Anticoagulation in patients with pulmonary arterial hypertension: An update on current knowledge.

Pulmonary hypertension is a severe clinical condition characterized by molecular and anatomic changes in pulmonary circulation. It is associated with increased pulmonary vascular resistance, which leads to right-sided heart failure if left untreated and, ultimately, death. Treatment of patients with pulmonary arterial hypertension (PAH) involves a complex strategy that takes into consideration disease severity, general and supportive measures, and combination drug regimens. Abnormalities of blood coagulation factors, anti-thrombotic factors, and the fibrinolytic system may contribute to a prothrombotic state in patients with idiopathic PAH. These physiologic changes, in concert with the presence of non-specific risk factors for venous thromboembolism such as heart failure and immobility, are thought to be the basis for oral anticoagulation in PAH. Several observational studies provide helpful information in favor of anticoagulation use in idiopathic PAH but not in other pulmonary hypertension etiologies. Guideline recommendations are based on the lack of prospective comparative trials in this regard. For that reason, large differences exist in the use of anticoagulants in different countries and centers. More studies should be carried out to clarify the risks and the potential benefits of anticoagulant use in a heterogeneous population of patients who are already at considerable life risk.

Implementation of a Hemostatic and Antithrombotic Stewardship program.

Hemostatic and antithrombotic (HAT) agents are high risk, high cost products. They require close monitoring and dose titration to adequately treat or prevent thrombosis while avoiding bleeding events. Incorporating the principles of inpatient anticoagulation management service into a stewardship program not only improves outcomes and decreases cost, but also improves transitions of care, exposes gaps in therapy management, and leads to the development of institution specific protocols and guidelines. We implemented a HAT Stewardship to provide real time clinical surveillance and management of these agents in an effort to optimize appropriate use, decrease serious adverse events, and minimize costs. The stewardship is staffed daily by an interdisciplinary team comprised of a pharmacist, hematology attending, and medical director. The stewardship focuses on (1) management of heparin-induced thrombocytopenia (HIT), (2) management of patients with Hemophilia A/B with inhibitors and acquired Factor VIII deficiency due to inhibitors, (3) oversight of anticoagulation in patients on extracorporeal membrane oxygenation and (4) assistance with anticoagulation management for patients with mechanical cardiac assist devices. Through implementation of this service, we have been able to demonstrate improved patient care and a positive economic impact exceeding the cost of this program by almost sixfold. Other centers should consider instituting a HAT Stewardship to maximize patient outcomes and minimize adverse events.

Effect of dabigatran on referrals to and switching from warfarin in two academic anticoagulation management services.

Dabigatran was expected to replace warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (AF) who are warfarin naive, difficult to maintain in therapeutic range, or at risk of warfarin-related bleeding complications. We hypothesized that the number of patients with nonvalvular AF referred to Anticoagulation Management Services would decrease sharply and that most would switch from warfarin to dabigatran. We evaluated the number of patients with nonvalvular AF referred to 2 large services, Anticoagulation Management Service 1 and Anticoagulation Management Service 2, 12 months before and after market entry of dabigatran. We also evaluated the number of patients who switched from warfarin to dabigatran. Anticoagulation Management Service 1 follows 1,225 patients with nonvalvular AF with mean CHADS2 and CHA2DS2-VASc scores of 2.0 and 3.5, respectively. Anticoagulation Management Service 2 follows 1,137 patients with nonvalvular AF with mean CHADS2 and CHA2DS2-VASc scores of 2.0 and 3.3, respectively. In the 12 months preceding market entry of dabigatran, patients with nonvalvular AF constituted 537 (31.4%) of the referrals sent to Anticoagulation Management Service 1 and increased to 793 (32.3%) in the following 12 months. For Anticoagulation Management Service 2, patients with nonvalvular AF constituted 617 (30.7%) of referrals before market entry of dabigatran and decreased to 495 (25.2%) of referrals. Eighty-one patients (6.6%) from Anticoagulation Management Service 1 and 44 (3.9%) from Anticoagulation Management Service 2 have switched from warfarin to dabigatran. The frequency of initial prescription of dabigatran for stroke prevention in AF and the frequency of transition from warfarin to dabigatran have been less than expected.

Improving anticoagulation management in patients with atrial fibrillation.

Three agents have recently been approved to reduce the risk of stroke and embolism, and one agent is in phase 3 trials. These drugs cause less serious bleeding and are simpler to manage, compared with warfarin, but they are not without their risks.

Hospital budget implications of substituting dabigatran for warfarin in an anticoagulation service.

The aim of our study was to assess hospital budget implications of substituting dabigatran for warfarin in patients enrolled in a large anticoagulation service. The study population was identified using criteria from randomized controlled trials of dabigatran. We obtained labor costs ($483 per patient) from the hospital's anticoagulation service budget, laboratory costs of international normalized ratio (INR) tests ($267 per patient), and wholesale costs of warfarin 5 mg tablets ($31 per patient) and dabigatran 150 mg capsules ($2464 per patient). A total of 1774 (93.5%) of 1898 patients were eligible to substitute dabigatran for warfarin. The annual projected hospital expense for anticoagulation with dabigatran was $4,371,136, attributable to drug cost alone. The annual projected cost of warfarin management was $1,385,494. This was comprised of $856,842 for labor, $473,658 for INR testing, and $54,994 for the drug cost of warfarin. Substitution will result in increased expense due to drug cost.

Dabigatran: a review of clinical and pharmacoeconomic evidence.

Dabigatran etexilate is the first commercially available oral direct thrombin inhibitor. A single trial has studied patients at risk for stroke associated with nonvalvular atrial fibrillation; in this trial, dabigatran 150 mg twice a day met the criteria for superiority over warfarin in preventing stroke and systemic embolism while reducing the rate of hemorrhagic stroke with a similar risk of major bleeding. For the treatment of venous thromboembolism, dabigatran 150 mg twice a day had comparable efficacy and safety versus warfarin. In contrast, dabigatran was less effective than enoxaparin 30 mg twice a day in venous thromboembolism prevention in orthopedic surgery. Advantages of dabigatran over warfarin include its lack of need for routine laboratory monitoring, a fixed-dose regimen, and potentially fewer clinically important drug interactions. Concerns include higher incidences of dyspepsia and gastrointestinal bleeding, twice-daily dosing, and lack of effective antidote. Additional drawbacks include higher drug cost versus warfarin, accumulation in case of renal impairment, higher discontinuation rates due to adverse events, and limited long-term safety and trial data. From a payer perspective, overall costs will be higher with dabigatran compared with warfarin, but dabigatran does meet the threshold to be considered a cost-effective therapy. In addition, the lack of need for regular laboratory monitoring is a quality of life advantage for patients on dabigatran. These observations suggest that dabigatran is a valuable addition to the therapeutic armamentarium for stroke prevention in selected patients with atrial fibrillation although caution should be exercised given the limited data on this agent and higher cost.