The European Society of Cardiology (ESC Working Group on Thrombosis) is calling for greater attention to be paid by health care staff to reducing bleeding in patients with acute coronary syndromes undergoing percutaneous coronary interventions, and for increased research in the field.
The position paper, published online in The European Heart Journal, summarises current knowledge regarding the epidemiology of bleeding in acute coronary syndromes and percutaneous coronary interventions, and provides a European perspective on management strategies to minimise the extent of bleeding and subsequent adverse consequences.
“Increasing progress in the treatment of acute coronary system – due to the combination of antithrombotic therapy in the acute phase and wider use of revascularisation techniques – has meant bleeding (previously a footnote in the therapeutic armamentarium) has come to play a far more significant role in patient outcomes,” said Philippe Gabriel Steg, the first author of the consensus article (Centre Hospitalier Bichaut-Claude Bernard, Paris, France).
Bleeding associated with percutaneous coronary intervention is caused by a combination of factors. “It may be as a result of antithrombotic treatments, or due to co-morbidities, such as gastric ulcers or renal dysfunction. Additionally there is the trauma that is created in the arteries from puncturing the vessels,” said Kurt Huber, a former chairman of the Working Group, (Wilhelminenspital Hospital, Vienna, Austria).
Emerging evidence exists of a strong and potentially modifiable association between bleeding and adverse outcomes. In 2006 a study by John Eikelboom, which examined the association between bleeding and death or ischaemic events in 34146 patients with acute coronary sysdrome enrolled in a clopidogrel study, 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.
Furthermore, in both the OASIS 5 and HORIZONS trials, subjects who showed a marked reduction in bleeding went on to show a subsequent reduction in mortality. “We are coming to appreciate that this may not be entirely coincidental,” said Steg.
One explanation proposed to explain the relationship between bleeding and adverse outcomes is that recognised predictors of bleeding may overlap with predictors of ischaemic events, with bleeding acting as a marker for increased ischaemic risk. “But a second possibility that is 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,” said Huber.
Any form of bleeding can have a clinical consequence. “For example, people who have a minor nose bleed or even bleeding gums when brushing their teeth may discontinue antiplatelet therapy if they have been implanted with a stent. The train of events might lead to in-stent thrombosis or even death,” said Steg.
Strategies clinicians can introduce to minimise percutaneous coronary intervention bleeding, says the position paper, include using radial as opposed to femoral access for angiography and , and adjusting the dose of anticoagulant agents, where ever possible, to body weight, age and renal function.
“One issue is that we are treating increasingly older populations who are more likely to have decreased renal function making the possibility of anticoagulant overdoses greater,” said Steg.
The Working Group on Thrombosis welcomes the recent efforts of the Bleeding Academic Research Consortium (BARC) to produce a consensus definition of bleeding for cardiovascular clinical trials. The BARC definition, just published in Circulation, has been produced by an independent group of academics, research organisations (including the ESC), industry and regulator representatives:
“These definitions are based on consensus rather than data driven, making it important that they are validated in future clinical trials,” said 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. “It is been well demonstrated that if the same study population is analysed with different scales completely different rates of bleeding are likely to be recorded, with the rate of bleeding varying three fold according to the definition used,” said Steg.
Bleeding, said the Thrombosis Working Group, 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 minimise the potential for bias with selective reporting of bleeding events,” said Steg.
For example, he said, investigators testing agents that have the potential to cause bleeding could minimise the reporting of adverse events by using a restrictive scale down playing bleeding; while investigators could over emphasis the safety of other agents by choosing sensitive scales.
Bleeding is an important subject for future research with gaps remaining in knowledge regarding the incidence of bleeding and the underlying mechanisms, concludes the position paper.
Important questions for investigation on including whether bleeding is truly causal in subsequent mortality or merely a marker of increases risk related to worse baseline characteristics; whether the outcomes for spontaneous bleeding differ from bleeding induced by percutaneous or surgical revascularisation procedures; and what should be the optimal transfusion strategy for patients with ACS?