Initial Treatment Of Hypertension Research Articles

Efficacy and safety of dual combination therapy of blood pressure-lowering drugs as initial treatment for hypertension: a systematic review and meta-analysis of randomized controlled trials.

To assess the efficacy and tolerability of dual combination of blood pressure (BP)-lowering drugs as initial treatment for hypertension. MEDLINE, Embase, CENTRAL were searched until August 2017 for randomized, double-blind trials of dual combination therapy vs. monotherapy in adults with hypertension who were either treatment naïve or untreated for at least 4 weeks. Regimens were classified with reference to usual daily 'standard-dose'; for example, <1 + <1 for a combination of two drugs both at less than one standard-dose. Random-effects models were used for meta-analysis. Thirty-three trials (13 095 participants) with mean baseline mean BP 155/100 mmHg were included. Compared with standard-dose monotherapy, dual combinations of <1 + <1, 1 + <1 and 1 + 1 (i.e. low-to-standard dose), showed a dose-response relationship in reducing SBP [mean differences (95% confidence interval) of 2.8 (1.6-4.0), 4.6 (3.4-5.7) and 7.5 (5.4-9.5) mmHg, respectively], and in improving BP control [risk ratio (RR) (95% confidence interval) 1.11 (0.92-1.34), 1.25 (1.16-1.35) and 1.42 (1.27-1.58), respectively]. Withdrawals due to adverse events were uncommon with low-to-standard dose dual combinations, with no significant difference compared with standard-dose monotherapy [2.9 vs. 2.2%; RR 1.28 (0.85 to 1.92)]. There were fewer data for higher dose dual combinations, which did not appear to produce substantial additional efficacy and could potentially be less tolerable. Compared with standard-dose monotherapy, initiating treatment with low-to-standard dose dual combination therapy is more efficacious without increasing withdrawals due to adverse events. CRD42016032822.

A10320 Combination therapy as initial treatment for hypertension

Log in or Register Subscribe to journalSubscribe Get new issue alertsGet alerts Submit your manuscript Enter your Email address: Wolters Kluwer Health may email you for journal alerts and information, but is committed to maintaining your privacy and will not share your personal information without your express consent. For more information, please refer to our Privacy Policy. Subscribe to eTOC Secondary Logo Journal Logo All Articles Images Videos Podcasts Blogs Advanced Search Toggle navigation Subscribe Register Login Articles & Issues Current IssuePrevious IssuesPublished Ahead-of-Print For Authors Submit a ManuscriptInformation for AuthorsLanguage Editing ServicesAuthor Permissions Journal Info About the JournalEditorial BoardAdvertisingOpen AccessSubscription ServicesReprintsRights and Permissions Latest ArticlesPodcastsTwitter All Articles Images Videos Podcasts Blogs Advanced Search

Abstract P388: Lifestyle Interventions Reduce the Need for Guideline-Directed Antihypertensive Medication

Introduction: The 2017 ACC-AHA Hypertension Guideline recommends lifestyle modification in the initial treatment of hypertension, and therapy with medications based on a threshold blood pressure determined by overall cardiovascular risk. In this secondary analysis of the ENCORE trial, we examined the effects of the DASH diet alone and in combination with weight loss and aerobic exercise on the indications for antihypertensive medication. Methods: Participants included 129 overweight or obese (BMI=25-40 kg/m 2 ) men and women between the ages of 40 and 80 years who had blood pressure 130-160/80-99 mmHg and who were not being treated with antihypertensive medications. Participants were randomized to 16 weeks of DASH diet plus behavioral weight management (consisting of nutritional counseling and a behavioral weight management program; DASH+WM), DASH diet alone (consisting of nutritional counseling without exercise or caloric restriction; DASH), or usual care controls (maintenance of usual exercise and dietary habits; UC). Results: The participants averaged 53.5±8.8 years of age; 68% (88 of 129) were female, and 60% (77 of 129) were white. Nineteen had an estimated 10-year atherosclerotic cardiovascular disease risk ≥ 10% by the Pooled Cohort Equations, and 1 had diabetes. Blood pressure averaged 138±9/86±6 mmHg. Criteria for treatment with antihypertensive medications, as defined in the 2017 ACC-AHA Hypertension Guideline, were present in 53% (68 of 129). Blood pressure fell by 16/10 mmHg in DASH+WM, 11/8 mmHg in DASH, and 3/4 mmHg in UC. The percentage of subjects with indications for antihypertensive medical therapy fell from 54% (25 of 46) to 15% (7 of 46) in the DASH+WM group and from 51% (20 of 39) to 23% (9 of 39) in the DASH group; and did not significantly change (55% [24 of 44] to 48% [21 of 44]) in the UC group (p = 0.001 for active treatments vs UC; p = 0.011 for DASH+WM vs DASH alone). Conclusions: In overweight or obese men and women with hypertension, lifestyle interventions dramatically decrease the number of individuals for whom guideline-directed antihypertensive medication is indicated.

Control of Blood Pressure and Cardiovascular Outcomes in Type 2 Diabetes.

High blood pressure in patients with diabetes mellitus results in a significant increase in the risk of cardiovascular events and mortality. The current evidence regarding the impact of intervention on blood pressure levels (in accordance with a specific threshold) is not particularly robust. Blood pressure control is more difficult to achieve in patients with diabetes than in non-diabetic patients, and requires using combination therapy in most patients. Different management guidelines recommend initiating pharmacological therapy with values >140/90 mm/Hg; however, an optimal cut point for this population has not been established. Based on the available evidence, it appears that blood pressure targets will probably have to be lower than <140/90mmHg, and that values approaching 130/80mmHg should be recommended. Initial treatment of hypertension in diabetes should include drug classes demonstrated to reduce cardiovascular events; i.e., angiotensin converting-enzyme inhibitors, angiotensin receptor blockers, diuretics, or dihydropyridine calcium channel blockers. The start of therapy must be individualized in accordance with the patient's baseline characteristics, and factors such as associated comorbidities, race, and age, inter alia.

Comparative effectiveness of an angiotensin receptor blocker, olmesartan medoxomil, in older hypertensive patients

The efficacy and safety of olmesartan medoxomil (OM) vs active control (AC) monotherapy among elderly patients aged 60-79years (N=4487) was evaluated by meta-analysis (25 studies). In all patients, change from baseline to end point in blood pressure (BP) was significantly greater with OM vs AC (-19.5/-11.9 vs -16.8/-10.7mm Hg). Greater proportions of OM- vs AC-treated patients achieved BP goals. In patients with impaired renal function (estimated glomerular filtration rate <60mL/min/1.73m2 ), OM treatment resulted in a greater mean change from baseline in systolic BP vs AC (-21.2 vs -18.7mm Hg, respectively) and a greater proportion of patients achieving BP goals. These parameters were similar in both groups for elderly patients with diabetes. OM was well tolerated with few adverse events. OM monotherapy can be used as an initial treatment for hypertension in elderly patients, including those with renal impairment or diabetes.

Hypertensive diabetic patients: incidence of cardiovascular and renal outcomes in a historical cohort over 11\xa0years

BackgroundDiabetics have increased risks for cardiovascular disease (CVD) and mortality, reducing their life expectancy by up to 15 years. Type 2 diabetes mellitus specifically increases the risk for cardiovascular mortality nearly fivefold. When hypertension is combined with diabetes, the risk of CVD is even greater.ObjectiveIdentify non-fatal cardiovascular outcomes and renal function impairment in a cohort of hypertensive patients in regular treatment in a reference treatment center, over 11 years of follow-up.MethodsHistorical cohort of hypertensive patients in regular treatment for at least 11 years in a specialized service for hypertension treatment. The exposed group was hypertensive diabetic patients at the beginning of the cohort, and the non-exposed group had hypertension without diabetes. The cohort began in 2004, with follow-ups in 2009 and 2015. Variables used: gender, race, age, physical activity, alcohol consumption, smoking, blood pressure, body mass index, glycated hemoglobin, diabetes and hypertension diagnosis times, treatment time in specialized service, non-fatal cardiovascular outcomes, and renal impairment assessed by creatinine clearance.Results139 patients participated in the study (55 diabetic hypertensive; 84 non-diabetic hypertensive), with an initial (2004) mean hypertension treatment time of 5.8 years. Females were the majority (75.5%) in both groups. Groups were similar regarding socio-demographic variables, but the group of hypertensive diabetic patients had higher frequency of obesity and uncontrolled BP, which persisted in all follow-ups. In 11 years of follow-up (2004–2015), the diabetic group had more cardiovascular events, with increased risk of acute myocardial infarction (RR 95% CI 1.6 12.2–95.0), stroke (RR 95% CI 1.3–6.1 27.7) and complications requiring hospitalization (RR 95% CI 1.6 2.2–3.0). Worsened renal function occurred more often in the non-exposed group, but in the end, the proportion of renal function loss was similar between groups.ConclusionsExposure to type 2 diabetes increased the risk of new cardiovascular outcomes over 11 years of follow-up of hypertensive patients. Diabetes by itself increased the risk of cardiovascular outcomes, justifying more intensive actions in this population.

Biomarkers in Pulmonary Vascular Disease: Gauging Response to Therapy

Biomarkers are increasingly being investigated in the treatment of pulmonary vascular disease. In particular, the signaling pathways targeted by therapies for pulmonary arterial hypertension provide biomarkers that potentially can be used to guide therapy and to assess clinical response as an alternative to invasive procedures such as right-sided cardiac catheterization. Moreover, the growing use of combination therapy for both the initial and subsequent treatment of pulmonary arterial hypertension highlights the need for biomarkers in this treatment approach. Currently approved therapies for pulmonary arterial hypertension target 3 major signaling pathways: the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, the endothelin pathway, and the prostacyclin pathway. Although the main biomarker used in practice and evaluated in clinical trials is N-terminal pro-brain natriuretic peptide, other putative biomarkers include the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine, NO metabolites including S-nitrosothiols and nitrite, exhaled NO, endothelins, cyclic guanosine monophosphate, cyclic adenosine monophosphate, and atrial natriuretic peptide. This review describes accessible biomarkers, related to the actual molecules targeted by current therapies, for measuring and predicting response to the individual pulmonary arterial hypertension treatment classes as well as combination therapy.

Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review

Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs. We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill-a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis. Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14-23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen. The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability. National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.

A quarter-dose quadpill for initial treatment of hypertension

A quarter-dose quadpill for initial treatment of hypertension

First-line combination therapy versus first-line monotherapy for primary hypertension.

Starting with one drug and starting with a combination of two drugs are strategies suggested in clinical guidelines as initial treatment of hypertension. The recommendations are not based on evidence about clinically relevant outcomes. Some antihypertensive combinations have been shown to be harmful. The actual harm-to-benefit balance of each strategy is unknown. To determine if there are differences in clinical outcomes between monotherapy and combination therapy as initial treatment for primary hypertension. We searched the Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 2), Ovid MEDLINE, Ovid Embase, LILACS, ClinicalTrials.gov, Current Controlled Trials, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to February 2016. We searched in clinical studies repositories of pharmaceutical companies, reviews of combination drugs in Food and Drug Administration and European Medicines Agency, and lists of references in reviews and clinical practice guidelines. Randomized, double-blind trials with at least 12 months' follow-up in adults with primary hypertension (systolic blood pressure/diastolic blood pressure 140/90 mmHg or higher, or 130/80 mmHg or higher if participants had diabetes), which compared combination of two first-line antihypertensive drug with monotherapy as initial treatment. Trials had to include at least 50 participants per group and report mortality, cardiovascular mortality, cardiovascular events or serious adverse events. Two authors independently selected trials for inclusion, evaluated the risk of bias and entered the data. Primary outcomes were mortality, serious adverse events, cardiovascular events and cardiovascular mortality. Secondary outcomes were withdrawals due to drug-related adverse effects, reaching blood pressure control (as defined in each trial) and blood pressure change from baseline. Analyses were based on the intention-to-treat principle. We summarized data on dichotomous outcomes as risk ratios with 95% confidence intervals. We found three studies in which a subgroup of participants met our inclusion criteria. None of the studies focused solely on people initiating antihypertensive treatment so we asked investigators for data for this subgroup (monotherapy: 335 participants; combination therapy: 233 participants). They included outpatients, and mostly European and white people. Two trials included only people with type 2 diabetes, whereas the other trial excluded people treated with diabetes, hypocholesterolaemia or cardiovascular drugs. The follow-up was 12 months in two trials and 36 months in one trial. Certainty of evidence was very low due to the serious imprecision, and for using a subgroup not defined in advance. Confidence intervals were extremely wide for all important outcomes and included both appreciable harm and benefit. The numbers of included participants and, hence the number of events, were too small to draw any conclusion about the relative efficacy of monotherapy versus combination therapy as initial treatment for primary hypertension. There is a need for large clinical trials that address the question and report clinically relevant endpoints.

Should we switch from bendrofluazide to chlorthalidone as the initial treatment for hypertension? A review of the available medication

INTRODUCTION Thiazide diuretics are commonly prescribed in the treatment of hypertension. However, thiazide diuretics may not all be equal in their ability to reduce cardiovascular disease outcomes. AIM To determine if bendroflumethiazide/bendrofluazide, the most commonly used diuretic for hypertension in New Zealand, is as effective as other diuretics in terms of cardiovascular disease outcomes. METHODS Using recent reviews of thiazide-like (chlorthalidone or indapamide) and thiazide-type diuretics (hydrochlorothiazide and bendrofluazide) and a separate search of bendrofluazide, data on cardiovascular disease outcomes was extracted. RESULTS Nineteen relevant papers with 21 comparisons were found. All thiazide-based diuretics have been reported in at least one trial showing them to be more effective than placebo for cardiovascular disease outcomes, with the exception of chlorothiazide. There were no comparisons of bendrofluazide alone with other medications, but there were two studies with either bendrofluazide or hydrochlorothiazide compared with β-blockers; however, the pooled relative risk (RR) was not significant (RR = 1.10 (95% CI, 0.84-1.43)). For chlorthalidone, there were four comparisons with other medications, and the summary RR was statistically significant for cardiovascular disease outcomes (RR = 0.91 (95% CI, 0.85-0.98)). Chlorthalidone was significantly more effective for some cardiovascular disease outcomes when compared with doxazosin, amlodipine and lisinopril. CONCLUSIONS All thiazide-based medicines available in New Zealand are effective in terms of cardiovascular disease outcomes compared with placebo when used for treating hypertension, with the exception of chlorothiazide. Of the diuretics available in New Zealand for hypertension, only chlorthalidone has been shown to be more effective than other blood pressure-lowering medicines. It may be time to change from using bendrofluazide and start using chlorthalidone as a treatment for hypertension.

Should Antihypertensive Treatment Recommendations Differ in Patients With and Without Coronary Heart Disease? (from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT

Thiazide-type diuretics have been recommended for initial treatment of hypertension in most patients, but should this recommendation differ for patients with and without coronary heart disease (CHD)? The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind hypertension treatment trial in 42,418 participants with high risk of combined cardiovascular disease (CVD) (25% with preexisting CHD). This post hoc analysis compares long-term major clinical outcomes in those assigned amlodipine (n = 9048) or lisinopril (n = 9,054) with those assigned chlorthalidone (n = 15,255), stratified by CHD status. After 4 to 8 years, randomized treatment was discontinued. Total follow-up (active treatment + passive surveillance using national databases for deaths and hospitalizations) was 8 to 13 years. For most CVD outcomes, end-stage renal disease, and total mortality, there were no differences across randomized treatment arms regardless of baseline CHD status. In-trial rates of CVD were significantly higher for lisinopril compared with chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared with chlorthalidone in those with and without CHD (overall hazard ratios [HRs] 1.10, p <0.001, and 1.38, p <0.001, respectively). During extended follow-up, significant outcomes according to CHD status interactions (p = 0.012) were noted in amlodipine versus chlorthalidone comparison for CVD and CHD mortality (HR 0.88, p = 0.04, and 0.84, p = 0.04, respectively) in those with CHD at baseline (HR 1.06, p = 0.15, and 1.08, p = 0.17) and in those without. The results of the overall increased stroke mortality in lisinopril compared with chlorthalidone (HR 1.2; p = 0.03) and hospitalized heart failure in amlodipine compared with chlorthalidone (HR 1.12; p = 0.01) during extended follow-up did not differ by baseline CHD status. In conclusion, these results provide no reason to alter our previous recommendation to include a properly dosed diuretic (such as chlorthalidone 12.5 to 25 mg/day) in the initial antihypertensive regimen for most hypertensive patients.

Monotherapy versus dual therapy for the initial treatment of hypertension (PATHWAY-1): a randomised double-blind controlled trial

IntroductionPrevious studies have suggested that more intensive initial therapy for hypertension results in better long-term blood pressure (BP) control. We test this hypothesis comparing initial monotherapy with dual therapy in...

Single-pill combination therapy in the initial treatment of marked hypertension: a propensity-matched analysis

Background: Many drugs combinations are available and equally recommended for the initial treatment of patients with marked blood pressure (BP) elevation and high cardiovascular risk. Hypothesis: To investigate safety and efficacy of such combination therapies. Methods: Prospectively collected data were retrospectively reviewed, inclusion criteria were: initial single-pill combination therapy, availability of clinical and echocardiographic 6-month follow-up. Six treatment groups were identified: Enalapril 20 mg+ Hydrochlorothiazide 12.5 mg (E/H), E 20 mg + Lercanidipine 10 mg (E/L), Ramipril 2.5 mg+ H 12.5 mg (R/H), Perindopril 5 mg+ Amlodipine 5 mg (P/A), Olmesartan 40 mg+ H 12.5 mg (O/H) and Telmisartan 40 mg+ H 12.5 mg (T/H). To avoid selection bias a Propensity score (goodness of fit: c-statistic 0.78, p = 0.0001) was used to select comparable cohorts of patients (n = 142 each). Results: After 4 weeks of treatment BP goal was achieved by 624/852 (73.2%) patients, and adverse events were registered in 24/852 (2.8%) patients. After 6 months, 562/624 (90.1%) patients maintained the BP goal. Six-month responder rate was significantly higher in the E/L (69.0%) and P/A (68.3%) groups (p = 0.05); especially among diabetics (52.0% and 51.0%, respectively; p = 0.003). Patients receiving E/L (−19.8 ± 3.2 mmHg) and P/A (−19.9 ± 4.6 mmHg) showed greater reductions of diastolic BP (p = 0.03); whereas reductions of systolic BP were similar between treatment groups (p = 0.46). Echocardiographic follow-up revealed greater left ventricular reverse remodeling among patients receiving ACE-inhibitors (E/L, R/H, E/H and P/A), but this trend did not reach statistical significance. Conclusions: Single-pill fixed-dose combination therapies are highly effective and safe in the study settings. Best clinical and echocardiographic outcomes were noted among patients receiving E/L, R/H and P/A.

Individualizing antihypertensive combination therapies: clinical and hemodynamic considerations.

While there are strong trial data to guide the selection of initial hypertension treatment choice and limited data to support second agent choice, beyond the first two agents, subsequent steps are empiric. As medications are added, the resulting polypharmacy may be complex, inefficient and poorly tolerated, resulting in low treatment adherence rates. The selection of antihypertensive drug therapy based on hemodynamic mechanisms is not new but became practical with the availability of noninvasive hemodynamic parameters using impedance cardiography. Individualized therapy based on hormonal or hemodynamic measurements can effectively control hypertension as shown in several small clinical trials. Hemodynamic measurements are obtained quickly, painlessly and can be used in a serial fashion to guide treatment adjustments. Current limitations relate to availability of the measurement device and personnel trained in its use, reimbursement for the measurements, expertise in interpretation of the measurements and systems to adjust medication and repeat measurements in a serial fashion until targets are attained. The potential utility of this approach increases with greater complexity of the medication regimen. Further studies are indicated and may advance options for individualized treatment of hypertensive patients.

Beta-Blockers Lose Luster for Hypertension Therapy

Beta-Blockers Lose Luster for Hypertension Therapy

PCV87 - Cost Effectiveness Analysis Of The Threshold For Initial Hypertension Treatment- A Markov Study Following The Jnc8 Guideline

PCV87 - Cost Effectiveness Analysis Of The Threshold For Initial Hypertension Treatment- A Markov Study Following The Jnc8 Guideline

Should African Americans with hypertension be treated differently than non-African Americans?

African Americans have a higher burden of hypertension, more severe blood pressure (BP) elevations, more concurrent risk-enhancing co-morbidities (e.g., diabetes), sub-clinical vascular injury at lower non-hypertensive BP levels, lower BP control rates, and significantly greater risk for adverse pressure-related clinical complications (e.g., stroke, heart failure) than whites. Randomized prospective data from hypertension endpoint trials show a virtually identical percentage reduction in CVD risk for a given magnitude of BP lowering, irrespective of the presence or absence of pre-treatment CVD across a broad range of BP down to pre-treatment BP levels of 110/70mm Hg. These data, mostly emanating from white populations, do not necessarily inform practitioners as to the level below which BP should be lowered in those with established, long-standing hypertension; however, these data do provide support for initiating hypertension treatment at lower than conventional BP thresholds. A Mendelian randomized study examining the impact of life-long lower SBP levels showed that lifelong exposure to 10mm Hg lower SBP was associated with an 82% lesser rate of SBP rise per decade and a 58% lower CHD risk that was much greater than the 22% reduction in CHD reported for the same magnitude of SBP reduction in clinical trials. Arguably, it is the hypertension treatment paradigm that merits reexamination. Earlier hypertension treatment in all populations prior to the onset of significant pressure-related target organ injury might conceivably prevent, or at least significantly attenuate, the well documented age-related rise in BP seen in most Western societies. In addition, this treatment paradigm might also reduce the significant residual CVD risk observed under the current recommended approach to hypertension treatment. This new approach to therapy would likely have substantial clinical and public health benefits in the high-risk, under-treated African American population that suffers outsized devastating consequences from inadequate control of BP.

Allopurinol on Hypertension: Insufficient Evidence to Recommend

To the Editor: In the review “Effect of Allopurinol on Blood Pressure: A Systematic Review and Meta-Analysis,” the authors conclude that allopurinol and other xanthine oxidase inhibitors may be used as adjunctive antihypertensive agent. This meta-analysis was performed that included heterogeneous studies as well as trials with poor methodological quality, eg, Siu and colleagues (2006) (an open, nonplacebo-controlled trial including individuals with and without hypertension in which allopurinol decreased only systolic blood BP); Kanbay and colleagues (2007) (open, nonrandomized, nonplacebo-controlled study enrolling normotensive and hypertensive individuals); and Kanbay and colleagues (2011) (an open, nonplacebo-controlled trial including adults with normal blood pressure. Positive results of allopurinol were seen in decreasing systolic but not diastolic BP). Inclusion of these studies may have strengthened the BP-lowering effect of allopurinol. Furthermore, one can reasonably assume that several studies enrolling normotensive individuals are inadequate to support the conclusion that allopurinol may be used to treat hypertension. In the systematic review “Pharmacotherapy for Hyperuricemia in Hypertensive Patients” (Cochrane Database of Systematic Reviews), which has more rigorous entry criteria, the authors found that, to date, there is only one study designed to answer whether allopurinol treatment has a positive effect in reducing BP in hypertensive individuals. Feig and colleagues conducted a double-blind, placebo-controlled, crossover trial that randomized 30 adolescents (11–17 years), newly diagnosed with stage I primary hypertension and with serum uric acid >6 mg/dL, to receive allopurinol 200 mg twice daily for 4 weeks and placebo for 4 weeks with a 2-week washout period between treatments. Although it was a well-conducted study, it had a few limitations, as follows: small sample size; exclusion of more severe hypertensive individuals; short duration of treatment, not sufficient to detect adverse events associated with allopurinol or to evaluate whether the effect on BP is sustained after long-term therapy; and the reserved external validity, extending only to adolescents with mild new diagnosis of hypertension. Another concern is how clinicians might interpret the conclusion of this review. Treatment with allopurinol is not free of risks and interactions. Although rare, serious side effects can be associated with allopurinol therapy, such as fatal Stevens-Johnson syndrome and chronic interstitial nephritis. Therefore, increased incidence of side effects can be observed with the increased prescription of allopurinol. Thus, in light of current evidence, recommendation (or encouraging use) of allopurinol or other hypouricemic agent as initial or adjuvant treatment of hypertension is premature and more “RCTs” are needed.

Chlorthalidone Versus Hydrochlorothiazide

TO THE EDITOR: Dhalla and colleagues' (1) retrospective observa-tional cohort study among older adults comparing chlorthalidonerecipients with hydrochlotothiazide (HCTZ) recipients departsmethodologically From other studies of antihypertensive drugs andhealth outcomes. First, there was no standardization in diagnosingcardiovascular events (CVEs). Second, the median follow-up forchlorthalidone recipients was only 255 days (8.4 months). The dif-ference in CVEs between the 2 drugs does not manifest until about9 months (Figure 1), implying that one half of the effect of chlottha-lidone is not reflected in the hazard ratio (HR). Third, the analysisincorporated total mortality into the primary outcome, somethingnot generally done because these medications have no effect on non-cardiovascular deaths.These problems bias the HR toward 1.00 (that is, toward find-ing no difference in health outcomes between the 2 medications).Despite these factors, the HR from DhaJla and associates' article is0.93, not different statistically from the HR of 0.79 (95% CI, 0.68to 0.92) from another retrospective observational cohort study thatavoids these methodological problems (2). Pooling these 2 HRs givesan HR of 0.87 (CI, 0.78 to 0.96; P = 0.005), an underestimate ofthe true benefit of chlorthalidone relative to HCTZ.Among chlorthalidone recipients and HCTZ recipients inDhalla and cowotkets' study, what are the HRs (95% CIs) for hos-pitalization for CVEs in those who became hypokalemic versus thosewith sustained notmokalemia? An analysis of ALLHAT (Antihyper-tensive and Lipid-Lowering Treatment to Prevent Heart AttackTtial), the largest hypertension trial available with approximately9000 chlotthalidone recipients, concludes, Thus, for most patients,concerns about potassium levels shotild not influence clinician's de-cision about initiating hypertension treatment with low-moderatedoses of thiazide diuretics (12.5-25.0 mg of chlorthalidone) (3).Dhalla and colleagues state incorrectly that our peet-teviewednetwork analysis (4) is conflicting with the network analysis pre-sented by Psaty and colleagues (5) in their letter to the editor andthat the latter analysis compared cblotthalidone and hydtochlo-rothiazide. Pet the title of their letter—Meta-analysis of HealthOutcomes of Chlorthalidone-Based vs Nonchlorthalidone-BasedLow-Dose Diuretic Thetapies—Psaty and associates comparedchlorthalidone-based diuretics with non-chlorthalidone-based di-uretics and used jtjst 3 trials for the nonchlorthalidone side of thenetwork: indapamide, HCTZ plus amlloride, and HCTZ plus tti-amtetene. Also, Psaty and coworkets did not include ALLHAT, theACCOMPLISH (Avoiding Catdiovasctilar Events Through Combi-nation Therapy in Patients Living With Systolic Hypertension) trial,ANBP2 (Second Australian National Blood Pressure Study), and theHDFP (Hypertension Detection and Follow-up Program) study, 4large trials strongly favoring chlorthalidone over HCTZ in networkanalysis (4).George C. Roush, MD, MPHUniversity of Connecticut School of Medicine and St. Vincent'sMedical CenterBridgeport, ConnecticutTheodore R. Holford, PhDYale University School of Public HealthNew Haven, ConnecticutAchuta K. Guddati, MBBS, PhDMassachusetts General HospitalBoston, MassachusettsPotential Conflicts of interest: None disclosed.References