Heterogeneity in Blood Pressure Response to 4 Antihypertensive Drugs: A Randomized Clinical Trial.

Importance: Hypertension is the leading risk factor for premature death worldwide. Multiple blood pressure-lowering therapies are available but the potential for maximizing benefit by personalized targeting of drug classes is unknown. Objective: To investigate and quantify the potential for targeting specific drugs to specific individuals to maximize blood pressure effects. Design, Setting, and Participants: A randomized, double-blind, repeated crossover trial in men and women with grade 1 hypertension at low risk for cardiovascular events at an outpatient research clinic in Sweden. Mixed-effects models were used to assess the extent to which individuals responded better to one treatment than another and to estimate the additional blood pressure lowering achievable by personalized treatment. Interventions: Each participant was scheduled for treatment in random order with 4 different classes of blood pressure-lowering drugs (lisinopril [angiotensin-converting enzyme inhibitor], candesartan [angiotensin-receptor blocker], hydrochlorothiazide [thiazide], and amlodipine [calcium channel blocker]), with repeated treatments for 2 classes. Main Outcomes and Measures: Ambulatory daytime systolic blood pressure, measured at the end of each treatment period. Results: There were 1468 completed treatment periods (median length, 56 days) recorded in 270 of the 280 randomized participants (54% men; mean age, 64 years). The blood pressure response to different treatments varied considerably between individuals (P < .001), specifically for the choices of lisinopril vs hydrochlorothiazide, lisinopril vs amlodipine, candesartan vs hydrochlorothiazide, and candesartan vs amlodipine. Large differences were excluded for the choices of lisinopril vs candesartan and hydrochlorothiazide vs amlodipine. On average, personalized treatment had the potential to provide an additional 4.4 mm Hg-lower systolic blood pressure. Conclusions and Relevance: These data reveal substantial heterogeneity in blood pressure response to drug therapy for hypertension, findings that may have implications for personalized therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02774460.

The Precision HYpertenSIon Care (PHYSIC) study: a double-blind, randomized, repeated cross-over study.

High blood pressure is the leading risk factor for premature deaths and a major cost to societies worldwide. Effective blood pressure-lowering drugs are available, but patient adherence to them is low, likely partly due to side effects. To identify patient-specific differences in treatment effects, a repeated cross-over design, where the same treatment contrasts are repeated within each patient, is needed. Such designs have been surprisingly rarely used, given the current focus on precision medicine. The Precision HYpertenSIon Care (PHYSIC) study aims to investigate if there is a consistent between-person variation in blood pressure response to the common blood pressure-lowering drug classes of a clinically relevant magnitude, given the within-person variation in blood pressure. The study will also investigate the between-person variation in side effects of the drugs. In a double-blind, randomized, repeated cross-over trial, 300 patients with mild hypertension will be treated with four blood pressure-lowering drugs (candesartan, lisinopril, amlodipine, and hydrochlorothiazide) in monotherapy, with two of the drugs repeated for each patient. If the study indicates that there is a potential for precision hypertension care, the most promising predictors of blood pressure and side effect response to the drugs will be explored, as will the potential for development of a biomarker panel to rank the suitability of blood pressure-lowering drug classes for individual patients in terms of anticipated blood pressure effects and side effects, with the ultimate goal to maximize adherence. The study follows a protocol pre-registered at ClinicalTrials.gov with the identifier NCT02774460.

A comparison of three different methods to determine arterial compliance in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

BACKGROUND: Several different techniques to evaluate arterial compliance have been described but have not been simultaneously tested in a large-scale, population-based setting. This study aimed to evaluate the feasibility and relation to cardiac risk of three of these techniques in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study. METHODS AND RESULTS: In the population-based PIVUS study (1016 participants aged 70), assessment of arterial distensibility by ultrasound in the carotid artery, by pulse wave analysis (augmentation index) and the stroke volume to pulse pressure ratio by echocardiography were successfully employed in 86, 92, 91 and 77% of the sample, respectively. All three indices of arterial compliance were inter-related (r = 0.19-0.34, P < 0.0001 for all). Although all three indices were significantly related to the Framingham risk score (r = 0.12-0.32, P = 0.0005-0.0001), only carotid artery distensibility and the stroke volume to pulse pressure ratio were independently associated with the Framingham score in multiple regression analysis (P < 0.0001 for both). CONCLUSIONS: All three indices to evaluate arterial compliance were feasible to obtain in a general elderly population and were inter-related. Although all of the techniques were correlated to Framingham risk score, only carotid artery distensibility and the stroke volume to pulse pressure ratio were independently related to coronary risk, suggesting complementary use of these two indices of arterial compliance in the future.

A comparison of three different methods to evaluate endothelium-dependent vasodilation in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

BACKGROUND: Three different techniques to evaluate endothelium-dependent vasodilation in the peripheral circulation have been described but not simultaneously tested in a large-scale population-based setting. This study aimed to evaluate the feasibility and usefulness of these techniques in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. METHODS AND RESULTS: In the population-based PIVUS study (1016 subjects aged 70 years), the invasive forearm technique with acetylcholine given in the brachial artery (EDV), the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD), and the pulse wave analysis method with beta-2-agonist (terbutaline) provocation were successfully used in 87%, 97%, and 86% of the sample, respectively. The results of EDV and pulse wave analysis were interrelated (r=0.12, P=0.0013), but no relationships were found with FMD measurements. All 3 techniques were correlated to the Framingham risk score (r=0.10 to 0.12, P=0.0007 to 0.001). In multiple regression analysis, however, only EDV and FMD were independently associated with the Framingham score. CONCLUSIONS: All 3 evaluated techniques were feasible to perform in a general elderly population. Both the invasive forearm technique and FMD were independently associated with increased coronary risk, suggesting that information on conduit artery and resistance artery endothelial function carry different, but important, information in the elderly. If the invasive technique cannot be used, the pulse wave based technique is an alternative.