Transcript Pharmacologic Options in the Invasive Management of Acute
Pharmacologic Options in the Invasive Management of Acute Coronary Syndrome
Ross J. Goodfellow, DO FACC FSCAI Health First Medical Group Cape Canaveral Hospital/Holmes Regional Medical Center Cocoa Beach & Melbourne, Florida
Disclosures
• • • Speaker Astra Zeneca Zoll Medical
Acute Coronary Syndrome (UA, NSTEMI, STEMI)
• • • 2014 Majority of patients undergo invasive strategy (cardiac cath within 24-48 hrs) • FRISC-II, RITA, ICTUS Meta-analysis demonstrated 19% RRR in CV Death or MI in patients managed with early invasive strategy
Risk Stratification: TIMI Risk Score
• • • • • • • Age 65 or older • 3 or more CAD risk factors DM, Smoking, HTN, HDL<40mg/dl, FamHx of premature CAD Known CAD ASA use in past 7 days 2 or more anginal episodes in 24 hours ST changes > 0.5mV
Positive cardiac biomarkers
ACS Pharmacology:
• • •
Invasive Strategy
• Decrease myocardial demand/increase supply • Beta Blockers, Nitrates, Calcium Channel Blockers • Analgesics • Morphine Oral Antiplatelet Agents • ASA, Clopidogrel, Prasugrel, Ticagrelor Intravenous Antiplatelet Agents • IIb/IIIa Antagonists (Abciximab, Eptifibitide, Tirofiban) Anticoagulants • Heparin, Bivalirudin, LMWH (Enoxaparin, Dalteparin)
Sites of action of antiplatelet and anticoagulant medications 1 ANGIOMAX Platelet activation GP IIb/IIIa inhibitors Heparin LMWH Aspirin and Thienopyridines AT AT Factor Xa
Thrombin
ADP/TXA 2 mediated platelet adhesion Prothrombin Plasma clotting factors Tissue factor Collagen
Vessel Injury
Fibrinogen Fibrin Platelet aggregation 1. Monroe DM et al. Arterioscler Thromb Vasc Biol 2002;22:1381-9 Please see important safety information and bleeding definitions on slides 64 and 65. Please see accompanying full Prescribing Information. 8
• • • •
Enoxaparin v. UFH
Meta-analysis of all trials demonstrates a 10% reduction in death or MI with enoxaparin over UFH No significant differences in major bleedings Meta-analysis included conservatively managed patients Largest trial of invasively treated patients (SYNERGY) showed increased bleeding with enoxaparin
• •
Oral Antiplatelet Agents
• ADP-P2Y12 interaction Amplifies platelet activation • • P2Y12 receptor antagonists • Thienopyridines Ticlopidine • • Clopidogrel (
PLAVIX
) Prasugrel (
EFFIENT
) • CPTP (Cyclopentyltriazolopyrimidine) Ticagrelor (
BRILINTA
)
CURE Trial
• • Unstable angina/NSTEMI ASA + Clopidogrel (300mg load/75mgqd) v. ASA alone • • N=12,562 20% RRR in CV Death, MI, and Stroke in • Clopidogrel group Driven by decreased nonfatal MI • • PCI-CURE Clopidogrel pre-treatment (6 days) pre-PCI associated with 31% RRR in primary endpoint
PCI-CURE
CURRENT-OASIS 7
• • • Rationale Attempt to address high on-treatment platelet reactivity seen in 10-30% pts.
Double-dose clopidogrel load/maintenance dose x 7 days v. • standard dose in ACS pts.
2 x 2 design also assessing ASA dose
Wiviott SD et al AHJ 152: 627,2006
Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI ASA Double-blind N= 13,600 CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1 o 2 o endpoint: CV death, MI, Stroke endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies: Pharmacokinetic, Genomic
Enrollment Criteria
Known Anatomy
•Inclusion Criteria Planned PCI for : Mod-High Risk UA/NSTEMI (TRS > 3) STEMI: < 14 days (ischemia or Rx strategy) STEMI: Primary PCI •Major Exclusion Criteria : –Severe comorbidity –Increased bleeding risk –Prior hemorrhagic stroke or any stroke < 3 mos –Any thienopyridine within 5 days –No exclusion for advanced age or renal function
Wiviott SD et al AHJ 152: 627,2006
15 10 5
HR 0.77
P=0.0001
HR 0.80
P=0.0003
Primary Endpoint CV Death,MI,Stroke
Clopidogrel 12.1
(781) 9.9 (643) Prasugrel HR 0.81
(0.73-0.90) P=0.0004
NNT= 46
0 0 30 60 90
Wiviott SD et al NEJM 357: 2001, 2007
ITT= 13,608
180
Days
270 360
LTFU = 14 (0.1%)
450
CV Death, MI, Stroke
Components of Endpoints
Clopidogrel Prasugrel HR 12.1
9.9
0.81
CV Death
2.4
2.1
0.89
Nonfatal MI
9.5
7.3
0.76
1.0
1.0
1.02
Nonfatal Stroke
3.2
3.0
0.95
All Cause Mortality uTVR Stent Thrombosis 0.5
Prasugrel Better
3.7
2.4
2.5
1.1
0.66
0.48
1
HR
Clopidogrel Better 2
Wiviott SD et al NEJM 357: 2001, 2007
15 10
CV Death / MI / Stroke
Balance of Efficacy and Safety
138 events Clopidogrel 12.1
9.9
HR 0.81
(0.73-0.90) P=0.0004
NNT = 46 Prasugrel
5
TIMI Major NonCABG Bleeds
0 0 30 60 90 180
Days
270
Prasugrel 35 events Clopidogrel
360
2.4
1.8
HR 1.32
(1.03-1.68) P=0.03
NNH = 167
450
Wiviott SD et al NEJM 357: 2001, 2007
3,0 2,3 1,5 0,8 Clopidogrel 1,8 0,9 1,4 0,0 TIMI Major Bleeds Life Threatening 0,9 1,1 Bleeding Events
Safety Cohort
(N=13,457) ICH in Pts w Prior Stroke/TIA (N=518) Clop 0 (0) % Pras 6 (2.3)% (P=0.02) Nonfatal 0,1 Fatal 0,4 0,3 0,3 ICH ARD 0.6% HR 1.32
P=0.03
NNH=167 ARD 0.5% HR 1.52
P=0.01
ARD 0.2% P=0.23
ARD 0.3% P=0.002
ARD 0% P=0.74
Wiviott SD et al NEJM 357: 2001, 2007
15
ITT= 13,608
10 5 0 0 30 60 90
Net Clinical Benefit
Death, MI, Stroke, Major Bleed (non CABG) Clopidogrel 13.9
Prasugrel 12.2 HR 0.87
P=0.004
9 -19 -28 0 -9 Events per 1000 pts + 6 -23 MI Major Bleed (non CABG)
180
Days
270
All Cause Mortality Clop 3.2% Pras 3.0 % P=0.64
360 450
Wiviott SD et al NEJM 357: 2001, 2007
UA/NSTEMI STEMI Male Female Age <65 65-74 >75 No DM DM BMS DES GPI No GPI CrCl < 60 CrCl > 60 OVERALL 0.5
B
Prasugrel Better
CV Death, MI, Stroke
Major Subgroups
Reduction in risk (%) 18 21 21 12 25 14 6 14 30 20 18 21 16 14 20 19 P inter = NS
1 HR 2 Clopidogrel Better
Wiviott SD et al NEJM 357: 2001, 2007
Prior Stroke / TIA
Yes No
Net Clinical Benefit
Bleeding Risk Subgroups Post-hoc analysis
Risk (%) + 54 -16 P int = 0.006
Age
>=75 < 75
P int = 0.18
-1 -16
Wgt
< 60 kg >=60 kg OVERALL 0.5
Prasugrel Better 1 HR
P int = 0.36
+3 -14 -13
2 Clopidogrel Better
Wiviott SD et al NEJM 357: 2001, 2007
August 30, 2009 at 08.00 CET
Ticagrelor (AZD 6140): an oral reversible P2Y 12 antagonist H O N N N H O O N N H N F Ticagrelor is a cyclo-pentyl triazolo-pyrimidine (CPTP) F S OH • – – – • – – – 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 all circulating platelets
PLATO study design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel 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 Primary safety endpoint: Total major bleeding PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack
K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 0 Clopidogrel HR 0.84 (95% CI 0.77
No. at risk Ticagrelor Clopidogrel 9,333 9,291 60 8,628 8,521 120 180 240 Days after randomisation 8,460 8,362 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval 8,219 8,124 6,743 6,743 Ticagrelor –0.92), p=0.0003
300 5,161 5,096 360 4,147 4,047 11.7
9.8
Hierarchical testing major efficacy endpoints All patients* Primary objective, n (%) CV death + MI + stroke Secondary objectives, n (%) Total death + MI + stroke Ticagrelor (n=9,333) 864 (9.8) Clopidogrel (n=9,291) 1,014 (11.7) HR for (95% CI) 0.84 (0.77
–0.92) 901 (10.2) 1,065 (12.3) 0.84 (0.77
–0.92) CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events Myocardial infarction CV death Stroke 1,290 (14.6) 504 (5.8) 353 (4.0) 125 (1.5) 1,456 (16.7) 593 (6.9) 442 (5.1) 106 (1.3) 0.88 (0.81
–0.95) 0.84 (0.75
0.79 (0.69
1.17 (0.91
–0.95) –0.91) –1.52) p value † <0.001
<0.001
<0.001
0.005
0.001
0.22
Total death 399 (4.5) 506 (5.9) 0.78 (0.69
–0.89) The percentages are K-M estimates of the rate of the endpoint at 12 months. <0.001
Secondary efficacy endpoints over time 5 4 7 6 Myocardial infarction Clopidogrel 6.9
Ticagrelor 5.8
3 2 No. at risk Ticagrelor Clopidogrel 1 HR 0.84 (95% CI 0.75
–0.95), p=0.005
0 0 60 120 180 240 Days after randomisation 300 360 9,333 9,291 8,678 8,560 8,520 8,405 8,279 8,177 6,796 6,703 5,210 5,136 4,191 4,109 Cardiovascular death 7 6 1 0 3 2 5 4 Clopidogrel HR 0.79 (95% CI 0.69
–0.91), p=0.001
5.1
4.0
Ticagrelor 0 60 120 180 240 Days after randomisation 300 360 9,333 9,291 8,294 8,865 8,822 8,780 8,626 8,589 7119 7079 5,482 5,441 4,419 4,364
Stent thrombosis (evaluated in patients with any stent during the study) Ticagrelor (n=5,640) Clopidogrel (n=5,649) HR (95% CI) Stent thrombosis, n (%) Definite Probable or definite 71 (1.3) 106 (1.9) 118 (2.1) 158 (2.8) Possible, probable, definite 155 (2.8) 202 (3.6) 0.67 (0.50
–0.91) 0.75 (0.59
–0.95) 0.77 (0.62
–0.95) p value 0.009
0.02
0.01
*Time-at-risk is calculated from first stent insertion in the study or date of randomisation
Time to major bleeding – primary safety event 15 10 Ticagrelor Clopidogrel 11.58
11.20
5 No. at risk Ticagrelor Clopidogrel HR 1.04 (95% CI 0.95
–1.13), p=0.434
0 0 60 9,235 9,186 7,246 7,305 120 180 240 Days from first IP dose 6,826 6,930 6,545 6,670 5,129 5,209 300 3,783 3,841 360 3,433 3,479
Total major bleeding 13 12 11 10 9 11.6
NS 11.2
NS 8.9
NS 8.9
Ticagrelor Clopidogrel 8 7 6 5 7.9
7.7
5.8
NS 5.8
4 3 2 NS 1 0.3
0.3
0 PLATO major bleeding TIMI major bleeding Red cell transfusion * PLATO life threatening/ fatal bleeding 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
Non-CABG and CABG-related major bleeding 9 8 7.4
NS 7.9
7 6 5.3
NS 5.8
5 p=0.026
4.5
3.8
4 3 p=0.025
2.8
2.2
Ticagrelor Clopidogrel 2 1 0 Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding
Holter monitoring & Bradycardia related events Holter monitoring at first week Ventricular pauses ≥3 seconds, % Ventricular pauses ≥5 seconds, % Ticagrelor (n=1,451) 5.8
2.0
Clopidogrel (n=1,415) 3.6
1.2
p value 0.01
0.10
Holter monitoring at 30 days Ventricular pauses ≥3 seconds, % Ventricular pauses ≥5 seconds, % Bradycardia-related event, % Pacemaker Insertion Syncope Bradycardia Heart block Ticagrelor (n= 985) 2.1
0.8
Ticagrelor (n=9,235) 0.9
1.1
4.4
0.7
Clopidogrel (n=1,006) 1.7
0.6
p value 0.52
0.60
Clopidogrel (n=9,186) 0.9
0.8
4.0
0.7
p value 0.87
0.08
0.21
1.00
Other findings All patients Dyspnoea, % Any With discontinuation of study treatment Ticagrelor (n=9,235) Clopidogrel (n=9,186) p value * 13.8
0.9
7.8
0.1
<0.001
<0.001
Neoplasms arising during treatment, % Any 1.4 Malignant 1.2 Benign 0.2 *p values were calculated using Fischer’s exact test 1.7 1.3 0.4
0.17
0.69
0.02
Conclusions • Reversible, more intense P2Y 12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in a broad population with ST- and non-ST-elevation ACS provides – Reduction in myocardial infarction and stent thrombosis – Reduction in cardiovascular and total mortality – No change in the overall risk of major bleeding Ticagrelor is a more effective alternative than clopidogrel for the continuous prevention of ischaemic events, stent thrombosis and death in the acute and long-term treatment of patients with ACS
IIb/IIIa Antagonists
• • Inhibit >80% of platelet aggregration Early studies demonstrated short and long term event reduction in ACS patients compared with • • heparin alone Driven by reduction in peri-procedural MI Increased bleeding • • Recent Trials ISAR-REACT 2, EARLY ACS, ACUITY
ACUITY Study Design – First Randomization Moderate- and high-risk unstable angina or NSTEMI undergoing an early invasive strategy (N=13,819) UFH/Enox + GP IIb/IIIa (n=4,603) Medical management Moderate and high Risk ACS (n=13,819) R* Bivalirudin + GP IIb/IIIa (n=4,604) PCI Aspirin in all clopidogrel; dosing and timing per local practice Bivalirudin Alone † (n=4,612) CABG *Stratified by pre-angiography thienopyridine use or administration †ANGIOMAX alone (with GP IIb/IIIa inhibition reserved for severe breakthrough ischemia and procedural complications during PCI) The safety and effectiveness of ANGIOMAX have not been established in patients with acute coronary syndromes (ACS) who are not undergoing PTCA or PCI.
Stone GW et al.
N Engl J Med
. 2006;355:2203-2216
Overall ACUITY Management Strategy (N=13,819) CABG (n=1,539) 11.1% 32.5% Medical Rx (n=4,491) 56.4% PCI (n=7,789) UFH/Enox + GP IIb/IIIa N = 2,561 Stone GW et al.
N Engl J Med
. 2006;355:2203-2216 Bivalirudin + GP IIb/IIIa N = 2,609 Bivalirudin alone N = 2,619
Primary Results – 30 Days UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone UFH/Enox+GP IIb/IIIa (N=2561) Bivalirudin+GP IIb/IIIa (N=2609) Bivalirudin alone (N=2619) 20%
P=.10
P=.057
13% 15% 12%
P=.16
P=.45
P=.32
P<.001
8% 9% 9% 7% 8% 4% 0% Net clinical outcome Composite ischemia Major bleeding (non-CABG) Stone GW et al.
Lancet.
2007;369:907-919.
Please refer to important ANGIOMAX safety information on slide 28 and see full Prescribing Information
Early and Late Mortality UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone 4,0 3,0 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone 30-day Estimate 0.9% 1.2% 1.1% P (log rank) — 0.45
0.63
1-year Estimate 3.1% 2.4% 2.2% P (log rank) — 0.70
0.48
2,0 1,0 0,0 0 31 62 92 123 154 185 215 246 277 308 338 369 400 Days from Randomization Data on file, The Medicines Company, Parsippany, NJ.
Please refer to important ANGIOMAX safety information on slide 28 and see full Prescribing Information p=0.78
H armonizing O utcomes with R evascular iz ati on and S tents in AMI
3602 pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine
R 1:1
UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) ( Bivalirudin monotherapy ± provisional GP IIb/IIIa) Emergent angiography, followed by triage to… CABG – Primary PCI – Medical Rx 3006 pts eligible for stent randomization
R 3:1
Paclitaxel-eluting TAXUS stent Bare metal EXPRESS stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 3 years; angio FU at 13 months Stone, GW N Engl J Med 2008;358:2218-30.
H armonizing O utcomes with R evascular iz ati on and S tents in AMI
Randomized 3602 pts with STEMI
R 1:1
UFH + GP IIb/IIIa N=1802 Bivalirudin N=1800 1-Year FU Eligible 1-Year FU 3-Year FU N=1774 28 N=1702 26 46 N=1628 17 57 • • • Not true MI* • • • • • • Withdrew • • • • • • Lost to FU • • • • • • Withdrew • • • • • • Lost to FU • • • 29 N=1771 22 53 N=1696 18 44 N=1634 * Biomarkers WNL and no DS >50% by core lab determination (30 day FU only) Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
3-Year Major Bleeding (non-CABG)
*
12 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 10 9.4% 8 10.5% 6 4 6.0% 6.9% 3-yr HR (95%CI) 0.64 (0.51, 0.80) P=0.0001
2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months * Intracranial, intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
Time in Months '
3-Year Cardiac Mortality
3 2 1 6 5 4 Heparin + GPIIb/IIIa (n=1802) 3.8% 2.1% Bivalirudin alone (n=1800) 3-yr HR (95%CI) 0.56 (0.40, 0.80) P=0.001
0 0 3 6 9 12 15 18 Months 21 24 27 30 33 36 5.1% 2.9% Time in Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
3-Year Reinfarction
10 9 8 7 6 5 4 3 2 1 0 0 3 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 6 9 4.4% 3.6% P=0.04
12 15 18 Months 21 24 27 30 33 36 8.2% 6.2% 3-yr HR (95%CI) 0.76 (0.59, 0.99) Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
Conclusions: Pharmacology Randomization
●
In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, the initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors at 3 years resulted in: – A significant 36% reduction in major bleeding and a significant 24% reduction in reinfarction, with non significantly different rates of stent thrombosis, TVR and stroke – A significant 44% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1000 patients treated with bivalirudin (NNT = 54 to save 1 life) Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2
Other Issues to Consider...
• • •
Timing of intervention Emergent v. Urgent (24-48 hours)
• • •
Access site Femoral, Radial, Brachial Closure device Maintaining access vessel patency (upper extremity)
My preferences
• • • Emergency PCI (STEMI, Unstable NSTEMI) Patient on antiplatelet therapy • • • Bivalirudin (or UFH) Reload in ED (Ticagrelor 180mg) IIb/IIIa antag as “bailout” Patient antiplatelet naive • • • Bivalirudin/UFH Lower threshold to use IIb/IIIa antagonist Oral antiplatelet on table (Ticagrelor)
My preferences (Cont’d)
• • • • Delayed angiography/PCI Bivalirudin/UFH IIb/IIIa antagonists if markedly rising enzymes Ticagrelor, Clopidogrel
The Future...
• • • • • CANGRELOR BRIDGE Trial • Cangrelor “bridging” decreased platelet reactivity in patients with prior stents scheduled for CABG CHAMPION-PHOENIX Trial • Cangrelor v. Clopidogrel in PCI patients • Early results show decreased ischemic events at 48 hours in cangrelor group v. clopidogrel Platelet function assays to guide antiplatelet Rx Pharmacogenomic Studies, etc.