ESC Addresses Bleeding in ACS and PCI Patients

June 30, 2011—The European Society of Cardiology (ESC) announced that the ESC Working Group on Thrombosis is calling for health care staff to focus on ways to reduce bleeding in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary interventions (PCIs), and for increased research in the field. In the position paper published online in The European Heart Journal, Philippe Gabriel Steg, MD, et al summarize current knowledge regarding the epidemiology of bleeding in ACS and PCI and provide a European perspective on management strategies to minimize the extent of bleeding and subsequent adverse consequences.

The ESC Working Group on Thrombosis also welcomed the recent efforts of the Bleeding Academic Research Consortium (BARC), an independent group of academics, research organizations (including the ESC), industry, and government health agencies. BARC produced a consensus definition of bleeding for cardiovascular clinical trials that was published by Roxana Mehran, MD, et al on June 14 in Circulation (2011;123:2736–2747).

“Increasing progress in the treatment of ACS—due to the combination of antithrombotic therapy in the acute phase and wider use of revascularization techniques—has meant bleeding (previously a footnote in the therapeutic armamentarium) has come to play a far more significant role in patient outcomes,” commented Dr. Steg.

Bleeding associated with PCI is caused by a combination of factors. Former Chairman of the Working Group, Kurt Huber, MD, stated, “It may be as a result of antithrombotic treatments, or due to comorbidities, such as gastric ulcers or renal dysfunction. Additionally, there's the trauma that is created in the arteries from puncturing the vessels.”

According to the ESC, emerging evidence exists of a strong and potentially modifiable association between bleeding and adverse outcomes. A 2006 analysis published by John Eikelboom, MD, et al in Circulation examined the association between bleeding and death or ischemic events in 34,146 patients with ACS who were enrolled in a clopidogrel study, and the investigators found that patients who experienced major bleeds had a fivefold higher incidence of death during the first 30 days, and a 1.5-fold higher incidence of death between 30 days and 6 months (2006;114:774–782). Furthermore, in both the OASIS 5 and HORIZONS trials, patients who showed a marked reduction in bleeding went on to show a subsequent reduction in mortality. Dr. Steg commented, “We're coming to appreciate that this may not be entirely coincidental.”

One proposed explanation of the relationship between bleeding and adverse outcomes is that recognized predictors of bleeding may overlap with predictors of ischemic events, with bleeding acting as a marker for increased ischemic risk. “But a second possibility that's being debated is that bleeding may have directly harmful consequences that set in motion a number of adaptive changes which themselves lead to adverse outcomes,” noted Dr. Huber.

Any form of bleeding can have a clinical consequence. Dr. Steg said, “For example, people who have a minor nose bleed, or even bleeding gums when brushing their teeth, may discontinue antiplatelet therapy if they've been implanted with a stent. The train of events might lead to in-stent thrombosis or even death.”

According to the position paper, strategies clinicians can introduce to minimize bleeding include using radial as opposed to femoral access for angiography and PCI, and adjusting the dose of anticoagulant agents, wherever possible, to body weight, age, and renal function. Dr. Steg noted, “One issue is that we're treating increasingly older populations who are more likely to have decreased renal function, making the possibility of anticoagulant overdoses greater.”

“These definitions are based on consensus rather than data driven, making it important that they're validated in future clinical trials,” stated Dr. Huber.

The publication is nevertheless considered a major advance since until now, there has been widespread confusion due to varying definitions of bleeding used in different clinical trials.

Dr. Steg commented, “It's been well demonstrated that if the same study population is analyzed with different scales, completely different rates of bleeding are likely to be recorded, with the rate of bleeding varying threefold according to the definition used.”

The Thrombosis Working Group advised that bleeding should be reported using more than one bleeding scale, one of which should be the BARC bleeding definition. “Using more than one scale offers a way to minimize the potential for bias with selective reporting of bleeding events,” said Dr. Steg. For example, investigators testing agents that have the potential to cause bleeding could minimize the reporting of adverse events by using a restrictive scale down-playing bleeding, while investigators could over-emphasize the safety of other agents by choosing sensitive scales.

The paper concludes that bleeding is an important subject for future research with gaps remaining in knowledge regarding the incidence of bleeding and the underlying mechanisms. Important questions for investigation include whether bleeding is truly causal in subsequent mortality or merely a marker of increased risk related to worse baseline characteristics, whether the outcomes for spontaneous bleeding differ from bleeding induced by percutaneous or surgical revascularization procedures, and what should be the optimal transfusion strategy for patients with ACS?