Incidence, outcomes, and management of bleeding in non-ST-elevation acute coronary syndromes
ABSTRACTAntithrombotic and antiplatelet drugs and percutaneous interventions have decreased the ischemic outcomes of non-ST-elevation acute coronary syndromes, but they pose risks of bleeding. The authors review the scope of the problem and ways to prevent and manage bleeding in this situation.
KEY POINTS
- The reported incidence of bleeding after treatment for non-ST-elevation acute coronary syndromes ranges from less than 1% to 10%, depending on a number of factors.
- Bleeding is strongly associated with adverse outcomes, although a causal relationship has not been established.
- Patients should be assessed for risk of bleeding so that the antithrombotic and antiplatelet regimen can be adjusted, safer alternatives can be considered, and percutaneous interventions can be used less aggressively for those at high risk.
- If bleeding develops and the risk of continued bleeding outweighs the risk of recurrent ischemia, antithrombotic and antiplatelet drug therapy can be interrupted and other agents given to reverse the effects of these drugs.
Bivalirudin
The direct thrombin inhibitor bivalirudin has been studied in three large randomized trials in patients undergoing percutaneous coronary interventions.20,37,41
The ACUITY trial37 was a prospective, open-label, randomized, multicenter trial that compared three regimens in patients with moderate or high-risk non-ST-elevation acute coronary syndromes:
- Heparin plus a glycoprotein IIb/IIIa inhibitor
- Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
- Bivalirudin alone.
Bivalirudin alone was as effective as heparin plus a glycoprotein IIb/IIIa inhibitor with respect to the composite ischemia end point, which at 30 days had occurred in 7.8% vs 7.3% of the patients in these treatment groups (P = .32, RR 1.08; 95% CI 0.93–1.24), and it was superior with respect to major bleeding (3.0% vs 5.7%, P < .001, RR 0.53; 95% CI 0.43–0.65).
The HORIZONS-AMI study41 was a prospective, open-label, randomized, multicenter trial that compared bivalirudin alone vs heparin plus a glycoprotein IIb/IIIa inhibitor in patients with ST-elevation acute coronary syndromes who were undergoing primary percutaneous coronary interventions. The two primary end points were major bleeding and net adverse events.
At 1 year, patients assigned to bivalirudin had a lower rate of major bleeding than did controls (5.8% vs 9.2%, HR 0.61, 95% CI 0.48–0.78, P < .0001), with similar rates of major adverse cardiac events in both groups (11.9% vs 11.9%, HR 1.00, 95% CI 0.82– 1.21, P = .98).41
Both OASIS 5 and HORIZONS-AMI are examples of clinical trials in which strategies that reduced bleeding risk were also associated with improved survival.
For cardiac catheterization, inserting the catheter in the wrist poses less risk
Bleeding is currently the most common noncardiac complication in patients undergoing percutaneous coronary interventions, and it most often occurs at the vascular access site.17
Rao et al12 evaluated data from 593,094 procedures in the National Cardiovascular Data Registry and found that, compared with the femoral approach, the use of transradial percutaneous coronary intervention was associated with a similar rate of procedural success (OR 1.02, 95% CI 0.93–1.12) but a significantly lower risk of bleeding complications (OR 0.42, 95% CI 0.31–0.56) after multivariable adjustment.
The use of smaller sheath sizes (4F–6F) and preferential use of bivalirudin over unfractionated heparin and glycoprotein IIb/IIIa inhibitor therapy are other methods described to decrease the risk of bleeding after percutaneous coronary interventions.20,41–49
IF BLEEDING OCCURS
Once a bleeding complication occurs, cessation of therapy is a potential option. Stopping or reversing antithrombotic and antiplatelet therapy is warranted in the event of major bleeding (eg, gastrointestinal, retroperitoneal, intracranial).31
Stopping antithrombotic and antiplatelet therapy
Whether bleeding is minor or major, the risk of a recurrent thrombotic event must be considered, especially in patients who have undergone revascularization, stent implantation, or both. The risk of acute thrombotic events after interrupting antithrombotic or antiplatelet agents is considered greatest 4 to 5 days following revascularization or percutaneous coronary intervention.15 If bleeding can be controlled with local treatment such as pressure, packing, or dressing, antithrombotic and antiplatelet therapy need not be interrupted.50
Current guidelines recommend strict control of hemorrhage for at least 24 hours before reintroducing antiplatelet or antithrombotic agents.
It is also important to remember that in the setting of gastrointestinal bleeding due to peptic ulcer disease, adjunctive proton pump inhibitors are recommended after restarting antiplatelet or antithrombotic therapy or both.
Importantly, evidence-based antithrombotic medications (especially dual antiplatelet therapy) should be restarted once the acute bleeding event has resolved.31
Reversal of anticoagulant and antiplatelet therapies
Unfractionated heparin is reversed with infusion of protamine sulfate at a dose of 1 mg per 100 U of unfractionated heparin given over the previous 4 hours.51,52 The rate of protamine sulfate infusion should be less than 100 mg over 2 hours, with 50% of the dose given initially and subsequent doses titrated according to bleeding response.52,53 Protamine sulfate is associated with a risk of hypotension and bradycardia, and for this reason it should be given no faster than 5 mg/min.
Low-molecular-weight heparin (LMWH) can be inhibited by 1 mg of protamine sulfate for each 1 mg of LMWH given over the previous 4 hours.51,52
However, protamine sulfate only partially neutralizes the anticoagulant effect of LMWH. In cases in which protamine sulfate is unsuccessful in abating bleeding associated with LMWH use, guidelines allow for the use of recombinant factor VIIa (NovoSeven).31 In healthy volunteers given fondaparinux, recombinant factor VIIa normalized coagulation times and thrombin generation within 1.5 hours, with a sustained effect for 6 hours.52
It is important to note that the use of this agent has not been fully studied, it is very costly (a single dose of 40 μg/kg costs from $3,000 to $4,000), and it is linked to reports of increased risk of thrombotic complications.54,55
Antiplatelet agents are more complex to reverse. The antiplatelet actions of aspirin and clopidogrel wear off as new platelets are produced. Approximately 10% of a patient’s platelet count is produced daily; thus, the antiplatelet effects of aspirin and clopidogrel can persist for 5 to 10 days.31,56
If these agents need to be reversed quickly to stop bleeding, according to expert consensus the aspirin effect can be reversed by transfusion of one unit of platelets. The antiplatelet effect of clopidogrel is more significant than that of aspirin; thus, two units of platelets are recommended.56
Glycoprotein IIb/IIIa inhibitors. If a major bleeding event requires the reversal of glycoprotein IIb/IIIa inhibitor therapy, the treatment must take into consideration the pharmacodynamics of the target drug. Both eptifibatide (Integrilin) and tirofiban (Aggrastat) competitively inhibit glycoprotein IIb/IIIa receptors; thus, their effects depend on dosing, elimination, and time. Due to the stoichiometry of both drugs, transfusion of platelets is ineffective. Both eptifibatide and tirofiban are eliminated by the kidney; thus, normal renal function is key to the amount of time it takes for platelet function to return to baseline.57 Evidence suggests that fibrinogen-rich plasma can be administered to restore platelet function.31,58,59
Abciximab (ReoPro). Whereas reversal of eptifibatide and tirofiban focuses on overcoming competitive inhibition, neutralization of abciximab involves overcoming its high receptor affinity. At 24 hours after abciximab infusion is stopped, platelet aggregation may still be inhibited by up to 50%. Fortunately, owing to abciximab’s short plasma half-life and its dilution in serum, platelet transfusion is effective in reversing its antiplatelet effects.31,57
