Acute Coronary Syndrome (ACS) includes unstable angina, acute infarctions, and sudden ischemic death, depending on the degree of coronary artery occlusion. One of the more significant findings over the past 20 years is the role of platelets in the pathogenesis of ACS. Platelet aggregation has been shown to be a key event in the formation of an occlusive thrombosis; the activation of the glycoprotein IIb/IIIa receptor is the final common pathway. These findings led to the development of three intravenous GIIa/IIIa inhibitors, abciximab, eptifibatide and tirofiban. All have shown benefit in numerous clinical trials in the acute treatment of ACS.
Despite these advances in our understanding of the pathophysiology and in our ability to manage acute events, recurring ischemic events remain a major contributor to morbidity and mortality from coronary artery disease. Prevention of coronary events would presumably be enhanced with the availability of orally bioavailable IIb/IIIa antiplatelet drugs.
A meta-analysis of four trials involving three oral GIIb/IIIa inhibitors was recently published. The EXCITE trial studied xemilofiban, the OPUS-TIMI 16 trial used orbofiban and the 2 SYMPHONY trials studied sibrafiban. The trials included more than 33,000 patients and the duration of clinical follow-up was greater than 30 days. All the drugs studied are prodrugs; the active compounds all inhibit the RGD (Arg- Gly- Asp) domain, one of several domains on the GIIb/IIIa receptor.
Three of the trials enrolled patients with ACS; the other, patients undergoing percutaneous coronary intervention (PCI). See the table below for a synopsis of the various study designs.
Overview of Randomized Placebo-Controlled Trials With Oral Glycoprotein IIb/IIIa Inhibitors
|
EXCITE (n=7232) |
OPUS (n=10 302) |
SYMPHONY (n=9169) |
2nd SYMPHONY (n=6637) |
|
|
Indication |
PCI |
ACS |
ACS |
ACS |
|
Study drug |
Xemilofiban 10 or 20 mg TID for 2 wk, then BID |
Orbofiban 50 mg BID or 50 mg BID for 30 d, then 30 mg BID |
Sibrafiban 3, 4, or 6 mg BID according to weight and creatinine |
Sibrafiban 3, 4, or 6 mg BID according to weight and creatinine |
|
Primary End point |
Death, MI, and recurrent revascularization |
Death, MI, recurrent ischemia, or stroke |
Death, MI, and severe recurrent ischemia |
Death, MI, and severe recurrent ischemia |
|
Concurrent aspirin |
Yes |
Yes |
No |
Yes (low dose only) |
|
Ticlopidine in stented patients |
Randomized |
Randomized |
Low-dose arm |
Low-dose arm |
|
Low dose, anticipated ADP inhibition, % |
30-60 |
40-60 |
>25 |
>25 |
|
High dose, anticipated ADP inhibition, % |
50-80 |
60-80 |
>50 |
>50 |
|
Follow-up duration, d |
182 |
300 |
90 |
90 |
|
ACS indicates acute coronary syndrome. |
||||
(reprinted with permission, Chew et al)
The results of the various studies have been generally poor. The only positive results were the reduction in need for urgent revascularization in each trial except EXCITE; pooled results were statistically significant. The two SYMPHONY trials showed an increase in the incidence of MI with drug vs. placebo, though the EXCITE and OPUS-TIMI 16 trials did not. None of the trials showed any statistically significant impact on MI. Major bleeding was also increased in all studies. Pooled analysis showed a statistical significance in this very undesirable effect.
The most concerning finding in all the studies was the increased risk of mortality during the follow-up period. Pooled results showed this was true with any oral glycoprotein IIb/IIIa used. Both the low-dose arm (with or without aspirin) and the high-dose arm (with or without aspirin) compared to aspirin alone showed increases in mortality; this effect was most prominent in the high-dose arm. In the absence of aspirin, the risks of death and MI were significantly increased.
Considering the benefits that are clearly associated with the IV forms of the glycoprotein IIb/IIIa inhibitors, how can the increased risk of MI and mortality with the oral preparations be explained? It could be expected that these adverse outcomes would be associated with the antiplatelet effect of the drugs, but this does not appear to be the case. A number of mechanisms have been postulated:
-Varying plasma levels between doses of the drugs which caused subtherapeutic platelet inhibition for a majority of the trial, but mortality risk was increased in those patients in the high- dose therapy groups, so better results with high doses is doubtful.-Interpatient variability in dose-response due to varying acuity, concomitant medications, renal function, and intrinsic platelet competence, but these effects are not well shown.
-A possible prothrombotic effect of the drugs, as evidenced by an increase in mortality in those patients not receiving aspirin. Recent evidence suggests that while glycoprotein IIb/IIIa inhibition prevents platelet aggregation, other platelet functions, i.e. secretion, procoagulant activity, platelet leukocyte interactions and p-selectin expression, are increased. The increase in prothrombotic activity may explain the benefit seen with concomitant administration of heparin in many studies.
-Speculation also surrounds the binding site for the oral agents as compared to the IV agents. The oral agents bind to the RGD domain of the platelet. In animal studies, time- and dose- dependent increases in cardiomyocite apoptosis has been shown with xemilofiban and orbofiban, an effect augmented by hypoxic conditions. This has not been shown with the IV agents, suggesting that the toxic effects are specific to the RGD peptide subclass.
It is obvious that a great deal of work remains to be done to improve outcomes and quality of life. More research is needed with oral IIb/IIIa inhibitors to discover the mechanisms of the "toxic effects" associated with this class of drug and to devise methods to overcome these effects or to better understand these toxicities in order to develop more effective treatments.
References: