Search

Plasma renin activity (PRA) is a predictive biomarker of blood pressure (BP) response to antihypertensives in European–American hypertensive patients. We aimed to identify the metabolic signatures of baseline PRA and the linkages with BP response to β-blockers and thiazides. Using data from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) trial, multivariable linear regression adjusting for age, sex and baseline systolic-BP (SBP) was performed on European–American individuals treated with metoprolol (n = 198) and chlorthalidone (n = 181), to test associations between 856 metabolites and baseline PRA. Metabolites with a false discovery rate (FDR) < 0.05 or p < 0.01 were tested for replication in 463 European–American individuals treated with atenolol or hydrochlorothiazide. Replicated metabolites were then tested for validation based on the directionality of association with BP response. Sixty-three metabolites were associated with baseline PRA, of which nine, including six lipids, were replicated. Of those replicated, two metabolites associated with higher baseline PRA were validated: caprate was associated with greater metoprolol SBP response (β = −1.7 ± 0.6, p = 0.006) and sphingosine-1-phosphate was associated with reduced hydrochlorothiazide SBP response (β = 7.6 ± 2.8, p = 0.007). These metabolites are clustered with metabolites involved in sphingolipid, phospholipid, and purine metabolic pathways. The identified metabolic signatures provide insights into the mechanisms underlying BP response.

BACKGROUND Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS Using systematic-phased approach, PRA’s clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by –15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS PRA at the previously established 0.60–0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs. TRIAL REGISTRATION NCT01203852, NCT00246519, NCT00005520.

Legacy data show that ∼40% of children with acute lymphoblastic leukemia (ALL) were cured with limited antimetabolite-based chemotherapy regimens. However, identifying patients with very-low-risk (VLR) ALL remains imprecise. Patients selected based on a combination of presenting features and a minimal residual disease (MRD) level

Only half of patients with hypertension (HTN) respond to any given antihypertensive medication. Heterogeneity in pathophysiologic pathways underlying HTN is a major contributor. Personalizing antihypertensive therapy could improve blood pressure (BP) reduction. The objective of this study was to assess the effect of pragmatic implementation of a personalized plasma renin activity (PRA)‐based smartphone app on improving BP reduction. Patients with untreated or treated but uncontrolled HTN were recruited. BP and PRA were measured at baseline with final BP measured at 6 months. Patient’s information was entered into the app and treatment recommendations were returned. Clinicians were at liberty to follow or disregard the app’s recommendations. BP levels and percent BP control among patients whose clinicians did and did not follow the app’s recommendations were compared using independent t‐test and Fisher’s exact test, respectively. Twenty‐nine European American patients were included (38% women) with mean age of 52 ± 9 years and median PRA of 1.3 ng/mL/hr (interquartile range 0.5–3.1 ng/mL/hr). Participants whose clinicians followed the app’s recommendations (n = 16, 55%) as compared with those whose clinicians did not (n = 13, 45%), had a greater reduction in 6‐month systolic BP (−15 ± 21 vs. −3 ± 21 mm Hg; adjusted‐P = 0.1) and diastolic BP (−8 ± 8 vs. −1 ± 8 mm Hg; adjusted‐P = 0.04). BP control at 6 months tended to be greater among patients whose clinicians accepted the app’s recommendations vs. those whose clinicians did not (63% vs. 23%, P = 0.06). This pilot study demonstrates that acceptance of the app’s recommendations was associated with a greater BP reduction. Future studies to confirm these pilot findings are warranted.

Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure (BP). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4-week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP: -9.6 ± 8.0 vs -5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP: -18.7 ± 13.8 vs -13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (-17.0 ± 13.2/-9.6 ± 7.5 vs -7.0 ± 18.6/-6.7 ± 9.3 mm Hg, adjusted P

Background: About half of patients with hypertension (HTN) respond to any given antihypertensive drug. Discordance in pathophysiologic pathways underlying HTN and anti-HTN mechanism of action are major contributors. Personalizing anti-HTN therapy could optimize blood pressure (BP) control. The objective of OPTI-BP was to assess the pragmatic implementation of a smartphone app used to guide physiologically optimal HTN treatment based on plasma renin activity (PRA). Methods: The smartphone app (PRA-HTN) and PRA testing was implemented in three primary care clinics. Patients with untreated or treated but uncontrolled HTN, aged 18-65 years, were recruited. BP and PRA were measured at baseline (and again as often as needed) with final BP measured at 6 months. PRA level and current anti-HTN meds are entered into the app and recommendations to optimize volume- and RAS blocking meds returned. Providers were at liberty to follow or disregard app recommendations. The primary outcome was BP change from baseline to 6 months. Independent t-test was used to compare BP responses of patients whose clinicians followed the app recommendations vs. those who did not. A multivariable linear regression analysis adjusting for baseline BP, age and sex was also conducted. Results: This analysis includes 29 white patients, including 11 (37.9%) women, with a mean age of 52 ± 9 years and a median baseline PRA of 1.3 ng/mL/hr (IQR 0.5-3.1 ng/mL/hr). Mean baseline BP between patients whose clinicians followed the app recommendations (n=16, 55%) vs. those who did not (n=13, 45%) was not statistically different ( P >0.05). After 6 months, the average BP change among patients whose clinicians followed the app recommendations was -14 ± 20/-7 ± 9 mmHg vs. -5 ± 21/-2 ± 9 mmHg among those who did not. In regression analysis, use of app recommended therapy was associated with greater mean BP difference of -13±8/-9±4 mmHg ( P =0.1/0.02). Conclusion: This pilot study demonstrates that PRA testing and implementation of recommendations from a smartphone app that utilizes PRA to optimize anti-HTN therapy was associated with good BP lowering among a relatively small cohort of patients. Future studies using larger sample sizes are warranted to confirm these preliminary findings.

Purpose : The purpose of this study was to compare clinical trials’ methodological quality between developing and developed countries, and its correlation with human development index. Data Sources : We systematically searched the PUBMED electronic database for published controlled clinical trials conducted in heart failure. Results were filtered using the “clinical trials” filter and dated from January 2009 to December 2013. Study Selection : From the 416 articles, 61 articles that met the selection criteria were selected. Each article was screened independently for inclusion by two independent raters. Data extraction : Out of the 61 included articles, 53 were from developed countries and only 8 were from developing countries. Each article was assessed for their quality by five independent raters using the JADAD quality scale. Results : Median quality score for developed countries was 3 (range 0-5), while for developing countries was 1.5 (range 0-4) (p-value 0.04). There is a statistically significant correlation between quality scores and the human development index (HDI) (rho= 0.275, p-value = 0.032). The only significant correlation between HDI indices and quality score was for education index (rho = 0.381, p-value = 0.003). Conclusions and Relevance : Our study indicated that there is a difference between the developing and the developed countries in terms of quantity and quality of clinical trials, mainly due to differences in the educational status. Based on that, we recommend to incorporate research in the curricula of the undergraduate medical education in developing countries and to initiate collaborative clinical research courses. Key-Words : Clinical trial quality, developing countries, developed countries, JADAD scale, human development index, heart failure.