Hamilton, ON - Discrepancies in current recommendations on the use of various antithrombotics in the European and US guidelines for the treatment of acute coronary syndromes is causing confusion, some clinicians have suggested [1].

The editorial, published in the May 10, 2008 issue of the Lancet, is written by Drs John Eikelboom (Hamilton General Hospital, ON), Gordon Guyatt (CLARITY Research Group, Hamilton, ON), and Jack Hirsh (Henderson Research Centre, Hamilton, ON). They say that discrepancies on recommendations regarding enoxaparin and fondaparinux between US and European guidelines undermines confidence in the integrity of guideline development, and they suggest that in the future such discrepancies may be avoided if both committees met and debated differences between their recommendations and if they included nonconflicted methodologists to ensure that criteria for evidence quality were applied consistently. But the chairs of both the US and European guidelines committees told heartwire that the authors of the Lancet perspective had misunderstood some of the recommendations and that actually the two sets of guidelines were not as different as had been suggested in the article.

The editorialists write: "The disagreements in the recommendations for enoxaparin and fondaparinux seem to stem from differences in both the interpretation of the trial data and from differences in the application of nearly identical criteria that were used by both committees to classify the evidence. Without an opportunity to review the reasoning behind each recommendation, it is difficult for readers to decide which recommendations to follow."

Eikelboom et al note that the American College of Cardiology (ACC)/American Heart Association (AHA) and the European Society of Cardiology (ESC) both updated their ACS guidelines last year [2,3]. "The committees reviewed the same research and used nearly identical criteria to rate the strength of the recommendations and to grade the quality of the evidence, but they interpreted the evidence for acute anticoagulant use differently and so reached different conclusions. Therefore, physicians who read recommendations from both the US and European societies might be confused."

They point out that the ACC/AHA gave enoxaparin and fondaparinux a class 1 rating for conservatively and invasively managed patients, implying that there is evidence or general agreement that the treatments are useful or effective. By contrast, the ESC gave enoxaparin a class 2 rating for conservatively and invasively managed patients, implying that there is conflicting evidence or divergence of opinion about the usefulness of enoxaparin, and did not recommend fondaparinux for patients undergoing urgent invasive procedures. "For clinicians, this is the most important area of disagreement between the guidelines, because it directly affects the choice of anticoagulant; unfortunately, it is also the hardest to explain," the authors state.

They suggest that the ACC/AHA must have placed greater weight than the ESC on the results of a meta-analysis that showed that enoxaparin compared with heparin reduced MI and did not increase bleeding. In contrast, the ESC seemed to place greater weight on the results of the SYNERGY trial (which showed that enoxaparin was as effective as heparin but was associated with more bleeding in invasively treated patients) and the OASIS-5 trial (which found that enoxaparin was as effective as fondaparinux but caused more bleeding and was associated with excess strokes and deaths at day 30).

Eikelboom et al note that the divergent recommendations for fondaparinux probably also reflect differences in the interpretation of the OASIS-5 trial, which showed an excess of catheter thrombosis in patients treated with fondaparinux undergoing PCI. This, they suggest, led the ESC not to recommend fondaparinux in invasively managed patients, "but the strong recommendation by the ACC/AHA for fondaparinux in invasively managed patients implies that they did not think the risk of catheter thrombosis to be an important issue, provided that a bolus dose of heparin is used at the time of the invasive procedure."

Chair of the AHC/AHA guidelines committee, Dr Jeffery Anderson (University of Utah, Salt Lake City), told heartwire that the Lancet editorial had somewhat misread the recommendations. He pointed out that although the ESC doesn't recommend fondaparinux for patients getting urgent revascularization, it has given the drug a 1A recommendation for delayed invasive therapy within three days. He added that the ACC/AHA recommendation for fondaparinux was for an invasive strategy within 48 hours, not an urgent strategy, and gives it a 1B, not a 1A, and it also specifies giving it with heparin.

"Thus, one could interpret the ACC/AHA guideline as being more conservative, not more liberal, for fondaparinux. The difference is the way 'early invasive' is defined. Reading the text carefully reveals similar concerns about catheter thrombosis by both societies, and neither advances fondaparinux particularly for invasive patients. So the editorial obviously doesn't fairly assess the very close overall agreement in the sense of both guidelines that is included in the text. However, OASIS-5 was a very large and well-done study that indicates fondaparinux as being successful for the overall efficacy and safety end points, regardless of strategy, despite the small excess of catheter thrombosis," Anderson commented.

Dr Jean-Pierre Bassand (University Hospital Jean-Minjoz, Besançon, France), who is head of the European ACS guidelines committee, also says the authors of the Lancet perspective have misunderstood some of the ESC recommendations.

He told heartwire that this was particularly true for the guidance on fondaparinux. "They say we do not recommend fondaparinux for patients who will have an intervention. That is not the case. The ESC guidelines state that fondaparinux is not recommended for the small minority of ACS patients who are so high risk that they need immediate intervention. But these are perhaps only about 5% of patients. Then we gave fondaparinux a 1A recommendation for all other patients, with the caveat that if they subsequently went to the cath lab, unfractionated heparin could be added. We gave fondaparinux the highest recommendation for almost all patients because we think it has the best efficacy/safety profile. Eikelboom et al say that discrepancies in the guidelines are causing confusion, but actually it is their misinterpretation of the ESC guidelines that is causing confusion. Their table in the Lancet article is misleading, and we have written to the Lancet to say so," Bassand commented.

On the suggestion that the US and European committees should talk to each other, Bassand said this was already the case. "We met three times with the Americans, and we had a US representative on our panel, so it cannot be said that there was no communication between the two groups," he noted.

But Bassand agreed that the European and US guidelines did differ somewhat on their recommendations for enoxaparin. He said the European committee had decided to focus primarily on the most up-to-date trials using contemporary clinical practice and so did not place much weight on the meta-analysis, which included mainly old trials. "We put more emphasis on the SYNERGY trial with enoxaparin, as this was the most recent trial. And we also considered the increased risk of bleeding seen with enoxaparin in this trial and in other settings, so we had no particular reason to give a 1A recommendation to enoxaparin," he told heartwire.

Dr Sanjay Kaul (Cedar Sinai Medical Center, Los Angeles) suggests that one reason for the discordant recommendations between the ACC/AHA and ESC guidelines is that the benefit/risk trade-off focuses only on efficacy outcomes in US guidelines but on both efficacy and safety in the European guidelines. "Thus, while enoxaparin gets a class 1A recommendation in the ACC/AHA guidelines (based only on equivalent efficacy with heparin), it is downgraded in the ESC guidelines (based on both equivalent efficacy but increased bleeding compared with heparin or fondaparinux)," he commented to heartwire.

"Ideally, guidelines must be written in a manner that communicates a clear, rational, and practical balance between clinically important magnitude of benefits and harms, not just statistically significant benefits," Kaul said. He adds: "Rigorous standardized analytical methodology that focuses on benefit/risk (and cost) assessment might also improve the quality of adjudication of evidence in guideline development."

Dr Magnus Ohman (Duke University, Durham, NC) has an understanding of both sides, as he was the US representative on the ESC guidelines committee. He commented to heartwire: "I think the difference between the US and EU guidelines are that the latter are more pragmatic and the former prescriptive. If you are a pragmatic cardiologist—you will like the ESC guidelines! It was a great honor for me to be the US representative on the ESC guidelines. I think this type of collaboration is really very useful. I wish we did more of it, as it is based on the same science, but different philosophy."