An Update on Oral Anti-platelet therapy in patients with non-st Myocardial Infarction. Disclosures

Transcription

1 An Update on Oral Anti-platelet therapy in patients with non-st Myocardial Infarction R. Scott Wright, MD, FACC, FESC, FAHA, Professor of Medicine Mayo Clinic Fall Managed Care Forum November Disclosures Consulting Roche/Genentech, Sanofi-Regeneron Updated August

2 ACS is driven by platelet thrombosis 2

3 Why are platelets so important in ACS? The final culprit that triggers the syndrome and obstructs coronary blood flow, producing clinical symptoms Platelet activation triggers a cascade that likely promotes vasospasm and further platelet thrombosis a vicious cycle 3

4 Options for platelet blockade The platelets have multiple receptors that activate with exposure to tissue factor or thrombus. Clinicians have multiple pathways to target with pharmacotherapy Multiple drug therapy gets to be expensive especially in the long-term 4

5 What are we certain of in 2013? Use of aspirin is strongly associated with risk reduction and improvement in survival Aspirin remains the single most cost effective therapy in ACS. Adding a second anti-platelet agent is now the standard of care in ACS Rx. 5

6 Class I and Class IIa Recommendations for Initial Management of UA/NSTEMI Diagnosis of UA/NSTEMI is likely or definite ASA (class I, LOE: A) Clopidogrel if ASA intolerant (class I, LOE: A) Select management strategy Initial conservative strategy or unknown Invasive strategy Initiate anticoagulant therapy (class I, LOE: A) Acceptable options include Enoxaparin or UFH (class I, LOE: A) Fondaparinux (class I, LOE: B)* Enoxaparin or fondaparinux preferred over other GP IIb/IIIa inhibitors (class IIa, LOE: B) Initiate anticoagulant therapy (class I, LOE: A) Acceptable options include Enoxaparin or UFH (class I, LOE: A) Bivalirudin (class I, LOE: B) Initiate clopidogrel (class I, LOE: B) Or Initiate Ticagrelor (Class I, LOE:C) CABG: maintenance ASA (class I, LOE: A) Wright et al: Circ 123, 2011 PCI: add 2nd antiplatelet agent (class I, LOE: A) P2Y12 (class I, LOE: B) or GP IIb/IIIa inhibitor (class I, LOE: A) (IV eptifibatide or tirofiban preferred) Next step per triage decision at angiography PCI: class I: Clopidogrel (if not begun precath) (LOE: A) or Prasurgrel (LOE: B) or Selectively, GP IIb/IIIa inhibitor (if not begun precath) (LOE: A) Rx: D/C GP IIb/IIIa inhibitors if begun and give clopidogrel per conservative strategy 6

7 Challenges facing management of non-st ACS in 2013 and beyond Single therapy with aspirin is no longer the standard of care every patient needs at least two oral anti-platelet agents DAPT Triple anti-platelet therapy should be used in some patients but should it be reserved for the cath lab with PCI and perhaps for certain high risk subsets prior to PCI? Selection of which agents to use for DAPT and TAPT remain a challenge 7

8 P2Y 12 Inhibitor Therapy Clopidogrel is established therapy with proven efficacy and is approved for: Medical management Invasive management Prasugrel is proven and approved for: Invasive management Stent thrombosis Ticagrelor is proven and approved for: Medical Invasive management

9 Challenges facing management of non-st ACS in 2013 and beyond DAPT with aspirin and clopidogrel is proven therapy in non-stemi for those being managed conservatively or invasively DAPT with aspirin and prasugrel is reserved only for those undergoing PCI DAPT with ticagrelor is effective for patients undergoing PCI but what about those managed conservatively? Clopidogrel vs Prasugrel TRITON TIMI 38 Trial Population tested Non-STEMI undergoing PCI STEMI undergoing PCI Head to head comparison for efficacy and safety in patients undergoing PCI

10 10

11 What about use of Prasugrel in those without PCI? Trilogy Trial Population tested Non-STEMI not undergoing PCI Head to head comparison for efficacy and safety in patients being managed medicaly

12 Study Design 9326 patients in 8 regions, 52 countries (Primary: 7243 patients < 75 years old) Medically Managed UA/NSTEMI Patients Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort Age < 75 years) Median Time to Enrollment = 4.5 Days Medical Management Decision 72 hrs (No prior clopidogrel given) 4% of total Medical Management Decision 10 days (Clopidogrel started 72 hrs in-hospital OR on chronic clopidogrel) 96% of total Clopidogrel mg LD + 75 mg MD Prasugrel 1 30 mg LD + 5 or 10 mg MD Clopidogrel 1 75 mg MD Prasugrel 1 5 or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, Stroke 1. All patients were on aspirin, and low-dose aspirin (< 100 mg) was strongly recommended. For patients < 60 kg or 75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1. Roe Mt et al NEJM 2012 Primary Efficacy Endpoint and TIMI Major Bleeding Through 30 Months (Age < 75 years; 7243) Endpoint (%) HR (95% CI): 0.91 (0.79, 1.05) P = 0.21 HR (95% CI): 1.31 (0.81, 2.11) P = 0.27 Roe MT et al NEJM

13 Dual anti-platelet therapy in NSTEMI There are many reasons why NSTEMI patients are not referred for PCI Some NSTEMI patients may have type II infarcts rather than type I Co-morbidities like renal failure may influence a decision for PCI. What about enriching the analyzed cohort for CAD using prerandomization coronary angiography? DAPT benefit without PCI CURE was enriched for subjects not undergoing urgent or early PCI Selection bias clearly impacts who is referred for angiography vs who is not referred for angiography The diagnosis of MI was based upon CK-MB elevation in CURE Small changes in ctnt or I in recent trials thus enriching these trials with Type II infarcts (infarcts likely not due to plaque rupture) 13

14 Baseline Characteristics: Angiographic Results (>50% Stenosis) Notes: 1. Non-obstructive = 30 - <50% stenosis 2. LM disease - 6.2% of subjects Primary Efficacy Endpoint to 30 Months (Age < 75 years) Angio N=3085 No Angio N= % vs 14.9% P = HR (95% CI): 0.77 (0.61, 0.98) 16.3% vs 16.7% P = HR (95% CI): 1.01 (0.84, 1.20) P interaction =

15 Myocardial Infarction Angio No Angio 7.2% vs 10.3% P = HR (95% CI): 0.74 (0.55, 1.00) 9.2% vs 10.6% P = HR (95% CI): 1.00 (0.79, 1.26) P interaction = 0.12 Stroke Angio No Angio 0.6% vs 2.4% P = HR (95% CI): 0.30 (0.13,0.71) 2.2% vs 2.0% P = HR (95% CI): 1.03 (0.58,1.83) P interaction =

16 TIMI Major Bleeding Angio No Angio 2.7% vs 1.4% P = HR (95% CI): 1.84 (0.93, 3.63) TIMI Major or Minor Bleeding Angio: No Angio: HR (95% CI): HR (95% CI): 1.68 (1.00, 2.83) 1.42 (0.83, 2.41) P interaction = % vs 1.5% P = HR (95% CI): 0.92 (0.47, 1.83) P interaction = 0.16 What have we learned with Prasugrel? It is effective and superior to clopidogrel in patients undergoing PCI The data do not support extending its label to the medically managed ACS patient Prasugrel may have superior efficacy in diabetic patients 16

17 Clopidogrel vs Ticagrelor PLATO Trial Population tested Non-STEMI/STEMI undergoing medical management Non-STEMI/STEMI undergoing PCI Head to head comparison for efficacy and safety 17

18 Primary End-Point MI CV Death 18

19 30 Days Stent Thrombosis 1 Year 19

20 P2Y 12 Inhibitor Therapy Clopidogrel is established therapy with proven efficacy and is approved for: Medical management Invasive management Prasugrel is proven and approved for: Invasive management Stent thrombosis Ticagrelor is proven and approved for: Medical Invasive management Oral Anti-platelet agents Are there issues or unique properties of these agents that allow us to tailor their use? CYP 2C19 issue Bleeding risks? Concurrent aspirin dosing concerns? Onset of anti-platelet action?

21 Oral Anti-platelet agents Are there issues or unique properties of these agents that allow us to tailor their use? CYP 2C19 issue Bleeding risks? Concurrent aspirin dosing concerns? Onset of anti-platelet action? FDA Warning on Clopidogrel March 12, 2010 The FDA issued a boxed warning about the diminished effectiveness of clopidogrel in patients with impaired ability to convert the drug into its active form. Should we consider off label use of Prasugrel to protect patients from this concern? 21

22 Clopidogrel A Pro-drug 15% of absorbed clopidogrel is activated by the Liver via several CYP450 isoenzymes Of these isoenzymes, CYP2C19 is responsible for 45% of the first step of activation. 22

23 CYP2C19 Variants Variants of CYP2C19 are responsible for the variability in clopidogrel active metabolite bioavailability CYP2C19*2 encodes a nonfunctional protein CYP2C19*3, *4, *5, *8 also exist ETHNICITY and CYP2C19*2 Distribution of CYP2C19*2 varies by ethnicity Chinese 50% have it African American 34% Caucasian 25% Hispanic 19% 23

24 Impact of CYP2C19*2 Multiple studies support an association between this allele variant and increased risk of CV events. The increase in risk ranges from 53% to 500% (OR 1.5 to 5.0) Mechanism of Action and Metabolic Pathways for Clopidogrel, Prasugrel and Ticagrelor CYP1A2 CYP2B6 CYP2C19 CYP2B6 CYP2C9 CYP2C19 CYP3A4 Active intestinal absorption P-gp (ABCB1) H 3 C S H COOCH 3 N CI Clopidogrel Esterases Inactive metabolites (85% of clopidogrel dose) O O N O S F Prasugrel O S Esterases O S H COOCH 3 N CI 2-oxo-clopidogrel O N F R CYP3A CYP2B6 CYP2D6 CYP2C9 CYP2C19 H COOCH 3 HOOC HS Pharmacologically active metabolite of clopidogrel HOOC HS O N F R P2Y 12 receptor banding Lancet, 2010 N N N N S HO N OH O OH Ticagrelor F F Inhibition of platelet activation

25 Recommendations for Additional Management of Antiplatelet and Anticoagulant Therapy-Table 4 Wright et al: Circ 123,

26 DAPT - Aspirin and a Glycoprotein IIb/IIIa inhibitor Timing and Role of intravenous anti-platelet therapy CAPTURE, PURSUIT and PRSIM-Plus established the benefit of IV 2b/3a antagonist therapy use when started upstream from the cath as a second anti-platelet agent Should this be updated in light of new evidence? Is there a continued role for 2b/3a agents? ACS 2b or ROUTINE USE SELECTIVE USE UFH or LMWH or Bivalirudin Plus IIb/IIIa Agent not PURSUIT Prism Plus Tactics TIMI 18 Ictus UFH or LMWH or Bivalirudin Decision on Invasive 2b? Strategy Angiography Initiate IIb/IIIa Agent PCI (Capture) 26

27 Advantages ROUTINE USE All are on Rx Benefit observed without invasive Rx (PURSUIT) Single Bolus of Eptifibatide SELECTIVE USE Cost effective ($) Risk of bleeding Use only in higher risk patients Disadvantages ROUTINE USE Bleeding Cost ($$$) Complicate referral to surgery SELECTIVE USE Delayed benefit in higher risk patients (potentially) benefit if routine Rx reduces risk of recurrent ischemia or urgent revasc. 27

28 Routine versus Selective Use of IIb/IIIa agents EARLY ACS Trial 9492 patients w/ ACS undergoing invasive strategy Primary EP (Superiority) 30 day rate of Death, MI, Recurrent ischemia requiring PCI or PCIrelated thrombotic occlusion Secondary EP Death or 30 d ACUITY Trial 9207 patients w/acs (moderate to high risk) undergoing invasive strategy Primary EP (non-inferiority) 30 day rate of Death, MI or unplanned revascularization Secondary EP s: Composite ischemia, major bleeding Routine versus Selective Use of IIb/IIIa agents EARLY ACS Trial 9492 patients w/ ACS undergoing invasive strategy Primary EP (Superiority) 30 day rate of Death, MI, Recurrent ischemia requiring PCI or PCIrelated thrombotic occlusion Secondary EP Death or 30 d ACUITY Trial 9207 patients w/acs (moderate to high risk) undergoing invasive strategy Primary EP (non-inferiority) 30 day rate of Death, MI or unplanned revascularization Secondary EP s: Composite ischemia, major bleeding 28

29 EARLY ACS Trial NEJM 2009;360: EARLY ACS Trial NEJM 2009;360:

30 Routine versus Selective Use of IIb/IIIa agents EARLY ACS Trial 9492 patients w/ ACS undergoing invasive strategy Primary EP (Superiority) 30 day rate of Death, MI, Recurrent ischemia requiring PCI or PCIrelated thrombotic occlusion Secondary EP Death or 30 d ACUITY Trial 9207 patients w/acs (moderate to high risk) undergoing invasive strategy Primary EP (non-inferiority) 30 day rate of Death, MI or unplanned revascularization Secondary EP s: Composite ischemia, major bleeding ACUITY Trial JAMA 2007;297:

31 ACUITY Trial JAMA 2007;297: Routine versus Selective Use of IIb/IIIa agents - Summary No Benefit to Routine Use of these agents prior to PCI in all patients EARLY ACS Trial 9492 patients w/ ACS undergoing invasive strategy Primary EP (Superiority) 30 day rate of Death, MI, Recurrent ischemia requiring PCI or PCIrelated thrombotic occlusion Secondary EP Death or 30 d ACUITY Trial 9207 patients w/acs (moderate to high risk) undergoing invasive strategy Primary EP (non-inferiority) 30 day rate of Death, MI or unplanned revascularization Secondary EP s: Composite ischemia, major bleeding 31

32 Recommendations for Antiplatelet Therapy-Table 2 Wright et al: Circ 123, Recommendations for Antiplatelet Therapy-Table 2 Wright et al: Circ 123,

33

34 ACC 2012 Guidelines July

35 Oral Anti-platelet agents Are there issues or unique properties of these agents that allow us to tailor their use? CYP 2C19 issue Bleeding risks? Concurrent aspirin dosing concerns? Onset of anti-platelet action? P2Y 12 Inhibitor Therapy Clopidogrel Prasugrel Ticagrelor Post PCI Yes Yes Yes Med Rx Yes No Yes Loading 600 mg 60 mg 180 mg Dose Daily 75 mg 10 mg 90 mg Dose % Platelet inhib 50-60% 60-70% 85-90% Aspirin Dose mg mg < 100 mg (Daily) Cost (daily) $0.33 $6.50 $

36 Recommendations for Antiplatelet Therapy-Table 2 Wright et al: Circ 123, Recommendations for Antiplatelet Therapy Wright et al: Circ 123,

37 Oral Anti-platelet agents Are there issues or unique properties of these agents that allow us to tailor their use? CYP 2C19 issue Bleeding risks? Concurrent aspirin dosing concerns? Onset of anti-platelet action?

38 CYP2C19 Variants Variants of CYP2C19 are responsible for the variability in clopidogrel active metabolite bioavailability CYP2C19*2 encodes a non-functional protein CYP2C19*3, *4, *5, *8 also exist ETHNICITY and CYP2C19*2 Distribution of CYP2C19*2 varies by ethnicity Chinese 50% have it African American 34% Caucasian 25% Hispanic 19%

39 Impact of CYP2C19*2 Multiple studies support an association between this allele variant and increased risk of CV events. The increase in risk ranges from 53% to 500% (OR 1.5 to 5.0) Recommendations for Additional Management of Antiplatelet and Anticoagulant Therapy-Table 4 Wright et al: Circ 123,

40 Optimal Dosing of Aspirin and Clopidogrel If both of these drugs are helpful, then higher doses might work even more, right? If you are not confused, then you are not thinking properly Bernard Gersh, ACC

41 Efficacy and Safety Outcomes for the Aspirin Dose Comparison Aspirin dose High (n=8,624) Low (n=8,639) Adjusted HR (95% CI) P CV death, MI, or stroke 356 (4.1%) 366 (4.2%) 0.98 ( ) 0.76 CV death, MI, stroke, or recurrent ischaemia 381 (4.4%) 417 (4.8%) 0.92 ( ) 0.23 CV death 156 (1.8%) 173 (2.0%) 0.90 ( ) 0.35 MI 196 (2.3%) 202 (2.4%) 0.97 ( ) 0.80 Stroke 37 (0.4%) 29 (0.3%) 1.26 ( ) 0.36 Recurrent ischaemia 31 (0.4%) 56 (0.7%) 0.56 ( ) Total mortality 160 (1.9%) 185 (2.1%) 0.86 ( ) 0.18 CURRENT-defined major bleed 128 (1.5%) 110 (1.3%) 1.18 ( ) 0.20 CURRENT-defined severe bleed 92 (1.1%) 76 (0.9%) 1.22 ( ) 0.20 TIMI-defined major bleed 79 (0.9%) 62 (0.7%) 1.29 ( ) 0.13 Fatal bleed 10 (0.1%) 9 (0.1%) 1.12 ( ) 0.80 Intracranial bleed 4 (0.05%) 3 (0.03%) 1.34 ( ) 0.70 Red-cell transfusion 2 units 100 (1.2%) 86 (1.0%) 1.19 ( ) 0.24 CABG-related bleed 8 (0.1%) 8 (0.1%) 0.99 ( ) 0.99 Haemoglobin drop 50 g/l 43 (0.5%) 34 (0.4%) 1.27 ( ) 0.30 Minor bleed 433 (5.0%) 370 (4.3%) 1.18 ( ) Events before PCI MI or stroke 23 (0.3%) 21 (0.2%) 1.09 ( ) 0.78 MI 21 (0.2%) 21 (0.2%) 0.99 ( ) 0.98 Stroke 2 (0.02%) 0 (0.0%) CURRENT-defined major bleed 8 (0.1%) 5 (0.1%) 1.58 ( ) 0.42 CURRENT-defined severe bleed 5 (0.1%) 2 (0.02%) 2.48 ( ) 0.28 TIMI-defined major bleed 4 (0.05%) 2 (0.02%) 1.98 ( ) 0.43 Events after PCI CV death, MI, or stroke 333 (3.9%) 345 (4.0%) 0.97 ( ) 0.68 CV death, MI, stroke, or recurrent ischaemia 342 (4.0%) 374 (4.3%) 0.92 ( ) 0.24 CV death 156 (1.8%) 173 (2.0%) 0.91 ( ) 0.38 MI 175 (2.0%) 181 (2.1%) 0.97 ( ) 0.75 Stroke 35 (0.4%) 29 (0.3%) 1.21 ( ) 0.45 Recurrent ischaemia 15 (0.2%) 34 (0.4%) 0.44 ( ) Total mortality 160 (1.9%) 185 (2.1%) 0.87 ( ) 0.20 CURRENT-defined major bleed 120 (1.4%) 105 (1.2%) 1.14 ( ) 0.32 CURRENT-defined severe bleed 87 (1.0%) 74 (0.9%) 1.18 ( ) 0.30 TIMI-defined major bleed 75 (0.9%) 60 (0.7%) 1.25 ( ) Major Outcomes at 30 Days, According to Dose of Clopidogrel Double dose n=12,520 Standard dose n=12,566 Hazard ratio (95% CI) P No. % No. % Primary outcome: death from cardio ( ) 0.30 vascular causes, myocardial infarction, or stroke Secondary outcomes Death from cardiovascular causes, ( ) 0.25 myocardial infarction, stroke, or recurrent ischemia Death from cardiovascular causes ( ) 0.57 Myocardial infarction ( ) 0.09 Stroke ( ) 0.95 Recurrent ischemia ( ) 0.72 Death from any cause ( ) 0.61 Safety outcome: bleeding Major Study criteria ( ) 0.01 Requiring RBC transfusion 2 U ( ) 0.01 CABG related ( ) 0.53 Severe ( ) 0.04 Leading to decrease in ( ) 0.13 hemoglobin level 5 g/dl Symptomatic intracranial ( ) 0.53 Fatal ( ) 0.85 TIMI criteria ( ) 0.03 Minor ( ) 0.01 NEJM 363:934,

42

43 Recommendations for Antiplatelet Therapy-Table 2 Wright et al: Circ 123, Anti-platelet therapy Practical thoughts Dual anti-platelet therapy for one year in post-acs patients is the gold standard -- Evidence suggests that clopidogrel works well and that the others are slightly better with higher bleeding risks -- Some centers use Ticagrelor for one month, then switch to clopidogrel not FDA Approved or established by trial evidence

44 Anti-platelet therapy Practical thoughts Patient adherence to DAPT for the first year after ACS is critical -- More efforts must be given to promote adherence -- Discontinuation of DAPT triggers some recurrent ACS events Use of aspirin after year-1 is usually adequate and is the Guideline based expectation Anti-platelet therapy Practical thoughts Guidelines are just that Guidelines The science evolves be prepare to alter strategy Decisions often need to be tailored to individual patient needs Remain vigilant for safety concerns

45 Anti-platelet therapy the Future? What are the future directions new therapies will take? Is it reasonable to develop new antiplatelet agents? Current therapies are very effective Can we afford new therapies? Bleeding risks less or more? A Tethering (transient adhesion) B Stable adhesion Platelet GP Ib/V/IX Platelet GP VI GP Ib/V/IX GP Ia/IIa GP Ib/V/IX VWF VWF Fibrinogen Collagen Subendothelium Subendothelium C Activation Thrombin ADP TXA 2 EPI Serotonin Platelet Release of TXA 2 ADP D Aggregation GP IIa/IIIa Fibrinogen VWF Platelet GP IIa/IIIa GP VI GP Ib/V/IX GP Ia/IIa GP VI GP Ib/V/IX GP Ia/IIa Platelet VWF Collagen VWF Collagen Subendothelium Kiefer and Becker: Circ 120:2488, 2009 Subendothelium

46 Investigational Inhibitors of Platelet Adhesion Receptor/ target and agent VWF GP Ib/V/IX GP VI Structure Company Status in development AjvW-2 Murine monoclonal antibody Ajinomoto Preclinical AJW200 Human monoclonal antibody Ajinomoto Preclinical R9.3 Oligonucleotide aptamer Academic Preclinical R9.14 Oligonucleotide aptamer Academic Preclinical ARC1779 Oligonucleotide aptamer Archemix Phase II clinical trial R9 557 Inhibitory peptide Academic Preclinical Monoclonal antibody K.U. Leuven Research and Development Preclinical 6B4 JAQ1 Monoclonal antibody Academic Preclinical OM2 Monoclonal antibody Otsuka Pharmaceutical Preclinical Soluble GPVI inhibitor Small inhibitory antibody decoy Academic Preclinical EXP3179 Angiotensin II type 1 receptor metabolite Merck Preclinical 2-I Recombinant protein inhibitor Academic Preclinical GP Ia/IIa Small molecule Synthetic I domain allosteric inhibitors inhibitor Academic Preclinical Collagen AAPP Recombinant protein inhibitor Otsuka Pharmaceutical Preclinical TGX-221 Isoform specific enzyme inhibitor Academic Preclinical PI3K Kiefer and Becker: Circ 120:2488,

47 Class I and Class IIa Recommendations for Initial Management of UA/NSTEMI Diagnosis of UA/NSTEMI is likely or definite ASA (class I, LOE: A) Clopidogrel if ASA intolerant (class I, LOE: A) Select management strategy Initial conservative strategy or unknown Initiate anticoagulant therapy (class I, LOE: A) Acceptable options include Enoxaparin or UFH (class I, LOE: A) Fondaparinux (class I, LOE: B)* Enoxaparin or fondaparinux preferred over other GP IIb/IIIa inhibitors (class IIa, LOE: B) Initiate clopidogrel (class I, LOE: B) Or Initiate Ticagrelor (Class I, LOE:C) Invasive strategy Initiate anticoagulant therapy (class I, LOE: A) Acceptable options include Enoxaparin or UFH (class I, LOE: A) Bivalirudin (class I, LOE: B) PCI: add 2 nd antiplatelet agent (class I, LOE: A) P2Y12 (class I, LOE: B) or GP IIb/IIIa inhibitor (class I, LOE: A) (IV eptifibatide or tirofiban preferred) Next step per triage decision at angiography Wright et al: Circ 123, 2011 CABG: maintenance ASA (class I, LOE: A) PCI: class I: Clopidogrel (if not begun precath) (LOE: A) or Prasurgrel (LOE: B) or Selectively, GP IIb/IIIa inhibitor (if not begun precath) (LOE: A) Rx: D/C GP IIb/IIIa inhibitors if begun and give clopidogrel per conservative strategy