Abstract
Thiazide diuretics (TDs) are a cost‐effective first‐line therapy for uncomplicated hypertension; however, they are less prescribed than other options. The authors aimed to assess the noninferiority of TDs relative to different classes of antihypertensive medications in relation to central blood pressure. Cross‐sectional data from the Quebec CARTaGENE project was used. Nondiabetic hypertensive participants on monotherapy for hypertension were studied. Separate adjusted models were constructed to establish noninferiority of TDs to non‐TD antihypertensive medications for central blood pressure measurements. Models included a set of potential confounders. Of the 1194 hypertensive participants, 7.4% were taking TDs. We found that TDs were comparable with non‐TD antihypertensive medications for central systolic blood pressure (adjusted regression coefficient, 0.45; 95% confidence interval, −1.61 to 2.50). No differences in other central measurements were noted. The results provide additional support that TDs are at least as effective as other first‐line medications for treating uncomplicated hypertension.
Elevated blood pressure (BP) is a well‐known predictor of cardiovascular risk and mortality and lowering BP is an effective means of reducing cardiovascular events.1, 2 Although lifestyle modification is important in the management of hypertension, most hypertensive patients require some level of pharmacologic treatment.3 The use of antihypertensive medication has remarkably increased in the past years. A large‐scale national survey documented that 77% of US adults with hypertension used at least one antihypertensive medication.4 In Canada, the implementation of the Canadian Hypertension Education Program (CHEP), which is responsible for the generation of the hypertension guidelines in Canada and their annual update, has resulted in improved diagnosis and management of hypertension in Canada.5, 6 In adults with hypertension without compelling indications for specific agents, existing guidelines emphasize that thiazide diuretics (TDs), when used as monotherapy, are as effective as calcium channel blockers (CCBs), angiotensin‐converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs), in lowering BP and preventing cardiovascular and renal endpoints.2, 7
Some studies have shown measurements of central systolic BP (cSBP) and central pulse pressure (cPP) to be better predictors of target organ damage and cardiovascular disease than peripheral (brachial) systolic BP (pSBP) or peripheral pulse pressure (pPP).8, 9 When compared with peripheral BP (pBP), central BP (cBP) offers a more accurate estimation of the load imposed on the aorta and the left ventricle, and, in turn, of the overall vascular damage and prognosis.10, 11 cBP can be measured noninvasively using pulse wave analysis (PWA), a technique based on applanation tonometry of the radial artery. PWA provides additional information, in particular the calculation of the augmentation index (AIx).12 AIx represents wave reflection, and an indirect measure of arterial stiffness.
In this study, we aimed to assess the noninferiority of TDs relative to different classes of antihypertensive medications in relation to cBP and AIx.
Material and Methods
The CARTaGENE Biobank
The CARTaGENE (CaG) is a large ongoing prospective health study intended to investigate modifiable environmental and lifestyle factors and the genomic determinants of chronic diseases.13 The CaG baseline assessment survey was conducted from July 2009 to October 2010 in a random sample of the adult population of the province of Quebec, aged between 40 and 69 years, from four metropolitan areas in the province (Montreal, Quebec, Sherbrooke, and Saguenay). Specific details regarding the survey sampling design and methodology have previously been described.13 A total of 19,995 men and women were enrolled, representing 1% of the Quebec population of the specific age group. All participants provided informed consent.
Survey participants completed detailed self‐administered and interviewer‐administered health questionnaires covering different areas of health and lifestyle habits. Participants also underwent noninvasive physical measurements of health indices, including anthropometric measurements, pBP, and cBP. Biochemical analyses were performed in one central laboratory and included measurements of circulating glucose, total cholesterol, high‐density lipoprotein cholesterol (HDL), and triglyceride levels.
Our main analysis was restricted to nondiabetic hypertensive participants in CaG taking monotherapy for uncomplicated hypertension and with both pBP and cBP measurements completed. Individuals with a history of diabetes were excluded on the basis of self‐reported diagnosis.
Medication Use Assessment
CaG participants were asked to bring containers of all their current prescription medications. Interviewers recorded the product names based on labels or verbally as reported by participants if containers were not available. We classified antihypertensive medications within the following categories: ACE inhibitors, ARBs, β‐blockers (BBs), CCBs, TDs, and other antihypertensive medications (including diuretics [excluding TDs], antiadrenergic agents, and agents acting on the renin‐angiotensin system [excluding ACE inhibitors and ARBs]). Participants who reported using only one active ingredient were defined as receiving monotherapy.
Hypertension Assessment and BP Measurements
Hypertension was considered in cases of a positive response to the question “Has a doctor ever told you that you had high blood pressure or hypertension?” Peripheral BP was measured in triplicate with an automated device using the oscillometric method (Omron IntelliSense Blood Pressure Monitor HEM‐907XL; Omron Healthcare, Inc, Lake Forest, IL); the mean of the three readings was recorded. Radial artery waveforms were recorded using applanation tonometry (SCOR‐Px SphygmoCor; AtCor Medical, Sydney, Australia). Previous studies have shown the validity of the derived central pressures and arterial waveforms with this system.14, 15 Specifically, the micromanometer records radial (peripheral) pressure waveforms, which are averaged and mathematically transformed using a generalized transfer function to derive an aortic (central) waveform.16 Mean arterial pressure (MAP), heart rate, and central AIx (cAIx) were also determined using the SphygmoCor software system.17, 18, 19
Covariates
A history of physician‐diagnosed stroke, myocardial infarction, chest pain, and renal disease was assessed by questionnaires. Participants who had been diagnosed with at least one of the above health conditions were classified as having one or more comorbidities. Body mass index (BMI) was classified into the following categories: normal/underweight (BMI <25 kg/m2), overweight (BMI between 25 and 30 kg/m2), and obese (BMI ≥30 kg/m2). The short version of the International Physical Activity Questionnaire (IPAQ)20 was used to categorize physical activity levels as low, moderate, or high. Alcohol intake was recorded as the average frequency of intake of any beverage (red or white wine, beer, spirit or liquor, and other kinds of alcohol) over the preceding 12 months and was divided into the categories of never drinking alcohol, once a week or less, and 2 to 3 times a week or more. Cigarette smoking was categorized as current (occasional or current daily use) or not smoking (past smokers and never smokers).
Statistical Analysis
Descriptive analysis included estimation of mean and median values, as well as standard deviations and interquartile ranges for continuous variables, and frequencies expressed as percentage for categorical variables. Multivariable linear models were employed to compare the mean values of cBP measurements across the classes of antihypertensive drugs taken as monotherapy. TDs were first compared with non‐TD antihypertensive medications (ie, ACE inhibitors, ARBs, BBs, CCBs, and other antihypertensive drugs). We then compared TDs with ACE inhibitors or ARBs, while excluding users of other antihypertensive drugs. The main objective of our analysis was to show noninferiority of the TDs against other antihypertensive medications in controlling cBP. Specifically, noninferiority would be demonstrated if the upper bound of the 95% confidence interval (CI) for the adjusted treatment effect β 1 was below the predefined margin, of Δ=3 mm Hg, for all cBP measurements.21 We obtained β 1 and its standard error (SE) by estimating separate multivariable models for each of the following outcomes: cSBP, central diastolic blood pressure (cDBP), MAP, cPP, and cAIx. All models included a prespecified set of potential confounders that were selected based on clinical knowledge. All models were adjusted for sex, age, BMI, physical activity, smoking status, alcohol intake, hypercholesterolemia (defined as a total serum cholesterol ≥6.5 mmol/L), comorbidities, and heart rate (beats per minute [bpm]). Model with AIx as the outcome was adjusted for height instead of BMI. Interactions between indicators of drug therapy and sex and between drug therapy and comorbidities were tested and included in the final multivariable model only if they were statistically significant (P<.05).
All statistical analyses were performed using R 2.13 (www.r-project.org) and SAS 9.2 (SAS Institute, Cary, NC).
Results
Among the 17,910 CaG participants with cBP measurements, 1194 were identified as nondiabetic participants with uncomplicated hypertension on antihypertensive monotherapy at the time of enrollment (Figure). Over 50% of these participants were treated with ACE inhibitors or ARBs. Only 7.4% of the participants were taking TDs (Table 1). Of those, 5.6% were taking hydrochlorothiazide (HCTZ) (n=67) and 1.8% were taking indapamide (n=21).
Figure 1.
Study flow chart.
Table 1.
Characteristics of the Study Population According to Antihypertensive Therapy
| Variables | Class of Antihypertensive Medicationsa | |||||
|---|---|---|---|---|---|---|
| ACE Inhibitors 268 (22.4) | ARBs 449 (37.6) | BBs 156 (13.1) | CCBs 187 (15.7) | Other 46 (3.9) | TDs 88 (7.4) | |
| Women | 104 (38.8)b | 219 (48.8)b | 76 (48.7)b | 106 (56.7) | 37 (80.4) | 56 (63.6) |
| Age, y | 57.4 (7.9) | 57.7 (7.5) | 56.7 (7.8) | 58.4 (7.3) | 56.5 (7.7) | 58.3 (7.2) |
| Height, m | 1.7 (0.1) | 1.7 (0.1) | 1.7 (0.1) | 1.7 (0.1) | 1.6 (0.1) | 1.6 (0.1) |
| BMI | ||||||
| Normal/underweight | 48 (19.4) | 81 (19.2) | 31 (22.6) | 39 (22.5) | 3 (7.5) | 16 (18.8) |
| Overweight | 119 (48) | 193 (45.8) | 51 (37.2) | 75 (43.4) | 24 (60.0) | 34 (40.0) |
| Obesity | 81 (32.7) | 147 (34.9) | 55 (40.1) | 59 (34.1) | 13 (32.5) | 35 (41.2) |
| IPAQ | ||||||
| Low | 36 (13.5) | 3 (1.1) | 193 (43.2) | 58 (37.2) | 11 (25.6) | 14 (16.5) |
| Moderate | 113 (42.3) | 76 (17) | 12 (2.7) | 63 (40.4) | 13 (30.2) | 34 (40.0) |
| High | 115 (43.1) | 166 (37.1) | 30 (19.2) | 5 (3.2) | 19 (44.2) | 37 (43.5) |
| Hypercholesterolemia | 25 (10) | 40 (9.8) | 23 (16.3) | 11 (6.4) | 5 (12.5) | 8 (9.9) |
| Comorbidities | ||||||
| Yes | 91 (34.0) | 124 (27.6) | 74 (47.4)b | 63 (33.7) | 20 (43.5) | 28 (31.8) |
| Current smoking status | ||||||
| Daily smoker | 34 (12.7) | 46 (10.3) | 18 (11.5) | 28 (15.1) | 8 (17.8) | 7 (8.0) |
| Occasional smoker | 12 (4.5) | 14 (3.1) | 4 (2.6) | 7 (3.8) | 1 (2.2) | 0 (0) |
| Past smoker | 114 (42.7) | 212 (47.6) | 69 (44.2) | 75 (40.3) | 15 (33.3) | 44 (50.6) |
| Never smoked | 107 (40.1) | 173 (38.9) | 65 (41.7) | 76 (40.9) | 21 (46.7) | 36 (41.4) |
| Current alcohol intake | ||||||
| ≥2–3 times a week | 135 (52.7) | 180 (42.2) | 61 (41.2) | 84 (48.3) | 17 (39.5) | 39 (45.9) |
| Once a week or less | 108 (42.2) | 213 (49.9) | 72 (48.6) | 78 (44.8) | 21 (48.8) | 41 (48.2) |
| Never | 13 (5.1) | 34 (8.0) | 15 (10.1) | 12 (6.9) | 5 (11.6) | 5 (5.9) |
| Peripheral SBP, mm Hg | 130.8 (14.1) | 131.1 (14.4) | 127.4 (15.0)b | 133.7 (13.5) | 130.9 (14.2) | 133.6 (15.8) |
| Peripheral DBP, mm Hg | 77.9 (9.5) | 77.4 (10.5) | 74.5 (10.2)b | 79.1 (9.6) | 80.4 (7.9) | 79.1 (10.6) |
| Heart rate, beats per min | 69.4 (10.8) | 69.7 (10.3) | 61.9 (9.6)b | 71.1 (11.0) | 72.4 (11.3) | 70.6 (11.4) |
| High BP onset | ||||||
| 1 y or less | 48 (18) | 74 (16.7) | 14 (9) | 27 (14.6) | 6 (13.0) | 12 (14.9) |
| 2–5 y | 98 (36.8) | 165 (37.2) | 35 (22.6) | 62 (33.5) | 17 (37.0) | 38 (43.7) |
| More than 5 y | 120 (45.1) | 205 (46.2) | 106 (68.4)b | 96 (51.9) | 23 (50.0) | 36 (41.4) |
Abbreviations: ACE, angiotensin‐converting enzyme; ARBs, angiotensin receptor blockers; BB, β‐blockers; BMI, body mass index; BP, blood pressure; CCBs, calcium channel blockers; DBP, diastolic blood pressure; IPAQ, International Physical Activity Questionnaire; Other, other antihypertensive agents, including diuretics (other than thiazides), antiadrenergic agents, agents acting on the renin‐angiotensin system (excluding ACE inhibitors and ARBs); SBP, systolic blood pressure; TD, thiazides diuretics. Values are expressed as number (percentage) or mean (standard deviation). aThe proportion of missing data was less than 10% for all variables. b P value <.05, based on chi‐square test for categorical and independent groups or t test for continuous variables for comparison between each drug class with TDs.
cBP means are shown for each antihypertensive group in Table 2. cSBP was 4.2 mm Hg higher in participants taking TDs when compared with BBs and 3.8 mm Hg higher when compared with ACE inhibitors, but in both cases the differences were not statistically significant. We found significant differences for cAIx in participants taking TDs than that of users of ACE inhibitors (P=.02). In addition, the average cDBP and MAP values for participants taking TDs were significantly higher than that of BB users (P=.01 in both cases).
Table 2.
Central Blood Pressure Measurements According to Antihypertensive Therapy
| Class of Antihypertensive Medications | ||||||
|---|---|---|---|---|---|---|
| ACE Inhibitors (n=268) | ARBs (n=449) | BBs (n=156) | CCBs (n=187) | Other (n=46) | TDs (n=88) | |
| Central SBP, mm Hg | 120.0 (118.3–121.7) | 120.6 (119.3–121.9) | 119.6 (117.3–121.9) | 123.5 (121.6–125.4) | 121.9 (118.3–125.5) | 123.8 (120.5–127.1) |
| Central DBP, mm Hg | 79.0 (77.8–80.2) | 78.5 (77.5–79.5) | 75.4 (73.8–77.0)a | 80.2 (78.8–81.6) | 81.5 (79.2–83.8) | 80.2 (78.0–82.4) |
| Central PP, mm Hg | 41.0 (39.7–42.3) | 42.1 (41.1–43.1) | 44.1 (42.3–45.9) | 43.2 (41.7–44.7) | 40.4 (36.9–43.9) | 43.6 (41.2–46.0) |
| MAP, mm Hg | 96.4 (95.1–97.7) | 96.6 (95.6–97.6) | 94.1 (92.3–95.9)a | 98.8 (97.3–100.3) | 99.1 (96.8–101.4) | 99.1 (96.7–101.5) |
| Central AIx, % | 25.8 (24.5–27.1)a | 27.2 (26.2–28.2) | 32.0 (30.3–33.7) | 28.4 (26.9–29.9) | 29.7 (26.8–32.6) | 30.1 (27.9–32.3) |
Abbreviations: ACE, angiotensin‐converting enzyme; AIx, augmentation index; ARBs, angiotensin receptor blockers; BBs, β‐blockers; CCBs, calcium channel blockers; DBP, diastolic blood pressure; MAP, mean arterial pressure; Other, other antihypertensive agents, including diuretics (other than thiazides), antiadrenergic agents, agents acting on the renin‐angiotensin system (excluding ACE inhibitors and ARBs); PP, pulse pressure; SBP, systolic blood pressure; TDs, thiazide diuretics. Values are expressed as mean (95% confidence interval). Student t test was performed to compare each drug class with TDs, and significant results are represented as a P<.05.
Table 3 summarizes the results of the multivariable linear regression analyses, with each row reporting the adjusted mean difference between users of TDs and non‐TDs and users of TDs and ACE inhibitors or ARBs, respectively, for each outcome. The use of TD monotherapy did not appear to be associated with different cBP measurements or AIx, as all upper 95% CIs were below the noninferiority margin previously defined (Table 3). Similarly, measures of cBP as well as AIx were comparable between participants taking TDs and those taking ACE inhibitors or ARBs. Interactions terms were not statistically significant and not reported.
Table 3.
Adjusted Regression Coefficients for Users of TD Monotherapy Compared With Users of Non‐TDs or ACE Inhibitors or ARBs
| Outcomes | Drug Groups: TD vs Non‐TD | Drug Groups: TD vs ACE Inhibitors/ARBs | ||||||
|---|---|---|---|---|---|---|---|---|
| Adjusted Coefficient | SE | P Value | 95% CI | Adjusted Coefficient | SE | P Value | 95% CI | |
| Central SBP | 0.445a | 1.047 | .007 | −1.606 to 2.496 | 0.265a | 1.061 | .005 | −1.814 to 2.344 |
| Central DBP | −0.954a | 1.161 | <.001 | −3.229 to 1.321 | −1.405b | 1.201 | <.001 | −3.759 to 0.949 |
| Central PP | −0.278a | 1.065 | .005 | −1.810 to 2.366 | −0.035b | 1.077 | .003 | −2.077 to 2.146 |
| MAP | −0.939a | 1.333 | .002 | −3.552 to 1.674 | −1.519b | 1.370 | .001 | −4.205 to 1.167 |
| Central AIx | −0.254b | 0.956 | <.001 | −2.127 to 1.619 | −0.308a | 0.961 | <.001 | −2.191 to 1.575 |
Abbreviations: AIx, augmentation index; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; SE, standard error; SBP, systolic blood pressure. Non‐thiazide diuretic Non‐(TD) antihypertensive includes angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β‐blockers, calcium channel blockers, and other antihypertensive agents (diuretics [other than thiazide‐type], antiadrenergic agents, and agents acting on the renin‐angiotensin system [excluding ACE inhibitors and ARBs]). In all models, TD was the reference category. aAdjusted for sex, age, quadratic age, body mass index (BMI), quadratic BMI, International Physical Activity Questionnaire, hypercholesterolemia, comorbidities, smoking, alcohol intake, heart rate, and high blood pressure onset date. bAdjusted for all previous variables and height instead of BMI.
Discussion
In this population survey, we found that TDs were noninferior when compared with other antihypertensive drugs in terms of cBP measurements and AIx. In our multivariate models, the 95% CIs excluded differences ≥3 mm Hg for central SBP, which has been shown to be epidemiologically and clinically significant.21 These results provide additional support for the growing body of evidence that suggests that TDs are at least as effective as other pharmaceutical options for treating mild to moderate uncomplicated hypertension.22, 23
Pharmacologic management of hypertension has dramatically improved worldwide in the past years, with increasing treatment and control rates, following recent guidelines and large trial findings.4, 24 The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommend a thiazide‐type diuretic as initial or concomitant therapy in most patients with hypertension.22, 25 These recommendations had a significant impact on antihypertensive prescription patterns, with increased utilization of TDs, especially in recently diagnosed patients,26, 27, 28, 29, 30 although the magnitude of impact may be smaller and of more limited duration than initially anticipated.31 In our study, the use of TDs as antihypertensive monotherapy was low, only 7.4% of the sample studied. This figure is lower than the 14% reported in a similar investigation, which, however, included patients with diabetes.32 A considerable proportion of nondiabetic hypertensive participants in CaG reported using TDs as a fixed‐dose combination tablet (19% of adults treated for hypertension), which can partially explain the low rate of TD monotherapy in our sample. This finding is consistent with the trend of increasing rates of TDs in fixed‐dose combinations.33
Our results show that cBP and AIx were equivalent in TD and non‐TD users. The comparison between TDs and ACE inhibitors/ARBs led to similar results. The effects of diuretics on cBP have not been studied as well as those on pBP. In placebo‐controlled trials, TDs lowered cSBP significantly less than pSBP, whereas other monotherapies lowered cSBP and pSBP to similar extents.34 The largest published trial in which cBP measurements were obtained was the Anglo‐Scandinavian Cardiac Outcomes Trial (ASCOT) substudy, Conduit Artery Function Evaluation (CAFE), in which two different regimens were compared (atenolol+thiazide‐based vs amlodipine+perindopril‐based therapy).9 There was a substantial reduction in cBP with the amlodipine‐based therapy compared with the atenolol‐based regimen, but this finding may be the result of BBs causing a slowing of heart rate.35 The substudy cohort of the Second Australian National Blood Pressure Trial (ANBP2) showed that neither pBP nor cBP differed between ACE inhibitor– and diuretic‐based regimens after approximately 4 years of treatment.36 Other small‐scale studies have also reported inconsistent findings regarding central effect of TDs and other antihypertensive agents.37, 38 This evidence suggests that the beneficial effect of TDs is mainly attributable to the decline in BP rather than to a change in the intrinsic properties of the arterial wall.
Study Strengths and Limitations
The strengths of our study include the use of a random sample, detailed ascertainment of baseline characteristics, including cBP measurements and medication data, which enabled the control of many potential confounders. The use of a population‐based sample enhances the generalizability of our findings beyond results generated from clinical trials as our study includes a random sample of the population for the targeted age group. Moreover, our sample size was adequate for our analyses. For our bivariate analysis, we estimated that our sample has sufficient power (>80%) to detect a difference as low as 5 mm Hg between TD and any other comparison groups, except for the group of “other antihypertensive.” For these estimates, we assumed a standard deviation of 13 mm Hg and an α value of 0.05. For the comparison with the “other antihypertensive” group, our sample size may not have had enough power to detect such a small difference in the BP measurements. For the multivariable regression analyses, our sample size was also adequate; we assumed an α value of 0.05 and that the set of predictors included in our models accounted for 50% of the variance of the outcomes.39 However, our study is subject to a number of limitations that should be highlighted. When selecting antihypertensive therapy, other factors besides hemodynamic parameters, must be taken into account. These include clinical endpoints, such as cardiovascular events, costs involved in the treatment, and potential side effects of the medications. Nevertheless, our findings provide important information on the cross‐sectional relationship between cBP measurements and antihypertensive therapy. cBP has been widely accepted as a surrogate for cardiovascular risk and some studies have suggested that cBP is a stronger predictor of cardiovascular events than peripheral BP.8, 10 Although CaG is an ongoing cohort study, with limited availability of clinical measurements, these topics can be addressed in future analysis when follow‐up and linkage with an administrative database become available. Confounding by indication could have potentially biased our results as it was not clear whether a given therapy was the first‐line medication or whether it was prescribed after the patient had failed initial therapy. It is also possible that participants starting on TDs have been prescribed other antihypertensive agents before. However, it may be reasonable to assume, at least in the majority of the cases, that if patients were nonresponders to the first‐line medication, a second class of drugs would have been added rather than switching to another form of monotherapy. Similarly, BP was measured at a single visit, and our results may not represent true BP control. Another limitation of the current study stems from the type of diuretics used; for example, chlorthalidone was chosen as the TD under study in the ALLHAT and other trials, while the diuretic most commonly prescribed in our population‐based sample was HCTZ.22 Whether the results obtained with chlorthalidone can be extrapolated to HCTZ is unclear40; however, no randomized controlled trial to date has compared the two medications head‐to‐head with respect to cardiovascular events. Nevertheless, results of two meta‐analyses have indicated no significant or minor differences between the two agents in preventing cardiovascular events, which can be related to HCTZ's shorter duration of action.41, 42
Conclusions
In this sample of a general nondiabetic population aged 40 to 69 years with uncomplicated hypertension, the use of TD monotherapy was not associated with either statistically or clinically significantly higher levels of either pBP or cBP measurements when compared with monotherapy with other antihypertensive classes. These findings reinforce the importance of diuretic agents as one of the first‐line therapies for uncomplicated hypertension.
Funding Sources
This work was funded by the Government of Canada through the Canadian Institutes of Health Research/Drug Safety and Effectiveness Network (CIHR/DSEN; grant number 298283). CARTaGENE project received financial support from Fonds de la recherche en santé du Québec (FRSQ), Genome Quebec, Réseau de médecine génétique appliquée (RMGA), Fonds québécois de la recherche sur la nature et les technologies (FQRNT), Canadian Foundation of Innovation, and the Canadian Partnership Against Cancer.
Disclosures
The authors declare no conflicts of interest.
Acknowledgments
We thank the CARTaGENE team for the generous support on data access and Dr Mitesh Shah for his support on drug classification.
J Clin Hypertens (Greenwich). 2015;17:848–854. DOI: 10.1111/jch.12622. © 2015 Wiley Periodicals, Inc.
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