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Patients who experience major bleeding in the hospital after primary percutaneous coronary intervention (PCI) are at increased risk for ischemic events, including mortality, for up to 3 years, according to a post hoc analysis from the HORIZONS-AMI trial published in the October 18, 2011, issue of the Journal of the American College of Cardiology.

In the main HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) trial, STEMI patients were randomized to bivalirudin or heparin plus a glycoprotein IIb/IIIa inhibitor. At 30 days, patients treated with bivalirudin had lower rates of major hemorrhagic complications and net adverse clinical events.

For the current substudy, investigators led by Roxana Mehran, MD, of Mount Sinai School of Medicine (New York, NY), evaluated the long-term impact of in-hospital major non-CABG bleeding on the 6.9% of 3,345 primary PCI patients who experienced the complication.

Interestingly, use of antiplatelet therapy was similar between patients who did and did not suffer major bleeding from discharge up to 3 years. The only exceptions were less use of aspirin at 1 year and more use of clopidogrel at 3 years among patients who suffered in-hospital major bleeding.

With regard to discharge medications, bleeding patients were less likely to receive beta-blockers and statins but more likely to be given diuretics, digoxin, and antiarrhythmic agents.

Higher Adverse Outcomes Out to 3 Years

At 3 years, patients with in-hospital major bleeding were twice as likely to have experienced MACE (composite of death, reinfarction, ischemia-driven TVR, or stroke) and more than 4 times as likely to have died as those without such bleeding. They also had higher rates of individual MACE endpoints but not of stent thrombosis (table 1).

Table 1. Three-Year Outcomes

According to the authors, exclusion of patients with large hematomas alone from the major bleeding group did not change the association of in-hospital major bleeding with increased long-term mortality.

In addition, in landmark analyses, rates of MACE and mortality were consistently higher among in-hospital bleeding patients over 3 time periods after PCI: within 1 month, from 1 month to 1 year, and from 1 year to 3 years (table 2).

Table 2. Landmark Analyses of Outcomes

 
In-hospital major bleeding was an independent predictor of increased 3-year mortality (HR 2.80; 95% CI 1.89-4.16; P < 0.0001) and remained so when only in-hospital survivors were considered (HR 2.26; 95% CI 1.43-3.54; P = 0.0004).

“There have been good studies before that looked at the consequences of bleeding out to a year,” said Dr. Mehran in a telephone interview with TCTMD. “The distinctive aspect of this study is that we did a landmark analysis to show that the adverse effects persist all the way out to 3 years.

Another unique feature of the study is that data were collected on medication use at both discharge and follow-up, Dr. Mehran said. The finding that bleeding patients received fewer beta blockers at discharge, “may be due to the fact that some were hypotensive and doctors were wary about giving [an antihypertensive],” she said, adding, “But I can’t explain the [failure to prescribe] statins.”

More frequent use of thienopyridines by bleeding patients at 3 years also is an interesting finding, Dr. Mehran observed. However, it may be explained by the fact that many of these patients suffered subsequent ischemic events and revascularizations and thus may have been restarted on antiplatelet therapy long after an initial course. Furthermore she cautioned, “remember that this occurred in a trial where aspirin and thienopyridine use was endorsed.”  

Exploring Potential Mechansims

In an accompanying editorial, Robert J. Applegate, MD, of Wake Forest School of Medicine (Winston-Salem, NC), suggests that the potential mechanisms behind the link between major bleeding and adverse outcomes should be divided into an early phase (from hospitalization to about 30 days) and a later phase. Candidate mechanisms for the early phase range from frank bleed out such as retroperitoneal hemorrhage to need for transfusion.

Reasons for enhanced ischemic risk during the later phase are more obscure, Dr. Applegate writes, prompting the question of whether bleeding is simply more likely to occur in those who are at risk of late adverse cardiac events despite best efforts to adjust for confounders, he adds.

“That’s the simplest answer, and there is an element of confounding for sure,” Sunil Rao, MD, of Duke University Medical Center (Durham, NC), told TCTMD in a telephone interview. “And it is hard to understand in mechanistic terms why an in-hospital bleeding event would be associated with persistently high risk for mortality.”

But he also put forward other possible explanations. “Might it sometimes be the response to bleeding rather than the event itself that increases risk?” Dr. Rao asked. Another unknown is whether patients who experience a bleeding event in the hospital also bleed later on, Dr. Rao said, adding, “Chances are if they do, they’re going to stop their aspirin and/or clopidogrel, and that may lead to a recurrent MI.” 

The Best Way to ‘Manage’ Bleeding: Avoid It

With regard to clinical management of ACS patients with post-PCI bleeding, Dr. Rao noted that the European ACS guidelines—unlike their American counterpart—devote a specific section to bleeding. “They say that any patient who presents with ACS should first be evaluated for bleeding as well as ischemic risk. And if you have to interrupt antithrombotic therapy, make sure you restart it as soon as possible,” he reported.

“But the most important thing clinicians can do is to implement so-called bleeding avoidance strategies, such as using appropriate dosing, [antithrombotic] drugs associated with lower bleeding risk, and the radial approach if you are experienced with it.” Dr. Rao said. 

It is also important to tell patients what to expect regarding the potential for bleeding, and let busy primary care physicians know that their patient has had an in-hospital bleeding event.

Even before that point, more and more interventionalists are being proactive, considering whether to implant a BMS rather than a DES, Dr. Rao noted. That means asking patients upfront how conscientious they are about taking medications, whether they have any major surgery coming up or have had major bleeding related to catheterization. It also includes looking at lab results for possible anemia or occult bleeding.

In the end, Dr. Mehran acknowledged frustration in trying to pin down the reasons for elevated mortality among bleeding patients. “It’s very hard to tease out because obviously we can’t randomize patients for bleeding vs. no bleeding.” Nonetheless, she added, “this is another piece of evidence that there are both early and late consequences, and we should do our best to avoid bleeding in the first place.” 

Study Details 

Patients with in-hospital major bleeding were older and more often female. They also more frequently had a history of congestive heart failure, a higher Killip class, and a lower body mass index. In addition, they were more likely to have diabetes, anemia, and renal insufficiency.

A 600-mg loading dose of clopidogrel and bivalirudin were administered less frequently while glycoprotein IIb/IIIa inhibitors were used more often in patients with bleeding.
 

Note: Dr. Mehran and several coauthors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

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Sources:
1. Suh J-W, Mehran R, Claessen BE, et al. Impact of in-hospital major bleeding on late clinical outcomes after primary percutaneous coronary intervention in acute myocardial infarction. The HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial. J Am Coll Cardiol;2011;58:1750-1756.

2. Applegate RJ. Long-term impact of periprocedural bleeding. Where does it end? J Am Coll Cardiol. 2011;58:1757-1759.

 

 

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