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After percutaneous coronary intervention (PCI), bleeding at locations other than the access site is common and associated with a fourfold increase in mortality at 1 year, according to a study published in the February 2011 issue of JACC: Cardiovascular Interventions. Use of bivalirudin, however, reduces both access site and nonaccess site bleeding compared with heparin plus a glycoprotein IIb/IIIa inhibitor (GPI).

Investigators led by Freek W. A. Verheugt, MD, of Radboud University Medical Centre (Nijmegen, The Netherlands), looked at data from 17,393 patients included in 3 randomized clinical trials of bivalirudin vs. heparin plus a GPI who underwent PCI for a range of indications from stable ischemia to STEMI:

• REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events)
• ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy)
• HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction)

Nonaccess Site Bleeding More Common

TIMI major/minor bleeding at 30 days—chosen as the primary endpoint because it was assessed in all 3 trials—occurred in 5.3% of the cohort; 1.6% were classified as major bleeding and 3.7% as minor bleeding. Of all bleeding events, 38.6% occurred at the access site, while the majority (61.4%) originated elsewhere. Moreover, the median time from enrollment to a bleeding event was 1.0 (IQR 0.0-1.0) day for access site bleeding and 2.0 (IQR 1.0-2.0) days for nonaccess site-related bleeding.

Among the 568 patients with a nonaccess site TIMI bleed, the researchers documented sources for 621 bleeds, including:

• Genitourinary (17.9%)
• Gastrointestinal (15.0%)
• Head and neck (10.1%)
• Pulmonary (3.7%)
• Intracranial (0.9%)
• Other (6.9%)

No location was identified for 45.2% of nonaccess site bleeds.

After adjustment for baseline and procedural characteristics, 30-day TIMI major/minor bleeding was associated with more than a threefold increase in 1-year mortality. Both access site and nonaccess site bleeding increased mortality, but the contribution of nonaccess site bleeding was almost twofold greater than that of access site bleeding (table 1).

Table 1. One-Year Mortality Linked to 30-Day TIMI Major/Minor Bleeding

Furthermore, the source of nonaccess site bleeding did not alter the mortality risk. It was strongly associated with nonaccess-site-only bleeding (HR 2.78; P = 0.0002), combined access site and nonaccess site bleeding (3.64; P < 0.0001), and indeterminate bleeding location (HR 4.72; P < 0.0001).

To determine the impact of antithrombotic therapy on the incidence of access and nonaccess site-related bleeding, 14,784 patients who were randomized to bivalirudin alone or heparin plus a GPI were assessed. Bivalirudin yielded a 38% reduction in TIMI major/minor bleeding and a 43% reduction in TIMI major bleeding compared with heparin plus a GPI. The antithrombin agent decreased TIMI major/minor bleeding for both access site (RR 0.45; P < 0.0001) and nonaccess site (RR 0.62; P < 0.001) events. Similar levels of reduction were found for all bleeding locations.

The number-needed-to-treat with bivalirudin was 71 to prevent 1 nonaccess site-related TIMI bleed (excluding CABG bleeding) and 74 to prevent 1 access site-related bleeding event.

“These findings reinforce the need to identify treatment strategies that diminish not only access site bleeding but, even more importantly, nonaccess site bleeding,” the authors state.

Why Nonaccess Site Bleeds May Be More Dangerous

In a telephone interview with TCTMD, Mauro Moscucci, MD, of the University of Miami Miller School of Medicine (Miami, FL), lauded the pooled analysis for providing individual patient-level data and using a common bleeding endpoint.

The most intriguing findings, he noted, are the greater contribution of nonaccess site bleeding to mortality compared with access site bleeding and the relatively high incidence of nonaccess site bleeding of indeterminate origin.

The main reason nonaccess site bleeds more often prove fatal than access site bleeds is that the latter typically comprise relatively small hematomas involving less blood loss, making them less likely to require transfusion, said study coauthor Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), in a telephone interview with TCTMD. Transfusion—especially with older stored blood—is associated with worse long-term outcomes, Dr. Moscucci explained.

He also offered additional possible explanations for the higher mortality risk associated with nonaccess site bleeding. First, the most common forms, gastrointestinal and genitourinary bleeding, may prompt discontinuation of dual antiplatelet therapy, thereby increasing the risk of stent thrombosis. Second, intracranial hemorrhage, though rare, is frequently fatal.

A Radial Angle

Understanding the differing prognoses of the 2 bleeding categories is especially relevant to practitioners of radial access PCI, Dr. Stone said. “We know that radial artery access markedly decreases the likelihood of access site bleeds, but in general those are not the most important,” he noted. And although a previous study showed that in this setting bivalirudin does not affect access site bleeding compared with heparin plus a GPI, it does reduce nonaccess site bleeds, he said.

In a similar vein, Dr. Moscucci said an important lesson of the study is that clinicians performing radial PCI should guard against becoming complacent about bleeding and should consider using antithrombotic agents associated with a lower bleeding rate.

In general, certain types of patients are at increased bleeding risk and warrant special attention, including close monitoring of anticoagulation, noted Dr. Moscucci. These include the morbidly obese, those with peripheral vascular disease or chronic renal failure, older patients, and women.

“In the 1990s we were more concerned about periprocedural MI [causing] worse long-term outcomes,” Dr. Moscucci observed. “Now the focus is shifting to bleeding, and when you look at the mortality data, there may be more [deaths] related to bleeding than to some ischemic complications. This paper has great value because it carries a very strong message about the importance of nonaccess site bleeding.”

Study Details

TIMI major bleeding was defined as a reduction of hemoglobin of at least 5 g/dl (or >15% in hematocrit) with or without overt bleeding, or any intracranial bleeding. TIMI minor bleeding was defined as a 3 to 5 g/dl decrease in hemoglobin (or 10% to 15% in hematocrit) with an observed source of bleeding or a hemoglobin drop of 4 to 5 g/dl (or 12% to 15% in hematrocrit) without an observed source. A transfusion of a unit of whole blood or packed red blood cells was factored into the evaluation of blood loss and considered the equivalent of 1 g/dl of hemoglobin or 3% in hematocrit.

Note: Dr. Stone and another coauthor are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

• Dr. Verheugt reports serving as a speaker for Bayer AG and receiving consulting honoraria from AstraZeneca.
• Dr. Stone reports serving as a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, and The Medicines Company.
• Dr. Moscucci reports no relevant conflicts of interest.

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