60 K-M estimated rate (% per year) 50 40 NS 30 21.6 21.0 NS 20 12.2 10.6 NS 10 1.0 0.8 0 Major CABG-related bleeding CABG-related TIMI major bleeding CABG-related TIMI minor bleeding CABG-related GUSTO severe bleeding CABG-related fatal bleeding Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. New Eng J Med. 2007;357:2001–15; NS = not significant

  23. Limitations • Retrospective analysis of a non-randomized subgroup of patients requiring CABG • selection bias, survivor bias or other confounders • The formal adjudication of causes of deaths in the main trial separated death from vascular and non-vascular cause, but a further subcategorization was not performed • a retrospective central review of the causes of post-CABG death is currently ongoing

  24. Conclusions • In ACS patients undergoing CABG within 7 days after stopping treatment with ticagrelor – a reversible, more intense P2Y12 receptor antagonist – is associated with • substantially fewer deaths – both total and CV • no change in the overall risk of CABG-related bleeding In ACS patients undergoing CABG surgery, ticagrelor is a more effective alternative to clopidogrel for the continuous prevention of cardiovascular and total death without an increase in major bleeding

More Related