Fondaparinux in ST-Segment Elevation Myocardial Infarction: Title and subTitle BreakThe Drug, the Strategy, the Environment, or All of the Above?

Antithrombotic therapy has become a major defense against the assault of atherosclerosis on society, and accordingly, “atherothrombosis” has become a commonly accepted term in the cardiovascular practice community. Understandably, exploration of the biology of atherothrombosis has led to the development of a variety of drugs intended to block coagulation and thereby prevent arterial thrombosis. The OASIS (Organization to Assess Strategies for Ischemic Syndromes) 6 trial reported in this issue of JAMA by the OASIS-6 Trial Group¹ represents another major milestone in this remarkable saga.

The OASIS-6 investigators conducted a large and complex trial assessing a strategy of use of fondaparinux in ST-elevation myocardial infarction (STEMI). Fondaparinux is a synthetic pentasaccharide that inhibits factor Xa in the coagulation cascade, in contrast to heparin, which predominately blocks thrombin, and to the low-molecular-weight species of heparin, which have mixed effects depending on the specific formulation. OASIS 6 is one of a pair of trials; its companion trial, the OASIS 5 trial,² evaluated a strategy of fondaparinux compared with enoxaparin in the setting of non–ST-elevation acute coronary syndromes.

The primary result of OASIS 6 was that the strategy of fondaparinux use was superior to “usual care” for reducing the 30-day risk of death or recurrent MI. However, this simple statement belies a more complex set of issues involved in the study design because usual care was a heterogeneous mixture of practices. A 7- to 8-day course of fondaparinux was compared with either no anticoagulation or unfractionated heparin; of the patients who were treated with heparin, 75% received unfractionated heparin for less than 48 hours. Furthermore, among patients treated with fibrinolytic therapy, the majority (73%) were treated with streptokinase, but a significant minority received tissue plasminogen activator, and another significant minority (28.9%) were treated with primary percutaneous coronary intervention (PCI). The OASIS investigators used stratified randomization in an effort to compensate for these differential perceived indications for antithrombotic therapy and PCI. However, there is no escape from the need to look deeper than the primary result to understand the scientific and pragmatic meaning of the trial results.

An advocate of fondaparinux could argue that the observed benefit reflects the superiority of the drug as a chemical entity. Indeed, the combination of OASIS 5² and OASIS 6¹ has established fondaparinux as a leading antithrombotic drug in the treatment of acute coronary syndromes. Regardless of how the data are evaluated, there is no evidence that fondaparinux is inferior to either unfractionated heparin or low-molecular-weight heparin for improving overall clinical outcomes. The value of fondaparinux is further enhanced by the remarkable reduction in bleeding observed in both trials. Indeed, the reduction in bleeding in the fondaparinux group compared with the group receiving no antithrombotic therapy observed in OASIS 6 defies a rational explanation but should give clinicians some confidence that at the dose used, fondaparinux has a desirable margin of safety.

Another possible explanation for the benefit could be the strategy in which fondaparinux was embedded, rather than the drug itself. In OASIS 6, fondaparinux is clearly superior to no antithrombotic drug. Indeed, considering that unfractionated heparin was given for less than 48 hours in 75% of patients, it becomes important when assessing the drug as a chemical entity to compare outcomes during the time patients were receiving active drug in both groups. The result in this case is not as encouraging for fondaparinux; it appears to yield roughly the same outcomes as unfractionated heparin during the first 72 hours. Thus, a skeptic could argue that OASIS 6 provides valuable proof, as in the recently published CREATE (Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation) trial,³ that anticoagulation reduces death and MI when compared with no anticoagulation but that there is no convincing evidence of difference between agents in this trial. This interpretation raises the larger question of whether anticoagulation should be continued for longer than 48 to 72 hours in all patients with STEMI.

A balanced view might be that the observed benefit is the result of the combined differential advantage of the drug and the dosing strategy. In that case, relevance of the result must be considered in the context of specific practice patterns. Of particular relevance is the significance of OASIS 6 to North American cardiology practice patterns. The trial enrolled only 26 patients in the United States and 7 patients in Canada. Primary PCI has been established as the preferred treatment for STEMI in North America because of demonstrated reductions in mortality.⁴ In the group undergoing primary PCI in OASIS 6, there was no advantage of fondaparinux and there was a clear excess of catheter thrombosis. The OASIS-6 Trial Group points out that giving unfractionated heparin at the time of PCI in patients randomized to receive fondaparinux ameliorated the problem, but in the absence of benefit, the extra anxiety caused by the now-uncertain risk of catheter thrombosis casts a pall over the use of fondaparinux in patients for whom the intent is to use PCI to achieve reperfusion. Thus, a reasonable conclusion from this trial is that fondaparinux is highly beneficial in patients in whom the noninterventional approach has been predetermined. Fondaparinux will be more preferred in settings in which the use of angiographic-based reperfusion is not routine.

Two other issues with regard to fondaparinux deserve comment for their unusual nature. First, the lower rate of bleeding with fondaparinux compared with placebo remains unexplained. The OASIS 6 investigators should provide more detailed analyses about this finding in future articles. Second, the absence of the need for dose adjustment is remarkable and deserves more explanation. Some experts predicted that fondaparinux would be useless when the phase 2 trial⁵ showed no dose-response relationship with efficacy. In retrospect, the advantage of a single dose for all patients is clear; in this era of recognition of the common occurrence of medical errors that lead to harm, a single dose would result in fewer medical errors because complex calculations of the type identified in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) registry⁶ would not be needed.

The results of the OASIS 6 trial are certain to lead to an outburst of competitive pronouncements by companies and by leaders in the clinical community about the question of which regimen is truly best. The multiple permutations and combinations of antithrombotic drugs are increasingly confusing to clinicians seeking the best options for their patients. How do physicians find a way out of this maze? Hopefully, the era in which individual clinical trials are considered to be the definitive answer to questions of clinical practice is coming to an end. Rather, clinical practices should be organized in a manner that allows for continuous learning based on observation of practice through collection of data, with randomized trials embedded within observational databases to answer specific questions about pragmatic choices in medical care. Just a few years ago, this would have seemed impossible but the impending widescale availability of electronic health records and professional databases promises to make the data readily available—the challenges are no longer technical. The largest advances in STEMI treatment are the findings that reperfusion is beneficial, that direct PCI is superior to lysis, and that treatment with aspirin, β-blockers, and angiotensin-system modulators in appropriate patients all save lives.

Due to the outstanding contributions of the OASIS 6 investigators, another degree of certainty can be added to the understanding that anticoagulation is also an essential element of STEMI care. True knowledge of the best mix of antithrombotics for each patient will come with development of a global network that truly provides an unbiased assessment of multiple medical permutations as part of a continuous learning effort.⁷