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Author: Kristin Watson, PharmD, BCCP

In the first part of this two-part series, boxed warnings for cilostazol (Pletal®) and dofetilide (Tikosyn®) were discussed. The boxed warnings for edoxaban (Savaysa®), prasugrel (Effient®) and ticagrelor (Brilinta®) will be discussed here (summarized in the Table).

Edoxaban is an oral factor Xa inhibitor approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) and for treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE).1 Unlike rivaroxaban (Xarelto®) and apixaban (Eliquis®), treatment of a venous thromboembolism (VTE) requires 5-10 days of parenteral anticoagulation before the patient can be switched to edoxaban.1–4 The requirement for an initial regimen of parenteral therapy is based on the design of the Hokusai-VTE trial. 4

Edoxaban was shown to be non-inferior to warfarin in preventing stroke/systemic embolism in patients with NVAF in the ENGAGE AF-TIMI 48 trial.4  However, subgroup analysis of the intent-to-treat population in this study revealed that edoxaban was less effective than warfarin in reducing the risk of ischemic stroke in patients with a creatinine clearance (CrCl) > 95 mL/min.1 The lower efficacy of edoxaban in this latter population is likely due to the fact that it is 50% renally eliminated, and concentrations are over 40% lower in those with a CrCl > 95 mL/min. Therefore, in line with the boxed warning for edoxaban, therapy should be avoided in patients with NVAF and a CrCl > 95 mL/min, and an alternative direct oral anticoagulant (DOAC) such as apixaban, dabigatran (Pradaxa®), or rivaroxaban should be used instead.2,3,5 Warfarin may be used in those unable to take a DOAC.

The recommendation to avoid edoxaban in those with a CrCl of > 95 mL/min is specific for its use in NVAF.1 However, some experts, including members of the ATRIUM Cardiology Collaborative, also recommend against its use for VTE treatment in patients with CrCl > 95 mL/min, as data are currently insufficient to support its use in this population.6 Until further data are available, the other DOACs approved to treat VTE (apixaban, dabigatran, or rivaroxaban) should be preferred in those with a CrCl > 95 mL/min. As with edoxaban, use of parenteral anticoagulant for 5-10 days is recommended for patients in whom dabigatran will be used for VTE treatment. 5,7

Prasugrel is a P2Y12 inhibitor with a quicker onset of action and more potent antiplatelet effects compared to clopidogrel. In the TRITON-TIMI 38 study, prasugrel was found to be more effective than clopidogrel at lowering the risk of ischemic events in patients with an acute coronary syndrome (ACS) undergoing coronary revascularization.8 The benefits of prasugrel were highest amongst patients at increased risk for thrombotic events (e.g., diabetes, prior myocardial infarction). However, subgroup analysis revealed net harm (i.e., combining the risks and benefits of therapy) in patients with a history of stroke or transient ischemic attack (TIA). In this latter subgroup, prasugrel was associated with an increased risk of major bleeding and intracranial hemorrhage. Additionally, there was no net benefit with prasugrel among patients 75 years or older or in those weighing < 60 kg. As a result, each of these subgroups is addressed in the boxed warning for prasugrel.

The maintenance dose of prasugrel in TRITON-TIMI 38 was 10 mg daily.8 However, a 5 mg/day maintenance dose was approved by the FDA for patients weighing < 60 kg.10 Although pharmacokinetic and pharmacodynamic data support the use of a 5 mg/day maintenance dose in patients of lower body weight, there is little clinical data supporting its use. The ELDERY-ACS trial attempted to evaluate the 5 mg dose among patients ≥ 75 years of age undergoing PCI for an ACS, but the trial had to be terminated early due to futility.11  The recently published ISAR-REACT 5 study compared the efficacy and safety of ticagrelor and prasugrel in patients presenting with an ACS in whom invasive coronary evaluation was planned.16  It was recommended that maintenance dose of prasugrel be lowered from 10 mg to 5 mg daily for those ≥ 75 years of age or weighed < 60 kg. Prasugrel was found to be more effective in reducing the risk of the primary composite efficacy endpoint (death, myocardial infarction or stroke). There was no difference in the risk of major bleeding between groups. The number of patients who received the 5 mg dose has not been reported. It is estimated that over 20% of patients in the prasugrel group may have received the 5 mg dose. It is not clear how many patients, if any, were ≥ 75 years of age and < 60 kg. There was no difference in the risk of the primary composite efficacy endpoint between those aged ≥ 75 years vs. < 75 or those ≥ 60 kg vs. < 60 kg. This study was not designed to detect differences in these subgroups. Anticipate that more detailed subgroup analysis publication is forthcoming. Check out a recent blog from @ZNoelPharmD for a more detailed critique of this trial and its clinical implications. The 5 mg dose is not currently recommended in American College of Cardiology/American Heart Association guidelines for patients with an ACS.12–14 Anticipate that these recommendations may change in future guidelines in light of the results of the ISAR-REACT 5 trial.

The boxed warning states that prasugrel may be considered in patients ≥ 75 years of age with diabetes or prior MI since these latter two subgroups appeared to derive the greatest benefit in TRITON-TIMI 38.10 However, only 22.3% of patients in this study were ≥ 75 years of age. 8 Prasugrel should be avoided in patients ≥ 75 years of age without diabetes or prior MI as the risk of bleeding (fatal and intracranial hemorrhage) negates any potential benefit.10 The risks and benefits of clopidogrel or ticagrelor do not appear to vary based on age.

In summary, prasugrel should only be considered for patients with ACS undergoing PCI. Prasugrel should not be administered to those with a history of stroke or TIA. Clopidogrel or preferably, ticagrelor should be prescribed. For ACS patients being managed with medication therapy only, clopidogrel or ticagrelor may be used.15  The 10 mg prasugrel maintenance dose should not be prescribed to those  age ≥ 75 years or < 60 kg; the 5 mg/day dose may be reasonable.

Ticagrelor is a potent P2Y12 inhibitor that was shown in the PLATO study to be more effective than clopidogrel at reducing the risk of death and ischemic endpoints in patients with ACS. Unlike TRITON-TIMI 38, patients in PLATO underwent coronary revascularization or were managed medically.17 Subsequent subgroup analysis revealed that ticagrelor was less effective when used concurrently with maintenance aspirin doses > 100 mg/day, although a plausible mechanism for this interaction has not been described.18 Regardless, these findings serve as the rationale for the boxed warning for ticagrelor, which recommends that concurrent aspirin  maintenance doses > 100 mg be avoided. In the United States, 81-mg tablets are readily available.12,13,19  Aside from the interaction potential, another reason for using aspirin 75-100 mg/day is that higher doses have not been shown to improve clinical outcomes but are associated with an increased risk of bleeding.20,21 Importantly, a one-time loading dose of aspirin 325 mg should still be administered in patients presenting with ACS regardless of the oral P2Y12 inhibitor used.

EDOXABAN – use is not recommended in patients with a CrCl > 95 mL/min.

PRASUGREL –  is only recommended for those undergoing coronary revascularization for an ACS. Instead, ticagrelor, preferably, or clopidogrel should be administered to those with a prior history of stroke or TIA. A 5 mg/day maintenance dose of prasugrel may be reasonable for those ≥ 75 years of age or weighing < 60 kg.

TICAGRELOR – an aspirin maintenance dose of 81 mg/day (i.e., < 100 mg/day) is recommended in combination with ticagrelor. Discuss the reason for this dose with your patients, as many purchase aspirin over-the-counter and may think more is better.

Kristin Watson, PharmD, BCCP

Dr. Watson is an associate professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in the ambulatory heart failure clinic at the Veterans Affairs Medical Center in Baltimore, MD. Follow her on Twitter @cards_pharm_gal

Reviewed by: Brent Reed, PharmD, BCCP


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  2. Eliquis (apixaban) [package insert].Princeton, NJ and New York, New York: Bristol-Myers Squibb Company and Pfizer Inc.; 2019.
  3. Xarelto (rivaroxaban) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2019.
  4. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. N Engl J Med. 2013;369(15):1406-1415. doi:10.1056/NEJMoa1306638
  5. Pradaxa(dabigatran etexilate) [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc.; 2019.
  6. Hull, RD, Lip GYH. (ed. Finlay G, Mandel J, Leung LLK) Venous thromboembolism: Anticoagulation after initial management – UpToDate. Accessed October 11, 2019.
  7. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361(24):2342-2352. doi:10.1056/NEJMoa0906598
  8. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med. 2007;357(20):2001-2015. doi:10.1056/NEJMoa0706482
  9. Roe MT, Armstrong PW, Fox KAA, et al. Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization. N Engl J Med. 2012;367(14):1297-1309. doi:10.1056/NEJMoa1205512
  10. Effient (prasugrel) [package insert]. Indianapolis, IN. Eli Lilly and Company; 2019.
  11. Savonitto Stefano, Ferri Luca A., Piatti Luigi, et al. Comparison of Reduced-Dose Prasugrel and Standard-Dose Clopidogrel in Elderly Patients With Acute Coronary Syndromes Undergoing Early Percutaneous Revascularization. Circulation. 2018;137(23):2435-2445. doi:10.1161/CIRCULATIONAHA.117.032180
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  13. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;68(10):1082-1115. doi:10.1016/j.jacc.2016.03.513
  14. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-e140. doi:10.1016/j.jacc.2012.11.019
  15. Husted Steen, James Stefan, Becker Richard C., et al. Ticagrelor Versus Clopidogrel in Elderly Patients With Acute Coronary Syndromes. Circulation: Cardiovasc Qual Outcomes. 2012;5(5):680-688. doi:10.1161/CIRCOUTCOMES.111.964395
  16. Schüpke S, Neumann F, Menichelli M, et al. Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. N Engl J Med. 2019;381:1524-34. doi: 10.1056/NEJMoa1908973
  17. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. doi:10.1056/NEJMoa0904327
  18. Mahaffey KW, Wojdyla DM, Carroll K, et al. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2011;124(5):544-554. doi:10.1161/CIRCULATIONAHA.111.047498
  19. Brilinta (ticagrelor) [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals LP.; 2016.
  20. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86.
  21. Peters RJG, Mehta SR, Fox KAA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108(14):1682-1687. doi:10.1161/01.CIR.0000091201.39590.CB
What’s in the Black Box? Examining the Evidence for Five Cardiac Medications? Part 2

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