Abstract
Hypertension is a major risk factor for cardiovascular disease. Evidence for optimal pharmacotherapy continues to accumulate at a very rapid pace; maintaining an up-to-date library of key articles for hypertension management can be challenging for busy clinicians. Further, there has been controversy surrounding the hypertension guidelines that were released in late 2013 and early 2014. The lack of congruence and simplicity in the current hypertension recommendations could result in delays with application of evidence to clinical practice. In order to facilitate clinicians’ efficient access to high-impact clinical trials evaluating the management of hypertension, this compilation of annotated bibliographies was created to serve as a resource for any health care professional participating in the management of adult patients with hypertension.
Introduction
The Cardiology Practice and Research Network of the American College of Clinical Pharmacy has been committed to the compilation of annotated bibliographies since 2004. These focused bibliographies have been developed as a resource for health care professionals to identify up-to-date publications in various cardiovascular therapeutic areas, including, but not limited to hypertension, 1,2 acute coronary syndrome, 3 heart failure, 4 and venous thromboembolism. 5 These bibliographies have become increasingly important, given the exponential increase in clinical trials and systematic reviews in recent decades, leaving clinicians with an overload of access to unfiltered information. 6
An added challenge for clinicians managing hypertension is the recent change to the process for which guidelines are developed and disseminated. For almost 40 years, the National Heart, Lung, and Blood Institute (NHLBI) published updated hypertension guidelines every 4 to 5 years; the last hypertension guidelines from the NHLBI were published in 2003. 7 In 2013, the NHLBI announced they would transfer guideline development to external professional organizations. 8 The American College of Cardiology (ACC) and American Heart Association (AHA) jointly accepted responsibility for developing new guidelines, which are expected in 2015. 9 Nonetheless, the members from the original 8th Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) published their recommendations. 10 The JNC 8 writing panel acknowledged that their recommendations were not sanctioned nor endorsed. In addition, the recommendations are not comprehensive but instead focus on 3 specific questions related to hypertension management. The publication of this recommendation from the JNC 8 panel created confusion, since the writing group retained the “JNC 8” title, which gave the recommendations an initial appearance of the formally endorsed guidelines that were the update to JNC 7. The report also sparked intense controversy that included an unprecedented publication of a dissenting minority view from the guideline committee regarding one of the recommendations and a request for The Journal of the American Medical Association to retract the JNC 8 guidelines. 11 –13 Further, other organizations also published guidelines in late 2013 (the American Society of Hypertension in October 2013 14 and a joint recommendation from the AHA/ACC and Centers for Disease Control in November 2013 15 ) that offer several discordant recommendations when compared to the JNC 8 committee’s recommendations. Although each of these guidelines offer helpful perspectives in the management of hypertension, it is important for clinicians to recognize that the official guidelines for hypertension management that are intended to replace the NHLBI guidelines have not yet been released.
The lack of congruency among these publications, ensuing debate, and delay of the official hypertension guidelines obfuscates consistent application of evidence for hypertension management, creating a pressing need for a consolidated summary of primary literature for clinicians, although the value of these bibliographies is not limited to this season of controversy. Although it is beyond the scope of this hypertension bibliography to compare the recent recommendations, or to engage in the ephemeral controversy, this bibliography serves clinicians by providing summations of recent high-impact clinical trials that may assist clinicians with application of the evidence published from 2008 through 2014. The summaries of landmark hypertension articles provided in this bibliography will be a valuable resource to clinicians managing hypertension for many years to come.
Articles
Guidelines/Statements
James PA, Oparil S, Carter BL, et al
2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2013;311(5):507-520. doi:10.1001/jama.2013.284427.
The JNC 8 writing panel published their unofficial recommendations to prevent additional delays considering the transfer of guideline development to external groups. This publication addresses 3 key questions in adults with hypertension, namely, (1) Does initiating antihypertensive therapy at specific blood pressure (BP) thresholds improve health outcomes? (2) Does treatment with antihypertensive pharmacologic therapy to a specified BP goal lead to improvements in health outcomes? and (3) Do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? JNC 8 provides 9 recommendations and 1 corollary recommendation based on these 3 questions and are, therefore, not a comprehensive set of guidelines. A key, high-profile recommendation from these guidelines is the recommendation to relax the target systolic BP in patients between 60 and 79 years of age to <150 mm Hg instead of the traditional <140 mm Hg. All JNC 8 panel members were not in agreement with this recommendation and a subsequent publication provides insight into the minority view. The panel also provided recommendations regarding BP targets in patients younger than 60 years of age and in those with chronic kidney disease and diabetes (target BP for all aforementioned groups <140/<90). It is important for clinicians managing hypertension to be aware that these “JNC 8” recommendations are not the formally endorsed guidelines that replace the JNC 7 guidelines. The guidelines that are intended to update the official guidelines from the NHLBI are expected to be released by the ACC/AHA in 2015.
Wright JT, Fine LJ, Lackland DT, et al
Evidence supporting a systolic blood pressure goal of <150 mm Hg in patients ≥60 years: the minority view. Ann Intern Med. 2014;160(7):499-503; doi:10.7326/M13-2981.
This publication is from a subgroup of 5 members of the JNC 8 writing panel that present their rationale for disagreeing with one of the recommendations provided by the JNC 8 committee. The group with the minority view discusses their rationale for disagreeing with the JNC 8 recommendation to raise the systolic BP target in patients aged over 60 years without diabetes or chronic kidney disease to <150 mm Hg. The minority group suggests that until clearer evidence is available, a systolic BP target of <140 mm Hg should be maintained for patients over 60 years old.
Weber MA, Schiffrin EL, White WB, et al
Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society Of Hypertension And The International Society Of Hypertension. J Clin Hypertens. 2014;16(1):14-26; doi:10.1111/jch.12237.
This publication is a joint recommendation from the American Society of Hypertension and the International Society of Hypertension. Recommendations provided by this set of guidelines are more comprehensive than JNC 8, are based to some degree on JNC 7 recommendations, and are more in line with the minority view as published by Wright and colleagues regarding BP targets for the elderly. These guidelines recommend a goal BP of <140/90 mm Hg for patients aged 55 to 80 unless a patient has albuminuria with chronic kidney disease, in which case, the guidelines support the target of <130/80 mm Hg as suggested by other expert groups. Recommendations also cover diagnosis, staging of hypertension, and nonpharmacologic treatment, which are aligned with JNC 7. The guidelines discuss pharmacologic management in detail and provide an algorithm for management that includes recommendations for patients with compelling indications. An important distinction of these guidelines from the JNC 7 recommendations is that beta blockers are not included as an option for initial therapy in patients outside a compelling indication. Several contributors to these recommendations were also authors for the JNC 8 recommendations. Overall, these recommendations provide some of the most comprehensive and up-to-date guidance available to clinicians at this time.
Calhoun DA, Jones D, Textor S, et al
Resistant hypertension: diagnosis, evaluation, and treatment a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51(6):1403-1419.
This consensus statement from the AHA defines resistant hypertension as BP which continues above target, despite therapy with 3 or more medications prescribed at optimal doses, ideally including one that is a diuretic. Patients who require 4 or more medications to reach BP target are also defined as being resistant. Common patient characteristics associated with resistant hypertension are outlined as are possible genetic factors related to resistant hypertension which the authors highlight should serve as areas of research in the future. A focus of the document is addressing possible etiologies for pseudoresistance and secondary causes of resistant hypertension, both of which should be considered prior to relegating patients to lifelong use of possibly unnecessary, or ineffective, antihypertensive therapies. With regard to management of resistant hypertension, the authors underscore first a proper assessment of patients with consideration given for 24-hour ambulatory BP monitoring, assessment of medication adherence, and for exacerbating medication and lifestyle factors as well as evaluation for secondary causes of hypertension (eg, obstructive sleep apnea, primary hyperaldosteronism, renal artery stenosis, and renal parenchymal disease). Pharmacologic options discussed for resistant hypertension largely focus on appropriate diuretic therapy, combination therapies, and use of mineralocorticoid receptor antagonists.
Aronow WS, Fleg JL, Pepine CJ, et al
ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2011;123(21):2434-2506.
With support from 10 different organizations, this consensus document serves as a complete reference regarding management of hypertension in the elderly (≥65 years of age). Detailed reviews are provided covering the scope and complications of hypertension in older patients as well as typical pathophysiologic aspects of hypertension in the elderly. The task force highlights that there is limited evidence available to recommend a particular BP target in older patients and it is unclear whether targets in patients aged 65 to 80 years old should be the same for those >80 years old. A systolic BP of <140 mm Hg is recommended if it can be reached without adverse reactions or complications in patients aged 65 to 80 years old. In patients over 80 years old, there is no clear BP target that can be recommended, but a systolic BP of 140 to 145 mm Hg is considered acceptable. It is recommended that treatment start in those with systolic BP at or above 160 mm Hg. Included in the document are detailed discussions reviewing antihypertensive agents and issues related to use in the elderly. Also reviewed are topics related to treatment in settings of particular compelling indications, resistant hypertension, pseudohypertension, and secondary causes of hypertension in the elderly.
Mancia G, Fagard R, Narkiewicz K, et al; for the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)
2013 ESH/ESC guidelines for the management of arterial hypertension. J Hypertens. 2013;31(7):1281-1357.
This document replaces the 2007 edition of joint guidance on hypertension management from the European Society of Hypertension and European Society of Cardiology. The guidelines continue to emphasize control of lifestyle factors for the prevention and treatment of hypertension (eg, reduction in sodium intake and alcohol consumption, weight control, exercise, and smoking cessation). Initiation of therapy for hypertension is recommended based on assessment of several patient factors including baseline BP, age, cardiovascular (CV) disease risk factors, and presence of target organ damage. The guideline task force recommends a systolic BP target of <140 mm Hg for most patients, highlighting there is limited evidence to support multiple systolic BP targets. For elderly patients with hypertension <80 years old and those >80 years old with acceptable mental and physical status, a target systolic BP of 140–150 mm Hg is recommended. A target diastolic BP of <90 is recommended for all patients except those with diabetes where a target of <85 mm Hg is recommended. Antihypertensive treatment strategies are discussed, including compelling indications for, and against, particular agents based on concomitant disease states and presence of target organ damage. Outside of compelling indications, or contraindications, recommended first-line antihypertensives are thiazide diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs); this expert panel also continues to include beta blockers as a first-line therapy option. Therapeutic selection based on a goal of BP control rather than specific use of any one agent versus another is recommended. The guidance document contains detailed discussions on treatment of hypertension in the old and young, women, patients with diabetes, heart disease, stroke, and peripheral arterial disease, and those with resistant and secondary hypertension.
Pharmacotherapy
Jamerson K, Weber MA, Bakris GL, et al
Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-2428.
The Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial was the first large comparison of 2 fixed dose combination therapies on cardiovascular outcomes in patients with hypertension. This was a double-blind, multi-center trial that randomized 11 506 patients with hypertension who were at high risk of cardiovascular events to benazepril 20 mg/d with either amlodipine 5 mg/d or hydrochlorothiazide (HCTZ) 12.5 mg/d, with upward dose titration if needed for BP control. The primary end point was the composite of CV events and death from CV causes. The trial was stopped early due to a benefit seen with the amlodipine–benazepril arm after a median of 30 months (mean 36 months). Primary event rates in those given benazepril–amlodipine were lower than those who received benazepril–HCTZ (9.6% vs 11.8%, hazard ratio [HR], 0.80, 95% confidence interval [CI] 0.72-0.90, P < .001). Differences in BP lowering between treatment arms were small but statistically different (mean BP at follow-up was 131.6/73.3 mm Hg vs 132.5/74.4 mm Hg in the amlodipine vs HCTZ groups, respectively, P < 0.001 for both systolic and diastolic). Secondary outcomes (fatal and nonfatal myocardial infarction [MI], revascularization procedures, and heart failure events requiring hospitalization) were reduced in the benazepril–amlodipine arm as well. Benefits were similar across gender and age subgroups. The study results are noteworthy in that a nonthiazide combination was shown to be superior to the thiazide-based strategy. Potential limitations of the study include use of a suboptimal HCTZ dose (mean daily dose of 19.3 mg) and use of HCTZ instead of chlorthalidone, the thiazide used in the landmark trials that influenced guidelines to recommend thiazide diuretics for first-line therapy. Adverse event rates were similar between the 2 groups. Overall, the study was well designed and demonstrated that benazepril and amlodipine combination therapy not only reduces BP but also provides important benefits with CV outcomes.
Yusuf S, Teo K, Anderson C, et al; for the Telmisartan Randomised AssessmenNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators
Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomized controlled trial. Lancet. 2008;372(9644):1174-1183.
The Telmisartan Randomised Assessment Study in ACE Intolerant subjects with cardiovascular Disease (TRANCEND) randomized 5962 patients with CV disease and/or diabetes with end-organ damage and previous intolerance to ACEI therapy in a double-blinded fashion to telmisartan 80 mg daily or placebo. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. Patients were treated for a median of 56 months with no difference in the primary outcome between telmisartan and placebo (15.7% vs 17%, respectively; HR 0.92, 95% CI 0.81-1.05, P = .216) in spite of greater reduction in BP in the telmisartan group compared to placebo. Several explanations for the lack of significance exist, including a genuine lack of benefit of telmisartan for reduction in cardiovascular events. However, the power of the study may have also precluded the ability to detect this modest 8% difference; the study was powered to identify a 19% difference between groups. Trial enrollment was slightly lower than goal and clinical event rates were less frequent than expected; therefore, the results could reflect a type II error. The TRANSCEND population had relatively high rates of concomitant statin, antiplatelet, and beta blocker therapies possibly reducing the groups baseline cardiovascular risk and muting potential benefits of telmisartan therapy. These considerations make assessment of clinical versus statistical significance of the TRANSCEND trial’s data difficult. However, given the overall lack of benefit with telmisartan versus placebo and the known benefit from historic trials in this patient population, ACEIs would remain preferred to ARB therapy. Importantly, although approximately 75% of the cohort had hypertension, this was not a hypertension trial by design. These data do provide insight, however, into the management of hypertension in patients with comorbid coronary disease. Further, a relevant finding from TRANSCEND is the positive tolerability data with telmisartan in patients with previous angioedema or renal dysfunction on ACEI therapy. These data may reassure clinicians with regard to use of ARB therapy in patients who may have historically been overlooked for this potentially beneficial therapy.
Yusuf S, Diener HC, Sacco RL, et al; for the PRoFESS Study Group
Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359(12):1225-1237.
The Prevention Regimen for Effectively Avoiding Secondary Strokes (PRoFESS) was a randomized controlled study utilizing a 2-by-2 factorial design to compare the combination of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan versus placebo on the reduction in secondary stroke of any kind. This is the report from the telmisartan versus placebo arm. Patients with prior stroke within the past 4 months were randomized to either telmisartan (10 146) or placebo (10 186) with median time from stroke to randomization of 15 days and mean follow-up of 30 months. After randomization, providers were authorized to treat BP according to the current hypertension guidelines. On average, patients were 66 years old and were mostly male (64.0%); mean baseline BP was 144.1/83.9 mm Hg. Occurrence of first recurrent stroke was similar between the telmisartan- and placebo-treated patients at 8.7% and 9.2%, respectively (HR 0.95, 95% CI 0.86-1.04, P = .23). No significant differences were found in secondary end points or among subgroups, nor was any interaction found based on background antiplatelet therapy. BP was reduced more in the telmisartan group compared to placebo (mean difference in systolic BP 3.8 mm Hg, in favor of telmisartan [statistics not reported]); adjustment for differences in BP did not affect the primary outcome. Several characteristics of this study need to be acknowledged that could have impacted the results. First, adherence with telmisartan was lower than placebo (rates of discontinuation in telmisartan group due to adverse reactions, 14.3% vs placebo 11.1%, P < .001). Second, in a post hoc analysis, telmisartan was found to reduce the primary end point after 6 months of treatment but not before; the difference in effect between the time periods was significant (P = .04). The effect of this therapy in relation to time is physiologically plausible and warrants further investigation. Again, like with the TRANSCEND trial, approximately 75% of the cohort had hypertension, therefore, this was not designed as a hypertension trial. These data provide some insight into the management of patients with hypertension after a stroke, but the design of the study limits full application. Overall, the data from PRoFESS do not support telmisartan therapy early after stroke for prevention of future cardiovascular events.
Yusuf S, Teo KK, Pogue J, et al; of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) investigators
Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547-1559.
The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) evaluated the noninferiority of telmisartan 80 mg daily (n = 8542) compared to ramipril 10 mg daily (n = 8576) or the combination of both (n = 8502). The primary outcome was death from CV causes, MI, stroke, or hospitalization for heart failure. Patients with a history of coronary, peripheral, or cerebrovascular disease or diabetes with presence of end-organ damage were enrolled and followed for a median of 56 months. The primary outcome showed that telmisartan was noninferior to ramipril; however, the superiority analysis demonstrated no significant difference between the arms. The rate of the primary outcome in the combination group was not different compared to the ramipril monotherapy group (relative risk [RR] 0.99, 95% CI 0.92-1.07). However, the combination arm had higher rates of renal dysfunction compared to ramipril (RR 1.33, P < .001). Discontinuation rates due to adverse events varied between arms and were lower with telmisartan compared to ramipril (influenced by hypotension and cough, RR 0.94, P = .02) and higher with combination compared to ramipril therapy (influenced by hypotension, renal impairment, and diarrhea, RR 1.2, P < .001). Blood pressure at baseline among the groups was 141.8/82.1 mm Hg. Patients randomized to telmisartan had a mean BP of 0.9/0.6 mm Hg lower than ramipril; the combination group had a mean BP of 2.4/1.4 mm Hg lower than ramipril (statistics not presented). Hyperkalemia was significantly higher in the combination group, but the discontinuation rate due to hyperkalemia was not presented. An important limitation of these data for the practitioner managing hypertension is that only 69% of patients had diagnosed hypertension, although subgroup analysis did not reveal any difference in the results based on baseline BP. Based on these data in patients with known vascular disease and high-risk diabetes, but without heart failure, ramipril or telmisartan alone appear to yield similar outcomes. However, combination therapy with ramipril and telmisartan should not be routinely used based on a lack of added benefit and an increased risk of renal dysfunction.
Mann JF, Schmieder RE, McQueen M, et al; on behalf of the ONTARGET investigators
Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomized, double-blind, controlled trial. Lancet. 2008;372(9638):547-553.
The benefits of using ACEI or ARBs to reduce the progression of albuminuria are established in those with advanced renal disease. However, neither the comparative effectiveness between ACEI and ARBs nor the comparative effectiveness of the combination of ACEI and ARBs on renal outcomes is known. This was a prespecified subanalysis of the ONTARGET trial (details are described earlier) with a primary composite outcome of first occurrence of any dialysis, renal transplant, doubling of serum creatinine, or death. Most patients did not have advanced renal disease at baseline. The frequency of the primary outcome between ramipril and telmisartan was similar (HR 1.0, 95% CI 0.92-1.09). However, combination therapy was associated with more frequent rates of the primary outcome compared to ramipril or telmisartan (HR 1.9, 95% CI 1.01-1.18, P = .037). These findings appear to be driven by dialysis, which was the only end point significantly greater when each component of the primary composite was assessed individually (HR 2.19, 95% CI 1.13-4.22). Interestingly, progression from microalbuminuria to macroalbuminuria was significantly decreased to a greater extent with combination therapy over single therapy, which is in contrast to other results of this subanalysis but is consistent with results from smaller studies and meta-analyses. These data support that renal effects between ACEIs and ARBs are similar in patients with established coronary disease and hypertension or diabetes with less advanced chronic kidney disease. However, the combination of ACEI and ARB does not improve renal outcomes and is associated with greater risks.
Parving HH, Brenner BM, McMurray JJV, et al; for the ALTITUDE Investigators
Cardiorenal endpoints in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012(23);367:2204-2213.
When the direct renin inhibitor aliskiren was introduced to the US market, data emerged suggesting benefit in renal disease and hypertension. Preliminary data demonstrated aliskiren plus losartan reduced albuminuria in patients with diabetic renal disease more than losartan alone. Whether the addition of aliskiren to standard therapy of ACEI or ARB therapy would reduce cardiovascular and renal events in a high-risk population was the rationale for the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) investigation. This was a randomized, placebo-controlled trial that enrolled 8561 patients with type 2 diabetes plus evidence of microalbuminuria, macroalbuminuria, or CV disease. The primary outcome was a composite of death from CV causes or first occurrence of cardiac arrest with resuscitation, nonfatal MI, nonfatal stroke, heart failure hospitalization, end-stage renal disease, kidney failure death, need for renal replacement therapy, or doubling of serum creatinine. Patients were randomized to aliskiren dose titrated to 300 mg daily or placebo in addition to standard therapy with ACEI or ARB. There was no difference in the primary end point between the groups (HR 1.08; 95% CI 0.98-1.20, P = .12). The trial was stopped prematurely due to excess risk of adverse events in the aliskiren group (median follow-up: 32.9 months). Although BPs were lower and reductions in urinary albumin to creatinine ratios were greater with combination therapy, the risk for hypotension (12.1% vs 8.3%, P < .001) and serum potassium ≥6 mmol per liter (11.2% vs 7.2%, P < .001) were significantly greater. ALTITUDE suggests that dual blockade of the renin–angiotensin–aldosterone system with aliskiren plus ACEI or ARB increases adverse events without benefit in this high-risk population.
Age-Based Treatment
Beckett NS, Peters R, Fletcher AE, et al
Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-1898.
Randomized trial data defining relative benefits and risks of antihypertensive treatment in people aged 80 years and over was inconclusive prior to the Hypertension in the Very Elderly Trial (HYVET). Some epidemiologic data suggested that treating very elderly patients with antihypertensive medication increased risk of death. HYVET is the largest trial enrolling the very elderly, aged 80 and older. In a randomized, double-blind, placebo-controlled fashion, 3845 patients from multiple countries (non-United States, primarily Europe and China) with persistently elevated hypertension (defined as >160 mm Hg systolic) were given either 1.5 mg/d sustained-release indapamide or placebo. Perindopril 2 to 4 mg/d or placebo could be added at follow-up visits to achieve a BP target of <150/80 mm Hg. Patients were a mean age of 83 years (range 80-105 years), with 27% >85 years. The trial was stopped early (1.8 years into study) after an interim intention-to-treat analysis showed a reduction in both the primary end point (fatal or nonfatal stroke) and death from any cause in the group receiving antihypertensive treatment. The primary end point was nonsignificantly reduced by 30% (95% CI −1 to 51; P = .06) and death from any cause was reduced by 21% (95% CI 4 to 35, P = .02). Secondary end points were reduced as well. Drug therapy was well tolerated and fewer adverse effects were reported in the treatment group. Some limitations of this trial include that it was not conducted in the United States and that BP treatment targets were higher than US standards of care. These limitations, however, do not refute the results, which clearly show the benefits of treatment in this population that is often underrepresented in clinical trials. This trial is highlighted in the 2011 consensus document from the ACCF and AHA evidence for treating hypertension in the very elderly patients.
Denardo SJ, Gong Y, Nichols WM, et al
Blood pressure and outcomes in very old hypertensive coronary artery disease patients: an INVEST substudy. Am J Med. 2010;123(8):719-726.
The International Verapamil SR-Trandolapril Study (INVEST) was a randomized controlled trial that enrolled 22 576 patients aged 50 years or older with hypertension and clinically stable CAD. The present analysis is a prespecified substudy of INVEST to evaluate the relationship of BP and adverse events among different age-groups. Patients were segregated by age (<60, 60-<70, 70-<80, and
Chlorthalidone Versus Hydrochlorothiazide
Kostis JB, Cabrera J, Cheng JQ, et al
Association between chlorthalidone treatment of systolic hypertension and long-term survival. JAMA. 2011;306(23):2588-2593.
A long-term assessment on life expectancy from treatment of isolated systolic hypertension was examined using data from the Systolic Hypertension in the Elderly Program (SHEP) trial. The original randomized, placebo-controlled trial, conducted from 1985 to 1990, established cerebrovascular and cardiovascular benefit of treating patients with isolated systolic hypertension with chlorthalidone-based therapy over placebo. After a 4.5-year follow-up, all patients were recommended to receive active treatment. By using long-term mortality data from the National Death Index (approximately 22 years after time of trial recruitment), the net gain in life expectancy from those randomized to active antihypertensive treatment compared to placebo was estimated. At 22 years, life expectancy was 105 days longer for all-cause death (95% CI −39 to 242, P = .07) and 158 days longer for cardiovascular death (95% CI 36-287, P = .009) for patients treated with chlorthalidone-based therapy for 4.5 years compared to those who received placebo. The gain in life expectancy free from cardiovascular death corresponded to approximately 1 day for each month of treatment. One important limitation is that the interventions provided to this cohort after the 4.5 years of follow-up were not standardized, as this part of the study is observational. Considering the average age of persons enrolled in SHEP was 72, this 22-year follow-up importantly adds to our understanding that treatment of hypertension in the elderly corresponds to clinically meaningful results. This study also provides a quantitative estimate of mortality benefit from early administration of antihypertensive treatment.
Dhalla IA, Gomes T, Yao Z, et al
Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults: a population-based cohort study. Ann Intern Med. 2013;158:447-455.
This retrospective, propensity-score matched study was conducted to compare the efficacy and safety of chlorthalidone and HCTZ in patients at least 66 years old. Patients with hypertension who were newly prescribed either chlorthalidone or HCTZ were identified (n = 10 384 and n = 19 489, respectively) utilizing national health care databases in Ontario, Canada. Each chlorthalidone patient was matched to 2 HCTZ participants using propensity score matching. The primary outcome was a composite of death or hospitalization with MI, heart failure, or stroke. Patients were an average of 73 years old and were followed for a median of 255 days for chlorthalidone (range 100-873 days) and 398 days for HCTZ (range 123-1307 days). The mean chlorthalidone dose was 27.3 mg per day and the mean dose of HCTZ was 18.3 mg per day. After adjusting for differences in baseline characteristics, no differences in the primary outcome between chlorthalidone and HCTZ were noted (adjusted HR 0.93, 95% CI 0.81-1.06). However, hospitalization for hypokalemia and hyponatremia was greater with chlorthalidone than in those prescribed HCTZ (HR 3.06, 95% CI 2.04-4.58 and HR 1.67, 95% CI 1.24-2.28, respectively). Post hoc analyses were conducted to explore relationships between diuretic dose and outcome. The risk of hospitalization for hypokalemia with chlorthalidone was present across a wide range of initial treatment doses. These results suggest chlorthalidone may be associated with increased risk without increased benefit. Importantly, chlorthalidone is approximately twice as potent as HCTZ; therefore, the mean daily doses used in this analysis may not be an optimal comparison. Overall, these data add to the conflicting evidence of which thiazide is optimal for the treatment of hypertension.
Ernst ME, Carter BL, Zheng S, et al
Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium. Am J Hypertens. 2010;23:440-446. doi:10.1038/ajh.2010.1.
Evidence supporting thiazide diuretics to reduce cardiovascular events in patients with hypertension is largely based on data using chlorthalidone, although HCTZ is more frequently prescribed in the United States. One potential reason for the preference of HCTZ may be related to concerns about more hypokalemia with chlorthalidone. This meta-analysis describes the effect of chlorthalidone and HCTZ on reduction in systolic BP and potassium. The hypothesis was that mean changes in systolic BP and potassium were equivalent for HCTZ and chlorthalidone within the 12.5 to 25 mg dose range. The primary end point was change in systolic BP and potassium occurring throughout the dose–response curves for HCTZ and chlorthalidone. Three tertiles of doses were evaluated (12.5-25 mg, >25-37.5 mg, >37.5-50 mg), but only the 12.5 to 25 mg dosage range was formally tested for equivalence. The authors found that chlorthalidone and HCTZ are not equivalent in reduction of systolic BP within the traditional dosage range of 12.5 to 25 mg. A comparison of mean changes of systolic BP across the dosage ranges at various durations of therapy confirmed that chlorthalidone produced greater reductions in systolic BP compared to hydrochlorothiazide. The difference in mean systolic BP across the 3 tertiles between HCTZ and chlorthalidone was 10 mm Hg, 10 mm Hg, and 2 mm Hg, in favor of chlorthalidone, respectively (P < .05 for all). Conversely, reductions in potassium were equivalent. However, comparison of the mean change in potassium at different dosages and study durations showed the reductions in serum potassium are statistically greater for chlorthalidone than for HCTZ, except within the 25 to 37.5 mg dosage range, where the effects are similar. The clinical significance of the difference in potassium found is questionable, since the absolute difference ranged from −0.1 to +0.2 mEq/L. Overall, the investigators concluded that chlorthalidone has greater systolic BP reductions than HCTZ; chlorthalidone may also produce slightly greater potassium loss, but the discordant findings between the equivalence analysis and comparison of the means suggest the difference may be minimal and should not preclude chlorthalidone use.
Roush GC, Holford TR, Guddati AK
Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analysis. Hypertension. 2012;59(6):1110-1117. doi:10.1161/HYPERTENSIONAHA.112.191106.
This systematic review and network meta-analysis was designed to add perspective to the controversy about the comparative effects between chlorthalidone and HCTZ, given the lack of a head-to-head trial. The investigators first performed a systemic review of randomized controlled trials with either chlorthalidone or HCTZ used as the first step agent. Next, the investigators conducted 2 different network analyses: one was a drug-adjusted analysis and the other was an office systolic BP analysis to eliminate the potential bias from the drug-adjusted analysis. In the drug-adjusted analysis, chlorthalidone was found to be superior to HCTZ for pooled CV events (MI, new coronary heart disease [CHD], and heart failure; for pooled data, RR 0.79, 95% CI 0.72-0.88, P < .0001). In the office systolic BP network analysis, chlorthalidone was also superior to HCTZ in reducing CV events (pooled data, RR 0.82, 95% CI 0.70-0.97, P = .025). Other end points evaluated included all-cause mortality, stroke, and heart failure. Although heart failure was reduced more by chlorthalidone in one pooled analysis, none of the other end points were significantly different between the drugs. Overall, the authors conclude that chlorthalidone reduces CV events by 21% relative to HCTZ. Although this is not a traditional randomized trial, the authors provided compelling rationale for statistical adjustment of the traditional limitations inherent to meta-analyses (eg, controlling for bias) and are transparent with their methodology. This is a strong analysis that provides persuasive evidence for the superiority of chlorthalidone over HCTZ in the absence of a randomized controlled trial.
Target Blood Pressure Trials
Cooper-DeHoff RM, Gong Y, Handberg EM, et al
Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010;304(1):61-68.
The International Verapamil SR-Trandolapril Study (INVEST) trial was a randomized, open-label study that reported a verapamil-based regimen was equivalent to an atenolol-based regimen in 22 576 patients with hypertension and stable CAD on all-cause mortality, nonfatal MI, and nonfatal stroke. The current analysis is an observational, secondary evaluation of CV outcomes in the subgroup of patients with diabetes (n = 6400) based on degree of BP control achieved (tight-control = systolic BP < 130 mm Hg; usual-control = systolic BP between 130 and140 mm Hg; uncontrolled = systolic BP > 140 mm Hg). The primary outcome was the first occurrence of all-cause death, nonfatal MI, or nonfatal stroke. The mean systolic BP reduction was 22.5 mm Hg in tight-control, 17.8 mm Hg in usual-control, and 12.9 mm Hg in uncontrolled group. The primary outcome was reduced in the tight-control and usual-control compared to the uncontrolled group (12.7%, 12.6%, and 19.8%, respectively; adjusted HR, 1.46; 95% CI, 1.25-1.71, P for trend, <.001). No differences were found between tight-control and usual-control (adjusted HR, 1.11; 95% CI, 0.93-1.32, P = .24). All-cause mortality rate was nonsignificantly higher in tight-control group compared to the usual-control group (11.0% and 10.2% respectively; adjusted HR, 1.20; 95% CI, 0.99-1.45, P = .06). However, the risk for all-cause mortality became significant during an extended follow-up analysis (up to 5 years after study follow-up; 22.8% tight-control vs 21.8% usual-control; adjusted HR, 1.15, 95% CI, 1.01-1.32, P = .04). Notable limitations of this study include the lack of randomization, and the observational and post hoc design. These results support targeting systolic BP between 130 and139 mm Hg rather than a more intensive target below 130 mm Hg in patients with CAD plus diabetes.
Cushman WC, Evans GW, Byington RP, et al; for the ACCORD Study Group
Effects of intensive blood pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) was a randomized, nonblinded trial comparing intensive BP control (systolic BP less than 120 mm Hg) with standard BP control (systolic BP less than 140 mm Hg) on the rate of major cardiovascular events among 4733 high-risk patients with type 2 diabetes. The primary outcome was first occurrence of a major CV event. The average BP after 1 year was 119.3/64.4 mm Hg in the intensive therapy group compared to 133.5/70.5 mm Hg in the standard therapy group. After a mean of 4.7 years of follow-up, no difference in the rate of the primary outcome between the groups was found (1.87% for intensive group vs 2.09% for standard group; HR with intensive therapy, 0.88, 95% CI, 0.73-1.06, P = 0.20). Serious adverse events were significantly higher in the intensive-therapy group (hypotension, bradycardia, hyperkalemia, hypokalemia, and increased serum creatinine, P < .05 for all). Two secondary outcomes were noted to favor intensive control: any stroke and nonfatal stroke (HR 0.59, 95% CI 0.39-0.89, P = .01 and HR 0.63, 95% CI 0.41-0.96, P = .03, respectively). Limitations include the open-label design, lower than expected rate of cardiovascular events, and restrictive age of the patients (patients less than 40 years old were excluded and patients 80 years of older were not included after the first phase of recruitment). The reduction in stroke with intensive control is consistent with other studies; however, the increase in adverse events with intensive therapy may have neutralized the stroke benefit, since no difference was found in the primary composite end point. This study does not support intensive BP control, even in high-risk patients with diabetes.
Bangalor S, Qin J, Sloan S, et al
What is the optimal blood pressure in patients after acute coronary syndromes? Relationship of blood pressure and cardiovascular events in the pravastatin or atorvastatin evaluation and infection therapy-thrombosis in myocardial infarction (PROVE IT-TIMI) 22 trial. Circulation. 2010;122(21):2142-2151.
The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombosis in Myocardial Infarction (PROVE IT-TIMI 22) trial was a randomized, double-blind controlled trial comparing intensive lipid lowering with atorvastatin 80 mg and moderate lipid lowering with pravastatin 40 mg after acute coronary syndromes. The objective of this post hoc analysis was to evaluate the ideal target for BP (n = 4162). Previous studies evaluating BP and cardiovascular outcomes in patients with stable CAD have shown a J- or a U-shaped curve. The primary outcome was first occurrence of death from any cause, MI, documented unstable angina requiring hospitalization, revascularization with either percutaneous coronary intervention or coronary artery bypass graft (CABG) surgery performed more than 30 days after randomization, and stroke. With an average follow-up of 24 months, the primary outcome occurred in 24% of patients. Systolic and diastolic BP both demonstrated a J- or U-shaped curve. A nadir of 136/85 mm Hg was identified by a nonlinear cox proportional hazard model, where the risk of the primary outcome was the lowest. The risk of primary outcome increased by 4.9-fold when systolic BP was less than or equal to 110 mm Hg and 1.2-fold when greater than 160 mm Hg. For diastolic BP, the risk of primary outcome increased 3.7-fold when less than or equal to 60 mm Hg and 2.1-fold when greater than 100 mmHg. Limitations of this analysis include the post hoc design and lack of randomization for BP comparison; these preclude determining causation of the observed increased primary event rates. Further, analysis was not adjusted for dosages of antihypertensive medications or for other potential confounders. Antihypertensive agents usually reduce both systolic and diastolic BP, making it difficult to associate events to either systolic or diastolic BP lowering, or both. The results of this study suggest that an appropriate target BP for patients after an acute coronary event is 130 to 140/80 to 90 mm Hg.
Bangalore S, Messerli FH, Wun CC, et al
J-curve revisited: an analysis of blood pressure and cardiovascular events in the treating to new targets (TNT) trial. Eur Heart J. 2010;31(23):2897-2908.
The Treating to New Targets (TNT) trial was a randomized, double-blinded comparison of atorvastatin 80 mg or 10 mg on the impact of intensive lipid lowering in 10 001 patients with stable heart disease on occurrence of a major cardiovascular event (CHD, nonfatal, nonprocedure-related MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke). The purpose of this subanalysis was to evaluate the relationship between systolic and diastolic BP and cardiovascular events. Patients were categorized into 10 mm Hg increments from <110 mm Hg to >160 mm Hg for baseline systolic BP and from ≤ 60 mm Hg to > 100 mm Hg for baseline diastolic BP. Patient characteristics were significantly different among the categories. The relationship between both systolic BP and diastolic BP followed a J-shaped curve. The risk of primary outcome was lowest with a BP of 146.3/81.4 mm Hg. The risk exponentially increased for the primary outcome when BP was less than 110 to 120/60 to 70 mm Hg. The risk of primary outcome when systolic BP was less than 110 mmHg was similar to systolic BP greater than 160 mmHg. The risk of stroke, which was a secondary outcome, was significantly lower with a systolic BP below 110 mm Hg. Notable limitations in this analysis include the post hoc design, lack of randomization based on BP targets, lack of controlling for confounders, and unmatched patient groups. Therefore, similar to other similarly designed analyses, causation cannot be determined. This study is consistent with other trials that show increased events at low BP and also supports a target systolic BP in the range of 140 mm Hg.
Appel LJ, Wright JT Jr, Greene T, et al
Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med. 2010;363(10):918-929.
The African-American Study of Kidney Disease and Hypertension (AASK) was a randomized trial evaluating the impact of intensive BP lowering (defined as mean arterial pressure [MAP] of 92 mm Hg) compared to standard BP lowering (MAP 102-107 mm Hg) among 1094 black patients with diastolic BP greater than 95 mm Hg and a glomerular filtration rate between 20 and 65 mL/min. This study had 2 phases: a trial phase (previously published), followed by a cohort phase (presented here). As patients completed the trial phase, they were invited to continue in the cohort phase, where all received therapy to target BP to less than 130/80 mm Hg (initial agents used: ramipril, metoprolol succinate, or amlodipine; other antihypertensives could be added if intolerant or if additional BP control was needed). Patients (mean age 54 years) were stratified based on the presence or absence of baseline proteinuria. The primary outcome of progression of chronic kidney disease (CKD) was defined as doubling of the serum creatinine level, a diagnosis of end-stage renal disease, or death. No difference between groups for either the trial or the cohort phase was found (cohort HR, 0.91, 95% CI, 0.77-1.08, P = .27). Blood pressure was lower in the intensive group in both phases (130/78 mm Hg vs 141/86 mm Hg in trial phase; 131/78 mm Hg vs 134/78 in cohort phase). An interaction between the randomized BP group and the log transformed protein to creatinine ratio for the primary outcome was found (P = .02 for interaction). In the absence of proteinuria, there was no difference between groups in both phases (HR 1.18, 95% CI, 0.93-1.50, P = .16). When proteinuria was present, there was a significant reduction in the primary outcome with intensive management (HR 0.73, 95% CI, 0.58-0.93, P = .01). This analysis is additive in that data are provided for a high-risk population with a paucity of evidence to guide management. Important limitations include lack of randomization, use of office BP rather than ambulatory BP for medication adjustments, and the use of proteinuria to define a threshold of effect. The results of this trial suggest that intensive BP control does not slow the progression of CKD, but the presence of baseline proteinuria may alter the effects. These data should be considered hypothesis generating since this is not a randomized controlled trial.
Resistant Hypertension
Chapman N, Dobson J, Wilson S, et al
Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007;49(4):839-845.
The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) trial randomized nearly 20 000 patients with hypertension to compare atenolol-based therapy and amlodipine-based therapy for the primary prevention of CHD in patients with hypertension. This is a post hoc analysis of the ASCOT-BPLA data in the 1411 patients who received spironolactone (mean dose 25 mg/d) as add-on treatment for uncontrolled BP. Patients were on a mean of 2.9 other antihypertensive medications for a median of 1.3 years. Spironolactone therapy resulted in a mean BP reduction of 21.9/9.5 mm Hg. Spironolactone was generally well tolerated; 6% of participants discontinued the drug because of adverse effects. The most frequent adverse events were gynecomastia or breast discomfort (6%) and hyperkalemia (2%). The mean increase in potassium was 0.4 mEq/L and mean increase in creatinine was 0.15 mg/dL. Spironolactone effectively lowered BP in patients with hypertension uncontrolled by approximately 3 other drugs. Limitations of this study include lack of randomization, lack of control (placebo or active), and observational design. Selection bias may have occurred in that only subjects with resistant hypertension were started on spironolactone. These patients may be more susceptible to the effects of aldosterone blockade, and the effect on BP may be greater in these patients. While a randomized trial assessing the efficacy of adding on spironolactone as a fourth-line antihypertensive agent is the best way to determine the safety and efficacy in resistant hypertension, this post hoc analysis of ASCOT-BPLA is the largest data set available to date. These data support the use of spironolactone in resistant hypertension and appears to be safe and reasonably well tolerated.
Václavík J, Sedlák R, Plachý M, et al
Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension. 2011;57(6):1069-1075.
The objective of this double-blind, placebo-controlled study was to assess the effect of adding spironolactone 25 mg/d on BP in patients with resistant hypertension. Inclusion criteria included office systolic BP greater than 140 mm Hg or diastolic BP greater than 90 mm Hg despite treatment with at least 3 antihypertensive drugs, including a diuretic. Patients were randomly assigned to receive spironolactone (n = 59) or a placebo (n = 58) for 8 weeks in addition to their antihypertensive medication. After 2 months of therapy, daytime ambulatory systolic BP decreased significantly in the spironolactone group (−5.4 mm Hg, P = .024), but no significant change was seen in diastolic BP. Spironolactone also reduced nighttime systolic BPs significantly (−8.6 mm Hg, P = .011) as well as office systolic BP readings (−6.5 mmHg, P = .011); however, again, no changes in diastolic BP values were found. At study end, the goal office systolic BP of less than 140 mm Hg was reached in 54.5% of patients using spironolactone and in 42.9% of patients using the placebo (P = .257). The results of this trial support earlier studies that the addition of spironolactone in patients with resistant hypertension (taking a mean of 4.5 antihypertensive drugs) led to significant decreases in systolic BP. Spironolactone led to significant but clinically irrelevant increases in serum potassium (0.3 mEq/L) and creatinine (0.08 mg/dL). Despite the small sample size and short duration of follow-up, the trial is noteworthy because it is the first randomized trial evaluating low-dose spironolactone for resistant hypertension in patients on 4 or more drugs. However, many clinical findings did not reach statistical significance, which may be due, in part, to the relatively small sample size.
Parthasarathy HK, Ménard J, White WB, et al
A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens. 2011;29(5):980-990.
Eplerenone was compared to spironolactone for efficacy and safety in patients with hypertension in this multicenter, randomized, double-blind study. Patients were randomized to a 16-week treatment period of spironolactone 75 to 225 mg once daily (n = 71) or eplerenone 100 to 300 mg once daily (n = 70) utilizing a titration to effect design. Doses were titrated if diastolic BP remained greater than 90 mm Hg. Inclusion criteria included primary aldosteronism, a seated diastolic BP at least 90 mm Hg and less than 120 mm Hg, and systolic BP less than 200 mm Hg. The primary outcome was the antihypertensive effect on diastolic BP. The mean eplerenone dose was 214 mg/d, while the mean spironolactone dose was 152 mg/d. Changes from baseline in the eplerenone group were systolic BP −9.9 ± 2.3 mm Hg and diastolic BP −5.6 ± 1.3 mm Hg, while changes in the spironolactone group were systolic BP −27.0 ± 2.3 mm Hg and diastolic BP −12.5 ± 1.3 mm Hg. The difference in systolic and diastolic BP between groups favored spironolactone (Δ systolic BP −17.1 mm Hg, P < .001 and Δ diastolic BP −6.9 mm Hg, P < .001). Changes in potassium and creatinine were small, but significant (spironolactone associated with greater magnitude of change). Although no differences were seen in overall adverse events reported between the groups, more patients taking spironolactone developed male gynecomastia (21.2% vs 4.5%; P = .033) and female mastodynia (21.1% vs 0.0%; P = .026). The doses used in this trial exceed the doses recommended in the eplerenone package labeling (100 mg/d) and the doses of spironolactone typically used (up to 100 mg/d) in the United States. Another limitation is that diastolic BP was used as the primary end point, which is contrary to the convention in recent hypertension trials utilizing systolic BP. However, this study supports the use of spironolactone over eplerenone for the treatment of hypertension in those with evidence of primary hyperaldosteronism, with reserving eplerenone use for patients with intolerances to spironolactone due to gynecomastia or mastodynia.
Symplicity HTN-1 Investigators
Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011;57(5):911-917.
The renal sympathetic nerves contribute to the complex pathophysiology of hypertension. Increased efferent sympathetic drive to the kidneys and an increased rate of sympathetic-nerve firing are generally seen in patients with hypertension. Previously, catheter-based renal sympathetic denervation significantly reduced BP up to 1 year postprocedure in patients with hypertension. This study extended the follow-up of that trial to 24 months. In a nonrandomized manner, 153 patients with resistant hypertension (systolic BP ≥ 160 mm Hg on ≥3 antihypertensive drugs, including a diuretic) were treated with radiofrequency ablation of their renal sympathetic nerves at 19 international centers. Office BP readings were reduced from the mean baseline level of 176/98 ± 17/15 mm Hg by −23/−11 mm Hg at 12 months (n = 64) and −32/−14 mm Hg at 24 months (n = 18). Over 90% of patients had an office systolic BP reduction of ≥10 mm Hg. These large BP reductions occurred in patients who were refractory to standard medical therapies, with no change in the number of antihypertensive medications at follow-up compared with baseline (5.0 vs 5.1; P = .11). The procedure complication rate was 3%, which included 3 groin pseudoaneurysms/hematomas and 1 renal artery dissection. Only 42% of the original cohort reached the 12-month follow-up and just 12% of the cohort reached the 24-month follow-up. It appears that catheter-based renal sympathetic denervation may be an option for patients with hypertension that is resistant to medical therapy, but limited safety and efficacy data are available out to 2 years. In addition, the lack of a control group may confound these results. It is unclear whether similar BP reductions can be attained by others with little to no experience performing this procedure.
Symplicity HTN-2 Investigators
Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. Lancet. 2010;376(9756):1903-1909.
Renal sympathetic denervation was assessed in a randomized, controlled manner in this study. Patients with treatment-resistant hypertension (taking three or more antihypertensive drugs) were enrolled (defined as baseline systolic BP ≥ 160 mm Hg or ≥150 mm Hg for patients with type 2 diabetes). The primary end point was change in office-based systolic BP at 6 months. There were 106 patients randomized to renal denervation (n = 52) or control (maintain previous treatment alone, n = 54); 94% of the patients in each group were assessed for the primary end point at 6 months. Baseline BP readings were similar between groups at baseline (intervention 178/96 mm Hg, control 178/97 mm Hg). Office-based BP measurements in the renal denervation group were reduced by 32/12 mm Hg (P < .0001), whereas there was no difference from baseline in the control group (change of 1/0 mm Hg). Between-group differences in BP at 6 months were significant (P < .0001). At 6 months, 84% of the patients who underwent renal denervation had a reduction in systolic BP of 10 mm Hg or more, compared with 35% of controls (p<0.0001). Patients in the intervention and control groups were on a mean of 5 antihypertensive medications at baseline and follow-up. No serious procedure-related or device-related complications were noted. The authors concluded that catheter-based renal denervation was shown to safely and substantially reduce BP in treatment-resistant patients with hypertension at 6 months. Although this study was randomized and controlled, several limitations exist, including the lack of blinding and lack of a sham control group (patients who received procedure but no actual renal denervation). SYMPLICITY trials 1 and 2 provided evidence of potential benefit with renal denervation for those with resistant hypertension. However, these results needed to be confirmed by the SYMPLICITY-3 trial, which included a sham control. A recent announcement from the study sponsor stated that renal denervation failed to meet the primary end point. Because these data have not been published, a critical assessment of the 3 SYMPLICITY trials in total cannot be provided. Given what is known at the time of this writing, data from the SYMPLICITY 1 and 2 trials should be interpreted with caution. Enrollment in on-going and future studies of renal denervation by Medtronic (sponsor of the Symplicity trials) has been suspended.
Chronotherapy
Hermida RC, Ayala DE, Mojón A, et al
Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010;27(8):1629-1651.
The circadian rhythm has been shown to contribute to the 24-hour variation in BP as well as affect the pharmacokinetics of medications. Consequently, the time of antihypertensive medications administration may impact the physiologic response. Blunted sleep BP decline (nondipper pattern) has been associated with increased risk of fatal and nonfatal CVD events. The objective of the Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares (MAPEC; Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study was to determine whether bedtime dosing with at least 1 antihypertensive medication (bedtime group) improves BP control and CVD risk reduction when compared to a regimen in which all medications are taken in the morning (awakening group). There were 2156 patients with hypertension randomized to the bedtime or awakening groups and followed for a median of 5.6 years. No difference in mean systolic ambulatory BP between groups (awakening group 154.4 mmHg vs bedtime group 155.7 mmHg, P = .144) or in the number of antihypertensive medications (mean of 2) was seen at baseline. At follow-up, patients in the bedtime group had lower sleep-time BPs and reduced prevalence of nondipping (defined as sleep-time SBP decline <10%; 34% vs 62%, P < .001). And, while there was a higher prevalence of controlled ambulatory BP (62% vs 53%, P < .001), differences between groups in the mean awake BP were small and nonsignificant. Patients in the bedtime group exhibited a lower risk of total CVD events compared to the awakening group (RR 0.39, 95% CI 0.29-0.51, P < .001). Changing the administration time of at least 1 antihypertensive medication is a cost-effective, simple strategy that improved ambulatory BP and reduced cardiovascular events. It is reasonable to employ this bedtime dosing regimen on a more routine basis in the treatment of hypertension, particularly if conventional dosing is unsuccessful. However, this alternative dosing strategy may contribute to medication adherence issues.
Hermida RC, Ayala DE, Mojón A, et al
Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care. 2011;34(6):1270-1276.
The objective of this study was to compare patients with hypertension and type 2 diabetes taking at least 1 antihypertensive medication at bedtime (bedtime group) with patients taking all their medications in the morning (awakening group) on BP control and CV risk reduction. This was a randomized, open-label, single-blinded study (end point adjudicating investigators were blinded to study arm assignment) that enrolled 448 patients on a mean of 2.5 antihypertensive medications. After a median follow-up of 5.4 years, patients in the bedtime group showed a lower mean asleep BP than patients in the awakening group (115.0 vs 122.4 mm Hg, P < .001) and higher prevalence of controlled ambulatory BP (62.5% vs 50.9%, P = .013). However, there was no significant difference in awake and clinic BP values. Patients treated at bedtime had a lower CV risk (all-cause death, MI, angina pectoris, and coronary revascularization, cerebrovascular events, heart failure, occlusion of lower extremities, and retinal arteries) than patients in the awakening group (HR 0.33, 95% CI 0.21-0.54, P < .001). Rates of major events (CV death, MI, and stoke) were also reduced in the bedtime group (adjusted HR 0.25, 95% CI 0.10-0.61, P = 0.003). For each 5 mm Hg reduction in asleep systolic BP, there was a 12% reduction in CV risk (P < .001). This study demonstrates that patients with diabetes benefit from bedtime dosing of antihypertensive medications. One explanation for this may be that the non-dipping BP pattern (defined as sleep-time SBP decline <10%) is predominant in patients with diabetes, and non-dipper patients with hypertension derive more benefit from bedtime dosing. These results are clinically important due to the increased risk of CVD that burdens patients with diabetes. In fact, the American Diabetes Association has included bedtime dosing of antihypertensive medications as an evidence level A recommendation in their 2014 Standards of Medical Care in Diabetes. 16
Hermida RC, Ayala DE, Mojon A, et al
Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J Am Soc Nephrol. 2011;22(12):2313-2321.
The clinical effect of ingestion time of antihypertensive medications and its effect on circadian patterns of BP in patients with CKD were studied in this open-label trial. Patients with CKD were randomly assigned either to take all prescribed antihypertensive medications upon awakening (awakening group, n = 332) or to take at least 1 antihypertensive medication at bedtime (bedtime group, n = 329) and were followed for a median of 5.4 years. There were no differences in baseline BP or the number of hypertension medications used between the 2 treatment groups. At follow-up, patients in the bedtime group had a lower mean sleep-time BP (P < .001) and better control of their ambulatory BP when compared to the awakening group (56% vs 45%, P = .003). Patients in the bedtime group had a reduced risk of total CV events (a composite of death, MI, angina, revascularization, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke) when compared to patients in the awakening group (adjusted HR 0.31, 95% CI 0.21-0.46, P < .001). A 14% risk reduction for CV events was seen for each 5 mm Hg decrease in mean sleep-time systolic BP (P < .001). In patients with CKD, nocturnal hypertension is the predominant BP pattern. The lack of sleep-time BP control and a nondipper BP pattern (defined as sleep-time systolic BP decline <10%) were the most prevalent factors among patients who had a CV event. Based on these data, health care providers who treat patients with CKD and hypertension may consider recommending patients take at least 1 antihypertensive medication at bedtime to improve nocturnal BP control and to reduce the risk for CV events. However, the 2013 Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline concluded that more information is needed prior to making this a routine practice. 17
Dietary Effects on Blood Pressure
Chen L, Caballero B, Mitchell DC, et al
Reducing consumption of sugar-sweetened beverages is associated with reduced blood pressure: a prospective study among United States adults. Circulation 2010;121(22):2398-2406. doi:10.1161/CIRCULATIONAHA.109.911164.
Sugar-sweetened beverages (SSBs) are the leading source of added sugars in the United States, with a mean SSB consumption of 28 ± 1 ounces/d for US adults. Preliminary data have found a positive association between consumption of SSB and BP. This is a prospective substudy of 810 patients randomized to PREMIERE, which was a landmark trial comparing the effect of lifestyle interventions on BP (JAMA. 2003;289:2083-2093). In this analysis, patients enrolled in the PREMIERE study with prehypertension or Stage 1 hypertension had overall dietary intake assessed by 2 unannounced recalls (1 weekday, 1 weekend) around study visits at baseline and at 6 and 18 months. Detailed dietary information was obtained, including consumption of regular soft drinks, lemonade, fruit punch, other sweetened beverages and diet drinks (defined as drinks sweetened with artificial sweeteners). Participants mean baseline BP was 134.9 ± 9.6/84.8 ± 4.2 mm Hg and mean baseline SSB intake was 10.5 ± 11.9 fluid ounces/d. Blood pressure was measured during follow-up using a standard protocol at baseline, 3, 6, 12, and 18 months. Among all participants, reduction of 1 SSB (12 ounces) per day reduced systolic BP by 1.76 mm Hg (95% CI 1.17-2.35, P < .001) and diastolic BP by 1.08 mm Hg (95% CI 0.69-1.47, P < .001). Patients who reduced their SSB intake the most (15.3 ± 9.9 fluid ounces/d) had the most dramatic BP reductions (systolic BP reduction 9.5 ± 4.3 mm Hg). When the results were adjusted for changes in weight, the magnitude of benefit was reduced, but the reduction in BP remained significant (systolic BP, P = 0.01; diastolic BP, P = .04). Change in consumption of diet beverages was not associated with change in systolic or diastolic BP. There was also no relationship between change in caffeine consumption and BP. Although this was an observational study, it highlights the importance of including dietary modifications as a component of BP management and provides context about the magnitude of impact that could be expected with reduced consumption of sugared beverages.
Blumenthal JA, Babyak MA, Hinderliter A, et al
Effects of the DASH diet alone and in combination with exercise and weight loss of blood pressure and cardiovascular biomarkers in men and women with high blood pressure. Arch Intern Med. 2010;170(2):126-135. doi:10.1001/archinternmed.2009.470
The Exercise and Nutrition Interventions for Cardiovascular Health (ENCORE) study was a prospective, randomized evaluation of 3 lifestyle modifications on BP and CV biomarkers (pulse wave velocity [PWV], flow-mediated dilation [FMD], baroreflex sensitivity [BRS], and LV mass index). Overweight men and women (BMI 25-41) with a systolic BP of 130 to 159 mm Hg or diastolic BP 85 to -99 mm Hg who were ≥35 years old and not taking antihypertensive medication were eligible. . Patients were randomized to a usual care (UC, no changes in diet), Dietary Approaches to Stop Hypertension alone (DASH-A), or to DASH plus weight management (DASH-WM). Patients in UC and DASH-A maintained an isocaloric diet and did not attempt weight loss; calorie reduction and supervised exercise were included in the DASH-WM group. At the end of the 4-month treatment period, compared to UC, BP was reduced by 12.5/5.9 mm Hg with the DASH-WM group and by 7.7/3.6 mm Hg in the DASH-A group (P < .001 for all). Compared to UC, active treatments (DASH-WM and DASH-A) resulted in lower PWV; no statistical difference was found between active treatments and UC for FMD, BRS, or LV mass index. However, BRS and LV mass index were improved with the DASH-WM group compared to the DASH-A group (P < .05 for both). Overall, these results confirm the efficacy of the DASH diet in reducing BP. Exercise and weight loss added to the DASH diet will result in even greater BP reductions; the magnitude of BP reduction when including all 3 strategies is similar to BP reduction seen with an antihypertensive medication. The effect of the DASH diet on CV biomarkers was less clear. These results suggest weight loss has a greater impact on BP reduction, although these results could also be due to limited power.
Ambulatory Blood Pressure Monitoring/Telemonitoring
McManus RJ, Mant J, Bray EP, et al
Telemonitoring and self-management in the control of hypertension (TASMINH2): a randomized controlled trial. Lancet. 2010;376(9736):163-172. doi:10.1016/S0140-6736(10)60964-6.
The Telemonitoring and Self-Management in the Control of Hypertension (TASMINH2) was an open-labeled, randomized, controlled trial evaluating the impact of hypertension self-management on BP. Patients randomized to the intervention group (n = 234) received training on measuring home BP with a validated device, interpreting the results, and instructions on medication titration that was predetermined by the family physician and study participant. Patients in the intervention group monitored their BP for the first week of each month. A color-coding system indicated if the reading was within goal, outside of goal but below safety limits, or outside of safety limits (green, yellow, and red, respectively). If result was “yellow” for 2 months, the patient adjusted their medication in accordance with the titration schedule; “red” results directed patients to their physician’s office. Readings were sent to physicians for informational purposes only. Patients in the control group (n = 246) received usual care. The primary outcome was change in mean systolic BP from baseline to follow-up visits (6 and 12 months). Overall, BP was lower in the intervention group compared to the control group (P = .002). Systolic BP was reduced by 3.7 mm Hg and 5.4 mm Hg at 6 and 12 months compared to the control group (P = .013 and .0004, respectively). Diastolic BP between groups did not differ (P = .092). Seventy percent of patients in the intervention group made at least 1 medication change and patients in the intervention group took more BP medications at 6 and 12 months. Importantly, patients taking more than 2 anti-hypertensive medications were excluded and patients with complex comorbidities (eg, coronary heart disease and diabetes) were not well represented (≤10%). Overall, this study provides evidence that self-management of hypertension may be feasible in appropriate lower-risk patients. The impact of self-management on hard clinical end points, in patients with more complex comorbidities, and cost-effectiveness needs evaluation.
Hodgkinson J, Mant J, Martin U, et al
Relative effectiveness of clinic and home blood pressure monitoring compared with ambulatory blood pressure monitoring in diagnosis of hypertension: systematic review. BMJ. 2011;342:d3621. doi:10.1136/bmj.d3621.
National guidelines recommend utilizing several office BP measurements for diagnosis of hypertension, though studies have shown both ambulatory and home BP monitoring correlate with end-organ damage better than office measurement. This systematic review was conducted to evaluate the accuracy of the diagnosis of hypertension utilizing clinic measurement or home measurement compared to a standard of ambulatory monitoring. Analyses were conducted to compare the sensitivity and specificity for diagnosis of hypertension made at thresholds of 140/90 mm Hg for clinic measurement and 135/85 mm Hg for home measurement. Compared with ambulatory BP monitoring, clinic measurement had a mean sensitivity of 74.6% (95% CI, 60.7%-84.8%) and specificity of 74.6% (47.9%-90.4%); home measurement had a mean sensitivity of 85.7% (78.0%-91.0%) and specificity of 62.4% (48.0%-75.0%). There was no significant difference in sensitivity or specificity between clinic and home measurements. These results suggest both clinic and home measurements are less sensitive and specific for diagnosing hypertension than ambulatory BP measurement. Importantly, there was substantial variation within the trials included in this analysis regarding patient population assessed, thresholds used, and description about equipment used; there were not enough studies in each category to evaluate statistical homogeneity. This review is key in that it exposes a potential limitation in our standard of care for diagnosing hypertension; the impact is that patients may be unnecessarily diagnosed and treated with medication.
Pharmacist Management
Green BB, Cook AJ, Ralston JD, et al
Effectiveness of home blood pressure monitoring, web communication, and pharmacist care on hypertension control: a randomized controlled trial. JAMA. 2008;299(24):2857-2867.
The electronic communications and home BP monitoring study (e-BP study) evaluated 2 Web-based BP monitoring and communication service interventions (1 was Web training only; the other was Web training plus pharmacist management) compared to usual care based on the Chronic Care Model of care delivery. Eligible patients (n = 778) with uncontrolled hypertension and no comorbid conditions were evaluated at 2 separate appointments prior to randomization to assure accurate assessment of eligibility. The randomization process was structured to maintain blinding through all web-training activities. The pharmacist intervention included an initial phone visit that concluded with presentation of a patient-specific action plan. Web communications with the pharmacist occurred every 2 weeks until BP control was obtained, then periodically thereafter. The 2 primary outcome measures were percentage of patients with BP less than 140/90 mm Hg and changes in systolic BP and diastolic BP at 12 months. Patients who were assigned to the pharmacist-care group were significantly more likely to obtain and maintain BP control as compared to other study arms (56% pharmacist vs 36% Web only vs 31% usual care), systolic BP and diastolic BP values were significantly reduced in pharmacist care as compared to other groups. The home BP monitoring and web-training only group did not improve unadjusted rates of BP control as compared to usual care group, though a significant improvement was found on systolic BP after adjustment (adjusted mean change −2.9 mm Hg, 95% CI −5.4 to -0.4, P = .02). The pharmacist-care group had a greater number of health care access points (secure message strings and patient-initiated phone calls) than other groups’ members. Limitations include exclusion of patients without internet access and patients who had comorbidities that altered target BP goals. Importantly, this study was not able to delineate the role of increased patient engagement as a factor impacting the results. This study demonstrated success with a novel care delivery method that is practical for contemporary clinical practice.
Bunting BA, Smith BH, Sutherland SE
The Asheville project: clinical and economic outcomes of a community-based long-term medication therapy management program for hypertension and dyslipidemia. J Am Pharm Assoc. 2008;48(1):23-31.
The Asheville Project was a pharmacist-directed, medication therapy management program conducted as an employee health benefit program in the Asheville, North Carolina area. This follow-up analysis assessed clinical and financial outcomes for the hypertension and/or dyslipidemia programs. The program included self-care instruction regarding CV risk reduction, face-to-face patient consultation with a pharmacist coach, and reduced copays for medications. The clinical outcomes assessed included BP and lipid markers. Economic and CV events were collected through prescription and medical claims databases. The study population was 50.4 years old, mostly white, and were educated (greater than 92% completed high school or equivalent program). The 423 patients who met inclusion criteria for the hypertension cohort demonstrated improvements in systolic BP and diastolic BP (11/4.8 mm Hg, P < .0001) from baseline to the end of 6 years follow-up. The percentage of patients meeting BP goals increased from 40.2% to 67.4% during the evaluation period. During this time, average health plan expenses for medical costs related to CV care decreased from US$1 362 to US$734 per person per year (PPPY) while medication copay costs increased (US$287 to US$846 PPPY). Overall, health plan savings exceeded increased CV medication costs by 12.6%. Total cardiovascular events and emergency department visits/hospitalizations were reduced, compared to historical controls (OR 0.47, 95% CI 0.33-0.67, P < .05 and OR 0.46, 95% CI 0.35-0.61, P < .00001, respectively). Limitations include lack of randomization, lack of control group, and multiple interventions at study outset (copay reduction and pharmacist coach). The modest return on investment noted in the cost analysis may be greater when applied to a more general population, as it evaluated direct costs and assessed a healthy population at baseline.
Weber CA, Ernst ME, Sezate GS, et al
Pharmacist-physician comanagement of hypertension and reduction in 24-hour ambulatory blood pressures. Arch Intern Med. 2010;170(18):1634-1639.
This study evaluated 175 patients in a 9-month prospective, cluster-randomized, controlled clinical trial. Patients were randomized to collaborative physician–pharmacist care (n = 100) or usual care (n = 75). The pharmacist met with patients in the intervention group at least every 2 months to identify potential barriers to compliance/adherence and drug therapy regimen as compared to JNC 7 recommendations. Pharmacists suggested drug therapy modifications to the patient’s primary care provider for consideration. The primary outcome measure was change in 24-hour mean ambulatory systolic and diastolic BP values between the intervention and control groups. Study participants were similar between the groups, except for a greater number of patients with a history of CABG surgery in the controls. Mean baseline office systolic and diastolic BP was 153.1/84.9 mm Hg in the intervention and 150.3/85.4 mm Hg in the control group. Approximately 24% of the cohort had diabetes; other comorbidities (eg, heart failure and myocardial infarction) were uncommon (<10%). Mean age was approximately 60 years. Ambulatory BP measurements were completed at baseline and at study completion. The pharmacist’s recommendation was accepted and implemented in 95.9% of the 267 cases within the intervention group. Reductions in ambulatory systolic and diastolic BP were reported, with the mean difference favoring the intervention group for daytime (Δ 9.7/4.7 mm Hg, P < .001 for both), nighttime (Δ 6.5/2.1 mm Hg, P = .004 and P = .12, respectively), and overall 24-hour timeframes (Δ 8.6/4.0 mm Hg, P < .001 for both). At the end of the study period, 75% of intervention patients met criteria for BP control as compared to 50.7% of usual care group (P < .001). This study is important because it supports a collaborative, team-based approach to BP management. Cost and scale analyses will be required to determine whether this intervention can be generalized to other populations in a meaningful and cost-effective fashion.
Margolis KL, Asche SE, Bergdall AR, et al
Effect of home blood pressure telemonitoring and pharmacist management on blood pressure control: a cluster randomized clinical trial. JAMA. 2013;310(1):46-56.
The HyperLink study was designed to assess the magnitude of BP improvement in a structured home telephone BP monitoring program, with pharmacists providing BP education and management during a 12-month intervention compared to usual care using a cluster randomized trial design. The durability of intervention was assessed at 18 months after the initial intervention. Sixteen clinics in an integrated health system with clinical pharmacist presence were randomly assigned to telemonitoring intervention (8 clinics) or usual care (8 clinics). Patients randomized to receive intervention met with pharmacists for a 1-hour, face-to-face visit initially, followed by telephone visits every 2 weeks until BP control was sustained for 6 weeks, at which point follow-up was done monthly through month 6. Calls were made bimonthly for months 7 to 12. The 450 participants (n = 228 in intervention; n = 222 in control) were well matched, with baseline BP of 148/85 mm Hg and equal attendance at visits at 6 and 12 months. Blood pressure was controlled in 48.5% of telemonitoring intervention and 25.1% of usual care patients at 6 and 12 months (investigators assumed those who did not complete visits were uncontrolled; P = .001). Mean differences in BP values between treatment and usual care groups, favoring the treatment group, were −10.7/−6.0 mm Hg, −9.7/−5.1 mm Hg, and −6.6/−3.0 mm Hg at 6, 12, and 18-month measures, respectively, with only 18-month diastolic BP not significantly lower. Although these findings mirror results seen with other care team-based BP intervention studies, the HyperLink study population is additive in that it also included patients with additional CV risk factors who were excluded from prior evaluations. Another important finding in this analysis is the sustainability of the results after completion of the intervention. Additional studies assessing long-term cost, efficacy, and durability measures are required to identify how to best apply this model in general practice.
Miscellaneous Article of Importance
Heerspink HJL, Ninomiya T, Zoungas S, et al
Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomized controlled trials. Lancet. 2009;373(9668):1009-15. doi:10.1016/S0140-6736(09)60212-9.
This systematic review and meta-analysis was conducted to assess the effect of treatments to reduce BP in patients with hypertension receiving maintenance dialysis. Robust data on CV end points in this population are lacking. Eight trials including 1679 patients followed between 12 and 36 months were evaluated; none of the studies were conducted in the United States. To be included, the study had to evaluate CV events, all-cause mortality, and/or CV mortality. Overall, treatment was associated with a lower risk of CV events compared with controls (RR 0.71, 95% CI 0.55-0.92, P = .009). However, there was heterogeneity in the magnitude of effect across the studies (I2 = 67.5%, P = .003); heterogeneity was also significant when studies were divided on the basis of inclusion or exclusion of hospital admission for heart failure (P = .006). All-cause mortality and CV mortality were reduced with treatment (RR 0.80, 95% CI 0.66-0.96 and RR 0.71, 95% CI 0.50-0.99, respectively; P < .05 for both). This systematic review is helpful in that it provides evidence to support treating BP in this complex population, when there is a paucity of evidence to guide patient care. One concern that has potentially precluded treatment was that lowering BP might increase risk of intradialytic hypotension. Observational studies suggested intradialytic hypotension was associated with increased adverse events and all-cause mortality. While this systematic review found BP treatment to be well-tolerated and associated with good outcomes, further prospective and controlled investigation is warranted to confirm these findings.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
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