September 12, 2008 (Munich, Germany) — Major bleeding was a significant predictor of 30-day mortality in the HORIZONS-AMI trial, which pitted bivalirudin against unfractionated heparin (UFH) plus a glycoprotein IIb/IIIa inhibitor in patients getting PCI for acute ST-segment-elevation MI (STEMI), according to a post hoc analysis [ color="blue">1] that addresses some leftover questions after the release of the trial's primary outcomes during the past year [ color="blue">2].
Among the trial's >3600 patients, those randomized to the bivalirudin arm had benefited with significantly lower 30-day rates of the study's two primary end points, which were major bleeding unrelated to CABG (p<0.001) and a composite of major bleeding or major adverse cardiac events (MACE) (p=0.005), as reported at meetings and in the literature, extensively covered by heartwire . The end point combining bleeding with MACE--itself a composite of death, reinfarction, stroke, or ischemia-driven target-vessel revascularization (TVR)--was called net adverse clinical events (NACE).
Investigators with HORIZONS-AMI also pointed to a significant decrease in all-cause mortality (0.047) with bivalirudin, which, they contended, was driven by the highly significant 40% drop in adjusted risk of major bleeding; patients in that group also saw a significant decrease in cardiac mortality (p=0.03) but not in noncardiac mortality.
But some observers of the trial questioned the value of the trial's mortality finding, noting it wasn't a primary end point and achieved significance that was only fair-to-middling, and downplayed the possibility that it was a substantially tied to the reduction in bleeding.
In what may seem a reply to such concerns, HORIZONS-AMI investigators conducted multivariate analyses of their data to clarify the relationship between the bleeding and mortality outcomes. As presented here at the European Society of Cardiology Congress 2008 by Dr Roxana Mehran (Columbia University, New York, NY), major non–CABG-related bleeding as well as reinfarction were both significant predictors of 30-day all-cause mortality in the trial, independent of baseline features and all other clinical events. A major bleeding event, on its own, raised the mortality risk by a factor of up to five (p<0.001), depending on the analysis.
Table 1. Hazard Ratiosa (HR) for Primary-End Point Components as Predictors of 30-Day Mortality in HORIZONS-AMI Multivariate Analysis
|End Point||HR (95% CI)||p|
|Ischemia-driven TVR||1.15 (0.31–4.20)||0.83|
|Major bleedingb||5.08 (3.10–8.35)||<0.001|
size="1"> a. Covariates included demographics, recent CV drug use, time from symptom onset to hospital arrival, obesity, functional status, renal function, anemia, platelet count, randomized treatment group, and clinical end points
b. Defined as intracranial hemorrhage; intraocular, retroperitoneal, or access-site bleeding (requiring surgery); hematoma >5 cm in diameter, hemoglobin decrease by >3 g/dL if there is an obvious cause or >4 g/dL without an obvious cause; reoperation for bleeding; or blood-product transfusion
"I think we have shown that major bleeding is a powerful independent determinant of mortality in ACS, in ST-segment-elevation MI, and in patients undergoing PCI, and is at least as important as MI or reinfarction," Mehran said in her presentation. "We've shown this with the ACUITY trial and now with HORIZONS-AMI." As heartwire has reported, ACUITY explored the use of bivalirudin prior to PCI in patients with non-ST-segment-elevation ACS.
HORIZONS-AMI, Mehran continued, demonstrates a "favorable balance" of reduced risk of bleeding complications and similar 30-day rates of reinfarction and in-stent restenosis with bivalirudin compared with UFH plus a GP IIb/IIIa inhibitor in "high-risk" STEMI patients treated with PCI. That balance, she said, was associated with a reduction in mortality with bivalirudin, "representing a new standard of care, hopefully, for patients with ST-elevation MI."
That major bleeding was independently prognostic in the trial, consistent with prior trials such as OASIS, she said, "validates the concept of 'net adverse clinical events' that includes bleeding and major adverse cardiac events as a surrogate for mortality, perhaps."
Stroke and ischemic TVR, the other two components of the NACE primary end point, were not independent predictors of 30-day mortality.
"We all knew that bivalirudin was going to reduce bleeding. I think the most important finding here is that, while it reduced bleeding significantly, it did not increase ischemic complications," Mehran told heartwire , invoking the study's primary findings. "That's the key message, that it was safe and didn't increase the overall major adverse cardiac events and, in fact, was associated with a decreased cardiac mortality at 30 days."
"We Need to Understand Bleeding Better"
Commenting on Mehran's presentation as the assigned discussant, Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) said the messages he got from HORIZONS-AMI are that "bivalirudin is a winner and deserves a prominent place in the STEMI environment. Bleeding is bad and should be a prominent area of investigation and interventional strategy."
The drug, he said, "has now been studied in almost 30 000 patients across the spectrum of interventional cardiology. It consistently comes out showing less bleeding than the comparators, and depending on the studies, more or less competitive rates of hard cardiac events. But we should also be reminded that there are robust data for glycoprotein IIb/IIIa inhibitors, particularly in high-risk patients who are troponin-positive."
And, he said, there is still "room for debate" regarding the consequences of bleeding. "We need to understand bleeding better, as to how much of the 'independent' [prognostic] effect of bleeding is a stand-in for other adverse characteristics." For example, "how much is [due to adverse effects of] transfusion and how much to the bleeding itself and the biological consequences of bleeding?"
The trial's 3602 patients with STEMI onset within 12 hours were randomized in an open-label fashion to receive either bivalirudin or UFH with a GP IIb/IIIa inhibitor (either abciximab or eptifibatide) on top of aspirin and clopidogrel; all patients underwent angiography and then were triaged to primary PCI, CABG, or medical-only therapy. Bivalirudin recipients were allowed provisional GP IIb/IIIa inhibitor for suboptimal PCI results.
Stent-eligible patients were randomized to receive a bare-metal stent or a TAXUS stent; 3124 successfully received the stents (the stent analysis will be presented at October TCT-2008 meeting, Mehran said.)
Table 2. Hazard Ratiosa (HR) for Reinfarction and Major Bleedingb (Removing Stroke and TVR From the Model) as Predictors of 30-Day Mortality in HORIZONS-AMI
|End Point||HR (95% CI)||p|
|Major non-CABG bleeding||4.66 (2.84-7.63)||<0.001|
size="1"> a. Covariates included demographics, recent CV drug use, time from symptom onset to hospital arrival, obesity, functional status, renal function, anemia, platelet count, randomized treatment group, and other clinical end points
b. Defined as intracranial hemorrhage; intraocular, retroperitoneal, or access-site bleeding (requiring surgery); hematoma >5 cm in diameter, hemoglobin decrease by >3 g/dL if there is an obvious cause or >4 g/dL without an obvious cause; reoperation for bleeding; or blood-product transfusion Mehran told heartwire that her group has felt strongly and their data support that bleeding complications are as important to outcomes as ischemic events. "Obviously, we understand that the ischemic complications are much more hazardous, and I think we've proved that. When you look at the hazard ratio for reinfarction compared with bleeding, bleeding is a lot less hazardous. But because it's a much more common event, it contributes to more deaths."
In HORIZONS-AMI, she had said when presenting the study, reinfarction was involved in 9.7% of the 93 deaths, while major non-CABG bleeding accounted for more than twice as many: about 22%.
"Advantages in a Busy Practice"
As both Mehran and Califf observed, bleeding risks in the primary-PCI setting have been tough to pin down, partly because of varying definitions for bleeding used in different trials and partly because many of the events that contribute to those definitions are soft end points.
"Bleeding is a variable dependent on clinical-practice patterns," Califf said. For example, transfusions are a nearly universal contributor to the major bleeding end point, but criteria for administering blood products vary widely geographically and from practice to practice. "One must always question, when there's a difference in bleeding, how much was due to differences in practice patterns and how much to the treatment itself," he said.
"And indeed it's not only differences in bleeding and transfusion, but also differences in the doses of drugs [such as UFH, GP IIb/IIIa inhibitor, and low-molecular weight heparin] that are given according to the prescribed guidelines." Whether or not such dosing "was up to standards," Califf said, "I believe that the whole series of [bivalirudin] trials indicate that the simpler regimen of bivalirudin [compared with UFH plus GP IIb/IIIa inhibitor] given with clopidogrel has many advantages in a busy practice."
For example, the potential for dosing errors is higher with two drugs rather than one, he noted. "There are many errors made with the dosing of heparin and glycoprotein IIb/IIIa inhibitors, and of course this excess dosing has consequences in terms of the risk of transfusion." HORIZONS-AMI, he noted, "was a real-world trial, so the fact that one drug may be easier to give, with fewer complications than the other regimens, is very important."
Mehran discloses research support from the Medicines Company, Boston Scientific, and Abbott Vascular. Califf said his center is conducting major trials with all of the companies represented in HORIZONS-AMI, including the Medicines Company, Schering, Centocor, Lilly, and Merck; that he himself is leading trials funded by Johnson & Johnson, Bayer, Schering, Merck, and Novartis; and that he has received consulting fees--which are donated to Duke or other nonprofits--from Johnson & Johnson, Bayer, Schering, Merck, Novartis, Lilly, and Bristol-Myers Squibb.
Mehran R. Impact of major adverse cardiac events and major bleeding on overall mortality in patients with STEMI: the HORIZONS AMI trial. European Society of Cardiology Congress 2008; August 31, 2008; Munich, Germany. Clinical trials update 1.
Heartwire from Medscape © 2008 Medscape
Cite this: Steve Stiles. Mortality Closely Tied to Major Bleeds at Primary PCI, HORIZONS-AMI Trial Finds - Medscape - Sep 12, 2008.