Best Evidence Analyses and Commentary

A Comparison of Modern Antithrombotic Agents
Shalyn Quigley, PharmD; PGY1 General Practice Resident, Millcreek Community Hospital in Erie, PA
March 2014

When hemostatic balance is interrupted by stasis, stress, or hypercoagulabilty, patients are at risk for venous or arterial thrombosis that may require medical prophylaxis or treatment. In the low shear venous system, thrombi are composed of red blood cells trapped by fibrin and manifest clinically as deep vein thrombosis (DVT). DVTs can cause post-thrombotic syndrome (PTS) or travel to the lungs where they become lodged and present as pulmonary embolism (PE). PEs may be one of many causes of chronic pulmonary hypertension and are known together with DVTs as venous thromboembolism (VTE). In the high shear arterial circulation, thrombi are primarily platelet aggregates that impede adequate blood flow and may result in myocardial infarction (MI), ischemic stroke, or limb gangrene.1


If the endothelium of a blood vessel is damaged (e.g. by a cholesterol plaque), the intrinsic coagulation pathway is activated to repair the vessel. This trauma also causes the release of tissue factor, which is responsible for activation of the extrinsic pathway. These two pathways utilize different clotting factors to reach a common pathway where factor Xa converts prothrombin into thrombin, which transforms fibrinogen into fibrin.1 Fibrin is responsible for platelet aggregation which binds platelets together at their GPIIb-IIIa receptors. These receptors are exposed by platelet activation when thrombin binds to the platelet’s protease-activated receptors (PARs) or adenosine diphosphate (ADP) binds to P2Y12 receptors. To keep the clot in place, von Willebrand factor is produced by the damaged vessel and facilitates platelet adhesion.2


Both coagulation and platelet aggregation are involved in thrombosis; therefore risk factors for various thrombotic events are evaluated and anticoagulant or antiplatelet agents are prescribed. Warfarin, heparin, heparin derivatives, aspirin, and clopidogrel have been successful in treating and preventing these types of events but are limited in their dosage forms, need for monitoring, and efficacy in certain patient populations. Patients who require rapid reversal of bleeding (i.e. trauma or emergent surgery), have a genetic predisposition to clopidogrel resistance, or indications for triple antithrombotic therapy will benefit from new options. Five oral antithrombotic agents (Table 1) have earned FDA-approval over the past four years. Prasugrel, dabigatran, rivaroxaban, ticagrelor, and apixaban each offer a unique pharmacologic profile.1 Anticoagulation previously gained versatility with the introduction of subcutaneous injections; patients could use the medications at home to treat and prevent embolic events. The low molecular weight heparin enoxaparin has proven efficacy but can still increase a patient’s risk for heparin-induced thrombocytopenia and fondaparinux, the original factor Xa inhibitor, is limited by its subcutaneuous route of administration.


Dabigatran was approved in 2010 for thrombus prevention in patients with nonvalvular atrial fibrillation (AF). The first approved oral anticoagulant since warfarin, the direct thrombin inhibitor demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism in patients with AF. Patients included in the approval trial scored a mean 2.1 on the CHADS2 scale for stroke risk in AF and the warfarin group was within therapeutic range for 64% of the trial. Dyspepsia was reported in 35% of the dabigatran group (24% warfarin group), possibly due to its tartaric acid core.5,9 The pharmacokinetics observed in this trial allowed for extrapolation of dosing recommendations in patients with severe renal impairment (CrCl 15-30 mL/min). Another trial evaluated patients with AF and mechanical heart valves. Results indicated an increased risk of thromboembolism and major bleeding with dabigatran when compared to warfarin.5 Post-marketing reports to the FDA have demonstrated higher rates of gastrointestinal bleeding and intracranial hemorrhage than had been identified in clinical trials.10


Rivaroxaban, an oral factor Xa inhibitor, was originally approved with the sole indication of prevention of VTE in orthopedic surgery patients. Since, it has gained FDA approval for VTE treatment, recurrent VTE prevention, and stroke and systemic embolism prevention in nonvalvular atrial fibrillation (AF). The ROCKET AF trial compared the risk of stroke in patients with AF treated with rivaroxaban or warfarin; patients had a mean CHADS2 score of 3.5 and the warfarin group was within therapeutic range 55% of the trial. Use is not recommended in patients with creatinine clearance below 15 mL/min.5

The approval of the next factor Xa inhibitor apixaban introduced a unique claim: superiority to warfarin in stroke and systemic embolism prevention in nonvalvular AF. The patients in the ARISTOTLE trial (comparing apixaban to warfarin) had a mean CHADS2 score of 2.1 and the warfarin group was within the therapeutic range 62% of the trial. Limitations to this option include twice daily dosing and adjustments for weight (<60 kg) renal function (SCr>1.5), and age (>80 years).4

The new antiplatelet agent prasugrel was shown to be superior to clopidogrel in reducing cardiovascular (CV) events in patients with acute coronary syndrome (ACS) managed with percutaneous coronary intervention (PCI). Prasugrel is contraindicated in patients with a history of transient ischemic attack (TIA) due to an increased risk of intracranial bleeding. As a result of prasugrel’s irreversible platelet inhibition and the 7-10 day lifespan of a platelet, prasugrel should be discontinued at least 7 days prior to a surgical procedure (ex. coronary artery bypass grafting).6


Patients with ACS can also take ticagrelor to reduce their risk of thrombotic CV events. Results of the PLATO trial indicate that ticagrelor is superior to clopidogrel in the reduction of stent thrombosis. Patients undergoing surgery should discontinue ticagrelor therapy at least 5 days prior to the procedure.7 Unlike clopidogrel, neither prasugrel nor ticagrelor rely on CYP2C19 activation of the drug and therefore present viable options for patients exhibiting clopidogrel resistance secondary to CYP2C19 slow metabolizer phenotypes.6-7


Although these agents are becoming commonly prescribed, none have the long-term safety or efficacy data of warfarin, heparin, aspirin, or clopidogrel. Therefore, they are still relatively unpredictable and have no complete antidotes for reversal in the case of bleeding. The ideal antithrombotic agent would be pharmacodynamically predictable, potent, low in price, and easy to administer. It would also have a rapid onset and offset of action,8 such as is being investigated with the intravenous antiplatelet agent cangrelor.1 While further research is being conducted, we can utilize these new oral agents in the specific populations they have been studied without the nuisance of monitoring.

References:

1. Weitz JI, Eikelboom JW, Samama MM. New antithrombotic drugs: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(2_suppl):e120S–e151S. doi:10.1378/chest.11-2294.

2. Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI. Antiplatelet drugs: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(2_suppl):e89S-e119S. doi:10.1378/chest.11-2293.

3. Xarelto [package insert]. Janssen Pharmaceuticals, Inc. Titusville, NJ. 2011.

4. Eliquis [package insert]. Bristol-Myers Squibb Company. Princeton, NJ. 2013.

5. Pradaxa [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT. 2013.

6. Effient [package insert]. Eli Lilly and Company. Indianapolis, IN. 2012.

7. Brilinta [package insert]. AstraZeneca LP. Wilmington, DE. 2013.

8. Cattaneo M. Update on antithrombotic therapy: new P2Y12 inhibitors. Circulation. 2010;121:171-179. doi: 10.1161/CIRCULATIONAHA.109.853069.

9. Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation. 2011;123:1436-1450. doi: 10.1161/CIRCULATIONAHA.110.004424.

10. U.S. Food and Drug Administration. FDA drug safety communication: update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran). Drug safety and availability. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm282724.htm. Published November 2, 2012. Accessed January 20, 2014.


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