The Importance of Bleeding: New Definition Proposed

July 08, 2011

July 8, 2011 (Paris, France, and New York, New York) — The issue of bleeding in ACS or PCI patients continues to be the focus of much attention, with two new consensus papers published in recent weeks--one in Europe, the other in the US--and a new standardized definition of bleeding proposed for use in cardiovascular clinical trials.

An author of the new European consensus paper [1], published online June 29, 2011 in the European Heart Journal, Dr Gabriel Steg (Centre Hospitalier Bichaut-Claude Bernard, Paris, France), commented to heartwire : "Our paper together with the US paper and the proposed new definition together show how bleeding is gaining in importance in the ACS and PCI field. It used to be thought that bleeding was unimportant, and everyone was completely focused on reduction of ischemic complications. If patients bled, they would just be transfused, and it was thought that would deal with it. But now there is a growing realization that bleeding is not just a benign side effect but that people who bleed are at higher risk of death. The jury is still out on whether bleeding is actually causal for mortality or not, but data are building up implicating a harmful effect of bleeding."

Data are building up implicating a harmful effect of bleeding

Steg added: "Our paper is a summary of evidence regarding the importance of bleeding and identification of issues that need to be looked at. We need to better figure out how to avoid bleeding as much as possible. This includes better management of the access site and more thought when it comes to prescribing antithrombotics. Many patients are currently overdosed with these agents."

He said the issues discussed in the paper were not specific to Europe. "The [European Society of Cardiology] ESC just felt it was the right time to summarize the evidence and issues raised. These are similar across the pond."

Bleeding Complications Are Decreasing

The US paper, published in the June 28, 2011 issue of the Journal of the American College of Cardiology, is more focused on actual ways of reducing bleeding in PCI patients [2]. The authors note that major bleeding complications among PCI patients have decreased over the past few years, which corresponds with a shift toward the use of bivalirudin and lower doses of heparin. They also point out that use of the radial approach is reducing access-site bleeding, but it is being adopted slowly in the US, with still only about 8% of PCIs conducted this way.

Commenting on the two papers, Dr Sunil Rao (Duke University, Durham, NC), who is a coauthor on both, told heartwire : "The European paper is a full-scale review of the whole field of bleeding complications. It is a very comprehensive consensus paper. The European Society of Cardiology is ahead of the curve when it comes to bleeding. They have had a section on bleeding in their guidelines for some time, while the US guidelines still haven't got this. The JACC paper is more focused on specific trends and controversies in bleeding in PCI."

Radial Access vs Closure Devices

Lead author of the JACC paper, Dr Harold Dauerman (University of Vermont College of Medicine, Burlington, VT), told heartwire that perhaps the main area viewed differently by the Europeans and US is how the PCI approach can affect bleeding. "In Europe, the number-one answer is radial access. This has been embraced in Europe much more so than in the US. We are not disputing that radial access reduces bleeding, but that is not the reason for the improvement in bleeding seen in the US in recent years, as it is still not being used much here. We are still mostly using femoral approach, along with vascular-closure devices to reduce bleeding."

He added that the radial approach tends to show greater benefits in those patients at higher risk for bleeding, "so I tend to use the radial approach in women, who are generally at higher bleeding risk, whereas in men I use the femoral approach with a vascular-closure device."

But there is much controversy surrounding these vascular-closure devices, which Dauerman says was the stimulus for the current JACC paper. He explained that he and his coauthors felt the need for clarification after recent conflicting messages about these devices. These were a registry study published in JAMA suggesting that closure devices were associated with lower bleeding rates, followed by an AHA statement recommending against the use of such devices. Dauerman comments: "This is obviously a controversial area. We thought that needed to be addressed."

The AHA statement puts operators who use these devices at medicolegal risk.

Dauerman and Rao disagree with the AHA statement, saying it relied on data from an earlier era of PCI with older devices and overinterpreted one particular meta-analysis (by Koreny et al) in which closure devices were associated with an increase in hematoma but only after sensitivity analysis. Dauerman commented: "I think it is a much grayer area than portrayed in the AHA statement, and the statement actually puts operators who use these devices at medicolegal risk." Rao added: "These devices are popular, as they allow patients to move around more quickly after the PCI, and they continue to be used in about half of procedures. We are calling for more trials of the newer devices, which operators seem to think are an improvement over older devices."

BARC: The New Standardized Definition of Bleeding

The new definition of bleeding, known as BARC (Bleeding Academic Research Consortium), is outlined in a paper published in the June 14, 2011 issue of Circulation [3].

The authors, led by Dr Roxanna Mehran (Mount Sinai Medical Center, New York, NY), explain that unlike ischemic clinical events, for which there is now general consensus on end-point definitions, there is much variation among the many bleeding definitions currently in use, which makes it difficult to interpret relative safety comparisons of different antithrombotic agents.

They propose a new consensus classification for bleeding, with six grades ranging from 0 (no bleeding) to 6 (fatal bleeding). Noting that validation of these proposed consensus definitions is still needed, Mehran et al urge trialists and sponsors to begin reporting bleeding events according to BARC definitions in all research efforts from this point forward, even if in conjunction with other definitions. "The universality of the definition . . . will allow comprehensive and consistent reporting of bleeding in future clinical investigations," they conclude.

An accompanying editorial by members of the FDA raises several questions about the new bleeding definition but concludes: "The FDA acknowledges the importance of BARC's global approach to a consensus set of bleeding definitions and encourages similar efforts. Although definitions are important, what is even more critical is how the data are collected. Through collaboration, we can address these issues and improve the quality and efficiency of clinical trials" [4].

Steg and Rao, who were both part of the BARC development team, emphasized to heartwire the importance of such a new standardized bleeding definition.

Steg said: "At the moment, we have several different bleeding scales that are used separately depending on what the particular trial is trying to show. One scale is used if bleeding is wanted to be highlighted. Another is used if the aim is to minimize bleeding. We urgently need a universal definition of bleeding. Even though the FDA has pointed out some criticism of the proposed new definition, it is a big step forward. We need to prospectively collect bleeding data from clinical trials and build a large database. The universal definition will help enormously in this regard."

Rao added: "It is an extremely challenging thing to do. Roxanna Mehran has corralled the top people from the clinical-trials groups active in this area to get together and come up with this new definition. It probably needs to be fine-tuned, but it is a huge achievement and a great start to have."

Rao described the FDA editorial as "appropriately skeptical." He commented: "They point out a few things that might be changed and said we needed prospective data. Yes, of course we need to test this prospectively. It is being included in at least one trial already, and we are calling for it to be included in all new trials where bleeding is measured. It doesn't have to be the only measure of bleeding used, but it would be good to have a standard definition that can be used to compare bleeding rates between trials."

Steg receives speaking/consulting fees from Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo/Lilly, Eisai, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Nycomed, Sanofi-Aventis, Sankyo, Servier, and the Medicines Company and holds stock in Aterovax. Dauerman consults for Abbott Vascular, Medtronic, St Jude, Novartis, the Medicines Company, and MD Scientific. Rao consults for and/or receives speaking fees from the Medicines Company, Terumo Medical, AstraZeneca, Daiichi-Sankyo Lilly, Bristol-Myers Squibb-Sanofi joint venture, Momenta Pharmaceuticals, and PolyMedix. Disclosures for the coauthors are listed in the papers.


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