The best magazine
Presenter: A. Michael Lincoff, MD, Cleveland Clinic (Cleveland, Ohio)
Bivalirudin, a small-molecule direct thrombin inhibitor with a naturally reversible mechanism of action, has been investigated as a replacement for unfractionated heparin in patients with unstable angina undergoing percutaneous coronary intervention (PCI). The drug, marketed under the brand name Angiomax (The Medicines Company; Parsippany, New Jersey), was approved by the US Food and Drug Administration in December 2000.
Previous trials have confirmed the benefits of bivalirudin, reporting that the drug reduced the incidence of major adverse cardiac ischemic events and partially reduced bleeding complications compared with heparin. It is suggested that bivalirudin may be an effective alternative to heparin, particularly for those patients with allergies to heparin and/or glycoprotein (GP) IIb/IIIa inhibitors. The drug may also offer potential advantages over the current use of heparin and adjunctive GP IIb/IIIa inhibitors, such as cost-effectiveness and procedural simplicity (ie, less time required for infusion).
Study Design
The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE) II is a double-blinded, multicenter, noninferiority trial designed to access whether the use of bivalirudin plus provisional GP IIb/IIIa inhibition during elective or urgent PCI could be equivalent or not inferior to the gold standard of heparin and a GP IIb/IIIa inhibitor for the prevention of ischemic complications in patients undergoing urgent or elective PCI.
The premise underlying the noninferiority analysis was the hypothesis that use of bivalirudin instead of heparin would allow for the omission, or at least the more selective use, of GP IIb/IIIa inhibitors -- a drug regimen currently considered routine in PCI settings but that has required some cost-benefit analysis to justify its use.
Patients were eligible for enrollment as long as they were to undergo PCI using an approved device and as long as they did not meet the following exclusion criteria:
Primary or rescue PCI in acute myocardial infarction (MI)
Fractionated or unfractionated heparin use within prior 6-8 hours
Bivalirudin use within prior 24 hours
Abciximab used within prior 7 days
Eptifibatide use within prior 12 hours
Warfarin treatment
Chronic renal insufficiency (serum creatinine > 4 mg/dL)
Thrombocytopenia (< 100,000)
Bleeding diathesis
Surgery within prior 6 weeks
The study's primary endpoint consisted of a quadruple composite measure of death, MI, urgent revascularization, or major hemorrhage at 30 days. Secondary endpoints included:
Triple endpoint of death, MI, and urgent revascularization at 30 days
Death, MI, and revascularization at 6 months
Death at 1 year
These secondary endpoints at 6 months and 1 year were prespecified to determine whether any differences noted at 30 days between the 2 groups would compromise long-term survival.
Results
Between October 2001 and August 2002, a total of 6010 patients were randomized to either intravenous bivalirudin (0.75 mg/kg bolus and 1.75 mg/kg/h for the duration of the procedure with provisional GP IIb/IIIa inhibitors (n = 2999) or heparin (65 U/kg) plus GP IIb/IIIa inhibitor therapy (abciximab or eptifibatide) (n = 3011) (Figure 1). All patients were treated with aspirin therapy, and pretreatment with a thienopyridine was strongly encouraged. Prior to randomization, physicians were required to identify in the study database whether abciximab or eptifibatide was to be used as the GP IIb/IIIa inhibitor in the heparin arm or as the provisional drug if patients were randomized to the bivalirudin group.
As reported earlier this year, baseline clinical characteristics, as well as the percentage of patients who received prior thienopyridine treatment and the time in which it was administered, were similar in both groups (Table 1).
Table 1. REPLACE-2: Baseline Clinical Characteristics, Thienopyridine Treatment, and Timing Before PCI
|
|
Bivalirudin (n = 2994) |
Heparin + GP IIb/IIIa (n = 3008) |
|---|---|---|
| Age (yrs) | 62.6 | 62.6 |
| Female (%) | 25.3 | 25.9 |
| Stable angina (%) | 26.1 | 24.4 |
| Positive stress test (%) | 30.9 | 31.5 |
| Diabetes (%) | 28.1 | 26.1 |
| Hypertension (%) | 66.0 | 68.0 |
| Past smoker (%) | 27.2 | 26.0 |
| S/P MI (%) | 37.4 | 36.7 |
| S/P PCI (%) | 34.5 | 35.3 |
| S/P CABG (%) | 18.0 | 18.8 |
| S/P CVA (%) | 2.5 | 2.2 |
| Prior thienopyridine (%) | 86.7 | 85.4 |
| Timing before PCI | ||
| < 2 hrs (%) | 26.6 | 26.1 |
| 2-48 hrs (%) | 56.9 | 56.1 |
| > 48 hrs (%) | 1.2 | 1.1 |
| Unknown (%) | 2.0 | 2.1 |
CABG, coronary artery bypass graft; CVA, cerebrovascular accident; GP, glycoprotein; MI, myocardial infarction; PCI, percutaneous coronary intervention
Median durations of drug infusion were significantly longer in the heparin/GP IIb/IIIa-treated group compared with patients treated with bivalirudin. Whereas the median duration of bivalirudin administration was only 0.73 hours, patients in the heparin-treated group had a GP IIb/IIIa median duration infusion of 18.0 hours for eptifibatide and 12.0 hours for abciximab. Provisional GP IIb/IIIa inhibitors were used in only 7.2% of bivalirudin patients.
30-day Follow-up Results
Published earlier this year in JAMA, at 30-day follow-up, there was no significant difference between the 2 groups for either composite endpoint. Patients randomized to bivalirudin showed a favorable trend toward a reduction in the primary quadruple composite endpoint (death, MI, urgent revascularization, and major bleeding) compared with the heparin and GP IIb/IIIa group (Figure 2).
The nonsignificant difference in the quadruple primary endpoint between the 2 groups fulfilled the strict statistical analysis criteria -- that bivalirudin would have better outcomes compared with heparin (based on event rates from prior angioplasty trials), and that the drug would not show "inferiority" to heparin plus GP IIb/IIIa therapy. (In other words, although the mean results showed bivalirudin to be superior, the error bars extended into the "heparin superior" side and, as a result, it was not possible to say that bivalirudin was superior; it was correct to say that bivalirudin is "noninferior.")
Bleeding Complications, MI rates, and Cost-effectiveness
With respect to the individual components of the primary composite endpoint, at 30 days, bivalirudin was associated with a significant reduction in all bleeding complications compared with heparin (Table 2).
Table 2. REPLACE-2: Incidence of Bleeding Complications
| Bleeding Complication | Bivalirudin (n = 2994) | Heparin + IIb/IIIa (n = 3008) |
P |
|---|---|---|---|
| Major bleeding (%) | 2.4 | 4.1 | < .001 |
| Minor bleeding (%) | 13.4 | 25.7 | < .001 |
| Thrombocytopenia (< 100K) (%) | 0.7 | 1.7 | < .001 |
| Blood transfusion (%) | 1.7 | 2.5 | .02 |
| Retroperitoneal hemorrhage (%) | 0.2 | 0.5 | .06 |
| Access site bleeding (%) | 0.8 | 2.6 | < .001 |
There was a higher rate of MI in patients treated with bivalirudin, which was primarily attributed to a nonsignificant increase in non-Q-wave MI, defined as a CK-MB elevation 5-10x normal values.
Importantly, in-hospital costs were significantly lower in the bivalirudin arm, by a difference of 405 US$ (P < .001).
6-Month Follow-up Results
The results presented at the Transcatheter Cardiovascular Therapeutics (TCT) 2003 meeting focused on the incidence of the 3 main individual endpoints at 6-month follow-up: death, MI, and revascularization. Complete follow-up was available for > 98% of patients. The same noninferior results noted at 30-day follow-up remained consistent; there was no significant difference in the rate of death, MI, or the need for revascularization at 6 months (Figure 3). Similarly, there was no significant difference in the rate of each endpoint in diabetic patients (N = 1624) treated with either the heparin or bivalirudin regimen (Figure 4).
Initially, there was some concern that, although insignificant, the higher rate of non-Q-wave MI noted in the bivalirudin arm at 30 days may translate into a higher rate of mortality at 6 months for bivalirudin-treated patients. Impressively, there was no excess in the number of deaths in the bivalirudin arm. In fact, there was a higher rate of all-cause mortality in patients treated with heparin at both 30-day and 6-month follow-up; between day 0 and day 30, 12 patients died in the heparin arm compared with 7 in the bivalirudin group, and between day 30 and 6 months, 28 patients died in the heparin arm vs 21 in the bivalirudin group (P = NS). There were fewer cardiovascular-related deaths in the bivalirudin arm vs the heparin group (16 vs 24). Overall, investigators reported that compared with heparin, the use of bivalirudin was associated with a 30% relative risk reduction in death at 6 months (from 1.35% to 0.95%; P = .148).
Between day 0 and day 30, 208 MIs occurred in bivalirudin patients and 198 in the heparin plus GP IIb/IIIa group (P = NS); the majority of MIs occurred within hours of the procedure. At 6-month follow-up, the incidence of MI in heparin and bivalirudin patients was 7.4% and 8.2%, respectively (P = .024); the majority were non-Q-wave MIs (Figure 5).Revascularization rates were also similar for the 2 groups and showed slight favor toward the heparin plus GP IIb/IIIa group (Figure 6).
On the basis of the results of the REPLACE-2 trial, investigators concluded that:
The 6-month follow-up results confirm the findings observed at 30 days, showing a noninferiority of bivalirudin vs heparin plus a GP IIb/IIIa inhibitor.
There was no evidence of increased 6-month mortality rates with bivalirudin.
The nonsignificant increase in the rate of non Q-wave MIs noted in bivalirudin patients at 30 days did not jeopardize late survival.
There was no increase in late MI rates.
There was a small but nonsignificant increase in target vessel revascularization rates in patients treated with bivalirudin.
The REPLACE-2 results confirm that the use of bivalirudin in patients undergoing elective or urgent PCI is equivalent to, if not better than, the current standard of care that traditionally consists of unfractionated heparin plus a GP IIb/IIIa inhibitor. There was some concern regarding the possible adverse impact of a nonsignificant increase in periprocedural non-Q-wave MI in the bivalirudin arm, but these results confirm similar 6-month mortality rates in both groups. Furthermore, there was no advantage of treating diabetic patients with the combination of heparin plus a GP IIb/IIIa inhibitor. It will be interesting to see whether bivalirudin will also replace heparin during other percutaneous interventions involving various patient populations. The 1-year survival data are expected to be presented at the upcoming American Heart Association Scientific Sessions.
Reference
Lincoff AM, Bittl JA, Harrington RA, for the REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention REPLACE-2 randomized trial. JAMA. 2003;289:853-863.
Source: ...