Author + information
- Ron Waksman, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Ron Waksman, Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010
The quest for early and optimal pharmacology therapy for patients with ST-segment elevation myocardial infarction (STEMI) who are undergoing primary percutaneous coronary intervention (pPCI) is ongoing. The superiority of pPCI over facilitated medical therapy with thrombolytic agents has been well established for patients presenting with STEMI (1). Door-to-balloon time has been detected as the pivotal predictor of survival improvement (2); however, the average door-to-balloon time for U.S. patients requiring hospital transfer to pPCI often exceeds 120 min, which is much longer than the 90-min target for optimal pPCI outcomes. Efforts are therefore targeted to shorten door-to-balloon times and to find the optimal medical therapy to restore blood flow to the infarcted artery during the time of STEMI diagnosis to presentation in the catheterization laboratory. Although glycoprotein (GP) IIb/IIIa inhibitors have proven to be beneficial in reducing clinical events when given to STEMI patients in the catheterization laboratory (3), pre-treatment with GP IIb/IIIa inhibitors prior to arrival in the catheterization laboratory has failed to demonstrate clinical benefit in clinical randomized trials.
The initial report from the On-TIME 2 (Ongoing Tirofiban In Myocardial infarction Evaluation) trial was that high-bolus dose (HBD) tirofiban, when given in the ambulance to STEMI patients who were to undergo pPCI, resulted in an improvement in ST-segment resolution, which is defined as a surrogate marker for myocardial perfusion and an indicator of improved clinical outcome (4). The trial did not, however, have sufficient power to detect the impact on mortality at 30 days. The On-TIME 2 investigators therefore designed a pre-specified pooled analysis of the placebo-controlled study phase and the open-label study phase and reported that in the ambulance, early administration of HBD tirofiban for patients with STEMI results in a reduction of major adverse cardiac events (MACEs) at 30 days and a trend toward reduction in mortality at 1 year, without a clinical difference in the bleeding rate (5). Based on these findings, the investigators concluded that early, pre-hospital initiation of HBD tirofiban, in addition to high-dose clopidogrel, improves the clinical outcome after pPCI in STEMI patients.
There are several deficiencies in this analysis that call for caution when interpreting the trial results. Although prespecified, this analysis pooled data from 2 phases with different study designs; the first phase was an open-label study, which is subject to inherent limitations, whereas the blinded phase was underpowered and failed to demonstrate any clinical benefit of HBD tirofiban over the placebo when analyzed alone. Even when the 2 study phases are combined, the power is suboptimal at 70%. The differences in trial design may also have affected the differences in the bail-out use of tirofiban, which was more often used in the open-label phase compared with the double-blind study phase (42% vs. 29%). Further, the clinical benefit conclusions were, in part, drawn from the decrease in MACEs at 30 days, with MACEs driven primarily by urgent target vessel revascularization (TVR). The authors allude to this TVR decrease as being an effect of early stent thrombosis reduction by the HBD tirofiban; however, the rates of stent thrombosis were not disclosed in their report. Notably, there was only a higher rate of urgent TVR in the open-label phase, which was not replicated in the larger, blinded phase. Therefore, the results of this study are not definitive and should be viewed only as hypothesis generating.
Nevertheless, the results from On-TIME 2 trial raise several important issues: 1) the value of early pharmacological therapy in patients presenting with STEMI; 2) the role of HBD tirofiban in this pre-treatment; and 3) will the new emerging antiplatelet agents change the paradigm of using GP IIb/IIIa inhibitors either pre-hospital or intraprocedurally?
Drug-to-Balloon Time: The Earlier the Better
Although the expression “the earlier the better” refers mainly to mechanical reperfusion of the infarcted artery, efforts are now aimed at determining how STEMI patients can undergo early anticoagulation safely and what pharmacotherapy is optimal for these patients. So far, facilitated PCI has, for the most part, failed across trials to demonstrate clinical benefit and was usually associated with an increase in bleeding (2,6,7). It is possible that both the optimal regimen and time of administration are critical to the success of pre-hospital pharmacological intervention and facilitated PCI may work under specific conditions. In the On-TIME 2 trial, the median duration of treatment to angiography with tirofiban or placebo/no tirofiban was 55 min. The transfer time is geography dependent, and early anticoagulation could play a larger role for patients with longer transport times to a catheterization laboratory that performs pPCI in rural areas. An important consideration with early anticoagulation is the accuracy in diagnosing STEMI in the ambulance. In the On-TIME 2 trial, false-positive STEMI was diagnosed in 5.8% of patients. This rate is acceptable but can be even lower with the dissemination of telemedicine, including the on-line transmission of electrocardiograms via smartphone to an experienced cardiologist who can administer medical therapy in the field.
An interesting observation from the study was the sex disparity in regard to the efficacy of the drug, which was found to be more efficacious in men. This can be explained by a difference in ischemic time, which was significantly longer for women and which also emphasizes the importance of minimizing the ischemic time with early reperfusion and its impact on outcome.
Is There a Role for HBD Tirofiban in Pre-Treatment of Patients With STEMI?
Standard antiplatelet therapy for today's STEMI patient is aspirin and a 600-mg loading dose of clopidogrel. The question is whether HBD tirofiban adds any benefit to the clopidogrel pre-load. Proponents of HBD tirofiban argue that it takes at least 2 h to obtain effective platelet inhibition with a 600-mg loading dose of clopidogrel compared with the immediate effect seen with HBD tirofiban. In addition, HBD tirofiban will inhibit platelet function for clopidogrel nonresponders, and, when administered early, it may help to lyse fresh thrombi (4). Nevertheless, in the On-TIME 2 trial, pretreatment with HBD tirofiban was not associated with statistically higher rates of Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 or less distal remobilization than in the control group. Thus, the key explanation for MACE reduction, according to the investigators, is improved ST-segment resolution both before and after PCI.
Findings from the On-TIME 2 pooled data analysis are not consistent with those of similar trials. In the AGIR-2 (Comparison of the Pre-hospital or Cath-lab Administration of High Doses Tirofiban in Patients Undergoing Primary Angioplasty) study, 320 STEMI patients within 6 h of symptom onset were randomized to HBD tirofiban infusion in the ambulance or in the catheterization laboratory. All patients also received a pre-hospital loading dose of clopidogrel, aspirin, and heparin. In the pre-hospital group, tirofiban was administered 48 min earlier than in the catheterization laboratory group. However, results showed no difference in TIMI III flow at initial angiography (the primary end point). There was also no difference in ST-segment resolution or peak levels of cardiac enzymes. Although not powered for clinical events, these data actually trended toward a worse effect in the pre-hospital group (8).
Further, in the FINESSE (Facilitated INtervention with Enhanced reperfusion Speed to Stop Events) trial, which examined facilitated PCI with early abciximab plus a one-half dose of the thrombolytic drug reteplase or with early abciximab alone, early reperfusion did not translate into any improvements in the primary end point (composite of all-cause death, ventricular fibrillation, cardiogenic shock, and congestive heart failure) or other clinical outcomes at 90 days (9). The difference in clinical outcome in the On-TIME 2 trial could be explained by the time interval from symptom onset to drug administration, which was shorter in On-TIME 2, and the fact that the control was placebo and not an active comparator as it was in similar trials. The lack of difference in bleeding rates between the treatment groups in On-TIME 2 can be explained by the use of low-dose heparin and/or an increase in the use of closure devices. Additionally, this could be a result of the level of the anticoagulation efficacy, which does not follow the usual pattern of a bleeding tax for efficacy gain.
Perhaps the most reassuring finding from On-TIME 2 was that even with a 600-mg clopidogrel loading dose, the GP IIb/IIIa inhibitor showed a potential benefit without a significant increase in bleeding; however, given the deficiencies of the study and the lack of clear clinical benefit, these results are not sufficient to change guidelines or routine practice.
Pre-Hospital Antiplatelet Therapy for STEMI Patients: One Drug Does Not Fit All
The use of GP IIb/IIIa inhibitors for STEMI patients continues to be challenged with the introduction of emerging antiplatelet therapy agents such as prasugrel and ticagrelor, which offer rapid onset with more reliable and more potent platelet inhibition compared with clopidogrel. Additionally, both have been shown to reduce clinical events, including stent thrombosis rates, compared with clopidogrel. Administration of prasugrel must await an angiogram; however, ticagrelor, with its short half-life, can be administered in the ambulance and can eliminate the risk of bleeding on cessation for patients who require urgent coronary artery bypass graft surgery. The question is whether new antiplatelet therapies, which have rapid onsets and are easy to administer, will substitute the need for upstream GP IIb/IIIa inhibitor use pre-hospital or perhaps in the catheterization laboratory. Meanwhile, the use of GP IIb/IIIa inhibitors for STEMI patients with ticagrelor and prasugrel of nearly 40% in PLATO (A Study of Platelet Inhibition and Patient Outcomes) (10) to up to 60% in TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38) suggests that interventional cardiologists are still comfortable with the use of GP IIb/IIIa inhibitors in combination with the new antiplatelet agents in high-risk STEMI patients. Interestingly, in TRITON–TIMI 38, the use of GP IIb/IIIa inhibitors did not improve efficacy nor was it associated with increased bleeding compared with prasugrel alone (11). HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) (12,13) was the first study to demonstrate a reduction in bleeding and mortality in the bivalirudin without GP IIb/IIIa inhibitor arm compared with the heparin plus GP IIb/IIIa inhibitor arm. This arm, however, was associated with higher rates of stent thrombosis in the first 24 h after the pPCI.
Although early pharmacologic intervention for STEMI patients is warranted and has the potential to expedite reperfusion of the infarcted vessel prior to arrival at the catheterization laboratory, the added value of GP IIb/IIIa inhibitors pre-hospital and/or in the catheterization laboratory remains in question in the era of the new, rapid-onset, potent antiplatelet agents and should be subjected to well-powered, prospective, randomized clinical trials.
Dr. Waksman has received a research grant from Schering Plough, and is on the Speakers Bureau of The Medicines Company.
↵⁎ Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
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