Presentation is loading. Please wait.

Presentation is loading. Please wait.

Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet Inhibition and patient O utcomes trial Outcomes in patients.

Similar presentations


Presentation on theme: "Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet Inhibition and patient O utcomes trial Outcomes in patients."— Presentation transcript:

1 Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet Inhibition and patient O utcomes trial Outcomes in patients with a Planned Invasive Strategy The PLATO trial was funded by AstraZeneca Dr. Cannon discloses research grants/support from the following companies: Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Intekrin Therapeutics, Merck, Merck/Schering Plough Partnership, Novartis and Takeda; and equity in Automedics Medical Systems Invasive

2 PLATO background In STEMI and UA/NSTEMI, current guidelines recommend 12 months of aspirin and clopidogrel Efficacy of clopidogrel is hampered by – slow and variable transformation to the active metabolite (e.g. 2C19) – modest and variable platelet inhibition – risk stent thrombosis and MI in poor responders – Irreversible effect – and increased risk of bleeding if urgent CABG is required PLATO = PLATelet inhibition and patient Outcomes; NSTEMI = non-ST segment elevation; STEMI = ST segment elevation; ACS = acute coronary syndromes; MI = myocardial infarction

3 Invasive Ticagrelor (AZD 6140): an oral reversible P2Y 12 antagonist Ticagrelor is a cyclo-pentyl- triazolo-pyrimidine (CPTP) Direct acting – Not a prodrug; does not require metabolic activation – Rapid onset of inhibitory effect on the P2Y 12 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 Invasive PLATO study design 6–12 months treatment PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624) Clopidogrel-treated or -naive; randomized <24 hours of index event At randomization, 13,408 (72%) of patients were specified by the Investigator: intent for invasive strategy Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding Clopidogrel (n=6,676) 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 (n=6,732) 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI)

5 Invasive Baseline and index event characteristics Characteristic Ticagrelor (n=6,732) Clopidogrel (n=6,676) Median age, years 61.0 Age 75 years, %12.513.9 Women, %25.225.3 Diabetes mellitus22.823.7 History, % Myocardial infarction Percutaneous coronary intervention Coronary-artery bypass graft 17.1 14.1 5.3 17.0 13.3 5.7 ECG and Troponin at entry, % Persistent ST-segment elevation ST-segment depression T-wave inversion 48.4 52.8 28.7 49.3 54.0 29.4 Troponin-I positive (central lab, first) %82.384.0 Median time from chest pain to rand., h8.89.0

6 Invasive Procedures and timing * Procedure Ticagrelor (n=6,732) Clopidogrel (n=6,676) Invasive procedures at index hospitalization, % (n) Coronary angiography Median (IQR), hours PCI during index hospitalization % (n) Median (IQR), hours UA/NSTEMI – PCI % (n) Median (IQR), hours STEMI - Primary PCI % (n) Median (IQR), hours Coronary by-pass surgery pre-discharge % (n) Median (IQR), hours 96.8 (6514) 0.62 (0.10, 3.70) 76.7 (5166) 0.77 (0.30, 2.75) 63.8 (1882) 2.63 (0.78, 21.10) 83.2 (3138) 0.47 (0.23, 0.95) 5.5 (372) 117 (47, 216) 96.9 (6471) 0.62 (0.12, 3.65) 77.1 (5148) 0.78 (0.32, 2.65) 64.8 (1854) 2.60 (0.87, 21.30) 82.7 (3149) 0.48 (0.23, 0.95) 6.1 (410) 121 (48, 218) * Time between randomization and first procedure

7 Invasive Co-medication Medication Ticagrelor (n=6,732) Clopidogrel (n=6,676) Anti-thrombotic treatment in hospital, % Aspirin Unfractionated heparin Low molecular weight heparin Fondaparinux Bivalirudin GP IIb/IIIa inhibitor 97.7 35.1 41.1 1.6 1.2 19.7 97.9 36.0 40.9 1.8 1.3 20.3 Other medication in hospital or at discharge, % Beta-blockade ACE /ARB Cholesterol lowering (statin) Proton pump inhibitor 85.5 87.0 95.4 54.4 86.1 86.8 95.5 53.7

8 Invasive Treatment Ticagrelor (n=6,732) Clopidogrel (n=6,676) Clopidogrel % Prior to hospitalization7.36.7 Open-label Clopidogrel pre-Randomization, % None or missing information 75 mg 300 mg 600 mg 55.3 8.3 19.3 17.1 54.7 8.1 19.8 16.6 Study drug Clopidogrel (or placebo for Tic) in first 24 h None 75 mg 300 mg 600 mg Total Clopidogrel (OL+IP) pre-Randomization to 24 h 300 mg 600 mg Premature discontinuation of study drug, % 1.5 44.2 46.4 8.0 69.1 30.9 23.1 1.4 44.2 46.5 8.0 69.9 30.1 21.8 Clopidogrel / Ticagrelor treatment

9 Invasive Primary endpoint: CV death, MI or stroke 0 0 5 10 15 60120180240 300360 Days after randomization K-M estimated rate (% per year) HR: 0.84 (95% CI = 0.75–0.94), p=0.0025 9.02 10.65 Clopidogrel Ticagrelor No. at risk Clopidogrel Ticagrelor 6,676 6,732 6,129 6,236 6,034 6,134 5,8814,815 4,889 3,680 3,735 2,965 3,0485,972 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

10 Invasive Hierarchical testing of major efficacy endpoints Endpoint* Ticagrelor (n=6,732) Clopidogrel (n=6,676) HR for ticagrelor (95% CI)p value Primary objective, % CV death + MI + stroke9.010.70.84 (0.75–0.94)0.0025 Secondary objectives, % Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events MI CV death Stroke 9.4 13.2 5.3 3.4 1.2 11.2 15.3 6.6 4.3 1.1 0.84 (0.75–0.94) 0.85 (0.77–0.93) 0.80 (0.69–0.92) 0.82 (0.68–0.98) 1.08 (0.78–1.50) 0.001 0.0005 0.002 0.025 0.646 Total (all-cause) death3.95.10.81 (0.68–0.95)0.010 *The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. By univariate Cox model

11 Invasive No. at risk Clopidogrel Ticagrelor 6,676 6,732 6,157 6,268 6,062 6,173 5,917 Days after randomization 4,849 4,924 3,706 3,766 2,987 3,078 060120180240300360 8 6 4 2 0 Cumulative incidence (%) Clopidogrel Ticagrelor 5.3 6.6 6,010 060120180240300360 8 4 2 0 Clopidogrel Ticagrelor 3.4 4.3 6 6,676 6,732 6,376 6,439 6,332 6,375 6,209 Days after randomization 5,114 5,141 3,917 3,591 3,164 3,2336,241 Myocardial infarction Cardiovascular death Cumulative incidence (%) HR 0.80 (95% CI = 0.69–0.92), p=0.002 HR 0.82 (95% CI = 0.68–0.98), p=0.025

12 Invasive All-cause mortality 6 4 2 0 0 60120180240 300360 Clopidogrel Ticagrelor Days after randomization K-M estimated rate (% per year) 5.08 3.94 HR 0.81 (95% CI = 0.68–0.95), p=0.01 No. at risk Clopidogrel Ticagrelor 6,676 6,732 6,376 6,439 6,331 6,375 6,2095,114 5,141 3,917 3,951 3,164 3,2336,241

13 Invasive Stent thrombosis Ticagrelor (n=6,732) Clopidogrel (n=6,676) HR for ticagrelor (95% CI) p value* Stent thrombosis, % Definite Probable or definite Possible, probable, or definite 1.0 1.7 2.2 1.6 2.3 3.1 0.62 (0.45–0.85) 0.72 (0.56–0.93) 0.72 (0.58–0.90) 0.003 0.01 0.003 ¶ Evaluated in patients with any stent during the study Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization * By univariate Cox model

14 Invasive Primary efficacy endpoint by clopidogrel loading dose Ticagrelor betterClopidogrel better 0.51.02.00.2 Ti.Cl. Total Patients KM % at Month 12 HR (95% CI) Hazard Ratio (95% CI) Clopidogrel loading dose (Pre-rand. + Study drug) Characteristic 40918.09.5 0.83 (0.67, 1.03)600 mg 9.511.2 0.85 (0.74, 0.96)300 mg p value (Interaction) 0.917 9314

15 Invasive Primary safety event: Major bleeding * No. at risk Clopidogrel Ticagrelor 6,585 6,651 5,215 5,235 4,984 4,947 4,786 Days after randomization 3,753 3,726 2,754 2,741 2,496 2,503 060120180240300360 10 5 0 15 Clopidogrel Ticagrelor 11.6 11.5 4,755 K-M estimated rate (% per year) HR 0.99 (95% CI = 0.89–1.10), p=0.88 * PLATO definitions

16 Invasive Life-threatening or fatal bleeding* K-M estimated rate (% per year) No. at risk Clopidogrel Ticagrelor 6,585 6,651 5,400 5,387 5,180 5,113 5,009 Days from first IP dose 3,934 3,890 2,898 2,866 2,635 2,634 060120180240 300 360 6 2 0 8 4,945 HR 1.04 (95% CI = 0.90–1.20), p=0.61 4 Clopidogrel Ticagrelor 5.9 6.0 * PLATO definitions

17 Invasive Total major 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. NEJM 2007;357:2001–15; NS = not significant NS 0 K-M estimated rate (% per year) PLATO major bleeding 1 2 3 4 5 6 7 8 9 10 12 11 13 TIMI major bleeding Red cell transfusion PLATO life- threatening/ fatal bleeding Fatal bleeding 11.5 11.6 8.0 8.9 8.8 6.0 5.9 0.20.3 Ticagrelor Clopidogrel

18 Invasive Ticagrelor Clopidogrel NS 0 K-M estimated rate (% per year) PLATO major bleeding 1 2 3 4 5 6 7 8 9 10 12 11 13 TIMI major bleeding 11.5 11.6 8.0 2.9 3.2 GUSTO severe bleeding* 4.7 4.1 2.8 2.3 1.9 1.7 Non-CABG and CABG-related major bleeding Non-CABG CABG *Preliminary – from eCRF

19 Invasive Bradycardia-related events and other findings All patients Ticagrelor (n=6,732) Clopidogrel (n=6,676)p value * Bradycardia-related event, % Any bradycardia event Symptomatic event Sick sinus syndrome or sinus pause AV Block II-III Temporary pacemaker used Permanent pacemaker implanted Considered serious adverse event 5.5 2.1 0.4 0.5 0.8 0.5 1.0 5.1 2.4 0.4 0.6 0.5 1.1 0.26 0.24 0.89 0.15 0.26 1.00 0.73 All patients Ticagrelor (n=6,732) Clopidogrel (n=6,676)p value * Dyspnea, % Any dyspnea event Requiring discontinuation of study- treatment 15.4 0.9 10.4 0.3 <0.0001 *p values calculated using Fishers Exact test

20 Invasive Therapeutic considerations Based on 1,000 patients admitted to hospital for ACS and planned for invasive strategy, using ticagrelor instead of clopidogrel for 12 months resulted in – 11 fewer deaths – 13 fewer myocardial infarctions – 6 fewer cases with stent thrombosis – No increase in major bleeding or need for transfusion – 6 patients may switch to thienopyridine treatment because of reversible symptoms of dyspnoea Treating 59 patients with ticagrelor instead of with clopidogrel for one year will prevent one event of CV death, MI or stroke Treating 88 will save one life (in one year)

21 Invasive Conclusions Ticagrelor, the reversible, more intense P2Y 12 antagonist, is a more effective alternative to clopidogrel for one year in ACS patients managed with an invasive strategy, for the continuous prevention of ischemic events, stent thrombosis and death without an increase in major bleeding


Download ppt "Ticagrelor compared with clopidogrel in patients with acute coronary syndromes – the PLAT elet Inhibition and patient O utcomes trial Outcomes in patients."

Similar presentations


Ads by Google