תרופות מעכבות טסיות חדשות ד"ר אלי לב מנהל שרות הצנתורים ח השרון מרכז רפואי רבין

Transcription

1 תרופות מעכבות טסיות חדשות ד"ר אלי לב מנהל שרות הצנתורים ח השרון בי""י מרכז רפואי רבין

2 1. Why should clopidogrel be replaced? 2. Prasugrel 3. Ticagrelor 4. Conclusions

3

4 CURE TRIAL ACS pts 20 % reduction in primary endpoint (N Engl J Med. 2001;345: )

5 PCI-CURE TRIAL ACS pts Pretreatment with clopidogrel vs. no pretreatment Reduction in CV death, MI or urgent TVR CURE Investigatots, Lancet :

6 Distribution of Response to (544 patients, platelet aggregation) 112 Serebrauny V et al. JACC 2004 Number of patients <= -20 [-10,0] [11,20] [31,40] [51,60] [71,80] [91,100] Change in Aggregation to 5µM ADP

7 Impact of Response on Stent Thrombosis 804 pts who had successful PCI with DES implantation Loaded with 600 mg clopidogrel,, platelet reactivity to ADP assessed hrs after loading 105 pts (13%) not responsive to clopidogrel ST incidence: 8.6% vs. 2.3% (non responders vs responders) P<0.001 ST Buonamici et al, JACC 2007 non responders responders

8 metabolism

9 Efficacy of clopidogrel is hampered by: Wide variability in response (variable platelet inhibition) Risk of stent thrombosis and MI in poor responders Slow and variable transformation to the active metabolite interaction with other drugs PPIs, genetic polymorphisms (about 25-30% carriers) Slow onset of action, long withdrawal - Platelet inhibition effect of 600 mg bolus after hrs, of 300 mg bolus after hrs

10 PRASUGREL (Effient( Effient) Theinopyridine (3 rd generation) P2Y12 receptor inhibitor Prodrug (similar to clopidogrel and ticlopidine) requires metabolism to form active metabolite Pharmacodynamic advantages: Increased IPA Rapid onset of IPA activity ( hour after 60 mg loading) More consistent IPA response (less inter-patient variability) Drug response not affected by CYP2C19 polymorphisms (Mega et al, Circ.ulation2009) nor by ABCB1 polymorphisms (Mega et al, Lancet 2010)

11 S 85% Inactive Metabolites (hydrolysis) O O N C C Cl Prasugrel: : Active Metabolite Formation Faster Onset of IPA O CH 3 O CH 3 Pro-drug Pre-hepatic metabolism - Hydrolysis Esterases in blood O C CH 3 O Sem Vasc Med 3:113, 2003 O S S O N F Prasugrel O N F O S N Cl HOOC * HS O N Cl OCH 3 Hepatic Metabolism Cytochrome P450 Active Metabolite HOOC * HS O N F

12 Healthy Volunteer Crossover Study Inhibition of Platelet Aggregation (%) Brandt J et al. AHJ 2007 IPA (20 µm M ADP) at 24 H (n=68) Interpatient Variability N = mg Responder* Nonresponder *Responder = 25% IPA at 4 and 24 h Prasugrel 60 mg Interpatient Variability

13 Prasugrel 10 mg MD vs. 75 mg MD: Higher IPA During Maintenance Dosing Inhibition of Platelet Aggregation (%) Loading Dose Pras 60 mg * *! * * * * Clop 600 mg! Clop 300 mg Maintenance Doses * * * Pras 10 mg * * * * Clop 75 mg Clop 75 mg mean ± SEM 20 µm M ADP * P<0.001 vs. Clop 300 mg or 600 mg LD P<0.001 vs. Clop 300! P<0.05 vs. Clop 300 P<0.05 vs Clop 300/ Payne CD et al. Presented at TCT Hours Time Days

14 TRITON TIMI-38 Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI ASA Double-blind blind n=13,500 CLOPIDOGREL 300 mg LD / 75 mg MD PRASUGREL 60 mg LD / 10 mg MD Median duration of therapy: 12 months 1 o endpoint: CV death, MI, Stroke 2 o endpoints: CV death, MI, Stroke, Rehosp-Recurrent Recurrent Ischemia CV death, MI, UTVR Wiviott SD et al. Am Heart J. 2006; 152:

15 CV Death/MI/Stroke (%) TRITON-TIMI TIMI 38: Primary End Point All ACS Population HR 0.77 ( ) P<0.001 HR 0.80 ( ) P< Days Prasugrel Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%) 12.1 (n=781) 9.9 (n=643) HR 0.81 ( ) P<0.001 ARR=2.2 NNT=46 ACS=Acute Coronary Syndrome; ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT=Number Needed to Treat Wiviott SD et al. New Engl J Med 2007;357:

16 15 TRITON-TIMI TIMI 38: Rates of Key Study End Points (All ACS) End Point (%) CV Death, MI, Stroke Non-CABG TIMI Major Bleeds Prasugrel Prasugrel Days After Randomization 12.1 (781) 9.9 (643) P< events P= events 2.4 (146) 1.8 (111) CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. New Engl J Med 2007;357:

17 Stent Thrombosis (%) TRITON-TIMI TIMI 38: ARC Definite/Probable Stent Thrombosis: Any Stent at Index PCI n=12,844 Prasugrel HR 0.48 ( ) P< RRR 52% NNT=77 ARR 1.22% Days ARC=Academic Research Consortium; ARR=Absolute Risk Reduction; HR=Hazard Ratio; NNT=Number Needed to Treat; PCI=Percutaneous Coronary Intervention; RRR=Relative Risk Reduction Wiviott SD et al. Lancet 2008;371:

18 Stent Thrombosis Rates at End of Study 4 Prasugrel Stent Thrombosis* (%) % RRR (1.2% ARR) P< % RRR (1.5% ARR) P< % RRR (1.1% ARR) P= N=6,422 N=6,422 n=2,865 n=2,878 n=3,237 n=3,224 All Stents Wiviott et al. Lancet. 2008;371(9621): Drug-eluting Stents *Stent thrombosis defined as Academic Research Consortium definite plus probable Based on Kaplan-Meier estimates; RRR = relative risk reduction; ARR = absolute risk reduction Bare-metal Stents

19 Stent Thrombosis

20 TRITON-TIMI TIMI 38: Other TIMI Bleeds at 15 Months (All ACS) (n=6,716) (n=6,741) Odds Ratio 4.73 P< % At risk 24/179 End Point (%) P= % 3.8% n=303 n=231 P< % 3.0% n=244 n= % At risk 6/189 TIMI Major or Minor Requiring Transfusion CABG-related TIMI Major Bleeding ACS=Acute Coronary Syndrome; CABG=Coronary Artery Bypass Graft surgery; HR=Hazard Ratio; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. New Engl J Med 2007;357:

21 TRITON-TIMI TIMI 38: Diabetic Subgroup Analysis (n=3,146) End Point (%) Prasugrel CV Death, MI, Stroke Non-CABG TIMI Major Bleeds HR 0.70 P<0.001 NNT= Days CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT= Number Needed to Treat; TIMI=Thrombolysis In Myocardial Infarction Adapted from Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL

22 TRITON-TIMI TIMI 38: STEMI Subgroup Analysis (n=3,534) P=0.01 Prasugrel 4 3 P=0.05 P=0.045 P=0.01 P= All cause Death CV death RE-MI Stent thrombosis Non CABG bleeding

23 Bleeding Risk Subgroups Therapeutic Considerations Reduced MD Guided by PK Age > 75 or Wt < 60 kg 16% Avoid Prasugrel Prior CVA/TIA 4% Significant Net Clinical Benefit with Prasugrel 80% TRITON-TIMI 38, NEJM 2007

24 TRITON-TIMI TIMI 38: Clinical Implications For every 1,000 patients treated with prasugrel compared with clopidogrel 23 MI s are prevented 6 more non-cabg TIMI major bleeds are experienced Over 15 months Number needed to treat is 46 to prevent one CV death, nonfatal MI or nonfatal stroke Number needed to harm is 167 to cause one non- CABG TIMI major bleed CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction MI Non CABG Major Bleeding Wiviott SD et al. New Engl J Med 2007;357:

25 Prasugrel Current Status Approved by FDA 07/2009 Class I indication for patients with STEMI (as an alternative to clopidogrel) ) by both AHA/ACC and ESC guidelines. Recommended for STEMI and diabetes by UK - NICE

26 HO HO O OH TICAGRELOR (Brilinta( Brilinta): an oral N N N S reversible P2Y 12 antagonist N N H N F F Ticagrelor is a cyclo-pentyltriazolo-pyrimidine (CPTP) Direct acting Not a prodrug; does not require metabolic activation Rapid onset of inhibitory effect on the P2Y 12 receptor Greater and more consistent inhibition of platelet aggregation vs clopidogrel Not affected by CYP2C19 and ABCB1 polymorphisms (Wallentin et al, Lancet 2010) Reversibly bound Degree of inhibition reflects plasma concentration Faster offset of effect than clopidogrel Functional recovery of all circulating platelets

27 Phrmakodynamics of ticagrelor onset offset study Ticagrelor Gurbel, et al, Circulation 2009

28 PLATO study design UA/NSTEMI (moderate-to-high risk) STEMI (if primary PCI) All receiving ASA; clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) 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-month exposure Primary endpoint: CV death + MI + Stroke Key secondary: CV death + MI + Stroke in patients intended for invasive management Total mortality + MI + Stroke CV death + MI + Stroke + recurrent ischaemia + TIA + arterial thrombotic events MI alone / CV death alone / Stroke alone / Total mortality Primary safety: Total major bleeding Wallentin et al, N Engl J Med 2009

29 K-M M estimate of primary efficacy event (composite of CV death, MI or stroke) Cumulative incidence (%) Ticagrelor HR 0.84 (95% CI ), p= No. at risk Ticagrelor Days after randomisation 9,333 8,628 8,460 8,219 6,743 5,161 4,147 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

30 K-M M estimates of time to secondary 7 efficacy endpoints Myocardial infarction Cardiovascular death!!! Cumulative incidence (%) Ticagrelor HR 0.84 (95% CI ), p=0.005 Cumulative incidence (%) Ticagrelor HR 0.79 (95% CI ), p= No. at risk Days after randomisation Days after randomisation Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8, ,482 4,419 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8, ,441 4,364

31 Stent thrombosis Evaluated in patients with any stent during the study % P=0.01 P= Ticagrelor Definite Definite or Probable Wallentin et al, N Engl J Med 2009

32 Major bleeding primary safety event 15 K-M estimated rate (% per year) Ticagrelor HR 1.04 (95% CI ), p= No. at risk Days from first IP dose Ticagrelor 9,235 7,246 6,826 6,545 5,129 3,783 3,433 9,186 7,305 6,930 6,670 5,209 3,841 3,479

33 K-M estimated rate (% per year) NS 11.2 PLATO major bleeding Total major bleeding 7.9 NS 7.7 TIMI major bleeding NS Red cell transfusion * NS PLATO lifethreatening/ 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. NEJM 2007;357: ; * Proportion of patients (%); NS = not significant Ticagrelor NS Fatal bleeding

34 Non-CABG and CABG-related major bleeding K-M estimated rate (% per year) p= p= NS NS 5.8 Ticagrelor 1 0 Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

35 Other findings All patients Ticagrelor (n=9,235) (n=9,186) p value * Dyspnoea, % Any <0.001 Requiring discontinuation of study treatment <0.001

36 Plato Invasive - All-cause mortality K-M estimated rate (% per year) Ticagrelor 2 HR 0.81 (95% CI = ), p= No. at risk Ticagrelor 6,732 6,439 6,375 Days after randomization 6,241 5,141 3,951 3,233 6,676 6,376 6,331 6,209 5,114 3,917 3,164 Cannon et al, Lancet 2010

37 PLATO STEMI - Primary endpoint: K-M estimated rate (% per year) CV death, MI or stroke Ticagrelor No. at risk Ticagrelor HR: 0.85 (95% CI = ), p= Months 4,201 4,229 3,887 3,892 3,834 3,823 3,732 3,011 3,730 3,022 2,297 2,333 1,891 1,868

38 PLATO STEMI - All cause mortality 7 K-M estimated rate (% per year) No. at risk Ticagrelor Ticagrelor HR 0.82 (95% CI = ), p= Months 4,201 4,005 3,962 3,876 3,150 2,413 1,993 4,229 4,029 3,989 3,912 3,195 2,471 1,

39 Therapeutic considerations Based on 1,000 patients admitted to hospital for ACS, using ticagrelor instead of clopidogrel for 12 months resulted in: 14 fewer deaths 11 fewer myocardial infarctions 6 88 fewer cases with stent thrombosis No increase in bleedings requiring transfusion 10 patients may switch to thienopyridine treatment because of reversible symptoms of dyspnoea Treating 54 patients with ticagrelor instead of with clopidogrel for one year will prevent one event of CV death, MI or stroke

40 Ticagrelor - Conclusions and Current Status Tested in a mod.-high risk ACS, including STEMI Reduction in MI and stent thrombosis Reduction in CV and total mortality!! No change in the overall risk of major bleeding!! FDA Advisory Committee recommended US FDA approval of Ticagrelor (Brilinta)) for ACS in 07/2010

41 Conclusions - general New anti-platelet drugs specifically ADP receptor antagonists - have been proven to be effective in large phase III trials More intense, predictable and rapid platelet inhibition translates to reduced ischemic complications (compared with clopidogrel) Bleeding price especially for prasugrel Special subgroups benefit the most (e.g. STEMI, diabetes) The various alternatives will create an opportunity for personalized medicine based on thrombotic / bleeding risk

42 THANK YOU