Multiple Antithrombotic Meds Before PCI in NSTE ACS Ups Bleeding Risk, Lowers Survival

Upstream use of multiple antiplatelet and anticoagulant medications in patients with non-ST-elevation acute coronary syndromes (NSTE ACS) awaiting diagnostic angiography is associated—not surprisingly—with a significantly increased risk of bleeding. This bleeding risk is in turn associated with a higher risk of death at 1 year, a new analysis shows.

Although the stacking of multiple antithrombotic therapies is intended to reduce the risk of ischemic events, the rate of bleeding is six to seven times higher than the risk of MI and that trade-off comes at a price, say investigators.

“These data are important for the big picture,” senior researcher Philippe Généreux, MD (Hôpital du Sacré-Coeur de Montréal, Canada), told TCTMD. “Overloading patients with antiplatelet therapy and multiple antithrombotic drugs is not trivial, is not benign, and is not without risk. Truly, I think the combination of a minimalistic approach for antithrombotic therapy before cath, with an early cath, is a solution.”

In light of the data, Généreux said patients should be treated with aspirin and low-molecular-weight heparin (LMWH)—both class IA recommendations from the American College of Cardiology/American Heart Association—but to minimize the risk of bleeding, physicians should resist the urge to load patients with clopidogrel, prasugrel, or ticagrelor. If platelet inhibition is needed, an agent such as short-acting cangrelor (Kengreal, Chiesi) can be given on the table, he said.

In an editorial accompanying the study, Michael Lee, MD, and Jonathan Gordin, MD (University of California, Los Angeles), state that an argument “could be made” to proceed to angiography as soon as possible to reduce the duration of upstream antithrombotic therapy. Evidence supports the invasive strategy in all but the lowest-risk NSTE ACS patients, but the benefits of immediate versus early angiography are not as clear.

The study, led by Björn Redfors, MD, PhD (Cardiovascular Research Foundation, New York, NY), and the editorial were published online yesterday in the Journal of American College of Cardiology.

The ACUITY Analysis

In this analysis of 13,726 patients with moderate- or high-risk NSTE ACS in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, the median time to coronary angiography was 4.7 hours. Bleeding before angiography occurred in 2.0% of patients, with 0.4% having a major bleeding episode. The MI rate prior to diagnostic angiography was 0.3%.

For those who did and did not bleed prior to angiography, the median time from randomization to coronary angiography was 4.5 and 27.9 hours, respectively. Individuals with bleeding were older and more likely to have renal insufficiency. They were also more likely to receive LMWH, less likely to receive bivalirudin, and more likely to receive an upstream P2Y12 receptor antagonist and glycoprotein IIb/IIIa inhibitor.

Overall, the bleeding risk was significantly higher among patients treated with multiple antithrombotic medications. Each additional medication used prior to coronary angiography translated into 33% higher risk of bleeding (adjusted HR 1.33; 95% CI 1.14-1.56). Patients who bled prior to angiography had longer hospitalizations and more in-hospital bleeding than those who didn’t bleed prior to the procedure.

At 30 days, bleeding before the diagnostic angiogram was associated with an increased risk of death (4.0% vs 1.5%; P = 0.0006) and this difference persisted at 1 year (8.5% vs 4.1%; P < 0.0001). After adjusting for the differences in comorbidities, bleeding prior to coronary angiography was associated with an 89% higher risk of death in the first year (adjusted HR 1.89; 95% CI 1.23-2.90).

Treatment Protocol 

James Orford, MD (Intermountain Medical Center Heart Institute, Salt Lake City, UT), who was not involved in the study, told TCTMD the higher risk of bleeding in a group of patients aggressively managed with anticoagulants and antiplatelets prior to angiography isn’t too surprising. He said treatment of NSTE ACS patients involves aspirin and heparin, but that some centers may load with clopidogrel or another thienopyridine.

The ACC/AHA clinical guidelines state that a P2Y12 inhibitor, in addition to aspirin, can be loaded in patients treated with an early invasive or ischemia-guided strategy (class IB). Orford said glycoprotein IIb/IIIa inhibitors would also be used sparingly and only in patients with clinical instability who would be moved quickly to the cath lab.

“Most of us have moved to a more conservative approach for ACS, with prompt angiography in the event the patient demonstrates signs of instability, which would be ongoing or recurrent chest pain, labile ST-segments on the electrocardiogram, or an interval increase in troponin,” he said.  

To TCTMD, Généreux said that for patients that can be safely delayed, aspirin alone should be enough.

“If you have an ACS—and ACS is a large disease—it all depends where your patient fits in terms of ischemic risk,” he said. “If you’re patient is at high risk for ischemia or MI, you should go the cath lab the same day or within a few hours of presenting. If you believe the patient is stabilized, doesn’t have positive biomarkers, and no ECG changes, you don’t need to give a lot of antiplatelet therapy.”

Overall, say the editorialists, the analysis shows that bleeding-avoidance strategies are “essential” in reducing the risk of recurrent ischemic events and improving long-term survival and stress that these strategies should start the moment the patient is admitted. “Bleeding cannot be seen as an isolated incident, because its ramifications continue throughout the hospitalization to discharge and beyond, influencing patient management and leading to worse outcomes,” write Lee and Gordin.

Note: Redfors, Généreux, and several other co-authors of the paper are faculty members of the Cardiovascular Research Foundation, the publisher of TCTMD.