Understanding the Options Available When Prescribing Dual Antiplatelet Therapy: Dose, Duration, Reversibility, Bleeding Profiles

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1 Understanding the Options Available When Prescribing Dual Antiplatelet Therapy: Dose, Duration, Reversibility, Bleeding Profiles Jessica L. Mega, MD MPH Cardiovascular Division Brigham and Women s Hospital Assistant Professor of Medicine Harvard Medical School Investigator, TIMI Study Group

2 Disclosures Received grants for clinical research or research supplies via the TIMI Study Group and Brigham and Women's Hospital from: Bayer Healthcare, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Johnson & Johnson, Sanofi-Aventis, Accumetrics, Nanosphere, NIH/NHLBI Served as a consultant for: Merck, Janssen

3 Platelets are Central To Coronary Thrombosis and Physiologic Hemostasis Adhesion Collagen GP la/lla bind Platelets von Willebrand Factor/GP lb bind Lipid core Thrombin Activation ADP 5 HT TXA 2 Aggregation Activated GP llb/llla Fibrinogen Handin RI. Harrison s Principles of Internal Medicine. Vol 1. 14th ed. NY, NY: McGraw-Hill; 1998:339. Schafer AI. Am J Med. 1996;101: STRIVE TM

4 The Transition from Unstable to Stable The good physician treats the disease; the great physician treats the patient who has the disease -Sir William Osler 3 Clinical Scenarios: 1. DAPT in Acute Management of ACS and Post-ACS Care 2. DAPT in Chronic Secondary Prevention 3. DAPT for PCI/Stenting

5 What are we treating with DAPT? ACS +/- PCI The First Year Vulnerable Stent Vulnerable Patient OR Curfman GD, et al. N Engl J Med. 2007;356:10. Meadows TA, Bhatt DL. Circ Res. 2007;100:

6 CURE: Primary Outcome by Type of Intervention Cumulative Hazard Rates Any Revascularization Group Placebo Clopidogrel RR:0.82 ( ) Days of Follow-up Cumulative Hazard Rates Medical Rx Group Placebo RR:0.80 ( ) Clopidogrel Days of Follow-up Cumulative Hazard Rates PCI Group Placebo RR:0.72 ( ) Clopidogrel Days of Follow-up Cumulative Hazard Rates CABG Group Placebo Clopidogrel RR:0.89 ( ) Days of Follow-up Adapted from Fox KAA, et al. Circulation. 2004;110:

7 Variable Response to Clopidogrel 20 Resistance = 31% 24 Hours After 300mg Clopidogrel N=96, Elective PCI Patients (%) (-20,-10) (0,10) (20,30) (40,50) >60 (-30,-20) (-10,0) (10,20) (30,40) (50,60) Platelet Aggregation Before and After Clopidogrel (%) Resistance = 10% platelet aggregation Gurbel PA et al., Circulation 2003;107:

8 Clopidogrel Active Metabolite Adherence S O C N Cl O CH 3 Pro-drug Clopidogrel Environmental Drug-Drug Genetics Kurihara A. et al. Drug Metab. Rev. 2005;37(S2):99 Tang M. et al. JPET 2006;319: % Inactive Metabolites O hce1 S HOOC * HS O N C Cl O N Cl Active Metabolite O CH 3 OCH 3 CYPs: 2C19 1A2 2B6 CYPs: 2C19 3A 2B6 2C9 Hydrolysis (Esterases) Oxidation (Cytochrome P450)

9 CYP2C19 and CV Outcomes N=1477 ACS/PCI Subjects Treated with Clopidogrel in TRITON-TIMI 38 CVD, MI, or Stroke Stent Thrombosis CV Death, MI, or Stroke (%) CYP2C19 Reduced-Function Allele Carriers Non-carriers Hazard Ratio 1.53 (95% CI ) P= Days After Randomization Number at Risk: Non-Carrier Carrier Definite or Probable Stent Thrombosis (%) Number at Risk: Non-Carrier Carrier Hazard Ratio 3.09 (95% CI ) P=0.015 CYP2C19 Reduced-Function Allele Carriers Non-carriers Days After Randomization * Carriers ~30% of the population Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, et al & Sabatine MS. N Eng J Med. 2009;119(19):

10 CYP2C19 and Treatment with Clopidogrel Predominantly for PCI CVD, MI, or Stroke N=9, % PCI 1 or 2 CYP2C19 RFA vs Non-Carriers Hazard Ratio (95% CI) P Value 1.57 ( ) CYP2C19 RFA vs Non-Carriers 1.55 ( ) CYP2C19 RFA vs Non-Carriers 1.76 ( ) Stent Thrombosis N=5,894 1 or 2 CYP2C19 RFA vs Non-carriers 2.81 ( ) < CYP2C19 RFA vs Non-Carriers 2.67 ( ) < CYP2C19 RFA vs Non-Carriers 3.97 ( ) RFA=reduced-function allele Risk Lower with Risk Higher with CYP2C19 Variant CYP2C19 Variant Mega JL, Simon T, Collet JP Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS. JAMA 2010;304(16):

11 Study Design Investigator-Initiated Study IND #: Patients Enrolled Stable CAD Pts on Clopidogrel 75 mg daily (>4 Weeks and <6 Months Post-MI or PCI) 2 Not Genotyped 333 Blinded Genotyping 247 CYP2C19*2 Non-Carriers 86 CYP2C19*2 Carriers (80 Heterozygotes; 6 Homozygotes) Randomized to various blinded sequences of daily doses of clopidogrel Randomized to various blinded sequences of daily doses of clopidogrel 75 mg 150 mg 75 mg 150 mg 75 mg 150 mg 225 mg 300 mg Each dose given for ~14 days followed by platelet function testing (VASP and VerifyNow P2Y 12 assays) and assessment for events

12 250 Non- Carriers Clopidogrel in CYP2C19*2 Heterozygotes vs. 75 mg in Non-Carriers PRU diff +61 P<0.001 CYP2C19*2 Heterozygotes HIGH PRU diff +24 P=0.02 Platelet Reactivity Units PRU diff -10 P= PRU diff -37 P<0.001 LOW Clopidogrel Daily Dose (mg) Mega JL, Hochholzer W, Frelinger AL 3rd, Kluk MJ, Angiolillo DJ, Kereiakes DJ, Isserman S, Rogers WJ, Ruff CT, Contant C, Pencina MJ, Scirica BM, Longtine JA, Michelson AD, Sabatine MS. JAMA 2011;306:2221-8

13 Clopidogrel Dose Comparison All Patients (PCI and non-pci) Double Standard HR 95% CI P N=12520 N=12566 CV Death/MI/Stroke CV Death/MI/Stroke/Rec Ischemia MI CV Death Stroke Major Bleeding TIMI Major Bleeding Fatal Bleeding CABG-related Bleeding Intracranial CURRENT-OASIS 7 Investigators. N Engl J Med 2010;363:930-42

14 Efficacy Outcomes: PCI Patients CV Death, MI, Stroke Definite Stent Thrombosis Clopidogrel Standard Clopidogrel Standard Cumulative Hazard Clopidogrel Double Adusted HR % CI P= % RRR Cumulative Hazard % RRR Clopidogrel Double HR % CI P= Days Days Mehta et al. Lancet 2010; 376:

15 Thienopyridines: Formation of Active Metabolite 85% Inactive Metabolites S O N C Cl Clopidogrel Kurihara A. et al. Drug Metab. Rev. 37(S2): 99 (2005) Tang M. et al. JPET 319: (2006) O S HOOC * HS O N hce1 C Cl O N Cl Active Metabolite O CH 3 O CH 3 OCH 3 CYPs: 1A2 2B6 2C19 CYPs: 3A 2B6 2C9 2C19 Pro-drug (Absorption) Hydrolysis (Esterases) Oxidation (Cytochrome P450) O C hce2 hce1 Gut C H 3 O O HOOC * HS S O N F Prasugrel S O N O N F F Active Metabolite CYPs: 3A 2B6 2C9 2C19 Farid N.A. et al. Drug Metab. Dispos. 35: (2007) Rehmel J.L.F. et al. Drug Metab. Dispos. 34: (2006) Williams E.T. et al. Drug Metab. Rev. 39(S1): 254 (2007)

16 Prasugrel vs. Clopidogrel Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds Clopidogrel Prasugrel Prasugrel Clopidogrel Days events HR 0.81 ( ) P= NNT = events HR 1.32 ( ) P=0.03 NNH = 167 Wiviott SD, Braunwald E, McCabe CH et al NEJM 2007

17 Prasugrel vs. Clopidogrel According to Clinical Scenario 6% 5% Clopidogrel Prasugrel Procedural HR 0.87 ( ) 4% CVD/MI 3% 2% Spontaneous HR 0.80 ( ) 1% Stent-related HR 0.47 ( ) 0% Days from Randomization Scirica BM et al ACC 2012

18 Ticagrelor (AZD 6140) H O H O O N N N N N H N F Ticagrelor is a cyclo-pentyltriazolo-pyrimidine (CPTP) S F O H Active, does not require metabolism Potent non-thienopyridine P2Y 12 antagonist Oral reversible P2Y 12 antagonist

19 Loading Dose * * 20 µm ADP- Final Extent * * * // Last Maintenance Dose * * * Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12) 60 IPA % 50 * // // // weeks Onset Maintenance Offset Time (hours) Gurbel PA, Circulation 2009

20 K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) Cumulative incidence (%) Clopidogrel Ticagrelor HR 0.84 (95% CI ), p= No. at risk Days after randomisation Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Adapted from Wallentin L, et al. N Engl J Med. 2009;361:

21 Non-CABG and CABG-related major bleeding K-M estimated rate (% per year) p= p= NS NS 5.8 Ticagrelor Clopidogrel 1 0 Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding Adapted from Wallentin L, et al. N Engl J Med. 2009;361:

22 What are we treating with extended DAPT? Long-Term Treatment (Stable Athero) Vulnerable Stent Vulnerable Patient OR Curfman GD, et al. N Engl J Med. 2007;356:10. Meadows TA, Bhatt DL. Circ Res. 2007;100:

23 CHARISMA Trial Design (n=15603) Patients age 45 years at high risk of Low dose ASA mg/day atherothrombotic events R Double-blind treatment up to 1040 primary efficacy events (CVD, MI, stroke) CAD, or Cerebrovascular disease, or Sx PAD, or Vascular risk factors 1-month visit Low dose ASA mg/day 3-month visit Visits every 6 months Final visit (Fixed study end date) Clopidogrel 75 mg/day (n=7802) Placebo 1 tablet/day (n=7801) Bhatt DL et al. Am Heart J 2004; 148:

24 CHARISMA: Primary Outcome ASA vs. ASA + Clopidogrel in 1º and 2º Atherothrombosis Prevention CV Death, MI, or Stroke (%) N=15,603 Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] P= Months since randomization *All patients received ASA mg/day Bhatt DL, Fox KA, Hacke W, NEJM 2006

25 CHARISMA Prior MI CV Death, MI, or Stroke (%) 10 N=3, % 8 Placebo + ASA Clopidogrel + ASA 6.6% HR=0.774 (95% CI [ ]) P= Months Since Randomization Bhatt DL et al. J Am Coll Cardiol. 2007;49: % risk reduction if prior MI

26 What are we treating with extended DAPT? Prolonged DAPT for STENTS Vulnerable Stent Vulnerable Patient OR Curfman GD, et al. N Engl J Med. 2007;356:10. Meadows TA, Bhatt DL. Circ Res. 2007;100:

27 Observational Data 6-Month Landmark Analysis Adj Cumulative Rates of Death or Nonfatal MI Percent Cumulative Incidence Rate P=0.021 for DES + C vs DES no C DES no C BMS no C BMS + C DES + C Months C = clopidogrel Eisenstein EL, et al. JAMA. 2007;297:

28 REAL-LATE & ZEST-LATE Trials 2701 Patients (>60% with ACS as indication for PCI) 57% SES, 24% PES, 19% ZES Cardiac Death or MI (%) P=0.17 Days from Randomization (12 months after stenting) Park et al. N Engl J Med 2010;362:

29 PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia study 1970 Patients underoing PCI (75% w/ ACS) 50% EES or ZES, 25% PES, 25% BMS 12 6 mo DAPT Death, MI, or Stroke (%) mo DAPT P= Hazard Ratio: 0.98 ( ) Valgimigli et al. Circulation 2009.

30 Bleeding with Prolonged DAPT 2 HR ~2.7 (~ ~6.7) TIMI Major Bleeding (%) HR 2.96 ( ) <=12 mos DAPT >=12 mos DAPT 0 REAL-LATE & ZEST-LATE PRODIGY Park NEJM 2010; Valgimigli Circulation 2012

31 Dual Antiplatelet Therapy (DAPT) Study 12 mos. 18 mos. DES n = 15,245 All patients on aspirin +open-label thienopyridine therapy for 12 months BMS n = 5,400 1:1 Randomization at month 12 50% of patients continue on Dual Antiplatelet Therapy 50% of patients receive aspirin + placebo Total 33 month patient evaluation including additional 3-month follow-up

32 Trial Schema N ~ 21,000 Stable pts with history of MI 1-3 yrs prior + 1 additional atherothrombosis risk factor* RANDOMIZE DOUBLE BLIND * Age >65 yrs, diabetes, 2 nd prior MI, multivessel CAD, or chronic non-end stage renal dysfunction Planned treatment with ASA mg & Standard background care Ticagrelor 90 mg bid Ticagrelor 60 mg bid Placebo Follow-up Visits Q4 mos for 1 st yr, then Q6 mos Min 12 mos and median 26 mos follow-up Event-driven trial Primary Efficacy Endpoint: CV Death, MI, or Stroke Primary Safety Endpoint: TIMI Major Bleeding

33 Summary When considering long-term antiplatelet therapy, we must consider the PATIENT and the STENT. In the very early phase, stent related events predominate, but rapidly are outweighed by spontaneous (patient related) events UP TO 1 YEAR Post ACS - Data for benefit in ACS (with or without PCI). PRIOR MI LONG TERM - More intensive APT appears beneficial in patients with PRIOR MI, and without high-risk of bleeding. Small studies suggest that prolonged DAPT (beyond 1 year) for the purpose of stent thrombosis protection may not outweigh risks, and larger trials are ongoing.

34 Over 1.5 million patients in the United States each year are admitted to the hospital with acute coronary syndromes (ACS). The most common underlying mechanism is the rupture or erosion of atherosclerotic plaque in the coronary artery, leading to the formation of an obstructive thrombus. During this process, platelet adhesion and activation are initiated. Platelet aggregation occurs when fibrinogen molecules bind to the activated platelet receptors, and subsequently forming cross-linking activated platelets. For this reason, patients with an ACS are treated with targeted antiplatelet therapies. Antiplatelet therapy with aspirin has been shown to significantly reduce cardiovascular events, especially in high-risk patients. Moreover, across the spectrum of ACS and in those undergoing percutaneous coronary interventions (PCI) with stenting, dual antiplatelet therapy with aspirin and a thienopyridine inhibitor of the platelet P2Y 12 adenosine diphosphate (ADP) receptor is standard of care. Currently, the most commonly prescribed thienopyridine is clopidogrel; however, the pharmacodynamic response to clopidogrel displays substantial inter-patient variability, and patients with coronary disease with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk of cardiovascular events. 1 Environmental, drug-drug, and pharmacogenetic factors (particularly in the CYP2C19 gene) explain in part the variable response to clopidogrel. 2 Newer antiplatelet agents are currently available, such as prasugrel, a 3rd-generation thienopyridine that achieves greater platelet inhibition than does clopidogrel with less variability. The TRITON-TIMI 38 trial demonstrated that treatment with prasugrel, compared with clopidogrel, resulted in a significantly lower rate of ischemic events but more bleeding among patients presenting with ACS with planned PCI. 3 Ticagrelor is another P2Y 12 inhibitor with a rapid onset of action and a high degree of platelet inhibition. The PLATO study found that ticagrelor versus clopidogrel in post-acs patients was associated with a reduction in cardiovascular death and ischemic events, without an increase in the rate of overall major bleeding but with an increase in the rate of non procedure-related bleeding. 4 Neither prasugrel

35 or ticagrelor appear to impacted by genetic variants in the CYP2C19 gene. Expanding the number of antiplatelet treatment options will allow physicians to tailor therapies. However, selecting the optimal strategy and duration of therapy for each patient will require evaluation of type of the index presentation (i.e., ACS or stable atherosclerotic disease), management decisions (i.e., PCI or medical management), and overall bleeding risk. 1. Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, Bhatt DL, Cattaneo M, Collet JP, Cuisset T, Gachet C, Montalescot G, Jennings LK, Kereiakes D, Sibbing D, Trenk D, Van Werkum JW, Paganelli F, Price MJ, Waksman R, Gurbel PA. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol.56(12): Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16): Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20): Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):