ACUITY and ACUITY Timing: Heparin, GP IIb/IIIa inhibitors (Upstream vs Deferred Use), and Bivalirudin -- Managing Moderate- to High-Risk ACS Patients

Luis Gruberg, MD, FACC

Disclosures

July 20, 2006

Editorial Collaboration

Medscape &

"The amount of data obtained are overwhelming and will need careful interpretation due to the study's significant implications, which may change the way adjuvant anticoagulation is given to ACS patients who undergo PCI."

Presenter: Gregg W. Stone, MD (Columbia University Medical Center, New York, NY), for the ACUITY Investigators

The current management of acute coronary syndrome (ACS) includes an early invasive strategy in moderate- to high-risk patients. Percutaneous revascularization is performed in approximately 55% of patients, 12% are treated surgically, and the remaining 33% are treated medically. ACS patients are also treated with triple antiplatelet therapy (aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors [GPI]) and either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). GPI therapy is given upstream (before the catheterization) or in the cath lab when the decision to perform angioplasty has been made.

While these pharmacologic treatments are effective in preventing ischemic complications, their use is associated with the risk of bleeding, which recently has been shown to significantly increase the risk of morbidity and mortality in ACS patients.[1] Bivalirudin is a synthetic direct thrombin inhibitor with properties that make it an attractive alternative to heparin. It inhibits thrombin-mediated platelet activation, has a short plasma half-life, and there is no requirement for anticoagulant monitoring.

Previous studies have shown that bivalirudin provides a similar level of protection from ischemic events as does a strategy of UFH + GPI, with a marked reduction in bleeding complications.[2] However, the comparison of bivalirudin vs heparin + GPI has not been evaluated in contemporary ACS patients.

The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY)[3] trial was designed to assess the effectiveness of bivalirudin (with or without GPI) vs UFH or LMWH + GPI in moderate- to high-risk ACS patients undergoing an invasive management strategy.

Investigators hypothesized that in moderate- to high-risk ACS patients undergoing an invasive strategy, the use of bivalirudin + GPI would result in fewer adverse ischemic events and less bleeding compared with heparin + GPI. In addition, they hypothesized that bivalirudin alone would result in similar rates of ischemic events, but with markedly reduced bleeding compared with heparin + GPI.

Study Design

Patients with moderate- to high-risk ACS were randomized to:

  • Heparins (UFH or LMWH) + GPI (control arm);

  • Bivalirudin + GPI; or

  • Bivalirudin alone.

Patients underwent angiography within 72 hours and were treated accordingly with angioplasty, surgery, or medical treatment. In the 2 GPI arms, a second randomization was performed at the anticoagulation level in which patients were randomized to upstream or cath lab administration of the assigned treatment.

Inclusion Criteria
  • Age ≥ 18 years

  • Chest pain ≥ 10 minutes and < 24 hours

  • At least 1 of the following:

    • New ST depression or transient elevation ≥ 1mm

    • Elevated enzymes

    • Documented coronary artery disease

    • All of the other 4 TIMI risk criteria

      • Age ≥ 65 years

      • Aspirin treatment within 7 days

      • ≥ 2 angina episodes within 24 hours

      • ≥ 3 cardiac risk factors

Exclusion Criteria
  • No angioplasty within 72 hours

  • Acute ST-elevation myocardial infarction or shock

  • Bleeding diathesis

  • Platelet count < 100,000

  • International normalized ratio (INR) > 1.5 control

  • Creatinine clearance < 30 mL/min

Primary Endpoint. Composite net clinical benefit, which consisted of a triple composite ischemic endpoint (death, myocardial infarction, and unplanned revascularization for ischemia) or major bleeding (non-bypass-related bleeding or reoperation for bleeding) at 30 days.

Results

A total of 13,819 patients randomized at 448 centers in 17 countries were enrolled in the study (Figure 1); approximately 57% of all patients were enrolled at US centers.

Figure 1. ACUITY: study design.

Baseline characteristics were well balanced between the 3 groups (Table 1).

Table 1. ACUITY: Baseline Characteristics
Characteristic Heparins + GPI
(n = 4603)
Bivalirudin + GPI
(n = 4604)
Bivalirudin Alone
(n = 4612)
Age (yrs) 63 63 63
Male (%) 71 70 69
Diabetes (%) 28 28 28
Hypercholesterolemia (%) 57 57 57
Hypertension (%) 67 67 67
Current smoker (%) 29 29 29
S/P MI (%) 32 31 32
S/P PCI (%) 39 38 40
S/P CABG (%) 18 17 18
Renal failure (%) 6 6 6
TIMI risk score
Low (0-2) (%) 16 15 17
Intermediate (3-4) (%) 54 56 55
High (5-7) (%) 30 29 30
CABG = coronary artery bypass graft; GPI = glycoprotein IIb/IIIa inhibitor; MI = myocardial infarction; PCI = percutaneous coronary intervention; S/P = status-post

The median time from admission to angiography was approximately 20 hours, and the median time from drug therapy to angiography/intervention was approximately 5.5 hours. Percutaneous coronary intervention (PCI) was performed in approximately 56% of all patients, and approximately 11% of all patients were referred for bypass graft surgery. The remaining patients (~32%) were treated medically.

The incidence of the primary endpoint at 30 days was identical for the control group and the bivalirudin + GPI group (Figure 2), proving noninferiority but not superiority.

Figure 2. ACUITY: 30-day primary endpoint -- heparins + GPI vs bivalirudin + GPI.

When treatment with heparins + GPI was compared with bivalirudin-alone treatment, the latter showed a significant reduction in the 30-day rate of the composite of ischemic events or major bleeding complications, proving noninferiority and even superiority (Figure 3).

Figure 3. ACUITY: 30-day primary endpoint -- heparins + GPI vs bivalirudin alone.

A summary of the primary endpoints is shown in Table 2. The incidence of the individual components of the ischemic composite endpoint was similar in all 3 groups; however, major bleeding was significantly lower in the bivalirudin-alone arm of the study.

Table 2. ACUITY: Primary Results at 30 Days
Endpoint Heparins + GPI
(n = 4603)
Bivalirudin + GPI
(n = 4604)
P NI* Bivalirudin Alone
(n = 4612)
P Sup*
Net clinical outcome (%) 11.7 11.8 < .001 10.1 .015
Ischemic composite (%) 7.3 7.7 .0007 7.8 .32
Death 1.3 1.5 -- 1.6 .34
MI 4.9 5.0 -- 5.4 .35
Unplanned revascularization (%) 2.3 2.7 -- 2.4 .78
All major bleeding (%) 11.8 11.1 .001 9.1 < .001
Non-bypass major bleeding (%) 5.7 5.3 -- 3.0 < .0001
*All P values vs control

GPI = glycoprotein IIb/IIIa inhibitor; MI = myocardial infarction; NI = noninferior; Sup = superior
Conclusions
  1. In patients with moderate-high risk ACS undergoing an early invasive treatment strategy with the use of GPI, bivalirudin is an acceptable substitute to either UFH or LMWH, but does not further improve outcomes.

  2. However, compared with either heparins + GPI or bivalirudin + GPI, the use of bivalirudin alone results in significantly greater net clinical benefit and enhanced survival free from adverse events at 30 days.

ACUITY Timing

It remains unknown whether GPI therapy should be initiated immediately (upstream) or whether it should be withheld until PCI is performed (deferred). ACUITY TIMING[4] was a prospective, randomized trial designed to specifically examine the outcomes associated with these 2 different time points of GPI administration.

As described above, ACUITY trial patients who were initially randomized to a GPI arm underwent a second randomization (regardless of assigned antithrombin therapy [heparins vs bivalirudin]) whereby GPI therapy was either administered upstream (n = 4605) or deferred (n = 4602) (Figure 1). Investigators hypothesized that deferred use would yield similar rates of adverse ischemic events, but would reduce the incidence of bleeding and would be more cost-effective compared with upstream GPI use.

Baseline characteristics of the 2 patient groups in the ACUITY TIMING trial were well balanced and similar to the overall patient characteristics noted in Table 1. The median time from randomization to GPI use was 0.6 hrs in the upstream group vs 4.6 hrs in the deferred-treatment group. Eptifibatide was used in the majority of all patients, regardless of whether they were randomized to upstream or deferred use. Overall exposure to GPI (including in those patients managed with angioplasty, bypass, or medical therapy) was 98.3% in upstream patients vs 55.7% of deferred patients.

There was no difference in the primary net clinical outcome composite of ischemic events and bleeding complications at 30 days between the 2 treatment groups, thus proving noninferiority (Figure 4).

Figure 4. ACUITY Timing: 30-day primary endpoint -- upstream vs deferred PCI-only GPI use.

There was also no difference in the composite of ischemic events endpoint at 30 days, but the incidence was slightly higher in the deferred group vs upstream use (7.9% vs 7.1%, respectively; P NI = .044). In addition, the rate of unplanned revascularization was significantly higher in the deferred-treatment group (Table 3).

Table 3. ACUITY Timing: Ischemic Composite Endpoint -- Individual Components at 30 Days
Endpoint Routine Upstream
(n = 4605)
Deferred PCI
(n = 4602)
P Sup
Ischemic composite (%) 7.1 7.9 .13
Death (%) 1.3 1.5 .48
MI (%) 4.9 5.0 .70
Unplanned revascularization (%) 2.1 2.8 .03
MI = myocardial infarction; PCI = percutaneous coronary intervention; Sup = superior

Despite the numerically higher rate of the ischemic composite endpoint in the deferred-treatment group, deferred use was associated with a significant reduction in major bleeding, proving both noninferiority (P NI = .0001) and superiority (P Sup = .009) (Figure 4). Overall, the risk of any non-bypass related ACUITY bleeding was reduced from 26.0% in the upstream group to 21.6% in the deferred treatment group (P < .001), and any TIMI bleeding was reduced from 7.3% in the upstream group to 5.1% in the deferred treatment group (P = .001).

An analysis of the data from the upstream arm was conducted to determine the influence on outcomes of longer exposure to GPI prior to angiography/intervention. Patients who were treated for more than 18 hours with GPI therapy had a significantly worse outcome compared with patients who received treatment for less than 18 hours (Figure 5). Longer duration of exposure to GPI was not associated with a significant difference in bleeding, however. In addition, patients in the bivalirudin-only arm of the ACUITY trial had significantly lower rates of bleeding complications compared with patients in either the upstream or deferred GPI groups (3.0% vs 6.1% vs 4.9%, respectively; P < .001).

Figure 5. ACUITY Timing: 30-day outcomes by time between GPI initiation and angiography/intervention in upstream patients.
Conclusions
  1. In moderate- to high-risk ACS patients undergoing an early invasive treatment strategy, withholding upfront GPI use for selective initiation in the cath lab only in patients undergoing PCI results in similar rates of adverse ischemic events, although a slight increase cannot be excluded.

  2. In the context of the entire ACUITY trial, both upstream and selective GPI strategies (with either UFH, LMWH, or bivalirudin) yielded inferior net clinical outcomes compared with bivalirudin alone.

Viewpoint

ACUITY was a well-planned, carefully designed, very complex trial that enrolled a large number of patients. The amount of data obtained are overwhelming and will need careful interpretation due to the study's significant implications, which may change the way adjuvant anticoagulation is given to ACS patients who undergo PCI. These results are very provocative and imply that the use of heparin (whether it is unfractionated or low-molecular-weight) in combination with GPI is inferior when compared with bivalirudin alone, regardless of when the GPI is initiated.

These results are mainly driven by a reduction in bleeding complications in patients treated with bivalirudin alone, and not by a decrease in ischemic events.

References
  1. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA. 2004;292:1555-1562. Abstract

  2. Lincoff AM, Bittl JA, Harrington RA, et al. 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. Abstract

  3. Stone GW, McLaurin BT, Ware JH, et al. Prospective, randomized comparison of heparin plus IIb/IIIa inhibition and bivalirudin with or without IIb/IIIa inhibition in patients with acute coronary syndromes: the ACUITY trial. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session; March 11-14, 2006; Atlanta, Georgia. Abstract 402-12.

  4. Stone GW, Cox DA, Pocock SJ, et al. Prospective, randomized comparison of routine upfront initiation versus selective use of glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes: the ACUITY Timing trial. Program and abstracts from the Innovation in Intervention: i2 Summit 2006; March 11-14, 2006; Atlanta, Georgia. Abstract 2045-5.

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