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The glycoprotein IIb/IIIa inhibitor abciximab given as an intracoronary rather than intravenous (IV) bolus in patients undergoing primary percutaneous coronary intervention (PCI) may improve short-term survival, according to a meta-analysis published online May 24, 2012, ahead of print in Heart.

But controversy exists over the paper’s potential retraction due to its failure to incorporate negative results from the largest randomized trial to date with the drug comparing the 2 delivery methods.

Investigators led by Federico Piscione, MD, of Federico II University (Naples, Italy), collected and analyzed patient-level data from 5 single-center trials (dating from 2006 to 2010) that randomized 1,198 STEMI patients to intracoronary (n = 611) or intravenous (n = 597) abciximab.

Clinical characteristics were similar between the treatment groups, except for lower TIMI flow grade in the IV group.

Primary Endpoint Reduced by Intracoronary Delivery

At 30 days, rates of the primary endpoint (composite of death and reinfarction), as well as death and TVR, were reduced in the intracoronary group compared with the IV group, although there was no difference in the incidence of reinfarction (table 1).

Table 1. Thirty-Day Outcomes

After correction for the baseline difference in TIMI flow grade, the reduced risk of death and reinfarction (adjusted HR 0.56; 95% CI 0.31-0.99; P = 0. 04) and death (adjusted HR 0.43; 95% CI 0.19-0.94; P = 0.03) was maintained in the intracoronary arm, while the advantage for TVR was lost (adjusted HR 0.56; 95% CI 0.30-1.04; P = 0.06).

Neither heterogeneity across the trials nor evidence of small-study effects was seen.

Multivariate analysis showed that older age (adjusted HR 1.05; P < 0.001), 3-vessel disease (adjusted HR 2.76; P < 0.001), and previous MI (adjusted HR 2.01; P = 0.03) predicted increased risk of the primary endpoint, while receiving intracoronary abciximab showed a trend toward decreased risk (adjusted HR 0.56; P = 0.05).

Plausible Mechanism for Intracoronary Effect

Explaining the rationale for intracoronary abciximab, the authors say that the high local concentrations achieved via that route should facilitate the drug’s diffusion in the thrombotic milieu, leading to dissolution of thrombi and debris at the site of the ruptured plaque and downstream. “These effects should translate into a significant reduction of infarct size, microvascular obstruction, and ‘slow-flow’ or ‘no-reflow’ phenomena,” they write. Moreover, they say the improvement in myocardial reperfusion may account for the clinical results highlighted in the current meta-analysis.

Despite the failure of subgroup analysis to uncover an interaction with the primary endpoint, Dr. Piscione and colleagues observe that a trend emerged toward greater efficacy with intracoronary abciximab in patients with an ischemic time of less than 3 hours. “This finding might be partly related to the fast-evolving process of thrombus formation during an acute coronary occlusion,” they hypothesize.

The authors acknowledge several limitations to the study. Follow-up was short-term, and none of the trials included in the meta-analysis was powered to evaluate clinical outcomes. Moreover, the final analysis did not include data from 1 of the originally identified  trials that found a greater degree of myocardial salvage with abciximab because of what the authorsors describe as “the inability of the principal investigator to provide clinical data.”

The Case of the Missing (Negative) Trial

Perhaps most importantly, the timing of the meta-analysis appeared to preclude inclusion of the most recent and largest randomized trial of intracoronary vs. IV abciximab, the AIDA STEMI trial. In this multicenter study (Thiele H, et al. Lancet. 2012;Epub ahead of print), no difference was seen between the 2 delivery routes for the primary endpoint, a composite of all-cause mortality, reinfarction, or new congestive heart failure at 90 days.

Interestingly, when the authors of the AIDA STEMI paper performed a pooled analysis including most of the trials covered in the current meta-analysis plus the AIDA STEMI results, they found no impact of intracoronary abciximab on death or reinfarction.

Holger Thiele, MD, of the University of Leipzig-Heart Center (Leipzig, Germany), lead author of AIDA STEMI and a coauthor of the current Heart paper, explained in an e-mail communication with TCTMD that he was barred by the trial’s contract research organization from complying with the request of Heart editor Adam D. Timmis, MD, for follow-up data for the current meta-analysis. In an e-mail communication with TCTMD, Dr. Timmis said he is considering whether or not to retract the paper.

Dr. Thiele defended the accuracy and relevance of the current meta-analysis. He added that before pursuing further randomized trials it is important to follow AIDA STEMI patients for a longer period to see if the reduced heart failure observed in the intracoronary abciximab group—the sole clinical outcome that benefited from intracoronary delivery in the trial—persists over time and perhaps has an impact on mortality. His team also is currently evaluating MRI data from a subset of AIDA STEMI patients to assess the effects of the different abciximab approaches on infarct size and microvascular obstruction.

Nonetheless, Dr. Thiele said, given the reduction in infarct size at 30 days with intracoronary abciximab observed in the recent INFUSE-AMI trial, which evaluated patients with large anterior MI who received bivalirudin (Stone GW, et al. JAMA. 2012;Epub ahead of print), a larger study using the same technology is warranted. Patients in that trial received abciximab via the ClearWay catheter (Atrium Medical, Hudson, NH).

Dr. Thiele said he currently uses intracoronary abciximab only in STEMI patients with reduced TIMI flow following PCI.

Looking to the future, he noted that “the newer oral antithrombotics surely will reduce the need for glycoprotein IIb/IIIa inhibitors.”

Related Stories:

• AIDA STEMI: No Advantage for Intracoronary vs. Intravenous Abciximab
• INFUSE-AMI: Bolus Abciximab Works, Thrombus Aspiration Doesn’t for Large STEMI
• Meta-analysis: Intracoronary vs. IV Abciximab Improves Survival in STEMI Patients

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