Samuel G. Johnson

Outcomes Associated With Combined Antiplatelet and Anticoagulant Therapy

BACKGROUND The use of antiplatelet therapy in combination with oral anticoagulants remains controversial. The objective of this study was to estimate and compare the incidence of adverse and coronary event rates between patients receiving warfarin monotherapy or warfarin and antiplatelet combination therapy. METHODS This was a retrospective, longitudinal, pharmacoepidemiologic analysis. Adult patients receiving warfarin managed by an anticoagulation service who had documented the use of antiplatelet agents (eg, aspirin, clopidogrel, and/or dipyridamole) [ie, the combination-therapy cohort] or their nonuse (ie, the monotherapy cohort) were identified as of September 30, 2005. Utilizing integrated, electronic medical records, anticoagulation-related adverse events (eg, death, hemorrhage, or thrombosis) and coronary events were identified during a 6-month follow-up period (October 2005 through March 2006). The proportions of events were compared between cohorts. Independent associations between the cohorts and the outcomes were assessed with adjustment for potential confounding factors. RESULTS Data from 2,560 patients in the monotherapy cohort and 1,623 patients in the combination-therapy cohort were analyzed. Patients in the combination-therapy cohort were more likely to have had anticoagulation-related hemorrhages (4.2% vs 2.0%, respectively; unadjusted p < 0.001) and coronary events (0.9% vs 0.3%, respectively; p = 0.009), but not death (0.1% vs 0.2%, respectively; unadjusted p = 0.186) or thrombotic events (0.3% vs 0.4%, respectively; unadjusted p = 0.812). With adjustment, combined warfarin and antiplatelet use was independently associated with hemorrhagic events (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.44 to 5.28), but not with coronary events (OR, 0.99; 95% CI, 0.37 to 2.62). CONCLUSIONS At the population level, the hemorrhagic risk associated with warfarin therapy combined with antiplatelet therapy appears to outweigh the benefits. These findings suggest that clinicians should carefully consider the risks and benefits when recommending combined antiplatelet therapy for patients receiving warfarin who do not meet the evidence-based criteria for such therapy.

Making Personalized Health Care Even More Personalized: Insights From Activities of the IOM Genomics Roundtable

Genomic research has generated much new knowledge into mechanisms of human disease, with the potential to catalyze novel drug discovery and development, prenatal and neonatal screening, clinical pharmacogenomics, more sensitive risk prediction, and enhanced diagnostics. Genomic medicine, however, has been limited by critical evidence gaps, especially those related to clinical utility and applicability to diverse populations. Genomic medicine may have the greatest impact on health care if it is integrated into primary care, where most health care is received and where evidence supports the value of personalized medicine grounded in continuous healing relationships. Redesigned primary care is the most relevant setting for clinically useful genomic medicine research. Taking insights gained from the activities of the Institute of Medicine (IOM) Roundtable on Translating Genomic-Based Research for Health, we apply lessons learned from the patient-centered medical home national experience to implement genomic medicine in a patient-centered, learning health care system.

Known knowns and known unknowns: Risks associated with combination antithrombotic therapy

BACKGROUND Use of antiplatelet therapy in combination with oral anticoagulants remains controversial. The purpose of this article is to review current consensus recommendations for antithrombotic therapy, to evaluate risks for bleeding among patients taking combination antithrombotic therapy, and lastly to review single-center data from Kaiser Permanente Colorado detailing clinical outcomes associated with combination therapy. METHODS This was a retrospective, longitudinal pharmacoepidemiologic review. Adult patients receiving warfarin managed by a clinical pharmacy service who had documented antiplatelet (aspirin, clopidogrel, and/or dipyridamole) use (combination therapy cohort) or non-use (monotherapy cohort) were identified as of September 30, 2005. Utilizing integrated, electronic medical records, anticoagulation-related adverse events (death, hemorrhage, thrombosis) and coronary events were identified during a six-month follow-up (October 2005 through March 2006). Proportions of events were compared between cohorts. Independent associations between the cohorts and the outcomes were assessed with adjustment for potential confounding factors. RESULTS Data from 2,560 monotherapy and 1,623 combination therapy patients were analyzed. Patients in the combination therapy cohort were more likely to have had anticoagulation-related hemorrhages (4.2% vs. 2.0%, unadjusted p<0.001). With adjustment, combined warfarin and antiplatelet use was independently associated with hemorrhagic (OR=2.75; 95% CI 1.44, 5.28) but not coronary (OR=0.99; 95% CI 0.37, 2.62) events. CONCLUSIONS At the population level, the hemorrhagic risk associated with warfarin therapy combined with antiplatelet therapy appears to outweigh the benefits. These findings suggest that clinicians carefully consider risks and benefits when prescribing antiplatelet therapy for patients taking warfarin who do not meet evidence-based criteria for that approach.

Adherence to amiodarone monitoring recommendations before and after implementation of a centralized pharmacy service: a cohort study.

The objective of this study was to determine whether patients enrolled in a centralized amiodarone monitoring service (AMS) were more adherent to amiodarone surveillance and whether the incidence of amiodarone-related toxicity differed for patients who were enrolled in the AMS. Amiodarone therapy was initiated in 917 patients in an integrated health care delivery system between October 1998 and December 2006. Electronic records were queried to establish the proportion of patients completing recommended amiodarone monitoring during the first year of therapy; specifically, thyroid stimulating hormone (TSH), alanine aminotransferase (ALT), electrocardiogram (ECG), and chest radiograph (CXR). Patients were assigned to the AMS or control cohort based on when amiodarone was initiated. Patients assigned to the AMS cohort were more likely to receive ALT monitoring at baseline, 6 months, and 1 year (68% vs 44%, P < .001; 86% vs 76%, P = .002; 84% vs 69%, P < .001; respectively) and ECG monitoring at baseline and 1 year (76% vs 58%; 96% vs 75%, P < .001, respectively). There was no difference in TSH monitoring at baseline, 6 months, and 1 year (55% vs 49%, P = not significant [NS]; 74% vs 70%, P = NS; 68% vs 64%, P = NS; respectively).

Pharmacogenetics and oral antithrombotic drugs.

Warfarin and other oral vitamin K antagonists (VKAs) have been the primary pharmacologic options with well-established efficacy data in high-risk patient populations. Warfarin dose requirements to achieve therapeutic anticoagulation are highly variable. This variability in response results in increased risk for adverse events, including thromboembolism and bleeding. Genetic variants in CYP2C9 and VKORC1 have been identified and shown to explain some of the variability in warfarin response. Prospective trials suggest that incorporation of genotype results in faster time to therapeutic range than without; however, whether these improvements result in improved clinical outcomes is unclear. The target-specific anticoagulants are alternatives to warfarin and do not require laboratory monitoring. Some pharmacogenetic variation in their clinical response may exist as well. Ongoing trials will provide a clearer picture of whether genotype-based warfarin dosing improves outcomes and may, therefore, subsequently be compared with the target-specific agents.

Impact of a clinical pharmacy research team on pharmacy resident research.

PURPOSE A successful initiative by Kaiser Permanente Colorado (KPCO) to support pharmacy resident research projects and the publication of project results in peer-reviewed journals is described. METHODS An observational study was conducted to evaluate the publication rates for resident research projects before and after the KPCO pharmacy department established a Clinical Pharmacy Research Team (CPRT) to encourage and enable resident research. All projects presented by KPCO residents at the annual Western States Conference (WSC) for Pharmacy Residents, Fellows, and Preceptors in the 10 years before the CPRT was established (1994-2004, the pre-CPRT group) and the 7 years after CPRT implementation (2005-11, the CPRT group) were included in the analysis. The proportions of presented projects in the two groups that were subsequently published in peer-reviewed journals were compared, with further analysis of project characteristics and publication outcomes. RESULTS A total of 66 resident research projects were presented at the WSC during the study period: 30 (45.5%) and 36 (54.5%) in the pre-CPRT and CPRT groups, respectively. Overall, 45 projects (68.2%) were published in peer-reviewed journals. Projects in the CPRT group were significantly more likely than those in the pre-CPRT group to result in peer-reviewed publications (publication rate, 86.1% versus 46.7%; p = 0.001). The median times from residency completion to publication in the pre-CPRT and CPRT groups were 30 and 23 months, respectively (p = 0.08). CONCLUSION An increase in the proportion of pharmacy resident research projects published in peer-reviewed journals was observed after the CPRT was established.

Thrombophilia testing patterns amongst patients with acute venous thromboembolism

BACKGROUND Thrombophilia testing has limited value in determining the selection and duration of anticoagulation therapy for venous thromboembolism (VTE), yet is commonly performed. This study describes the patterns and appropriateness of thrombophilia testing in a large cohort of patients with acute VTE. MATERIALS AND METHODS This was a retrospective study of a random sample of patients with a validated diagnosis of acute VTE diagnosed between January 1, 2004 and December 31, 2010. Events were identified from administrative data and verified via manual review. Patients were grouped by thrombophilia testing status and compared on patient characteristics and thrombophilia testing results and appropriateness. RESULTS Of 1314 patients with validated VTE, 315 (24%) underwent thrombophilia testing, 62 (20%) of whom had ≥ 1 positive test. Tested patients were younger and more likely to have had a family history of VTE. Factor V Leiden (17%) and prothrombin G20210A mutation (4%) were the most commonly detected thrombophilias. Only 31 (10%) of tested patients met eligibility criteria for thrombophilia testing (i.e., at least one strong thrombophilic risk factor present) and were tested at least 90 days following unprovoked index VTE. CONCLUSIONS Thrombophilia is commonly evaluated in patients without a clear indication for testing and during times where results may be unreliable. Future studies are needed to assess interventions aimed at reducing inappropriate thrombophilia testing without adversely affecting patient outcomes.

An Examination of the Association Between Therapeutic Anticoagulation Control and Glycemic Control for Patients with Diabetes on Oral Anticoagulation Therapy

Background: Observations by pharmacists monitoring anticoagulated patients suggested that patients with diabetes often require more frequent international normalized ratio (INR) monitoring than patients without diabetes. The purpose of this investigation was to examine the association between glycemic control and therapeutic anticoagulation control.Methods: Patients with diabetes who were receiving warfarin therapy monitored by the Kaiser Permanente of Colorado Clinical Pharmacy Anticoagulation Service were eligible for inclusion. Patients were included if they had a diagnosis of diabetes mellitus type 1 or 2, aged ≥18 years, and had initiated anticoagulant therapy ≥120 days before their most recent hemoglobin A1C measurement. The primary outcome was the correlation between hemoglobin A1C value and percent of time in the patient-specific INR range. Multivariate analysis was undertaken to regress percent of time in INR range on an A1C value ≥8.0 while adjusting for other possible explanatory variables.Results: A total of 911 patients with diabetes were included in the study. Subjects with an A1C value ≥8.0 had similar characteristics as those subjects with an A1C value < 8.0. Correlation analysis revealed no relationship between percent of time spent in INR range and A1C value (Spearman Correlation Coefficient = 0.012, p = 0.805). Multivariate analysis revealed no relationship between percent of time spent in INR range and A1C value ≥8.0 (Odds Ratio = 1.00; 95% Confidence Interval = 0.99, 1.01) when adjusting for possible explanatory variables.Conclusions: For patients with diabetes on warfarin anticoagulation therapy, there is no association between glycemic control and therapeutic anticoagulation control. However, anticoagulation therapy providers should manage these patients with the same diligence and care as patients without diabetes.

Executive leadership: Critical to developing clinical pharmacy programs and services.

Few clinical pharmacy service programs were ever “gifted” to any pharmacy department. In reality, each program was evaluated on its merits and costs. Ultimately, business cases were developed and justified before authorization was given. So, why are some departments seemingly better able than

A descriptive evaluation of warfarin use in patients with pulmonary arterial hypertension

INTRODUCTION Although warfarin is often recommended for pulmonary arterial hypertension (PAH) management to mitigate thrombotic risk and improve survival, limited information exists to guide anticoagulation therapy. The purpose of this study was to compare and contrast warfarin therapy monitoring requirements and outcomes in patients with PAH and atrial fibrillation (AF) receiving long-term anticoagulation. MATERIALS AND METHODS Patients initiated on warfarin for PAH between January 1, 2000 and December 31, 2008 were matched by warfarin initiation date (±90 days), age (±5 years), chronic disease score (±1 points), and sex to patients initiated for AF. The primary study endpoint was frequency of INR monitoring per 30 days of observation. Secondary endpoints included indicators of INR control and warfarin-related adverse events. RESULTS AND CONCLUSION A total of 84 patients were included - 18 and 66 in the PAH and AF groups, respectively. Patients with PAH had a higher median rate of INR measurements per 30 days compared to patients with AF (median=2.0, interquartile range [IQR]=1.5 - 2.3 vs. median=1.6, IQR=1.3 - 2.0, p=0.046). There were no differences between groups with respect to percent of INR measurements in range, overall time in therapeutic range (TTR), or warfarin-related adverse events (all p>0.05). Study results suggest that patients with PAH may be more difficult to manage as seen through more frequent INR monitoring. Potential management difficulties did not translate to a lower performance on indicators of INR control or increased risk of warfarin-related adverse events.