Implications of an inpatient warfarin dosing nomogram on safety outcomes post-discharge.

Many hospitals have implemented warfarin dosing nomograms to improve patient safety. To our knowledge, no study has assessed the impact inpatient warfarin initiation has in both medical and surgical patients, on safety outcomes post discharge. To evaluate the impact of a suggested institutional nomogram for the initiation of warfarin, the primary endpoint was the incidence of bleeding throughout follow up. Secondary endpoints included the composite of INR changes ≥0.5/day and INR >4. Patients were followed for a period of 2 weeks post-discharge. The composite endpoint was evaluated for an effect on reaching therapeutic INR, time to reach therapeutic INR, and bleeding events throughout follow up. A single center retrospective study comparing the safety of adherence vs. non-adherence to a warfarin nomogram. A total of 206 patients were included, 73 patients in the nomogram adherence vs. 133 in the nonadherence arm. There was no difference in the proportion of patients who bled throughout the follow up period, adherence 9.6% vs. nonadherence to the nomogram 13.5%, p = 0.407. There was however a statistical difference in the mean total number of bleeding events, 0.096 (7/73) in the adherence vs. 0.158 (21/133) in the non-adherence arm, p = 0.022. There was also no difference in the composite endpoint, 19.2% in the adherence vs. 28.6% in the non-adherence arm p = 0.180. A positive correlation between the inpatient composite and risk of bleeding throughout follow up was noted. The findings of this study support adherence to the nomogram as opposed to non-adherence.

How one academic medical center has managed potency changes with unfractionated heparin.

The United States Pharmacopeia recently changed the standards for unfractionated heparin (UFH) resulting in reduction in potency by about 10 %. Despite the reduction in potency, no new recommendations for UFH dosing were recommended. A retrospective review was conducted on patients receiving UFH and at least one activated partial thromboplastin time (aPTT) after start of infusion. Patients receiving UFH prior to April 2010 were collected as old UFH potency patients versus those receiving UFH after May 1st, 2010 were defined as new UFH potency patients. The primary endpoint was time to a therapeutic aPTT. Secondary endpoints included the number venous thrombotic events (VTE) and bleeding events during hospitalization through 30 days post discharge. Thrombotic events were defined as acute coronary syndrome, ischemic stroke, and VTE. Bleeding was defined in accordance with the GUSTO bleeding scale. A total of 359 patients were included for evaluation, 181 in the old UFH group and 178 in the new UFH group. The primary endpoint was similar between groups with an average time of 18.8 ± 25.4 versus 20.8 ± 22.2 h in the old and new UFH groups respectively (p = 0.092). Patients receiving old UFH and an initial bolus had higher aPTTs (96.6 ± 43.7 s) than those receiving new UFH and an initial bolus (76.7 ± 34.5 s) (p = 0.003). There was no difference found between groups in regards to bleeding or thrombotic events during hospitalization or through 30 days. In patients receiving UFH, dosed per the institutions' nomogram, no clinically significant outcomes were found between the old and new UFH potencies.

A case of unsuccessful treatment of heparin-induced thrombocytopenia (HIT) with fondaparinux.

Heparin-induced thrombocytopenia (HIT) is a rare immune-mediated complication associated with unfractionated heparin and to a lesser extent with low-molecular weight heparins. The American College of Chest Physicians recommends treating patients with suspected HIT with a non-heparin product regardless if thrombosis is present. The direct thrombin inhibitors are the preferred agents for the treatment of acute HIT (lepirudin, argatroban [Grade 1C]). Fondaparinux is also suggested as an alternative with a lower level of evidence (Grade 2C). The evidence supporting the use of fondaparinux in the treatment of HIT is limited, but the evidence of fondaparinux causing HIT is even less. We present a case of a patient who developed complications with fondaparinux when used in the acute setting of HIT.

Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic.

The objectives of this retrospective cohort study are to evaluate the accuracy of pharmacogenetic warfarin dosing algorithms in predicting therapeutic dose and to determine if this degree of accuracy warrants the routine use of genotyping to prospectively dose patients newly started on warfarin. Seventy-one patients of an outpatient anticoagulation clinic at an academic medical center who were age 18 years or older on a stable, therapeutic warfarin dose with international normalized ratio (INR) goal between 2.0 and 3.0, and cytochrome P450 isoenzyme 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes available between January 1, 2007 and September 30, 2008 were included. Six pharmacogenetic warfarin dosing algorithms were identified from the medical literature. Additionally, a 5 mg fixed dose approach was evaluated. Three algorithms, Zhu et al. (Clin Chem 53:1199-1205, 2007), Gage et al. (J Clin Ther 84:326-331, 2008), and International Warfarin Pharmacogenetic Consortium (IWPC) (N Engl J Med 360:753-764, 2009) were similar in the primary accuracy endpoints with mean absolute error (MAE) ranging from 1.7 to 1.8 mg/day and coefficient of determination R (2) from 0.61 to 0.66. However, the Zhu et al. algorithm severely over-predicted dose (defined as >or=2x or >or=2 mg/day more than actual dose) in twice as many (14 vs. 7%) patients as Gage et al. 2008 and IWPC 2009. In conclusion, the algorithms published by Gage et al. 2008 and the IWPC 2009 were the two most accurate pharmacogenetically based equations available in the medical literature in predicting therapeutic warfarin dose in our study population. However, the degree of accuracy demonstrated does not support the routine use of genotyping to prospectively dose all patients newly started on warfarin.

Assessment of eptifibatide dosing in renal impairment before and after in-service education provided by pharmacists.

BACKGROUND: Anticoagulant and antithrombotic agents are frequently cited as sources of medication errors. Several factors increase the risk of receiving excess dosing of glycoprotein IIb/IIIa inhibitors in the management of acute coronary syndrome (ACS), including older age, female gender, elevated serum creatinine, a history of diabetes mellitus, and a history of heart failure. In June 2003, the manufacturer of eptifibatide released a recommendation adjusting infusion rate downward to 1 mcg per kg per minute for eptifibatide in patients with renal impairment, defined as an estimated creatinine clearance (CrCl) < 50 ml per minute. Eptifibatide is known to accumulate in patients with renal impairment, thereby increasing hemorrhagic risk. OBJECTIVE: To assess the impact of education on physician adherence to the renal dosing recommendation for eptifibatide at 2 academic medical centers. The primary outcome measure was the proportion of patients with renal impairment dosed appropriately with eptifibatide before and after in-service education provided by a clinical pharmacist. Secondary outcome measures included the difference in the improvement in dosing adherence between the 2 sites and the influence of patient variables on the incidence of bleeding events. METHODS: This prospective study was conducted in patients with renal impairment who received eptifibatide for the medical management of unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI) or for the interventional management of chronic stable angina, UA, NSTEMI, or ST-elevation myocardial infarction (STEMI, not a Food and Drug Administration-approved use). Patient data were assessed at 2 tertiary care teaching institutions between June 2003 and December 2005. The preeducation phase for the sites ran from June 2003 through April 2005 for Site A and from June 2003 through May 2005 for Site B. The posteducation phase ran from May 2005 through December 2005 for Site A and from June 2005 through December 2005 for Site B. At site A, a 1-hour educational seminar on ACS management strategies was employed, in which 5 minutes focused on adherence of prescribers to the guideline for renal dosing recommendations for eptifibatide. This tutorial was accomplished through (1) an in-service provided by 1 clinical pharmacist to the cardiology department, and (2) handouts containing the renal dosing recommendations for eptifibatide along with dosing for other medications used to manage ACS. The intervention at Site B involved an eptifibatide-focused seminar presented to cardiologists by a clinical pharmacist, 10 minutes of which was devoted to renal dosing recommendations that included (1) a summary of literature supporting the infusion rate reduction in patients with renal impairment and (2) the specific updated dosing recommendation for eptifibatide. The data collected in retrospective chart review included patient demographics, baseline laboratory values, and risk factors for bleeding. An appropriate eptifibatide dose was defined as a physician order for a continuous infusion of 1 mcg per kg per minute in patients with an estimated CrCl < 50 ml per minute. RESULTS: A total of 148 patients with renal impairment who received eptifibatide were evaluated (106 in the preeducation phase and 42 in the posteducation phase). A significant increase in the adherence rate for eptifibatide dosing in patients with renal impairment was observed from 36.8% in the preeducation phase to 69.0% in the posteducation phase (P < 0.001) for the 2 sites combined. The incidence of major and minor bleeding was 16.7% in the preeducation phase and 14.3% in the posteducation phase (P = 0.742). When bleeding incidence was stratified by the appropriateness of infusion, the incidence of major and minor bleeding was also similar for appropriate dosing (1 mcg per kg per minute, 16.4%) versus inappropriate dosing (2 mcg per kg per minute, 15.7%; P = 0.916). CONCLUSION: This educational intervention provided by a clinical pharmacist was associated with improved prescriber adherence to dosing recommendations for eptifibatide in patients with renal impairment. Improved adherence to the dosing guideline and administration of an appropriate infusion rate were not associated with reduction in either minor or major bleeding events.

An overview of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction to heparin products leading to a prothrombotic state. Devastating clinical sequelae may result, including venous or arterial thromboembolism, limb amputation, and death. Heparin cessation alone is insufficient to manage HIT. Pharmacotherapy with argatroban or lepirudin is essential. This article reviews the pathogenesis, diagnosis, and pharmacotherapy of HIT.

Lepirudin-induced thrombocytopenia following subcutaneous administration.

PURPOSE: A case of lepirudin-induced thrombocytopenia is reported. SUMMARY: A 61-year-old white man arrived at the emergency department with complaints of pain in his left thigh that worsened with walking. His medical history was significant for extensive thromboses over a period of six months. He had recently been discharged from the hospital for suspected heparin-induced thrombocytopenia (HIT) while on enoxaparin. A venous duplex scan revealed two new deep venous thromboses in the left common, superficial, and popliteal veins. The patient was admitted and initiated on aspirin 325 mg and warfarin sodium 2 mg daily. Intravenous lepirudin with an activated partial thromboplastin time (aPTT) goal of 60-80 seconds was also started. Because of his recurrent thrombotic event, a new International Normalized Ratio (INR) goal of 3.0-3.5 was established for warfarin therapy. Eighteen days after admission, the patient's INR and aPTT were high; therefore, his warfarin dose was reduced and i.v. lepirudin was changed to subcutaneous administration. The patient was transferred to the intensive care unit (ICU) and, 5 days later, he developed melena. During the 7 days of treatment with subcutaneous lepirudin, a drop in platelet counts was observed. Subcutaneous lepirudin was discontinued after resolution of melena, and i.v. lepirudin was restarted. After 15 days, his platelet counts increased and he was switched back to subcutaneous lepirudin, which again led to a drop in platelets. After 27 days in the ICU, the patient's INR and aPTT remained high. Lepirudin was discontinued and i.v. bivalirudin was initiated. His platelet count increased and he was discharged. Eleven days later, the patient was found unresponsive with left-sided fasciculations. The patient died secondary to respiratory arrest as a consequence of intracranial hemorrhage. CONCLUSION: A 61-year-old white man with a history of thromboses and suspected HIT developed thrombocytopenia possibly associated with receiving two courses of subcutaneous lepirudin. Careful monitoring of platelet counts are warranted in patients who have a history of HIT and are receiving subcutaneous lepirudin.

Pharmacy-managed anticoagulation: assessment of in-hospital efficacy and evaluation of financial impact and community acceptance.

BACKGROUND: The dangers of thrombosis are well known and yet current therapy presents a paradox; effective methods of pharmacological anticoagulation are available, but underemployed. The risks associated with the use of anticoagulants, especially warfarin, and the requirement of meticulous dosing with subsequent vigilant monitoring provides some explanation for this discrepancy. Efforts have been made to address this incongruity and increase anticoagulation treatment while mitigating complications; these include the development of dosing nomograms, patient self-monitoring of anticoagulation status, and increased pharmacist participation in anticoagulation management. Although the latter option has proven effective in outpatient clinics, its in-hospital application has received less attention. Therefore, our primary goal was to review the published literature to evaluate the efficacy of in-hospital, pharmacy-managed anticoagulation. In addition, our secondary goals were to assess the potential financial benefit and community acceptance of such pharmacist management. METHODS: Potentially relevant studies were identified by searching PubMed; however, because some pharmacy journals are not included in this database, we also used internet search engines to locate articles. We subsequently employed the Science Citation Index to find additional papers that had referenced articles identified by our initial searches. RESULTS: Several pilot studies, focusing primarily on adherence to warfarin dosing guidelines, found general equivalence between pharmacist and physician management and specifically illustrated the potential benefit gained simply through adherence to protocols. Nevertheless, these studies frequently lacked appropriate statistical analysis and examined small, and often heterogeneous, patient groups. Larger comparative studies also possessed some of the same flaws; however, taken together the equivalence and, in some cases improvement, in patient outcomes (e.g., greater control of International Normalized Ratios and decreased length of hospital stay) that they demonstrated suggest the value of increased pharmacist participation in anticoagulation therapy. Studies using heparin-based anticoagulation reported similar positive findings and hence support the warfarin results. Both published studies examining financial implications of in-hospital pharmacy management indicated potential for considerable savings. Finally, although we identified no in-hospital studies of community acceptance, positive survey results indicted that the majority of physicians and patients accepted pharmacy-managed outpatient anticoagulation. CONCLUSIONS: The reported outcomes of pharmacy-managed in-hospital anticoagulation therapy appear at least equal, and sometimes superior, to those obtained through standard care; however, the lack of large well-designed trials prevents drawing definitive conclusions. Nevertheless, the continued and likely increased future need for anticoagulation in general and warfarin therapy in particular suggests that increased pharmacist involvement could enhance the quality of patient care.