Dartmouth Hitchcock Medical Center Optimizing the Pharmacoinvasive Approach to Acute ST Segment Elevation Myocardial Infarction: Use of Half dose Thrombolytic Therapy in Combination with Glycoprotein IIb/IIIa Receptor Inhibitors Compared with Full dose Thrombolytic Therapy in the Setting of Routine Urgent Post-thrombolytic Percutaneous Coronary Intervention Pantila Vanichakarn, Rayson C.Yang, Sheila M. Conley, Tamara A. Anderson, James T. Devries, Bruce J. Friedman, Bruce D. Hettleman, John E. Jayne, Aaron V.Kaplan, Craig A. Thompson, John F. Robb, Jeremiah R. Brown, Nathaniel W. Niles Dartmouth Hitchcock Medical Center February 2010

Pantila Vanichakarn, MD DISCLOSURES Pantila Vanichakarn, MD I have no real or apparent conflicts of interest to report.

Background Several randomized trials, including the recent TRANSFER-AMI Trial, have shown that STEMI patients presenting to a non-PCI hospital, who cannot be transferred for primary PCI within 90 minutes, benefited from a pharmacoinvasive reperfusion strategy of routine PCI within 6 hrs of initial thrombolytic therapy compared with stand alone thrombolytic therapy. Two recent FINESSE Trial follow-up studies strongly suggested that a similar pharmacoinvasive strategy improved survival in high risk STEMI patients transferred for PCI within 4 hrs of presentation compared with a primary PCI strategy. If a pharmacoinvasive approach to STEMI patients requiring transfer for PCI emerges as the preferred strategy, it is not clear which of the various thrombolytic regimens used in the successful trials leads to superior results.

The goal of the current study is to use a single center STEMI patient registry to compare angiographic and clinical outcomes in “real world” patients after treatment with either full dose thrombolytic or half dose thrombolytic combined with GP IIb/IIIa inhibitor in the course of a pharmacoinvasive reperfusion strategy Objective ? Should I get rid of the statement that prior angiographic studies have shown….

The Region Upper CT Valley, intersection of interstates along Vt/NH border 20 Referral Hospitals Zone 1 = the local referral hospitals Zone 2 = remote referral hospitals ~40 Ambulance services 2 Helicopters based at PCI Center

Methods A single center STEMI registry from 2001 to 2009. 1645 patients were enrolled in the STEMI registry 1629 patients with ECG evidence of STEMI, new LBBB, or acute true posterior MI 1223 patients presented to a non-PCI center 904 patients were treated with either full dose lytics or half dose lytics +GP2b3a inhibitors 769 patients were transferred emergently to DHMC after thrombolysis 720 patients were taken to cath lab as per “pharmacoinvasive strategy” *need correct numbers from Jeremiah and add %

Methods - Treatment All Patients received either t-PA, r-PA, or TNK at package insert dose for acute myocardial infarction or t-PA, r-PA, or TNK at 50% of package insert dose in combination with either Abciximab (package insert dose for PCI) Eptifibatide (package insert dose for acute coronary syndrome) Tirofiban (package insert dose for acute coronary syndrome) and Heparin: Dose: 12 units/kg/h IV; Start: 60 units/kg IV x1; Max: 4000 units/bolus; 1000 units/h; adjust dose to target aPTT 50-75s Pre-cath lab clopidogrel was not routine. However, If clopidogrel was not given pre cath a loading dose of was routinely given in the cath lab at the time of the intervention All patients underwent catheterization within 4 hrs of arrival at the PCI hospital and 92% had PCI attempted. A stent was placed in 97% of PCI procedures.

Methods - Endpoints Angiographic endpoints % TIMI 3 flow % Patency (TIMI flow 2 or 3) % Procedural success Clinical endpoints % 30-day mortality % long-term mortality % MACE = %30 day mortality, deteriorating Killip class or shock at cath lab presentation, in-hospital recurrent MI, in-hospital congestive heart failure or in-hospital repeat revascularization (PCI or CABG) % ICH = % incidence of intracranial hemorrhage demonstrated by CT scan % TIMI major hemorrhage = %incidence of any intracranial, retroperitoneal, intraocular hemorrhage or clinically overt hemorrhage associated with a fall in hemoglobin of > 5 g/dL) TIMI flow 0 = no flow, no thrombus penetration TIMI flow 1 = thrombus penetration, no flow to distal vessel TIMI flow 2 = flow to distal vessel significantly slower than normal TIMI flow 3 normal flow to distal vessel

Methods - Statistical analysis All statistical tests were performed at a significance level of 0.05 (two-sided) Group comparisons of continuous variables were performed using a student’s t-test Group comparisons of nominal variables were performed using Chi-square Comparison of binary outcomes were performed using logistic regression (OR) and Cox’s proportional hazard modeling (HR) on propensity matched patients with 95% confidence intervals with adjustment for TIMI risk score STATA Software TIMI risk

Baseline Characteristics Full dose lytics Half dose lytics p value N Age (years) Female (%) Prior MI (%) Diabetes (%) TIMI risk score Symptom onset to presentation (min) Door-to-balloon time (min) Lytic agent (%) TNK r-PA t-PA IIb/IIIa inhibitor (%) Abciximab Eptifibatide Tirofiban 163 65.6±13.7 33.1 20.8 23.2 3.9±2.5 184±32 268±103 69.3 27.6 3.1 557 58.7±10.6 26.2 21.3 2.8±2.1 188±13 225±88 60.1 37.9 2.0 17.4 54.0 28.6 <0.001 ns 0.047

Unadjusted Outcomes Full dose lytics Half dose lytics p value N Pre-PCI TIMI 3 flow (%) Patency = TIMI 2 or 3 flow (%) PCI success (%) 30-day death (%) 30-day death or recurrent MI (%) MACE (%) ICH (%) TIMI major hemorrhage (%) LV EF at cath (%) 163 30.38 59.49 94.7 8.6 15.8 19.6 1.2 4.3 48.5±14.1 557 45 76.5 97.1 7.1 14.9 1.1 1.8 50.4±12.0 0.001 <0.001 ns 0.032 0.005

Adjusted outcomes: Odds ratio for Half dose compared to Full dose

Adjusted outcomes: Odds ratio for Half dose compared to Full dose

Limitations Single center registry data Low number of patients in the full dose thrombolytic group weakened the power of the sample to detect a clinically relevant difference in outcomes as significant Not a randomized trial Regression analysis and propensity modeling may not completely adjust for the differences between the two groups Pre cath clopidogrel was not used routinely in either group of patients studied here although it was given routinely early in the course of the STEMI (at the time of PCI)

Conclusions In this “real world” single center STEMI patient registry study, the combination of half dose thrombolytic plus GP IIb/IIIa inhibitor regimens did indeed achieve more frequent TIMI 3 flow in the infarct related artery at the time of catheterization than full dose thrombolytic regimens. In the setting of a pharmacoinvasive reperfusion strategy there was no difference in the rate of intracranial hemorrhage or peripheral bleeding complications between thrombolytic treatment groups. A larger randomized trial will be necessary to definitively determine which thrombolytic regimen works best when a pharmacoinvasive approach is planned.