Influence of Age on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage

Objective We assessed the influence of age on warfarin dose, percentage time in target range (PTTR), and risk of major hemorrhage. Design Warfarin users recruited into a large prospective inception cohort study were categorized into three age groups: young (younger than 50 yrs), middle aged (50–70 yrs), and elderly (older than 70 yrs). The influence of age on warfarin dose and PTTR was assessed using regression analysis; risk of major hemorrhage was assessed using proportional hazards analysis. Models were adjusted for demographic, clinical, and genetic factors. Setting Two outpatient anticoagulation clinics. Participants A total of 1498 anticoagulated patients. Outcomes Warfarin dose (mg/day), PTTR, major hemorrhage. Results Of the 1498 patients, 22.8% were young, 44.1% were middle aged, and 33.1% were elderly. After accounting for clinical and genetic factors, compared with young warfarin users, warfarin dose requirements were 10.6% lower among the middle aged and an additional 10.6% lower for the elderly. Compared with young patients, middle-aged and elderly patients spent more time in target international normalized ratio (INR) range (p<0.0001), despite having fewer INR assessments (p<0.0001). Compared with young warfarin users, absolute risk of hemorrhage was marginally higher among the middle aged (p=0.08) and significantly higher among the elderly (p=0.016). Compared with young warfarin users, after adjustment, the relative risk of hemorrhage increased by 31% for each age category (p=0.026). Conclusions In a real-world setting, despite achieving better anticoagulation control, elderly patients had a higher risk of major hemorrhagic events. As the population ages and the candidacy for oral anticoagulation increases, strategies that mitigate the elevated risk of hemorrhage need to be identified

Prevalence and Correlates of Low Medication Adherence in Apparent Treatment-Resistant Hypertension

Low medication adherence may explain part of the high prevalence of apparent treatment-resistant hypertension (aTRH). The authors assessed medication adherence and aTRH among 4026 participants taking ≥3 classes of antihypertensive medication in the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) trial using the 4-item Morisky Medication Adherence Scale (MMAS). Low adherence was defined as an MMAS score ≥2. Overall, 66% of participants taking ≥3 classes of antihypertensive medication had aTRH. Perfect adherence on the MMAS was reported by 67.8% and 70.9% of participants with and without aTRH, respectively. Low adherence was present among 8.1% of participants with aTRH and 5.0% of those without aTRH (P<.001). Among those with aTRH, female sex, residence outside the US stroke belt or stroke buckle, physical inactivity, elevated depressive symptoms, and a history of coronary heart disease were associated with low adherence. In the current study, a small percentage of participants with aTRH had low adherence

Genetic Contributors of Incident Stroke in 10,700 African Americans with Hypertension: A Meta-Analysis from the Genetics of Hypertension Associated Treatments and Reasons for Geographic and Racial Differences in Stroke Studies

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals. Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance. Results: We identified 10 statistically significant (p \u3c 5.00E-08) and 90 additional suggestive (p \u3c 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 (LINC01443-LOC644669). Additional variants of interest were located in or near the COL12A1, SNTG1, PCDH7, TMTC1, and NTM genes. Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p-value \u3c5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately. Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing

PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs

Pathway analysis of genome-wide data improves warfarin dose prediction

Background: Many genome-wide association studies focus on associating single loci with target phenotypes. However, in the setting of rare variation, accumulating sufficient samples to assess these associations can be difficult. Moreover, multiple variations in a gene or a set of genes within a pathway may all contribute to the phenotype, suggesting that the aggregation of variations found over the gene or pathway may be useful for improving the power to detect associations. Results: Here, we present a method for aggregating single nucleotide polymorphisms (SNPs) along biologically relevant pathways in order to seek genetic associations with phenotypes. Our method uses all available genetic variants and does not remove those in linkage disequilibrium (LD). Instead, it uses a novel SNP weighting scheme to down-weight the contributions of correlated SNPs. We apply our method to three cohorts of patients taking warfarin: two European descent cohorts and an African American cohort. Although the clinical covariates and key pharmacogenetic loci for warfarin have been characterized, our association metric identifies a significant association with mutations distributed throughout the pathway of warfarin metabolism. We improve dose prediction after using all known clinical covariates and pharmacogenetic variants in VKORC1 and CYP2C9. In particular, we find that at least 1% of the missing heritability in warfarin dose may be due to the aggregated effects of variations in the warfarin metabolic pathway, even though the SNPs do not individually show a significant association. Conclusions: Our method allows researchers to study aggregative SNP effects in an unbiased manner by not preselecting SNPs. It retains all the available information by accounting for LD-structure through weighting, which eliminates the need for LD pruning

Multi-site investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy

CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes which are both related to CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions. This article is protected by copyright

Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection

Purpose Genotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19. Methods We assembled a cohort of patients from eight sites performing CYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug–genotype interaction and time to receiving a CYP2C19 substrate. Results Nine thousand one hundred ninety-one genotyped patients (17% nonwhite) with a mean age of 68 ± 3 years were evaluated; 4701 (51%) of patients received two or more CYP2C19 substrates and 3835 (42%) of patients had a drug–genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25 ± 10 days. Conclusions More than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient’s lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed

Cost-effectiveness of CYP2C19-guided antiplatelet therapy in patients with acute coronary syndrome and percutaneous coronary intervention informed by real-world data

Current guidelines recommend dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitors following percutaneous coronary intervention (PCI). CYP2C19 genotype can guide DAPT selection, prescribing ticagrelor or prasugrel for loss-of-function (LOF) allele carriers (genotype-guided escalation). Cost-effectiveness analyses (CEA) are traditionally grounded in clinical trial data. We conduct a CEA using real-world data using a 1-year decision-analytic model comparing primary strategies: universal empiric clopidogrel (base case), universal ticagrelor, and genotype-guided escalation. We also explore secondary strategies commonly implemented in practice, wherein all patients are prescribed ticagrelor for 30 days post PCI. After 30 days, all patients are switched to clopidogrel irrespective of genotype (nonguided de-escalation) or to clopidogrel only if patients do not harbor an LOF allele (genotype-guided de-escalation). Compared with universal clopidogrel, both universal ticagrelor and genotype-guided escalation were superior with improvement in quality-adjusted life years (QALY’s). Only genotype-guided escalation was cost-effective ($42,365/QALY) and demonstrated the highest probability of being cost-effective across conventional willingness-to-pay thresholds. In the secondary analysis, compared with the nonguided de-escalation strategy, although genotype-guided de-escalation and universal ticagrelor were more effective, with ICER of$188,680/QALY and $678,215/QALY, respectively, they were not cost-effective. CYP2C19 genotype-guided antiplatelet prescribing is cost-effective compared with either universal clopidogrel or universal ticagrelor using real-world implementation data. The secondary analysis suggests genotype-guided and nonguided de-escalation may be viable strategies, needing further evaluation