ACCOAST: Prasugrel Pretreatment Increases Bleeding in NSTE-ACS

AMSTERDAM, The Netherlands—Among patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) who were scheduled to undergo catheterization, pretreatment with prasugrel does not reduce the rate of major ischemic events at 30 days, according to results presented on September 1, 2013, at the European Society of Cardiology Congress. The study, simultaneously published in the New England Journal of Medicine, stopped enrollment early because pretreatment increased bleeding complications.

For the ACCOAST trial, Gilles Montalescot, MD, PhD, of Pitié-Salpêtrière Hospital (Paris, France), and colleagues enrolled 4,033 patients with NSTE-ACS and positive troponin at 171 centers in 19 countries from December 2009 to November 2012. Patients underwent coronary angiography within 2 to 48 hours after randomization to pretreatment with either prasugrel (n = 2,037; 30-mg loading dose plus an additional 30 mg with PCI) or placebo (n = 1,996; followed by 60-mg prasugrel given with PCI).

More Bleeding with Pretreatment

PCI was performed in more than half (68.7%) of patients at a median time of 4.3 hours after the initial loading dose. CABG was the strategy chosen in 6.2% of patients and medical therapy was opted for in 25.1%.

After 7 days, the incidence of the primary composite endpoint (CV death, MI, stroke, urgent revascularization, or GPI rescue therapy) and its individual components did not differ between the treatment groups (table 1).

Table 1. Outcomes at 7 Days

 

Pretreatment
(n = 2,037)

No Pretreatment
(n = 1,996)

HR (95% CI)

P Value

Primary Endpoint

10.0%

9.8%

1.02 (0.84-1.25)

0.81

CV Death

0.3%

0.5%

0.69 (0.26-1.80)

0.44

MI

5.8%

5.5%

1.07 (0.83-1.39)

0.60

Stroke

0.4%

0.5%

0.78 (0.31-1.98)

0.60

Urgent Revascularization

1.1%

1.3%

0.83 (0.47-1.46)

0.52

GPI Bailout

3.7%

3.9%

0.96 (0.70-1.31)

0.79

 

There were also no differences in the secondary efficacy endpoints of combined CV death, MI, and stroke; all-cause death; or stent thrombosis at 7 or 30 days. Prasugrel pretreatment was not associated with decreases in ischemic events (P = 0.93) or definite/probable stent thrombosis (P = 0.25) during the waiting period for coronary angiography compared with placebo. Each of these findings held true when analyses were restricted to the cohort of patients who underwent PCI.

Bleeding complications were higher in the pretreatment group compared with controls at 7 days (table 2).

Table 2. Bleeding Complications at 7 Days

 

Pretreatment
(n = 2,037)

No Pretreatment
(n = 1,996)

HR (95% CI)

P Value

TIMI Major Bleeding

2.6%

1.4%

1.90 (1.19-3.02)

0.0006

Non-CABG-related TIMI Major Bleeding

1.3%

0.5%

2.95 (1.39-6.28)

0.003

Life-threatening Bleeding

0.8%

0.2%

5.56 (1.63-19.0)

0.002

Non-CABG-related TIMI Major or Minor Bleeding

3.0%

1.0%

3.02 (1.82-5.01)

< 0.001

 

TIMI minor bleeding events were also increased with pretreatment compared with no pretreatment (HR 2.50; 95 CI 1.42-4.37; P < 0.001). There was however, no excess of fatal bleeding or intracranial hemorrhage with pretreatment. All results were confirmed at 30 days.

Bleeding events were predominantly associated with PCI or CABG and occurred early in patients who underwent PCI. Although subgroup analyses found that bleeding occurred less often in patients who were young, had high body weight, and had radial PCI access, pretreatment was still associated with higher bleeding incidence across all subgroups.

A pharmacodynamic substudy found greater platelet inhibition in the pretreatment group vs. the placebo group at a median of 4.8 hours after the first loading dose, “which may have contributed to the increased rate of bleeding complications in the pretreatment group,” according to Dr. Montalescot and colleagues. By 2 hours after the second loading dose, antiplatelet activity was similar in the 2 groups.

Best to Wait Until After Confirmation

“Prasugrel, when administered as pretreatment, was biologically effective at the time of catheterization or PCI, as shown by results of the pharmacodynamic substudy, but pretreatment with prasugrel did not reduce the incidence or thrombotic complications in either the overall population or among patients undergoing PCI,” the authors write.

“This suggests stronger antiplatelet therapy does not prevent the occurrence of a myocardial infarction before catheterization or after PCI,” they add.

Although there is a paucity of data supporting pretreatment with clopidogrel in patients with NSTE-ACS, “this practice has become commonplace and has often been extended to new oral P2Y12 antagonists,” Dr. Montalescot and colleagues note. “Our results support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy.”

Diagnostic coronary angiography is not only conformational but is “central for determining the treatment strategy,” they emphasize.

Guidelines Challenged

In an editorial accompanying the paper, John F. Kearney Jr, MD, of the University of Massachusetts Medical School (Worcester, MA), said the results highlight the difference between first-and second-generation P2Y12 inhibitors. “Clopidogrel produces irreversible, but sometimes incomplete P2Y12 inhibition through conversion of the drug in active metabolite,” he writes. But “prasugrel, although also a prodrug, undergoes more efficient metabolism, producing faster and more complete platelet inhibition, thus obviating the need for pretreatment.”

The study supports the approach of administering prasugrel to NSTEMI patients who are selected for an early invasive strategy only after angiographic definition of their coronary anatomy, he says. “It remains to be seen whether a similar strategy would be applied to ticagrelor.”

The findings will surely impact clinical practice, according to discussant Marco Roffi, MD, of University Hospital (Geneva, Switzerland). “While pretreatment with P2Y12 inhibitors in those with NSTEMI was commonly believe to be efficacious, ACCOAST shows us that in the presence of a short pretreatment window there is no benefit. And there is definitely a price to pay in terms of bleeding,” he said adding that the results clearly challenge the class I indication of P2Y12 inhibitors in NSTEMI.

Potential For Streamlined Hospital Care

Discussant George D. Dangas, MD, PhD, of Mount Sinai Medical Center (New York, NY), said the results are not unexpected, given similar findings of both the EARLY ACS and ACUITY Timing trials.

“The results of this trial should be spinned in a positive way for the interventional community because we no longer will need to pretreat patients with an agent they don’t need,” he added.  “However, we must know that agents like prasugrel are extremely efficacious when given at the cath lab. . . . It’s a positive finding that narrows our choices and focuses on the procedure.”

Note: George D. Dangas, MD, PhD, is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 

Sources:

  1. Montalescot G, Bolognese L, Dudek D. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;Epub ahead of print.
  2. Kearny JF. P2Y12 inhibition in patients with NSTEMI—Can later be better? N Engl J Med. 2013;Epub ahead of print.

 

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Disclosures
  • ACCOAST was funded by Daiichi Sankyo and Eli Lilly.
  • Dr. Montalescot reports conflicts of interest with multiple device and pharmaceutical companies.
  • Dr. Kearny reports no relevant conflicts of interest.

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