In the wake of significant progress in the treatment of acute coronary syndromes (ACS) thanks to advances in percutaneous coronary intervention (PCI) and adjuvant antithrombotic regimens, focus has increasingly turned to the potential downside of these therapies, namely, increased bleeding. Growing data suggest the complication carries a mortality risk that may undermine improvements in therapeutic efficacy.

Responding to this growing perception, the Working Group on Thrombosis of the European Society of Cardiology (ESC) reviewed key issues surrounding bleeding in ACS patients, including the frequency and types of events and their clinical consequences. The group also made recommendations on reporting and managing the complication and highlighted outstanding questions for future research.

The position paper, written by a team led by Philippe Gabriel Steg, MD, of Hôpital Bichat-Claude Bernard (Paris, France), was published online June 29, 2011, in the European Heart Journal.

Although most data on the incidence of bleeding come from randomized, controlled trials, these may in fact underestimate the frequency of the complication, the authors note. Registry studies probably provide more reliable ‘real world’ estimates, although they render interpretation difficult due to changes in antithrombotic agents and bleeding management over time. Nonetheless, several factors have consistently been found to put patients at higher risk of bleeding:

• Older age
• Female sex
• Lower body weight
• Use of invasive procedures
• Renal insufficiency
• Certain genotypes 

Recommendations for Minimizing, Managing Bleeding

Because of the potential seriousness of bleeding, the ESC authors outline a number of recommendations to help minimize the risk.

Avoid overdosing. Use the minimal effective dose and adjust the dose to a patient’s weight, age, and renal function. 

Use the shortest possible duration. Continuation of dual antiplatelet therapy beyond 1 month after BMS implantation and 12 months after DES implantation should be considered an exception rather than the rule.

Choose the appropriate drugs. For example, in NSTE-ACS patients, fondaparinux should be selected over enoxaparin, while in STEMI patients, bivalirudin should be given rather than unfractionated heparin and a glycoprotein IIb/IIIa inhibitor.  

Reduce GI bleeding. To lower the risk of ulcer complications in patients at high bleeding risk, aspirin dosage can be safely reduced. Addition of a proton pump inhibitor (PPI) is recommended for such patients. 

Prevent access site bleeding. Use of a smaller sheath size, timely sheath removal, and radial access have been shown to reduce periprocedural bleeding.

Pay special attention to patients on triple therapy. BMS are preferred to allow early discontinuation of clopidogrel. Choice of a post-PCI antithrombotic strategy should be based on individual risk-benefit ratio.  

In the face of a bleeding event, no general guideline can be given, the ESC panel acknowledges. Significant bleeding should be monitored closely and transfusions considered if the patient is hemodynamically unstable. Partial or complete cessation of antithrombotic therapy and even use of an antagonist may be required. However, in stented patients, the benefit of discontinuation of even 1 agent should be carefully weighed against the increased risk of stent thrombosis. If antithrombotic therapy is interrupted, it should be restarted as soon as bleeding resolves.

Typically, minor bleeding during the acute phase of an ACS does not require medical attention, the paper states. But after discharge, even nuisance bleeding can have serious consequences if it prompts patients to stop therapy, making them vulnerable to recurrent ischemic events, the authors stress.

Goals for Clinical Research

The authors recommend that in future research, data on risk factors for major bleeding in ACS patients should be collected and analyzed to identify subgroups that may require special tailoring of antithrombotic treatment. Furthermore, to build up an evidence base for this purpose, bleeding definitions in trials should be not only clinically relevant but also uniform, to compare results across trials with different protocols and populations. In addition, bleeding should be reported using the new Bleeding Academic Research Consortium (BARC) definitions and at least 1 other scale, and include the ‘number needed to harm.’

Specifically, bleeding events should be characterized by:

• Timing of the event in relation to presentation
• Organ system involved
• Precipitating or contributing therapies, including invasive and antithrombotic
• Severity, such as nadir hemoglobin, number of RBC units transfused, or need for hospitalization

Finally, the authors highlight several outstanding questions they believe deserve further exploration, such as:

• To what extent and during what time frame is there an increased risk of mortality related to bleeding?
• Does spontaneous bleeding differ in prognostic implications from bleeding induced by revascularization?
• Is transfusion truly harmful? What should the optimal transfusion strategy be for ACS patients?
• In which ACS subsets should single, dual, triple, or quadruple (including anticoagulant) treatment be administered?

Europeans ‘Ahead of the Curve’

In a telephone interview, coauthor Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), said that American ACS guidelines contain nothing comparable to this full-blown ESC review. “The Europeans have been ahead of the curve on this issue,” he told TCTMD. Although the arrival of this position paper on the heels of the publication of the BARC definitions is coincidental, Dr. Rao noted, “it underscores the fact that professional societies and clinicians are really now starting to pay attention to the prognostic impact of major bleeding complications, particularly in high-risk populations like ACS patients.

“Now that we have multiple options for therapy, clinicians are starting to think: What’s the best combination for this particular patient that will maximize both efficacy and safety?” he added.

The fact that the ESC has spelled out recommendations for managing bleeding is quite helpful, Dr. Rao added.  For example, he noted, “they tell clinicians that if in their judgment they can manage a bleeding event without stopping antithrombotic therapy, they should do that because one of the drivers of the association between bleeding and adverse outcomes is taking patients off their medications,” he observed.

Likewise, it is important for doctors to alert patients starting new antithrombotic medications that they may experience gum bleeding, for example, Dr. Rao said, adding, “But we should also remind them that they are on those drugs for a good reason. In fact, 1 study showed that 11% of patients who had nuisance bleeding after DES placement stopped taking clopidogrel.”

To Dr. Rao, one of the more interesting—and vexing—issues addressed in the paper is when to give a transfusion. Clinicians vary widely in their practice, he noted, and there are no adequate randomized data to define an appropriate threshold for transfusion. Because of its potential for adverse effects, however, in patients without overt bleeding, the ESC recommends against transfusion to maintain a predefined hemoglobin level in hemodynamically stable patients with a hematocrit above 25% or a hemoglobin level above 8 g/dL.

Messages for Trialists, Researchers

The paper also includes messages to trialists, Dr. Rao indicated. “Clinicians hope to practice based on the best evidence, and if they have difficulty obtaining or interpreting the evidence, then that’s trialists’ fault,” he asserted. When researchers design a trial, in addition to using standard definitions like BARC, they should collect and report a wide range of data, he said, because different physicians care about different kinds of bleeding, and they deserve to have information to guide their decision making.  

A key unresolved issue is the question of whether bleeding is primarily a marker or a mediator of clinical risk, Dr. Rao observed. “I can’t believe that all bleeding events directly cause MIs or death. And I can’t believe that bleeding is simply a marker of someone who is sicker. I think it’s really a combination of both,” he said. “But unless we get good mechanistic studies of the changes that occur on the macro and micro levels, we’re not going to move the field forward.”

“I’m hopeful that over the next 3 to 5 years we will get some answers [to the outstanding questions raised in the paper],” Dr. Rao said. “Meanwhile, statements like this position paper will keep bleeding in the front of the academic community’s mind. We need to collect more granular data in clinical trials because the field is moving toward more and more potent therapies.”

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