MULTIcentre evaluation of Single high-dose. acute myocardial infarction study

Transcription

1 MULTIcentre evaluation of Single high-dose Tirofiban bolus TiRofiban vs. versus with sirolimus eluting stent or barein metal stent in during primary PCI STEMI acute myocardial infarction study M. Valgimigli, MD, PhD ClinicalTrials.gov number, NCT On behalf of Multistrategy Investigators M. Valgimigli, MD, PhD On behalf of Multistrategy Investigators ClinicalTrials.gov number, NCT229515

2 Disclosures Disclosures Speaker s bureau: Iroko,Merck, Medicure Research grant: Iroko, Eli Lilly Advisory Board: Iroko, Eli Lilly, Medicine company

3 Background There is limited data on the comparison between vs. Tirofiban at high bolus dose (HDB: 25 µg/kg over 3 min) 4 RCTs have so far contrasted these two drugs in 719 pts undergoing PCI of whom less than 3 were recruited in the setting of STEMI 1,2 1: Valgimigli et al. JAMA 25; 2: Danzi et al. Am J Cardiol 24;

4 Trial Design INCLUSION CRITERIA: INCLUSION CRITERIA: Aspirin mg orally or 25 mg mgfor orally or 25with mg STChest pain >3 min Chest pain for >3 min with STintravenously, followed by intravenously, followed by segment elevation 1 segment elevation 1 mm mm in in two two mg orally indefinitely mg orally indefinitely or or more more contiguous contiguous leads, leads, or or with aa new withclopidogrel new left left bundle-branch bundle-branch 3 then block 3 mg mg orally orally and andblock then mg/day mg/day for for Admission either within at 33 months Admission either within h h of of at least least months No exclusion criteria based symptom or 12 symptom onset onset or between between 12 on: Unfractioned Heparin and and h h after after onset onset with with (4-7 U/kg) (4-7 U/kg) Haemodynamic Status evidence of ischemia evidence of continuing continuing ischemia Target Target ACT ACT of of at at least least 2 2 secs secs Angiographic Findings EXCLUSION EXCLUSION CRITERIA: CRITERIA: Those Those related related to to controindications controindications to to the the use use of of glycoprotein glycoprotein IIb/IIIa IIb/IIIa inhibitors inhibitors

5 Trial Design STEMI all-comer Patients Aspirin + Clopidogrel + UFH Before Arterial Sheath Insertion 1:1 Tirofiban* Tirofiban* 1:1 SES 1:1 BMS SES Coronary Clinical FUAngiography±PCI 1, 4, 8 ms, Stenting was the default strategy in pts 1yr and then to 5 with a RVD 2.5 mmyearly at visualup estimation *: given as a bolus of 25 µg/kg, followed by an hour infusion at.15 µg/kg/min BMS

6 Study Primary Endpoints Pharmacology Arm Non-inferiority Non-inferiority basis basis 5% Σ ST segment elevation resolution within 9 after last balloon tt-ekg Stent Arm Superiority Superiority basis basis Cumulative rate of MACE, defined as overall death, Reinfarction or TVR within 8 months Valgimigli et al. Am Heart J. 27 Jul;154(1):39-45

7 Study Primary Endpoints Power Analysis With 6 pts randomized and type I error Assumed event rates Endpoint Test Tirofiban SES BMS Σ5% N-Inf. >85% STR MACE 8% Sup. 85% 85% δ 9%* 16% 27% *: ~5% of previously reported Σ5% STR between vs. placebo in the ACE trial (Antoniucci et al. J Am Coll Cardiol 23) Power

8 Study Organization Sponsor: University of Ferrara, Italy Data Management: Medical Trial Analysis, Switzerland Site and data monitoring: Medical Trial Analysis, Italy ; Sermes C.R.O., Spain Clinical Events Committee: P. Agostoni (Chair), Belgium, E. Meliga, The Netherlands. ECG core lab: MTA, C. Arcozzi (Chair) Angiographic core lab: MTA, P. Malagutti (Chair) DSMB: P. Vranckx, (Chair), Belgium

9 MULTISTRATEGY P.I.s and Sites G Campo Ferrara R Moreno Madrid G Percoco Lagosanto T Piva Ancona M Anselmi Verona I Sheiban Torino L Bolognese Arezzo G Pasquetto Mirano S Colangelo Torino F Prati Rome N de Cesare Zingonia M Nazzaro Rome A Rodriguez B. Aires J Fernández Huelva M Ferrario Pavia J Mieres B Aires

10 13 Patients Assessed for Eligibility 285 Excluded 153 Not Meeting Inclusion 72% Randomized Randomized Criteria 132 Refused to Participate 1:1:1:1 and Uncoated Stent (n=186) and Sirolimus-Stent (n=187) Tirofiban and Uncoated Stent (n=186) Tirofiban and Sirolimus-Stent (n=186) 1 pt withdrew consent 99% received 97% received PCI 9% received Abc+BMS 99% qualified as STEMI 3% non-interpretable ECG 1% received 99% received PCI 87% received Abc+BMS 1% qualified as STEMI 2% non-interpretable ECG N=179 N=179 N=182 N=182 1% received Tirofiban 98% received PCI 95% received Tir+BMS 99% qualified as STEMI 1% non-interpretable ECG 97% 1% received Tirofiban 98% received PCI 89% received Abc+BMS 99.5% qualified as STEMI 4% non-interpretable ECG N=184 N=184 N=177 N=177 N=186 N=186 N=186 N=186 ST ST Segment Segment Resolution Resolution Study Study N=186 N=186 8 month Follow-up Study N=186 N=186 1%

11 ST Segment Resolution Rationale for choosing this endpoint in STEMI ST segment resolution correlates with infarct size and infarct transmurality Circulation 24;11(21):e56-1. as assessed at MRI or SPECT Jama 25;293(9): Eur Heart J. 27 Jun;28(12): ST segment resolution has strong and independent prognostic implications in terms of both death or the composite of death or MI Lancet 1997;35(978):615-9 Interventions in STEMI which improve ST segment resolution have a consistent effect on outcomes and viceversa N Engl J Med. 28 Feb 7;358(6): J Am Coll Cardiol 23;42(11): Jama 25;293(9):

12 ST Segment Resolution Internal Validity Assessment of the Chosen 1 Endpoint 1 Death/MI Free Survival (%) 98 ST-Res 5% P=.23 at Log Rank test 92 9 ST-Res <5% Days after Randomization

13 ST Segment Elevation Tirofiban P=.78 Units 2 P=.62 1 ΣST segment (mm) Number of ECG leads with ST

14 Primary Endpoint 5% Σ ST segment resolution Tirofiban P<.1 for non-inferiority* % 85.3% *: at ITT and PP Analysis (Heterogeneity: χ2 6.22, P=.718) H: 85%

15 1 Endpoint: 5% ST segment resolution Subgroup Analysis RISK RATIO (95% CI) PRIMARY END POINT Tirofiban Overall 85.3 < 65 yr 65 yr % P-VALUE Non-inferiority Superiority Male Female < Diabetes No Diabetes <.1 Killip class 1 Killip class < Bare Metal Stent Sirolimus-Eluting Stent Single-vessel disease Double-vessel disease Triple-vessel disease < < Prespecified Non-inferiority Limit 83.6 Anterior Myocardial infarction Non Anterior Myocardial infarction Time to Tx 4 hr Time to Tx > 4 hr Creatinine Clearance 6 ml/min Creatinine Clearance < 6 ml/min Tirofiban Better Better.74

16 ECG Analysis Core Lab Evaluation N=722 N= Tirofiban 85.3% 83.6% 8 Percentile Percentage of ST segment resolution at 9' 1

17 3-Day Outcomes Efficacy Endpoints (CEC adjudicated) P=.85 4% 4 P=.98 Tirofiban Stent Thrombosis (ARC) P=.22 P= % 2, 5 P=.56 1% 1 MACE -, 5 Death/MI utvr Definite Def/Prob

18 3-Day Outcomes Safety Endpoints (DSMB adjudicated) 8% 8 Tirofiban P=.4 6% 6 P=.4 4% 4 P=.82 P=.44 P=.3 2% 2 % Major Minor TIMI-Bleeding - 2 Valgimigli et al, JAMA 28 RBC Tranfusion Tranfusion Severe Any Thrombocytopenia

19 Does Thrombocytopenia impact on patient outcome? PLT <1K 3 25 P=.2 P=.8 PLT >1K P= >5X ~ 3.5X Death Death/MI >2.5X 1 5 MACE

20 Differential impact of Thrombocytopenia on mortality 25 PLT <1K PLT >1K P>.99 P=.29 Tirofiban 5 Rate of thrombocytopenia was.8% in tirofiban vs. 4.% in abciximab group, p=.4

21 8 Month Outcomes MACE (CEC adjudicated) Major Adverse Cardiovascular Events (%) % 9.8% 1 Tirofiban 5 P=.3 at Log-rank test Days after Randomization Valgimigli et al, JAMA 28

22 Probability of Death or Myocardial Infarction (%) 8 Month Outcomes Death/MI (CEC adjudicated) % 5.9% 5 Tirofiban P=.55 at Log-rank test Days after Randomization Valgimigli et al, JAMA

23 ARC Stent Thrombosis (CEC adjudicated) 6% 6 4.5% Tirofiban P=n.s. 4, 5 P=n.s. P=n.s. 3% 3 1.5% 1, 5 % Definite Definite - 1, 5 Valgimigli et al, JAMA 28 Definite/Probable Definite/Probable Definite/Probable Definite/Probable Possible Possible

24 Similar Short and long-term anti-ischemic ischemic effect 9 6 Meta-analysis analysis of of 7 RCT RCT including 2,213 pts pts Tirofiban OR=.69 P= Death 3 Days OR=.87 P=.52 Death/MI 3 Days OR=.82 P=.29 Death 8/12 Mos

25 Pharmaco-economic Analysis Drug utilization and major procedural resources between groups were similar; Duration of HDB tirofiban infusion was longer 19.97h v h (p<.1) whereas, amount of Glycoprotein inhibitor and number of required vials of drug was higher for : 53/patient; 1, every 188 treated pt Tirofiban

26 Summary Our study provides evidence that in a broad population of largely unselected patients undergoing angioplasty for ST-elevation myocardial infarction: Tirofiban enables non-inferior STR within 9 after intervention and similar outcomes at 8 months than The safety profile favoured the use of tirofiban for a lower incidence of thrombocytopenia which has prognostic implications Tirofiban appeared a more cost-efficient drug than abciximab