Ticagrelor: A review of the data leading to FDA approval

The thienopyridines clopidogrel and ticlopidine, along with aspirin, have been the mainstay of antiplatelet therapy in patients with acute coronary syndromes.

However, ticlopidine (Ticlid, Roche) use has been limited because of its hematologic adverse effects, including neutropenia. Several limitations are now recognized with clopidogrel (Plavix, Sanofi-Aventis), including the need for early discontinuation before surgery and variable efficacy due to genetic abnormalities and drug interactions. A new thienopyridine, prasugrel (Effient, Eli Lilly), was approved in 2009 by the FDA. However, similar to the other thienopyridines, it requires conversion by the liver to an active moiety. Prasugrel also has a box warning for stroke due to an increase in death, along with an increased risk for bleeding in underweight (<60 kg) and elderly patients (>75 years).

Zachary A. Stacy

Ticagrelor (Brilinta, AstraZeneca), a cyclopentyl-triazolo-pyrimidine, is a new antiplatelet agent with structural similarities to adenosine. Ticagrelor reversibly inhibits the P2Y12 receptors on platelets, preventing platelet activation and, consequently, aggregation. Unlike the thienopyridines, it does not require metabolic activation. The onset of action is 1.5 to 3 hours, with a steady state reached in 2 to 3 days, and an elimination half-life of 6 to 13 hours. This pharmacokinetic profile may translate into clinical advantages over clopidogrel, including a faster time to steady state and shorter time for reversal. Besides bleeding, several unique adverse effects were observed in ticagrelor clinical trials. Dyspnea, ventricular pauses of at least 3 seconds, and hyperuricemia are likely attributed to the structural similarity to adenosine.

Comparisons in trials

In the DISPERSE-2 trial, ticagrelor 90 mg twice daily, ticagrelor 180 mg twice daily and clopidogrel 300 mg once, followed by 75 mg daily, were compared to assess the safety and tolerability of ticagrelor. Rates of protocol-defined major or minor bleeding at 4 weeks were not significantly different between ticagrelor 90 mg (9.8%; P=.43), ticagrelor 180 mg (8%; P=.96) and clopidogrel (8.1%). However, this study found statistically significant increased rates of dyspnea and asymptomatic ventricular pauses with ticagrelor compared with clopidogrel.

The ONSET/OFFSET study compared ticagrelor 180 mg loading dose followed by 90 mg twice daily and clopidogrel 600 mg loading dose followed by 75 mg daily. The study found a greater inhibition of platelet aggregation (IPA) with ticagrelor within 24 hours (P<.0001) and 6 weeks (P<.0001) compared with clopidogrel. With regard to offset, those treated with ticagrelor had a lower IPA 72 to 120 hours after the last dose (P≤.05), but no differences between the groups were observed thereafter.

The RESPOND trial was a randomized, crossover investigation comparing ticagrelor and clopidogrel in patients with stable coronary artery disease identified as non-responders or responders to a prior dose of clopidogrel. Patients received either ticagrelor 180 mg loading dose followed by 90 mg twice daily or clopidogrel 600 mg loading dose followed by 75 mg daily. The primary outcome was the proportion of clopidogrel non-responders who responded to ticagrelor based on platelet aggregation measurements 4 hours after the last dose. In the non-responder cohort, more patients responded to ticagrelor than to clopidogrel (75% vs. 13%, P<.001). This study demonstrated that ticagrelor provides antiplatelet activity in patients who are not responsive to clopidogrel.

Valerie Raney

PLATO trial and FDA approval

The PLATO study compared ticagrelor 180 mg loading dose followed by ticagrelor 90 mg twice daily and clopidogrel 300 mg loading dose followed by clopidogrel 75 mg daily. PLATO enrolled more than 18,000 patients, all of whom had been diagnosed with acute coronary syndrome (ACS) and who had received aspirin. The primary outcome, a composite of death

from vascular causes, myocardial infarction or stroke at 12 months, occurred in 9.8% of patients taking ticagrelor vs. 11.7% of patients given clopidogrel (HR=0.84; 95% CI, 0.77-0.92). This finding was driven by a significant reduction in myocardial infarction and death from vascular causes; there was no difference in reduction of stroke. No differences in major bleeding (P=.43) or overall life-threatening/fatal bleeding (P=.70) were observed. However, ticagrelor was associated with more non-intracranial fatal bleeding (0.1% vs. 0.3%, P=.03) and fatal intracranial bleeding (0.1% vs. 0.01%, P=.02). Other adverse effects that occurred more often with ticagrelor included dyspnea (13.8% vs. 7.8%, P<.001); ventricular pauses of at least 3 seconds (5.8% vs. 3.6%, P=.01); hyperuricemia (14% vs. 7%, P<.001); and an increase in serum creatinine (10% vs. 8%, P<.001).

In 2010, the FDA postponed approval to better understand why patients treated with ticagrelor in the PLATO trial did worse based on the primary outcome in US centers compared with non-US centers (HR=1.25, 95% CI, 0.93-1.67). One proposed theory for this inconsistency includes the aspirin dose. The median dose of aspirin in the US patients was 325 mg daily compared with 100 mg daily in the non-US patients. Patients treated with 100 mg or less of aspirin (HR=0.77; 95% CI, 0.69-0.86) had a better outcome on ticagrelor compared with patients taking 300 mg or more (HR=1.45; 95% CI, 1.01-2.09). Clinicians should consider this clinically significant drug interaction when managing patients with ACS.

Ticagrelor was approved by the FDA in July with an indication to reduce the rate of thrombotic cardiovascular events in patients with ACS. Co-administration of low-dose aspirin is recommended with a box warning to avoid doses greater than 100 mg. Ticagrelor has shown promising pharmacokinetic advantages over clopidogrel, including a faster onset and shorter half-life. Although rapid, the offset is not immediate, so managing patients who require emergent surgery will still be challenging, with a 5-day washout period still encouraged. Clinicians should consider the role of ticagrelor by balancing the increased risk for bleeding with the significant reduction in vascular death and MI.

Zachary A. Stacy, PharmD, BCPS, is associate professor of pharmacy practice at the St. Louis College of Pharmacy; Valerie Raney, PharmD, is a clinical pharmacy specialist at St. Luke’s Hospital, Chesterfield, Mo.

Rhonda M. Cooper-DeHoff, PharmD, MS, who supervised this column, is associate professor in the department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville.

For more information:

• Angiolillo DJ. Am Heart J. 2008;156:S10-S15.
• Cannon CP. J Am Coll Cardiol. 2007;50:1844-1851.
• Gurbel PA. Circulation. 2009;120:2577-2585.
• Gurbel PA. Circulation. 2010;121:1188-1199.
• Patrono C. Chest. 2008;133:199S-233S.
• Wallentin L. N Engl J Med. 2009;361:1045-1057.
• Wiviott SD. N Engl J Med. 2007;357:2001-2015.

Disclosure: Dr. Stacy serves on the speakers bureau for AstraZeneca and Bristol-Myers Squibb. Dr. Raney reports no relevant financial disclosures.

Dale Shepard

I’m not certain that I agree with some of the claims regarding the benefit associated with ticagrelor. When looking at the pharmacokinetics of the agent — the claim is that it’s a better drug because its onset of action is quicker and half-life is shorter — I’m not sure the data really support that conclusion. The thought is that we have to worry about conducting elective surgery in patients undergoing clopidogrel therapy. Ticagrelor has a more rapid onset, but there are bleeding complications with the therapy itself that do not exist with clopidogrel, and the recommendation is still to wait 5 days before elective surgery. I suspect that you pick up side effects without getting a huge benefit; we’re trading one set of toxicities for another.

Certainly, there are issues with neutropenia when using Ticlid but we worry about bleeding in elective surgeries with clopidogrel because it’s an irreversible inhibitor and it stays in the body a long time. But there is a black box warning about risk for bleeding with ticagrelor, so we take the theoretical bleeding complication with clopidogrel and replace it with a drug that has a known 12% chance of major bleeding. Moreover, everyone using ticagrelor is at risk for that bleeding, not just patients undergoing a procedure. I think ticagrelor just presents a different risk-benefit.

Clopidogrel, for the most part, is a pretty safe drug. There are patients who will benefit from ticagrelor, there might be fewer MIs, but it’s not without risk. This is a relatively new drug and over time, we may find that bleeding is more of a problem than the initial trials might have suggested.

From a pharmacology standpoint, there is probably too much focus on the pharmacokinetics of ticagrelor. The bigger difference between the drugs is their mechanism of action. Clopidogrel is an irreversible inhibitor of platelet function. This new drug is a reversible inhibitor, but the half life for both is 6 hours. Ticagrelor is different but not better. The bleeding issues are concerning.

– Dale Shepard, MD, PhD

Solid tumor staff oncologist and pharmacologist, Cleveland Clinic Taussig Cancer Institute

Disclosure: Dr. Shepard reported no relevant financial disclosures.