From the April issue of CardioSource Interventional News—In the cath lab, balancing ischemic risk with bleeding risk is a tightrope that interventionalists struggle to make their way across. With last year’s approval of ticagrelor in July, as well as the earlier approval of prasugrel in July 2009, and the inevitable addition of a generic form of the ubiquitous clopidogrel, the decision-making process for cath lab anticoagulation becomes continually more complex. In the recent CRT 2012 meeting, two speakers, Steve Steinhubl, MD, and Jorge F. Saucedo, MD, addressed this key concern.

The presentation led off with a cut-to-the-chase assault on the core question: “What is the right antiplatelet and when should it be used in the United States?” Tracing the evolution of clopidogrel usage, Dr. Steinhubl, director of cardiovascular wellness at Geisinger Health System in Danville, Pennsylvania, reviewed the CURRENT OASIS-7 trial. The trial included unstable angina or acute MI patients scheduled to undergo angiography within 72 hours of hospital arrival.

Investigators tested a high-dose clopidogrel regimen (600 mg loading dose [LD], followed by 150 mg/day for 7 days) against the standard regimen (300 mg LD followed by 75 mg/day). While there was no significant difference for the combined primary endpoint of CV death, MI, and stroke, among the two-thirds of patients (n = 17,232) undergoing PCI, there was a 15% relative risk reduction in CV death, MI, or stroke with the doubled clopidogrel dose (p = 0.036), and a 42% relative risk reduction in definite stent thrombosis (p = 0.001). TRITON TIMI-28 compared prasugrel with clopidogrel, demonstrating a significant 19% reduction in CV death, MI, and stroke with prasugrel (9.9% vs. 12.1%; p = 0.0004), with the number needed to treat at 46. TIMI major non-CABG bleeds, however, were significantly higher with prasugrel (2.4% vs. 1.8%; p = 0.03), with the number needed to harm at 167. Among 4% of 3,534 STEMI patients requiring CABG surgery, major bleeding occurred in 18.8% of those receiving prasugrel versus 2.7% of those receiving clopidogrel—an 8.2-fold increase (p = 0.0033). “For us, there’s no way we will pretreat with prasugrel unless we’re 100% sure the patient is going to have PCI,” Dr.Streinhubl said.

The international, multicenter, double-blind, randomized PLATO trial compared ticagrelor (180 mg LD, 90 mg twice daily thereafter) and clopidogrel (300-600 mg LD, 75 mg daily thereafter), looking at prevention of CV events in 18,624 patients admitted to the hospital with acute coronary syndromes (ACS) with or without ST-segment elevation. The cumulative incidence of the primary efficacy endpoint (composite of CV death, MI, and stroke) was 16% lower with ticagrelor after 3 years (9.8% vs. 11.7%; p = 0.0003). The rate for the same endpoint at 30 days was reduced by 12% in the ticagrelor group (4.8% vs. 5.4%; p = 0.045). The surprising finding of an increased risk of CV death, MI, and nonfatal stroke in US patients (HR = 1.27) for ticagrelor versus clopidogrel was thought to be attributable to aspirin doses ≥300 mg, because the increased risk disappeared completely in analysis of patients receiving aspirin doses ≤100 mg.1 Dr. Steinhubl’s recommendations:

• Clopidogrel 600 mg LD and 150 mg in-hospital, followed by 75 mg daily for most patients.
• Prasugrel for ACS patients undergoing PCI with known anatomy and not already pretreated; risk/benefitratio favors ≤1 month. 
• Ticagrelor appears to be a good choice for all ACS patients, and potentially the longer the better, although that needs to be confirmed.

He cautioned against giving ticagrelor on top of 325 mg of aspirin—a dose conferring no added benefit, but increasing risk.

How to Switch?

Interventionalists preferring the newer agents regularly treat arriving patients who are already receiving clopidogrel. In his presentation “How to Switch from Clopidogrel to Prasugrel or Ticagrelor,” Dr. Saucedo, professor of medicine at Oklahoma University Medical Center, Oklahoma City, pointed to a general lack of studies on switching from clopidogrel maintenance therapy to prasugrel or ticagrelor in a non-acute setting, and of clinical endpoint studies on switching to the newer agents.

Reviewing the limited data, Dr.Saucedo cited a study of healthy volunteers receiving 81 mg aspirin daily.2 Maximal platelet aggregation (MPA) was brought down to about 38% in patients who received 600 mg LD of clopidogrel followed by a 75 mg maintenance dose (MD), compared with an MPA of about 25% with prasugrel at a 60 mg LD followed by a 10 mg MD.

In the crossover phase of PRINCIPLE TIMI-44, investigators compared the effects of a 60 mg LD and 10 mg daily MD of prasugrel with high-dose clopidogrel (600 mg LD and 150 mg daily MD) on laboratory measures of platelet function.3 They observed statistically significantly greater platelet inhibition with prasugrel at all timepoints studied during both LD and MD phases. Specifically, inhibition of platelet aggregation at 6 hours favored prasugrel over clopidogrel (74.8% vs. 31.8%; p < 0.0001). During the MD phase, IPA with 20 μmol/L ADP also was higher in subjects receiving prasugrel versus clopidogrel (61.3% vs. 46.1%; p < 0.0001).

In the SWAP study, post-ACS patients (n = 100) receiving 75 mg clopidogrel and daily aspirin (81-325 mg) were randomized to further maintenance with clopidogrel 75 mg, prasugrel 10 mg, or prasugrel 60 mg LD followed by 10 mg MD. Mean MPA in the maintenance phase was slightly above 50% for clopidogrel, and around 40% for the prasugrel arms.4

The rate for poor responders, defined as patients with MPA >60% who were in the maintenance phase after 7 days, was 21% in the clopidogrel group, 6% for those receiving a placebo LD and 10 mg prasugrel MD, and 3% for those receiving the prasugrel 60 mg LD and 10 mg MD. Poor responder rates (See figure to the right figure) were 0% for the patients receiving the prasugrel LD at 2 and at 24 hours, respectively (compared with 16% for clopidogrel MD at both time points, and 20% and 15% for the placebo LD with 10 mg prasugrel MD, respectively).

If you’re thinking about switching in the acute phase,” Dr. Saucedo said, “we think that hyporesponsiveness [to antiplatelet therapy] is playing a role in the acute event, and maybe 10 mg of prasugrel is not the ideal dose,” Dr. Saucedo said. The RESPOND trial included 100 non-responders to clopidogrel. In analysis of a crossover phase, there was a consistent and significant absolute increase in inhibition of platelet aggregation of around 20% in the ticagrelor phase versus the clopidogrel phase for both groups.5

In PLATO, rates for the primary efficacy endpoint (vascular death/MI/stroke) were lower with ticagrelor than with clopidogrel (15.8% vs.17.8%), regardless of whether patients had received clopidogrel plus aspirin (11.8% vs. 14%) or aspirin alone or no therapy (8.2% vs. 10%), respectively, prior to the index event (p = 0.43).

Dr. Saucedo concluded, “Patients can be transitioned from clopidogrel to ticagrelor or from an MD of clopidogrel to prasugrel without interruption of antiplatelet effect.” He also said that patients with ACS who have received an LD of clopidogrel may be started on ticagrelor (180 mg LD) and continued with an MD of 90 mg twice daily.

Session moderator, Ron Waksman, MD, from Washington Hospital Center in Washington, DC, posed the question: “You have a patient with STEMI who was loaded in the field with 600 mg clopidogrel. He’s now in the cath lab and you want to give him prasugrel. How do you do it?  Do you give him a 60 mg LD? A 30 mg LD? Or no LD and switch right away to the MD?”

Dr. Saucedo responded: “My current practice is to give him a 60 mg LD. However, TRIPLET trial data, which we hope will be available this summer, should answer that question from the platelet aggregation viewpoint.”

References

1. Mahaffey KW, et al. Circulation. 2011;124:544-54.
2. Payne CD, et al. Platelets. 2008;19:275-281.
3. Wiviott SD, et al. Circulation. 2007;116:2923-32.
4. Angiolillo DJ, et al. J Am Coll Cardiol. 2010;56:1017-23.
5. Gurbel PA, et al. Circulation. 2010;121:1188-99.

“Clopidogrel, Prasugrel, Ticagrelor: Which and When?” 2012;1(1):17-18.

Keywords: Healthy Volunteers, Acute Coronary Syndrome, Stroke, Risk Reduction Behavior, Thiophenes, Ticlopidine, Piperazines, Blood Platelets, Stents, Thrombosis, Platelet Aggregation, Organoplatinum Compounds, United States

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