Adam P. Bress

Generalizability of SPRINT Results to the U.S. Adult Population

BACKGROUND In SPRINT (Systolic Blood Pressure Intervention Trial), a systolic blood pressure (SBP) goal of <120 mm Hg resulted in lower cardiovascular disease (CVD) risk compared with an SBP goal of <140 mm Hg. OBJECTIVES The purpose of this study was to estimate the prevalence, number, and characteristics of U.S. adults meeting SPRINT eligibility criteria and determine the broader population to whom SPRINT could be generalized. METHODS We conducted a cross-sectional, population-based study using data from the National Health and Nutrition Examination Survey, 2007 to 2012. The SPRINT inclusion criteria were age ≥50 years, SBP 130 to 180 mm Hg depending on the number of antihypertensive medication classes being taken, and high CVD risk (history of coronary heart disease, estimated glomerular filtration rate of 20 to 59 ml/min/1.73 m(2), 10-year CVD risk ≥15%, or age ≥75 years). Exclusion criteria were diabetes, history of stroke, >1 g in 24 h of proteinuria daily, heart failure, estimated glomerular filtration rate <20 ml/min/1.73 m(2), or receiving dialysis. Treated hypertension was defined by self-reported use of medication to lower blood pressure with ≥1 class of antihypertensive medication identified through a pill bottle review. RESULTS Overall, 7.6% (95% confidence interval [CI]: 7.0% to 8.3%) or 16.8 million (95% CI: 15.7 to 17.8 million) U.S. adults, and 16.7% (95% CI: 15.2% to 18.3%) or 8.2 million (95% CI: 7.6 to 8.8 million) adults with treated hypertension met the SPRINT eligibility criteria. Among both the overall U.S. population and adults with treated hypertension, the percentage meeting SPRINT eligibility criteria increased with older age, was higher among males than females, and was higher among non-Hispanic whites compared with non-Hispanic blacks or Hispanics. Of U.S. adults eligible for SPRINT, 51.0% (95% CI: 47.8% to 54.1%) or 8.6 million (95% CI: 8.0 to 9.1 million) were not treated for hypertension. CONCLUSIONS A substantial percentage of U.S. adults meet the eligibility criteria for SPRINT.

Poor warfarin dose prediction with pharmacogenetic algorithms that exclude genotypes important for African Americans.

Objectives Recent clinical trial data cast doubt on the utility of genotype-guided warfarin dosing, specifically showing worse dosing with a pharmacogenetic versus clinical dosing algorithm in African Americans. However, many genotypes important in African Americans were not accounted for. We aimed to determine whether omission of the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G>A genotype affects performance of dosing algorithms in African Americans. Methods In a cohort of 274 warfarin-treated African Americans, we examined the association between the CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*11 alleles and rs12777823 G>A genotype and warfarin dose prediction error with pharmacogenetic algorithms used in clinical trials. Results The http://www.warfarindosing.org algorithm overestimated doses by a median (interquartile range) of 1.2 (0.02–2.6) mg/day in rs12777823 heterozygotes (P<0.001 for predicted vs. observed dose), 2.0 (0.6–2.8) mg/day in rs12777823 variant homozygotes (P=0.004), and 2.2 (0.5–2.9) mg/day in carriers of a CYP2C9 variant (P<0.001). The International Warfarin Pharmacogenetics Consortium (IWPC) algorithm underdosed warfarin by 0.8 (−2.3 to 0.4) mg/day for patients with the rs12777823 GG genotype (P<0.001) and overdosed warfarin by 0.7 (−0.4 to 1.9) mg/day in carriers of a variant CYP2C9 allele (P=0.04). Modifying the http://www.warfarindosing.org algorithm to adjust for variants important in African Americans led to better dose prediction than either the original http://www.warfarindosing.org (P<0.01) or IWPC (P<0.01) algorithm. Conclusion These data suggest that, when providing genotype-guided warfarin dosing, failure to account for variants important in African Americans leads to significant dosing error in this population.

Feasibility of implementing a comprehensive warfarin pharmacogenetics service.

To determine the procedural feasibility of a pharmacist‐led interdisciplinary service for providing genotype‐guided warfarin dosing for hospitalized patients newly starting warfarin.

Cost-Effectiveness of Sacubitril-Valsartan Combination Therapy Compared With Enalapril for the Treatment of Heart Failure With Reduced Ejection Fraction.

OBJECTIVES The objective of this study was to determine the cost-effectiveness and cost per quality-adjusted life year (QALY) gained of sacubitril-valsartan relative to enalapril for treatment of heart failure with reduced ejection fraction (HFrEF). BACKGROUND Compared with enalapril, combination angiotensin receptor-neprilysin inhibition (ARNI), as is found in sacubitril-valsartan, reduces cardiovascular death and heart failure hospitalization rates in patients with HFrEF. METHODS Using a Markov model, costs, effects, and cost-effectiveness were estimated for sacubitril-valsartan and enalapril therapies for the treatment of HFrEF. Patients were 60 years of age at model entry and were modeled over a lifetime (40 years) from a third-party payer perspective. Clinical probabilities were derived predominantly from PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). All costs and effects were discounted at a 3% rate annually and are presented in 2015 U.S. dollars. RESULTS In the base case, sacubitril-valsartan, compared with enalapril, was more costly (

Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic–Americans and African–Americans

60,391 vs.

The effect of pharmacogenetic profiling with a clinical decision support tool on healthcare resource utilization and estimated costs in the elderly exposed to polypharmacy

21,758) and more effective (6.49 vs. 5.74 QALYs) over a lifetime. The cost-effectiveness of sacubitril-valsartan was highly dependent on duration of treatment, ranging from

Role of cytochrome P450 genotype in the steps toward personalized drug therapy

249,411 per QALY at 3 years to

Evaluation of Dabigatran Bleeding Adverse Reaction Reports in the FDA Adverse Event Reporting System during the First Year of Approval

50,959 per QALY gained over a lifetime. CONCLUSIONS Sacubitril-valsartan may be a cost-effective treatment option depending on the willingness-to-pay threshold. Future investigations should incorporate real-world evidence with sacubitril-valsartan to further inform decision making.

Effect of intensiveversus standard blood pressure treatment according to baseline prediabetes status: A post hoc analysis of a randomized trial

AIM The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. PATIENTS & METHODS The following were assessed in a cohort of 260 African-Americans and 53 Hispanic-Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. RESULTS Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs 0.18; p < 0.05) allele frequencies were higher in Hispanic-Americans compared with African-Americans. Multiple regression analysis in the Hispanic-American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African-Americans after adjusting for known genetic and clinical predictors. CONCLUSION In our cohort of inner-city Hispanic-Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic-Americans.

Trends in Antihypertensive Medication Discontinuation and Low Adherence Among Medicare Beneficiaries Initiating Treatment From 2007 to 2012

Abstract Objective: To compare healthcare resource utilization (HRU) and clinical decision-making for elderly patients based on cytochrome P450 (CYP) pharmacogenetic testing and the use of a comprehensive medication management clinical decision support tool (CDST), to a cohort of similar non-tested patients. Methods: An observational study compared a prospective cohort of patients ≥65 years subjected to pharmacogenetic testing to a propensity score (PS) matched historical cohort of untested patients in a claims database. Patients had a prescribed medication or dose change of at least one of 61 oral drugs or combinations of ≥3 drugs at enrollment. Four-month HRU outcomes examined included hospitalizations, emergency department (ED) and outpatient visits and provider acceptance of test recommendations. Costs were estimated using national data sources. Results: There were 205 tested patients PS matched to 820 untested patients. Hospitalization rate was 9.8% in the tested group vs 16.1% in the untested group (RR = 0.61, 95% CI = 0.39–0.95, p = 0.027), ED visit rate was 4.4% in the tested group vs 15.4% in the untested group (RR = 0.29, 95% CI = 0.15–0.55, p = 0.0002) and outpatient visit rate was 71.7% in the tested group vs 36.5% in the untested group (RR = 1.97, 95% CI = 1.74–2.23, p < 0.0001). The rate of overall HRU was 72.2% in the tested group vs 49.0% in the untested group (RR = 1.47, 95% CI = 1.32–1.64, p < 0.0001). Potential cost savings were estimated at