Spontaneous Bleeding After PCI Tied to Worse Long-term Mortality

For patients who undergo PCI, spontaneous bleeding after hospital discharge signals a greater risk of long-term mortality, according to a study published in the April 14, 2015, issue of the Journal of the American College of Cardiology. The strength of the relationship is similar to that seen between MI and mortality.Take Home: Spontaneous Bleeding After PCI Tied to Worse Long-term Mortality

“This is important because as our armamentarium becomes more diverse and potent, we have the ability to both prolong our dual antiplatelet therapy [DAPT] as well as make it more powerful with the use of newer antiplatelet agents,” lead author Dhruv S. Kazi, MD, MSc, of San Francisco General Hospital (San Francisco, CA), told TCTMD in a telephone interview. “We have to be aware of the fact that these bleeds are at least correlated with adverse outcomes that are similar in magnitude to the [MI-associated outcomes] that we’re trying to avoid in the first place.”

Dr. Kazi and colleagues examined data from 32,906 patients aged 30 years and older (mean age 64 years; 29.9% female) who underwent PCI in the integrated healthcare delivery system of Kaiser Permanente Northern California between 1996 and 2008 and survived for at least 7 days after discharge. In all, 14% of patients underwent PCI for ACS, and the rest had elective procedures.

Between days 7 and 365, there were 530 spontaneous bleeds requiring hospitalization (77.2% GI, 15.3% intracranial, and 7.5% other) that occurred a median of 100 days after discharge. There were also 991 MIs at a median of 127 days postdischarge.

During a mean follow-up of 4.42 years, 4,048 patients died. The crude annual death rate was 9.4% for patients who had a spontaneous bleed, 7.6% for those who had an MI, and 2.6% for those who had neither event.

After adjustment for time-updated demographics, comorbidities, periprocedural events, longitudinal laboratory results, and medication use, patients had an elevated mortality risk after both spontaneous bleeding (HR 1.61; 95% CI 1.30-2.00) and MI (HR 1.91; 95% CI 1.62-2.25). Findings were similar regardless of whether the indication for PCI was elective or urgent.

Further adjustment for the longitudinal use of antiplatelets yielded comparable results, indicating that the association between bleeding and mortality did not arise subsequent to patients stopping the drugs, the authors say.

Causality Unclear

The relationship between procedure-related major bleeding and post-PCI mortality has been established in several studies, including a 2013 analysis of data from the CathPCI Registry. The current study, according to Dr. Kazi and colleagues, expands on those findings by demonstrating a similar association between postdischarge, nonprocedural bleeding and mortality.

What remains unclear, they say, is whether bleeding directly gives rise to mortality or serves as a marker for poor prognosis. They list several potential mechanisms directly linking spontaneous bleeding to mortality, including activation of the coagulation cascade; increases in prothrombotic cytokines; induction of hypovolemia and anemia, which “reduce oxygen delivery and cause reflex tachycardia”; and adverse effects of blood transfusions.

But even though there is biological plausibility to a causal relationship, the definitive answer will come from future randomized trials evaluating the impact of bleeding reduction strategies—such as proton pump inhibitors—in the postdischarge setting, Dr. Kazi said.

In the meantime, however, “it would be valuable for us as a cardiology community to be careful and to personalize the therapies based on a combined assessment of both thrombotic events and bleeding,” he said. Bleeding risk scores are available, he added, although it remains to be seen whether using them improves outcomes.

The authors argue that an assessment of the net clinical benefit of treatment is particularly important “because major bleeds outnumbered MIs in the intervention arms of pivotal trials leading to the approval of both ticagrelor [Brilinta; AstraZeneca] and prasugrel [Effient; Eli Lilly/Daiichi Sankyo].”

‘Sobering Reminder’ of Difficulty in Balancing Risks, Benefits

In an accompanying editorial, Sunil V. Rao, MD, of the Duke Clinical Research Institute (Durham, NC), also speculates on the potential mechanisms linking postdischarge bleeding to mortality, suggesting—as the authors do—that bleeding could either directly worsen outcomes or serve as a marker of greater risk.

“Despite the lack of clear data linking bleeding to mortality, prevention of hemorrhagic complications seems prudent,” Dr. Rao says. “The first step is to identify patients at risk. Risk models for bleeding are available, but many were developed in patients hospitalized with [ACS] or undergoing PCI and focus on in-hospital rather than posthospital events.”

What with the uncertainty surrounding the use of such risk scores, he says, “[i]t may be more important to universally use bleeding reduction strategies in patients treated with DAPT. The vast majority of significant bleeding events with oral antiplatelet therapy originate from the [GI] tract. Therefore, management approaches aimed at reducing the GI bleeding risk, including a reduction in the aspirin dose and concomitant therapy with proton pump inhibitors, should be used in patients on long-term DAPT.”

The study, Dr. Rao concludes, “serves as a sobering reminder that despite marked advances in pharmacotherapy and PCI technology, clinicians and patients still face the classic tradeoff between reduction in ischemia and increased bleeding risk. Prudent use of existing risk models and strategies proven to reduce long-term bleeding risk, applied in the context of clinical judgment, are key to achieving the best long-term outcomes in patients undergoing PCI.”

 


Sources:
1. Kazi DS, Leong TK, Chang TI, et al. Association of spontaneous bleeding and myocardial infarction with long-term mortality after percutaneous coronary intervention. J Am Coll Cardiol. 2015;65:1411-1420.

2. Rao SV. The conundrum of reducing ischemic and bleeding events after PCI [editorial]. J Am Coll Cardiol. 2015;65:1421-1423.

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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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Disclosures
  • The study was funded in part by the American Heart Association; Kaiser Permanente Northern California Division of Research; Stanford University; and the University of California, San Francisco.
  • Dr. Kazi reports no relevant conflicts of interest.
  • Dr. Rao reports having received consulting income from Terumo Medical and The Medicines Company and research funding from Bellerophon.

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