Key articles and guidelines in the management of pulmonary arterial hypertension: 2011 update.

Pharmacotherapeutic approaches for the management of pulmonary arterial hypertension (PAH) have expanded greatly in the last 10 years. Pulmonary arterial hypertension is a relatively rare disease and is associated with myriad disease processes. The older term for PAH, primary PAH, has been changed to represent these differences and to distinguish it from postcapillary PAH associated with left-sided heart failure. Limitations in evaluating treatment approaches for PAH include its rarity, the small number of patients included in clinical trials, and issues regarding the use of placebo-controlled trials in a disease with such a high mortality rate if left untreated. Management options include the use of prostacyclin and prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase inhibitors, as well as traditional background therapy with diuretics, digoxin, calcium channel blockers, and warfarin. Numerous drugs are under investigation to evaluate their possible roles in management. Combination therapy is increasingly becoming a standard approach to therapy, with mounting literature to document effectiveness. Current or emerging roles for the pharmacist in the management of PAH largely involves ensuring access to drug therapy, facilitating specialty pharmacy dispensing, and providing patient counseling. Newer roles may include future drug development, optimized use of investigational drugs, and specialized disease management programs. This compilation includes a series of articles identifying important literature in cardiovascular pharmacotherapy. This bibliography focuses on pharmacotherapeutic management of pulmonary arterial hypertension (PAH). Most of the cited works present the results of significant human clinical studies that have shaped the management of patients with PAH. Limited primary literature is available for some topics, so in addition, consensus documents prepared by expert panels are reviewed. This compilation may serve as a teaching tool, reference resource, or update of the literature for pharmacy clinicians, physicians, and students.

Accuracy of the pharmacogenetic dosing table in the warfarin label in predicting initial therapeutic warfarin doses in a large, racially diverse cohort.

STUDY OBJECTIVES: To compare the accuracy of the pharmacogenetic dosing table included in the warfarin label with two empiric dosing strategies in predicting initial therapeutic warfarin doses, and to identify factors that influence the accuracy of the table. DESIGN: Retrospective cohort study. DATA SOURCE: International Warfarin Pharmacogenetic Consortium database. PATIENTS: A total of 3727 racially diverse patients receiving stable doses of warfarin who had international normalized ratios (INRs) between 2.0 and 3.0. MEASUREMENTS AND MAIN RESULTS: Mean absolute error (MAE) and mean percentage of patients whose predicted doses were within 20% of their actual therapeutic doses (percentage within 20%) were compared between the pharmacogenetic table and two empiric dosing strategies. In the first strategy, warfarin 5 mg/day was used, and in the second strategy, dosing varied depending on the patient's race. The mean percentage of patients whose actual doses were within the ranges of the table (percentage within range) was also calculated. Warfarin dosing using the table resulted in a lower MAE (10.9 mg/wk) and a higher percentage within 20% (41.5%) than both empiric dosing strategies (MAE 12.3-12.6 mg/wk, percentage within 20% of 31.8-32.7%). In addition, using the table showed similar MAE, mean percentage within 20%, and mean percentage within range across the different racial groups. Dosing according to the table had higher mean percentage within 20% (56.4% vs 15.4%) and higher mean percentage within range (53.3% vs 19.2%) in the intermediate-dose group (> 21 but ≤ 49 mg/wk) than in the low-dose group (≤ 21 mg/wk). Being female and taking amiodarone were identified as factors that significantly increased the likelihood that the patient's predicted dose would be outside of 20% of their actual therapeutic dose or outside the range of the pharmacogenetic table. CONCLUSION: Using the pharmacogenetic dosing table included in the warfarin label resulted in higher accuracy of dosing prediction than two empiric dosing strategies. The table had similar accuracy across racial groups and better accuracy in patients receiving an intermediate dose of warfarin. When the table is used for warfarin dosing, women and patients receiving amiodarone may require more intensive monitoring of their warfarin therapy.

Emergency department management of patients on warfarin therapy.

STUDY OBJECTIVE: To characterize warfarin management in the emergency department (ED). METHODS: This was a retrospective, cross-sectional, observational study of patients who were receiving warfarin and were discharged from a tertiary care, academic urban ED between June and August 2007. We abstracted patient demographics, presenting complaint, international normalized ratio (INR) if tested, indication for warfarin if documented, new medications administered or prescribed in the ED, and discharge instructions. Presenting complaints were categorized according to whether they were warfarin-related and concerning for thrombosis or bleeding. The primary outcome measure was the prevalence of warfarin therapy. The secondary outcome measures were frequency with which ED providers obtained an INR result, response to nontherapeutic results, administration or prescription of interacting medications, and percentage of patients receiving recommendations for anticoagulation follow-up. RESULTS: Two percent (111/7,195) of all patients presenting to and discharged from the ED during the study period were found to be receiving warfarin. Seventy-one percent (79/111) had an INR checked. Nontherapeutic INRs were recorded for 49% (39/79) of patients; ED providers intervened to address these results in 21% (8/39) of cases. Seventy-one percent (5/7) of patients with a supratherapeutic INR received an intervention compared with 9% (3/32) of patients with a subtherapeutic INR. Seventeen percent (19/111) and 13% (14/111) of patients received or were prescribed potentially interacting medications, respectively. Recommendations for specific anticoagulation follow-up were documented for 19% (21/111) of all patients. CONCLUSION: Patients receiving warfarin frequently present to the ED and often have nontherapeutic INRs. Potential areas for improvement in ED management include greater attention to subtherapeutic INRs, interacting medications, and discharge planning.

Survey on warfarin pharmacogenetic testing among anticoagulation providers.

AIMS: Our study aimed to assess anticoagulation providers' perception and knowledge of warfarin pharmacogenetic testing, and to identify barriers to using it in their clinical practice. MATERIALS & METHODS: An online survey that included 5 perception and 5 knowledge questions about the testing was conducted on anticoagulation providers in North America. Participants were also asked to rank the three most significant barriers to using it. RESULTS: The survey response rate was 22%. Over 40% of 448 providers participating in the study were undecided about the testing's potential clinical benefits. On average, providers correctly answered 2 out of 5 knowledge questions. Self confidence in interpreting test results significantly predicted the providers' accuracy of the interpretation. The top three barriers were inadequate literature evidence, testing's impracticality and unproven applicability. CONCLUSION: Most of the providers did not respond to the survey. Our study suggests inadequate literature evidence influences providers' perception and their use of the testing. In addition, provider education on warfarin pharmacogenetics may be necessary for testing's widespread use.

Pharmacogenetics: from discovery to patient care.

PURPOSE: The basic concepts of pharmacogenetics, pharmacogenetic study approaches, factors to consider when applying pharmacogenetic discoveries to patient care, and potential roles for pharmacists in pharmacogenetics are discussed. SUMMARY: The Food and Drug Administration (FDA) has recognized pharmacogenomics as an opportunity to identify new biomarkers that may expedite the drug development process. Currently, there are over 50 drugs with pharmacogenetic discoveries on their labeling. Sequence variations in drug disposition genes can alter the pharmacokinetics of a drug, while sequence variations in drug target genes can change the pharmacodynamics of the drug. The two most common strategies to test a pharmacogenetic question are the candidate-gene approach and genomewide association study. Given the complex interplay among the many factors that influence a drug dose, determination of an appropriate dose of a particular drug for a given patient will eventually require knowledge about both genetic and nongenetic factors that affect drug disposition and pharmacodynamics. Many factors can influence the application of pharmacogenetic discoveries to patient care. Before these discoveries find widespread application in clinical practice, additional work is needed, including randomized clinical trials to evaluate the clinical utility of a pharmacogenetic test, the development of guidelines for the clinical use of various pharmacogenetic tests, and provider education on pharmacogenetics. CONCLUSION: Pharmacogenetics has made significant progress in the past decade, and many pharmacogenetic discoveries have now been included on FDA-approved drug labeling. Pharmacogenetic discoveries may further promote safe and effective use of medications by more accurately predicting an individual's drug response.

A review of three stand-alone topical thrombins for surgical hemostasis.

BACKGROUND: Topical thrombins are active hemostatic agents that can be used to minimize blood loss during surgery. Before 2007, the only topical thrombins available were derived from bovine plasma. Antibody formation to bovine thrombin and/or factor V, with subsequent risk of cross-reactivity with human factor V, and hemorrhagic complications associated with human factor-V deficiencies have been described in case reports of surgeries in which bovine thrombins were used. This risk is now included in the boxed warning section of the bovine thrombin prescribing information. In 2007 and 2008, 2 new topical thrombins from nonbovine sources received approval for use from the US Food and Drug Administration. The 3 active topical thrombins that are currently marketed are bovine plasma-derived thrombin, human plasma-derived thrombin, and human recombinant thrombin. OBJECTIVE: The purpose of this review was to evaluate the literature on the efficacy and safety of topical thrombins and discuss the pharmacoeconomic considerations associated with their use. METHODS: PubMed, EMBASE, and International Pharmaceutical Abstracts were searched for relevant papers published in English through October 10,2008, using the terms thrombin, human recombinant thrombin, bovine thrombin, plasma derived thrombin, and topical thrombin. Manufacturer-provided materials were also reviewed. Abstracts and unpublished data, as well as evaluations of sealants, adhesives, glues, and other hemostats that contain thrombin mixed with fibrinogen and other clotting factors, were excluded. RESULTS: Four randomized, double-blind studies involving the active, stand-alone topical thrombins were found. The bovine thrombin involved in these studies was the predecessor to the currently marketed, highly purified bovine formulation. No studies comparing the human products, studies involving the highly purified bovine preparation, or placebo-controlled studies involving bovine thrombin were found. In a Phase III comparison of human recombinant thrombin and bovine thrombin, the percentages of patients who achieved hemostasis within 10 minutes of topical thrombin application were 95.4% and 95.1%, respectively (95% CI, -3.7 to 5.0). The incidence of hemostasis within 10 minutes was also similar in a Phase III comparison of human plasma-derived thrombin and bovine thrombin (both, 97.4% [95% CI, 0.96 to 1.05]). In the study that compared human recombinant and bovine thrombin, the incidence of antiproduct antibody formation was 21.5% (43/200) in the bovine thrombin group and 1.5% (3/198) in the human recombinant thrombin group (P < 0.001); patients with antibodies to bovine thrombin had numerically higher incidences of bleeding or thromboembolic events than did patients without these antibodies (19% vs 13%; P value not reported). Human plasma-derived thrombin is available as a frozen sterile solution that must be thawed before application, whereas the human recombinant and bovine plasma-derived products are supplied as unrefrigerated sterile powders that must be reconstituted before use. The human thrombins are more costly than bovine thrombin on a per-vial basis. The average wholesale prices (US $, 2008) for 5000-IU vials of bovine thrombin and human recombinant thrombin were $87.85 and $103.20, respectively; the average wholesale price for a 4000- to 6000-IU vial of human plasma-derived thrombin was $96.00. CONCLUSIONS: Topical thrombins vary in the ways in which they are manufactured and their safety profiles, storage requirements, and costs. Human recombinant thrombin and human plasma-derived thrombin have each been shown to have hemostatic efficacy comparable to that of bovine thrombin. Bovine thrombin carries the risk of formation of cross-reactive antibodies to bovine thrombin, factor V, and other impurities that may be present in these formulations. Immunogenicity data for the currently marketed, highly purified bovine thrombin relative to older formulations of bovine thrombin could not be found. Whether the potential safety advantage justifies the added cost of the human products remains to be established.

Clinical pharmacy consultation for pharmacogenetic testing.

The clinical application of pharmacogenetic testing will help to bring personalized medicine into clinical practice. Due to the complex process involved in delivering pharmacogenetic testing, optimal clinical implementation of pharmacogenetic tests will require the coordinated effort of multiple disciplines including medicine, clinical laboratory medicine and clinical pharmacy. This will help to bridge the gap between the basic and laboratory science, and the clinical application of these results. How may clinical pharmacy contribute to the clinical application of pharmacogenetic testing as a member of a multidisciplinary team? In this perspective, we propose a potential new role for pharmacists: as an interpreter of pharmacogenetic test results. Interpreting the results of pharmacogenetic tests, particularly, those intended to guide drug dosing, requires an understanding of pharmacogenetics, pharmacokinetics and pharmacodynamics. Pharmacists who are knowledgeable in these areas may play an important role in interpretation of the test results.

The influence of ethnicity on warfarin dosage requirement.

BACKGROUND: The optimal dose of warfarin varies among individuals, and the prediction of a maintenance dose is difficult. Ethnicity has been reported to influence warfarin dosing. OBJECTIVE: To quantitate the influence of ethnicity on warfarin dose requirement. METHODS: We conducted a retrospective cohort study at a university anticoagulation clinic to evaluate the influence of ethnicity on warfarin dose. Inclusion criteria included age > or = 18 years, target international normalized ratio (INR) 2-3, and warfarin management within the clinic for > or = 3 months with a minimum of 5 clinic visits. We collected clinical and demographic data including age, gender, weight, ethnicity, disease states, concomitant medications, indication, weekly warfarin dosage, and INR. To assess potential confounders, multivariate, repeated-measures regression analysis was used to identify and adjust for variables that may influence the maintenance dose of warfarin. RESULTS: Of the 345 patients who met the inclusion criteria, 27% were Asian American, 6% Hispanic, 54% white, and 14% African American. The adjusted mean (95% CI) weekly warfarin doses for patients with an INR goal of 2 to 3 were Asian Americans 24 mg (21 to 27), Hispanics 31 mg (25 to 37), whites 36 mg (34 to 39), and African Americans 43 mg (39 to 47) (p < 0.001). Additional factors found to influence warfarin dose requirement included age, weight, concomitant use of amiodarone, and diagnosis of venous thromboembolism. CONCLUSIONS: Warfarin dose requirements vary across ethnic groups even when adjusted for confounding factors, suggesting that genetic variation contributes to interpatient variability.

Impact of pharmacists' interventions on the pediatric discharge medication process.

BACKGROUND: To our knowledge, as of August 19, 2004, the impact of pharmacists' interventions on pediatric patients and their caregivers' ability to obtain discharge medications from community pharmacies in a timely fashion has not been described. OBJECTIVE: To evaluate the impact of pharmacists' interventions on patients' likelihood of obtaining medications within 24 hours of hospital discharge. METHODS: Patients meeting study criteria were randomized to an intervention or control group. The intervention was a proactive program of discharge planning by the pharmacy team. All study patients received a follow-up telephone interview to assess the amount of time needed to obtain medications and caregivers' knowledge of how to administer medications. A multivariate linear regression was conducted to assess the association between variables such as insurance, place of residence, number of prescribed medications, and the probability to obtain medications within 24 hours of hospital discharge. RESULTS: The final analysis included 81 control patients and 91 intervention patients. After controlling for a number of factors, the intervention group was able to have obtained medications within 24 hours more often than the control group (84% vs 69%; p = 0.027). Caregivers' knowledge of how to correctly administer medications did not differ between the 2 groups. CONCLUSIONS: Our results suggest that the coordinated efforts of pharmacists' interventions during the discharge process may have a positive impact. Our observations may be used to establish criteria for identifying patients at risk for problems with obtaining medications at discharge.

Famotidine and long QT syndrome.

Numerous drugs have been implicated in causing a prolonged QT interval and Torsades de pointes. However, the association of famotidine and acquired long QT syndrome has rarely been reported. We report 2 cases of famotidine-associated acquired long QT syndrome.