Hemostasis and Thrombosis Issues

SEPTEMBER 16, 2011
Charles H. Brown, MSPharm, RPh, CACP

Ticagrelor (Brilinta) Approved
The FDA approved a third new drug, ticagrelor (Brilinta; AstraZeneca), a novel, oral, reversible, direct-acting platelet aggregation inhibitor. Like other thienopyridines, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y12. Ticagrelor has a binding site different from ADP, however, making it an allosteric antagonist, and the blocking is reversible. It is indicated for prevention of thrombotic events (stroke or heart attack) in patients with acute coronary syndrome (ACS) or myocardial infarction (MI) with ST elevation.

The approval comes with a boxed warning that use of ticagrelor with aspirin doses above 100 mg/day decreases the effectiveness of the medication. It has a more rapid onset of action, shorter duration, and more pronounced platelet aggregation inhibition than clopidogrel, according to the results of the PLATO trial. Because it acts faster and has a shorter duration of action than clopidogrel, ticagrelor is dosed with a 180-mg loading dose and 90 mg twice daily thereafter with aspirin.

Selected Ticagrelor Drug Facts

  • Pregnancy Category: C
  • Protein binding: >99.7%
  • Metabolism: hepatic cytochrome P450 (CYP)3A4
  • Excretion: biliary
  • Peak concentrations: ticagrelor = 1.5 hours; active metabolite = 2.5 hours
  • Half-life: ticagrelor = 7.0 hours; active metabolite = 8.5 hours

Selected Drug Interactions

  • Increased blood levels: inhibitors of CYP3A4, such as ketoconazole, possibly grapefruit juice, and simvastatin
  • Decreased blood levels: rifampicin, and possibly St. John’s wort
  • Increases blood levels of digoxin

Use in Specific Populations
Blood levels increased (12%-23%) in elderly patients, Asian women, and patients with mild hepatic impairment. In Japanese individuals, blood levels are 40% higher than in Caucasians.

Five Potential Benefits to Consider

  • There is a death benefit from ticagrelor use: treating 71 patients prevented 1 death according to data from the clinical trial.
  • Stent thrombosis reduction post-ACS was demonstrated.
  • No statistically significant bleeding hazard was found.
  • There are no labeling restrictions (ie, black box warnings), and no weight restrictions on its use.
  • Ticagrelor can be used in all types of ACS.

Five Potential Disadvantages to Consider

  • Twice-daily dosing due to short half-life may present compliance issues with patients not taking second dose, possibly resulting in a stent thrombosis.
  • Because it is a new drug class, some uncertainty may exist without a long history of use; international PLATO outcome data were superior to data in North America, where aspirin doses were higher.
  • Cost (average wholesale price) of Brilinta/day is higher than Plavix or Effient.
  • Due to higher cost, Brilinta may not be covered by insurance carriers.
  • The 13.8% rate of dyspnea post-ACS, even though most are benign, may be confusing to health care providers, especially for patients being discharged post-ACS.

Dabigatran (Pradaxa) Update
Caution may be needed with dabigatran use in elderly individuals with low body weight. According to a study published in the Archives of Internal Medicine in July 2011, 2 frail elderly women in France fared badly when taking dabigatran for stroke prevention in atrial fibrillation (AF).

An 84-year-old woman taking 75 mg of dabigatran twice daily for AF who weighed just 40 kg developed massive rectal bleeding, experienced cardiac arrest, and died. In the other case, an 89-year-old woman weighing 45 kg who had been taking 110 mg twice daily for AF for 5 months was found to have increased bleeding times and an elevated plasma level of dabigatran when tested prior to cochlear implant surgery. She had suffered recurrent nosebleeds for a week prior to this surgery. Treatment with dabigatran was stopped and the outcome was favorable in this case.

Monitoring dabigatran plasma levels or thrombin times may be needed in patients at high risk of bleeding.

Discontinuation of Low-Dose Aspirin and Increased Risk of Myocardial Infarction
In a study published in BMJ in July 2011, it was reported that individuals 50 to 84 years with a history of cardiovascular events who stop taking low-dose aspirin are at increased risk of nonfatal MI compared with those who continue treatment. Despite strong evidence supporting the protective effects of low-dose aspirin, discontinuation rates of around 50% have been reported in patients who have been taking aspirin for several years.

Mr. Brown is professor emeritus of clinical pharmacy and a clinical pharmacist at Purdue University College of Pharmacy, Nursing, and Health Sciences, Department of Pharmacy Practice, in West Lafayette, Indiana. This column’s information is based on current studies and references, but it may be changed without notice with newer studies or with different patient populations.

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