Author + information
- Received April 27, 2010
- Revision received May 20, 2010
- Accepted May 31, 2010
- Published online August 1, 2010.
- Guido Parodi, MD, PhD⁎,⁎ (, )
- David Antoniucci, MD⁎,
- Eugenia Nikolsky, MD†,
- Bernhard Witzenbichler, MD‡,
- Giulio Guagliumi, MD§,
- Jan Z. Peruga, MD∥,
- Thomas Stuckey, MD¶,
- Darius Dudek, MD#,
- Ran Kornowski, MD⁎⁎,
- Franz Hartmann, MD††,
- Alexandra J. Lansky, MD†,
- Roxana Mehran, MD† and
- Gregg W. Stone, MD†
- ↵⁎Reprint requests and correspondence:
Dr. Guido Parodi, Division of Cardiology, Careggi Hospital, Viale Pieraccini 17, Florence I-50134, Italy
Objectives This study sought to assess the relationship between 1-year mortality and baseline patient risk in the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial.
Background The HORIZONS-AMI trial showed that bivalirudin compared with unfractionated heparin (UFH) plus glycoprotein IIb/IIIa inhibitors (GPI) decreased major bleeding and 30-day and 1-year mortality in patients undergoing primary percutaneous intervention for acute myocardial infarction.
Methods Patients in the HORIZONS-AMI trial were classified as low, intermediate, and high risk according to the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) risk score based on 7 clinical variables.
Results Among 2,530 CADILLAC-score evaluable HORIZONS-AMI trial patients, 1,522 (60%) were classified as low risk, 531 (21%) as intermediate risk, and 477 (19%) as high risk. The mortality rates in the bivalirudin and UFH plus GPI arms, respectively, were 0.4% and 1.2% (p = 0.09) in the low-risk group, 4.2% and 4.1% (p = 0.99) in the intermediate-risk group, and 8.4% and 15.9% (p = 0.01) in the high-risk group. Among high-risk patients, there was also a decreased rate of recurrent myocardial infarction in patients randomized to bivalirudin as compared to UFH plus GPI (3.6% vs. 7.9%, p = 0.04).
Conclusions In high-risk patients undergoing primary percutaneous coronary intervention for acute myocardial infarction, bivalirudin compared with UFH plus GPI reduces 1-year mortality and recurrent myocardial infarction. (HORIZONS-AMI trial; NCT00433966)
Several studies on primary percutaneous intervention (PCI) for acute myocardial infarction (AMI) have shown that the benefit provided by PCI and antithrombotic adjunctive therapies is related to the risk of the patient, with the benefit increased in high-risk patients (1–3). All effective antithrombotic and anticoagulant adjunctive therapies are associated with an increased risk of bleeding, and it has been shown that bleeding complications may have a significant negative impact on clinical outcome by decreasing or even eliminating the anti-ischemic benefit of the antithrombotic treatment (4,5). In the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial, the direct thrombin inhibitor bivalirudin (Angiomax, The Medicines Company, Parsippany, New Jersey) compared with unfractionated heparin (UFH) plus a glycoprotein IIb/IIIa inhibitor (GPI) resulted in reduced major bleeding, decreased 30-day and 1-year mortality, and enhanced freedom from net adverse clinical events in patients with AMI undergoing primary PCI (6,7). The aim of this study is to assess the potential relationship between the benefit provided by bivalirudin as compared with UFH plus GPI and the patient risk profile in the HORIZONS-AMI patient cohort.
The HORIZONS-AMI trial was a prospective, open-label, randomized, multicenter trial that compared bivalirudin with UFH plus a GPI in patients with ST-segment elevation AMI undergoing primary PCI. The study design and inclusion and exclusion criteria have been reported extensively elsewhere (8). Briefly, consecutive patients 18 years of age or older who presented within 12 h after the onset of symptoms and who had ST-segment elevation AMI of 1 mm or more in 2 or more contiguous leads, new left bundle-branch block, or true posterior myocardial infarction (MI) were enrolled in the study. The study was approved by the institutional review board or ethics committee at each participating center, and all patients gave written informed consent.
Study protocol and randomization
Patients were randomly assigned, in an open-label fashion and in a 1:1 ratio, to treatment with UFH plus a GPI (the control group) or to treatment with bivalirudin. Unfractionated heparin was administered as an intravenous bolus of 60 IU/kg of body weight, with subsequent boluses targeted to an activated clotting time of 200 to 250 s. Bivalirudin was administered as an intravenous bolus of 0.75 mg/kg, followed by an infusion of 1.75 mg/kg/h. If UFH was administered in a patient in the bivalirudin group, bivalirudin was started 30 min later but in all cases before PCI. Both antithrombin agents were discontinued, as specified by the protocol, at the completion of angiography or PCI but could be continued at low doses if they were clinically indicated. GPI were administered before PCI in all patients in the control group and could be administered as provisional treatment in the bivalirudin group in patients with no reflow after PCI or with giant thrombus. Abciximab or eptifibatide were allowed as GPI at discretion of the investigator. Aspirin (325 mg given orally or 500 mg administered intravenously) was given in the emergency room, after which 300 to 325 mg was given orally every day during the hospitalization and 75 to 81 mg every day thereafter indefinitely. A loading dose of clopidogrel (either 300 mg or 600 mg, at the discretion of the investigator), or ticlopidine (500 mg) was administered before catheterization, followed by 75 mg of clopidogrel or 500 mg of ticlopidine every day for at least 6 months (1 year or longer recommended). Emergency coronary angiography was performed after randomization, followed by triage, at the discretion of the physician, to PCI, coronary artery bypass grafting, or medical management, as described previously (8).
Two primary end points were pre-specified: major bleeding and the combined adverse clinical events defined as the combination of major bleeding or a composite of major adverse cardiovascular events including death, reinfarction, target vessel revascularization for ischemia, and stroke. Major bleeding was defined as intracranial or intraocular hemorrhage, bleeding at the access site with a hematoma ≥5 cm in diameter or that required intervention, decrease in hemoglobin concentration ≥4 g/dl without an overt source of bleeding, or ≥3 g/dl with an overt source of bleeding, reoperation for bleeding, or blood product transfusion. Major bleeding and the other study end point, defined elsewhere, were adjudicated by an independent clinical events committee that was unaware of the treatment assignments. Analyses of the primary end points were planned at 30 days and at 1 year. The primary end point of this current analysis of the HORIZONS-AMI trial dataset is 1-year mortality.
Baseline patient risk assessment
The CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) risk score was used to attribute a risk category to the single patient. The CADILLAC risk score has been already validated as a prognostic index in patients undergoing primary PCI and enables accurate identification of high-risk patients as compared with other similar risk scores for patients with AMI (9,10). Patients were classified as low (score from 0 to 2), medium (score from 3 to 5), and high risk (score ≥6) based on 7 available variables: angiographic baseline left ventricular ejection fraction <40% (score 4), renal insufficiency (creatinine clearance <60 ml/min) (score 3), Killip class 2 or 3 (score 3), post-PCI TIMI (Thrombolysis In Myocardial Infarction) flow grade <3 (score 2), age >65 years (score 2), anemia (baseline hematocrit level <39% for men, and <36% for women) (score 2), and 3-vessel coronary artery disease (score 2).
Categorical outcomes were compared by means of the chi-square test or Fisher exact test. Continuous variables were compared by means of the Wilcoxon rank sum test. Event rates for each of the risk classes (low, medium, and high) were calculated. The discriminatory capacity of the model was assessed using the area under the receiver-operator characteristic curve, and the difference between model-predicted and observed event rates (goodness-of-fit) was evaluated with the Hosmer-Lemeshow test (p > 0.05 considered to indicate lack of deviation between the model and observed rates). Time-to-event outcomes, determined with Kaplan-Meier methods, were compared by means of the log-rank test. For all analyses, a 2-sided p < 0.05 was considered statistically significant. All statistical analyses were performed by SAS version 8.2 (SAS Institute, Inc., Cary, North Carolina).
Out of 3,602 patients enrolled in the HORIZONS-AMI trial, 2,530 could be classified by the CADILLAC risk score. The reasons for patients' exclusion were as follows: 1) baseline left ventricular ejection fraction was not available in 562 patients; 2) baseline blood samples for hematocrit and creatinine values were not drawn in 326 patients; and 3) final TIMI flow grade was not assessed by the core lab in 213 patients. Patients excluded from the analysis because of unavailability of 1 or more variables of the CADILLAC score differed from patients for whom the CADILLAC score was available in several characteristics. Excluded patients were more likely to be older and to have anemia and renal insufficiency, and a post-procedural TIMI flow grade <3 (Table 1). There was no difference in the baseline clinical characteristics between patients randomized to bivalirudin or UFH plus GPI and who were considered for this analysis except for a higher percentage of current smokers in the bivalirudin arm and hypertensive patients in the control arm (Table 2). Among the 2,530 evaluable patients, 1,522 patients (60%) were classified as low risk, 531 patients (21%) as intermediate risk, and 477 patients (19%) as high risk.
There was no difference in follow-up rate between patients randomized to bivalirudin (96%) and those randomized to UFH plus GPI (96.5%). The 1-year mortality rate was 0.8%, 4.1%, and 12.4% in low-, intermediate-, and high-risk patients, respectively (Fig. 1). The CADILLAC risk score provided an accurate identification of high-risk patients, and the area under the receiver-operator characteristic curve was 0.834 with a Hosmer-Lemeshow value of 0.09. The mortality rates in patients randomized to bivalirudin or UFH plus GPI were 0.4% and 1.2% in low-risk patients (relative risk [RR]: 0.34, 95% confidence interval [CI]: 0.09 to 1.25, p = 0.09), 4.2% and 4.1% in intermediate-risk patients (RR: 1.00, 95% CI: 0.44 to 2.28, p = 0.99), and 8.4% and 15.9% in high-risk patients (RR: 0.53, 95% CI: 0.32 to 0.89, p = 0.01), respectively (Fig. 1). The greatest benefit in mortality in the high-risk cohort was primarily within the first 2 months, which was then maintained over the remainder of the year (Fig. 2). The 1-year mortality rate in the patient group excluded because of unavailability of the CADILLAC score (n = 1,072) was 5% and was identical in the 2 randomization arms (28 deaths in 555 patients randomized to bivalirudin, and 26 deaths in 517 patients randomized to UFH plus GPI), whereas bleeding rate was lower in patients randomized to heparin (5.8% vs. 7.9%, respectively).
Other clinical events
Table 3 summarizes the clinical events during the 1-year follow-up. There were no differences in nonfatal ischemic events between the 2 arms according to the risk profile except for a higher rate of recurrent MI in high-risk patients randomized to UFH plus GPI (7.9% vs. 3.6%, p = 0.042). Major bleeding rates increased progressively from low-risk to high-risk patients in both randomization arms. Major bleeding rates in patients randomized to bivalirudin were 3% in low-risk patients, 7.2% in intermediate-risk patients, and 12.9% in high-risk patients. The corresponding major bleeding rates in patients randomized to UFH plus GPI were 6.9%, 9.8%, and 17.9% respectively. Randomization to bivalirudin reduced major bleeding rates in all 3 risk groups; however, the reduction reached significance in the low-risk patient group only. The interaction tests between randomization and risk category were statistically not significant for all the considered 1-year events (Table 3).
The main finding of the present analysis is that in the HORIZONS-AMI trial the reduction in mortality in patients randomized to bivalirudin as compared with UFH plus GPI was mainly driven by a difference in mortality in the high-risk patient group, whereas no difference could be revealed in the intermediate-risk group, and only a trend favoring bivalirudin was revealed in the low-risk group. The difference in mortality in the high-risk patient group between bivalirudin and UFH plus GPI peaked at approximately 60 days and was maintained at 1-year follow-up. Moreover, in the same high-risk group, randomization to bivalirudin was associated with a significant decrease in nonfatal recurrent MI. Thus, the study results suggest that, at least for hard end points such as death and MI, the extent of the benefit provided by bivalirudin parallels the risk of the patient.
As expected, randomization to bivalirudin was associated with a decrease in major bleeding. However, this effect was not uniformly distributed in the 3 risk categories and was more evident in the low-risk patient group, whereas the difference in the high-risk group between bivalirudin and UFH and GPI was less pronounced and did not reach statistical significance. This finding suggests that the benefit provided by bivalirudin in terms of death and recurrent MI could not be explained solely by the effect on bleeding. Moreover, stratification of patients according to the CADILLAC score was able to show a progressive increased risk of major bleeding from low- to high-risk patients in both randomization arms, confirming that a worse baseline risk profile is associated with an increased risk of hemorrhagic complications regardless of the antithrombotic/anticoagulant treatment administered.
Previous studies have shown that periprocedural bleeding in patients undergoing PCI is associated with an increased risk of ischemic events and that bleeding adversely affects short-term and long-term mortality (4,5). However, in 2 previous trials comparing bivalirudin with UFH plus GPI, the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2) (11) and ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trials (12), the dramatic decrease in bleeding provided by bivalirudin resulted in only trends and not a statistically significant decrease in mortality. In the ARNO (Antithrombotic Regimens aNd Outcome) trial (13) that compared bivalirudin with UFH in 850 patients pre-treated with 600 mg of clopidogrel undergoing elective PCI, bivalirudin provided a significant decrease both in bleeding and ischemic complications (cardiac death, MI, and unplanned target vessel revascularization) and major bleeding was an independent predictor of ischemic events. The analysis in the entire HORIZONS-AMI patient cohort suggests a strong relation between major bleeding and mortality (6,7). It is possible that the sample size of HORIZONS-AMI high-risk patients with a CADILLAC score available is too small to show a significant difference in terms of bleeding or to avoid the confounding effect of many other variables besides the worse baseline risk profile that are linked to bleeding, such as the dose and duration of an antithrombotic treatment, the maintenance of femoral sheath in PCI patients after the procedure, the cutoff of hematological parameters used for blood transfusion, or the criteria used for discontinuation of antithrombotic treatment. Again, most of the deaths are not directly due to a fatal bleeding; the link between bleeding and mortality is not easily nor fully explained in most studies; and the mechanism or mechanisms of death remain largely speculative.
A further possible explanation of the decreased mortality and recurrent MI in the high-risk bivalirudin patient group as shown by the current analysis might be linked to the antiplatelet effect of bivalirudin that, differently from UFH, inhibits platelet activation and aggregation (14). However, this mechanism seems unlikely, considering that this effect of bivalirudin is widely counterbalanced in the UFH plus GPI arm by the potent platelet aggregation inhibition provided by routine administration of GPI. Whatever the mechanism or mechanisms involved in the benefit of bivalirudin in terms of death and recurrent MI in high-risk patients, the results of the present analysis support bivalirudin treatment as a standard of care for high-risk patients undergoing primary PCI for AMI (6).
This is a non–pre-specified post-hoc, subgroup analysis, and the results of the study should be considered hypothesis-generating only. The analysis was limited to patients with a CADILLAC score available, and nearly 30% of patients of the HORIZONS-AMI cohort were excluded because of unavailability of the CADILLAC score. This missing patient percentage may be considered expected because the most frequent reason for the exclusion was the unavailability of the left ventricular angiography; excluded patients were older and more frequently had renal insufficiency, both markers of increased risk of contrast-induced nephropathy. Moreover, the 1-year mortality rate of 5% in the excluded patient group was identical in the 2 arms, suggesting that a bias effect favoring bivalirudin in the subgroup of patients classified as high-risk patients according to the CADILLAC score is unlikely. Moreover, the expected relatively high percentage of patient exclusion using the CADILLAC score is justified by the superior accuracy of this score in risk stratification as compared to other score systems (10). On the other hand, we must underline that some variables of the CADILLAC score are not usually available at the time of primary PCI therapy selection. We cannot exclude the play of chance to explain the revealed difference in mortality between high-risk patients randomized to bivalirudin and patients randomized to UFH plus GPI. However, different from the main HORIZONS-AMI study, which was not powered for mortality, the current analysis focused on high-risk patients who have a very high mortality rate making it unlikely that the revealed difference is a result of chance.
The HORIZONS-AMI trial was sponsored by the Cardiovascular Research Foundation with unrestricted grant support from Boston Scientific Corporation and The Medicines Company. Dr. Guagliumi has received research grants from Medtronic, Boston Scientific, Abbott Vascular, Lightlab Imaging and is a consultant for Boston Scientific and Volcano. Dr. Stone is a member of the Scientific Advisement Board for Boston Scientific and Abbott Vascular and is a consultant for The Medicines Company. Dr. Witzenbichler receives lecture fees from The Medicines Company, Boston Scientific, and Abbott Vascular. Dr. Stuckey has served on the Speakers' Bureau and Advisory Board for Boston Scientific. Dr. Mehran has received consulting honoraria fees from Abiomed, Abbott Vascular, Access Closure, Accumetrics, AstraZeneca, Brocco Diagnostics, Cardiva, Cordis, Daiichi-Sankyo, Eli Lilly, Gilead, Guerbet, The Medicines Company, Regado Biosciences, St. Jude, and Therox and recieves grant support (to Columbia University) from BMS/Sanofi-Aventis. All other authors report that they have no relationships to disclose.
- Abbreviations and Acronyms
- acute myocardial infarction
- glycoprotein IIb/IIIa inhibitors
- myocardial infarction
- percutaneous coronary intervention
- unfractionated heparin
- Received April 27, 2010.
- Revision received May 20, 2010.
- Accepted May 31, 2010.
- American College of Cardiology Foundation
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