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

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

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

CURE TRIAL ACS pts 20 % reduction in primary endpoint (N Engl J Med. 2001;345:494-502)

PCI-CURE TRIAL ACS pts Pretreatment with clopidogrel vs. no pretreatment Reduction in CV death, MI or urgent TVR CURE Investigatots, Lancet 2001 358: 527-33

Distribution of Response to (544 patients, platelet aggregation) 112 Serebrauny V et al. JACC 2004 Number of patients 96 80 64 48 32 16 0 <= -20 [-10,0] [11,20] [31,40] [51,60] [71,80] [91,100] Change in Aggregation to 5µM ADP

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 12-18 18 hrs after loading 105 pts (13%) not responsive to clopidogrel ST incidence: 8.6% vs. 2.3% (non responders vs responders) 9 8 7 6 5 4 3 2 1 0 P<0.001 ST Buonamici et al, JACC 2007 non responders responders

metabolism

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 2-4 4 hrs, of 300 mg bolus after 4-6 6 hrs

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 (0.5-1 1 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)

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

Healthy Volunteer Crossover Study Inhibition of Platelet Aggregation (%) 100.0 80.0 60.0 40.0 20.0 0.0-20.0 Brandt J et al. AHJ 2007 IPA (20 µm M ADP) at 24 H (n=68) Interpatient Variability N = 68 300 mg Responder* Nonresponder *Responder = 25% IPA at 4 and 24 h Prasugrel 60 mg Interpatient Variability

Prasugrel 10 mg MD vs. 75 mg MD: Higher IPA During Maintenance Dosing Inhibition of Platelet Aggregation (%) 100 80 60 40 20 0 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 300/75 0 0.25 0.5 1 2 4 6 24 3 4 5 6 7 8 9 Payne CD et al. Presented at TCT 2006. Hours Time Days

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; 152:627-35.

CV Death/MI/Stroke (%) 15 10 5 0 TRITON-TIMI TIMI 38: Primary End Point All ACS Population HR 0.77 (0.67-0.88) P<0.001 HR 0.80 (0.71-0.90) P<0.001 0 30 60 90 180 270 360 450 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 (0.73-0.90) 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;357:2001-2015

15 TRITON-TIMI TIMI 38: Rates of Key Study End Points (All ACS) End Point (%) 10 5 0 CV Death, MI, Stroke Non-CABG TIMI Major Bleeds Prasugrel Prasugrel 0 30 60 90 120 180 270 360 450 Days After Randomization 12.1 (781) 9.9 (643) P<0.001 138 events P=0.03 35 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;357:2001-2015

Stent Thrombosis (%) 3 2 1 TRITON-TIMI TIMI 38: ARC Definite/Probable Stent Thrombosis: Any Stent at Index PCI n=12,844 Prasugrel 2.35 1.13 HR 0.48 (0.36-0.64) P<0.0001 RRR 52% NNT=77 ARR 1.22% 0 0 30 60 90 180 270 360 450 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;371:1353-1363

Stent Thrombosis Rates at End of Study 4 Prasugrel Stent Thrombosis* (%) 3 2 1 52% RRR (1.2% ARR) P<0.0001 64% RRR (1.5% ARR) P<0.0001 2.35 2.31 1.13 0.84 48% RRR (1.1% ARR) P=0.0009 1.27 2.41 0 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):1353-1363. 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

Stent Thrombosis

TRITON-TIMI TIMI 38: Other TIMI Bleeds at 15 Months (All ACS) (n=6,716) (n=6,741) Odds Ratio 4.73 P<0.001 13.4% At risk 24/179 End Point (%) P=0.002 5.0% 3.8% n=303 n=231 P<0.001 4.0% 3.0% n=244 n=182 3.2% 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;357:2001-2015

TRITON-TIMI TIMI 38: Diabetic Subgroup Analysis (n=3,146) End Point (%) 18 16 14 12 10 8 6 4 2 Prasugrel CV Death, MI, Stroke Non-CABG TIMI Major Bleeds 17.0 12.2 HR 0.70 P<0.001 NNT=21 2.6 2.5 0 0 30 60 90 180 270 360 450 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

TRITON-TIMI TIMI 38: STEMI Subgroup Analysis (n=3,534) 7 6 5 P=0.01 Prasugrel 4 3 P=0.05 P=0.045 P=0.01 P=0.4 2 1 0 All cause Death CV death RE-MI Stent thrombosis Non CABG bleeding

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

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 -23 +6 Non CABG Major Bleeding Wiviott SD et al. New Engl J Med 2007;357:2001-2015

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

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

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

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

K-M M estimate of primary efficacy event (composite of CV death, MI or stroke) Cumulative incidence (%) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Ticagrelor HR 0.84 (95% CI 0.77 0.92), p=0.0003 11.7 9.8 No. at risk Ticagrelor 0 60 120 180 240 300 360 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

K-M M estimates of time to secondary 7 efficacy endpoints Myocardial infarction Cardiovascular death!!! 6.9 7 Cumulative incidence (%) 6 5 4 3 2 1 0 5.8 Ticagrelor HR 0.84 (95% CI 0.75 0.95), p=0.005 Cumulative incidence (%) 6 5 4 3 2 1 0 5.1 4.0 Ticagrelor HR 0.79 (95% CI 0.69 0.91), p=0.001 0 60 120 180 240 300 360 0 60 120 180 240 300 360 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 8,626 7119 5,482 4,419 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8,589 7079 5,441 4,364

Stent thrombosis Evaluated in patients with any stent during the study % 3 2.5 2 P=0.01 P=0.02 1.5 1 Ticagrelor 0.5 0 Definite Definite or Probable Wallentin et al, N Engl J Med 2009

Major bleeding primary safety event 15 K-M estimated rate (% per year) 10 5 0 Ticagrelor HR 1.04 (95% CI 0.95 1.13), p=0.434 11.58 11.20 0 60 120 180 240 300 360 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

K-M estimated rate (% per year) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 11.6 NS 11.2 PLATO major bleeding Total major bleeding 7.9 NS 7.7 TIMI major bleeding NS 8.9 8.9 Red cell transfusion * NS 5.8 5.8 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;357:2001 15; * Proportion of patients (%); NS = not significant Ticagrelor NS 0.3 0.3 Fatal bleeding

Non-CABG and CABG-related major bleeding K-M estimated rate (% per year) 9 8 7 6 5 4 3 2 p=0.026 4.5 3.8 p=0.025 2.8 2.2 7.4 NS 7.9 5.3 NS 5.8 Ticagrelor 1 0 Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

Other findings All patients Ticagrelor (n=9,235) (n=9,186) p value * Dyspnoea, % Any 13.8 7.8 <0.001 Requiring discontinuation of study treatment 0.9 0.1 <0.001

Plato Invasive - All-cause mortality K-M estimated rate (% per year) 6 5.08 4 3.94 Ticagrelor 2 HR 0.81 (95% CI = 0.68 0.95), p=0.01 0 0 60 120 180 240 300 360 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

PLATO STEMI - Primary endpoint: K-M estimated rate (% per year) 12 11 10 9 8 7 6 5 4 3 CV death, MI or stroke Ticagrelor 11.0 9.3 2 1 0 No. at risk Ticagrelor HR: 0.85 (95% CI = 0.74 0.97), p=0.02 0 1 2 3 4 5 6 7 8 9 10 11 12 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

PLATO STEMI - All cause mortality 7 K-M estimated rate (% per year) 6 5 4 3 2 1 0 No. at risk Ticagrelor Ticagrelor HR 0.82 (95% CI = 0.68 0.99), p=0.04 0 1 2 3 4 5 6 7 8 9 10 11 12 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 1,980 6.0 4.9

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

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

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

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