Antihypertensive And Lipid-Lowering Treatment To Prevent Heart Attack Trial Research Articles

The New American Guidelines on Hypertension: A Favorable Opinion

The New <scp>A</scp>merican Guidelines on Hypertension: A Favorable Opinion

I brazilian position paper on antihypertensive drug combination.

Arterial hypertension (AH) is a highly prevalent disease, and is a major cardiovascular (CV) risk factor1; therefore, achieving blood pressure (BP) control goals as soon as possible is paramount to reduce that risk2. That means that approximately 70% of hypertensive individuals will need antihypertensive drug combination3, and up to 30% of hypertensive individuals are estimated to use four or more drugs to achieve BP control4. Thus, drug combination is currently described as an important strategy to manage AH, providing effective and safe BP reduction. Drug choice is based on effective BP reduction and CV outcomes. Despite the existence of a significant number of drugs to treat AH, their control rates are still very low, contributing to the high CV morbidity and mortality rates observed in Brazil and worldwide1,2. According to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Hypertension Optimal Treatment (HOT) Study, only 26% and 33% of the patients, respectively, could control their BP with monotherapy, while in the Losartan Intervention for Endpoints Reduction (LIFE) Study, 90% of the patients needed combined therapy for that purpose3 . Drug combination is mainly aimed at increasing antihypertensive efficacy, with fewer adverse events. It is worth noting the importance of considering therapy adherence. The pathophysiology of AH involves multiple factors and mechanisms, making its control difficult when only one drug is used, because counterregulatory mechanisms that attenuate the antihypertensive effect of the drug can occur. The association of drugs with different mechanisms of action has a greater impact on BP reduction as long as there is pharmacokinetic compatibility and no disparity of effects and properties3-5. Thus, the choice of the drugs to be combined should contemplate two aspects: synergism of the mechanisms of action and opposition to counterregulatory mechanisms triggered after the beginning of therapy with a certain drug. The desired antihypertensive efficacy is more likely to be achieved by using lower doses of the drugs involved. Thus, fewer adverse events are observed, with no loss of antihypertensive drug potency3-5. Another important aspect is that drugs should be preferably combined in a single galenic presentation, facilitating their administration, and assuring lower cost, with a consequent improvement in treatment adherence2,6.

Do Bayesian adaptive trials offer advantages for comparative effectiveness research? Protocol for the RE-ADAPT study

BackgroundRandomized clinical trials, particularly for comparative effectiveness research (CER), are frequently criticized for being overly restrictive or untimely for health-care decision making.PurposeOur prospectively designed REsearch in ADAptive methods for Pragmatic Trials (RE-ADAPT) study is a ‘proof of concept’ to stimulate investment in Bayesian adaptive designs for future CER trials.MethodsWe will assess whether Bayesian adaptive designs offer potential efficiencies in CER by simulating a re-execution of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study using actual data from ALLHAT.ResultsWe prospectively define seven alternate designs consisting of various combinations of arm dropping, adaptive randomization, and early stopping and describe how these designs will be compared to the original ALLHAT design. We identify the one particular design that would have been executed, which incorporates early stopping and information-based adaptive randomization.LimitationsWhile the simulation realistically emulates patient enrollment, interim analyses, and adaptive changes to design, it cannot incorporate key features like the involvement of data monitoring committee in making decisions about adaptive changes.ConclusionThis article describes our analytic approach for RE-ADAPT. The next stage of the project is to conduct the re-execution analyses using the seven prespecified designs and the original ALLHAT data.

Risk of Hospitalized Gastrointestinal Bleeding in Persons Randomized to Diuretic, ACE‐Inhibitor, or Calcium‐Channel Blocker in ALLHAT

Calcium channel blockers (CCBs) are an important class of medication useful in the treatment of hypertension. Several observational studies have suggested an association between CCB therapy and gastrointestinal (GI) hemorrhage. Using administrative databases, the authors re-examined in a post-hoc analysis whether the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants randomized to the CCB amlodipine had a greater risk of hospitalized GI bleeding (a prespecified outcome) compared with those randomized to the diuretic chlorthalidone or the angiotensin-converting enzyme inhibitor lisinopril. Participants randomized to chlorthalidone did not have a reduced risk for GI bleeding hospitalizations compared with participants randomized to amlodipine (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.92-1.28). Those randomized to lisinopril were at increased risk of GI bleeding compared with those randomized to chlorthalidone (HR, 1.16; 95% CI, 1.00-1.36). In a post-hoc comparison, participants assigned to lisinopril therapy had a higher risk of hospitalized GI hemorrhage (HR, 1.27; 95% CI, 1.06-1.51) vs those assigned to amlodipine. In-study use of atenolol prior to first GI hemorrhage was related to a lower incidence of GI bleeding (HR, 0.69; 95% CI, 0.57-0.83). Hypertensive patients on amlodipine do not have an increased risk of GI bleeding hospitalizations compared with those taking either chlorthalidone or lisinopril.

The metabolic cost of lowering blood pressure with hydrochlorothiazide

BackgroundThe landmark Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) placed a new spotlight on thiazide diuretics as the first-line therapy for hypertension. This is concerning as thiazide-diuretics may contribute to comorbidities associated with the current epidemic of obesity. Previous randomized clinical trials have linked thiazide diuretic treatment to insulin resistance, metabolic syndrome, and increased incidence of type 2 diabetes.MethodsThis proof of concept, longitudinal, randomized, double–blind study evaluated the effects of the angiotensin II receptor blocker Valsartan and the specific thiazide diuretic Hydrochlorothiazide (HCTZ) on hepatic triglyceride level (primary outcome), as well as triglyceride levels within other organs including the heart, skeletal muscle, and pancreas. Additionally, we evaluated whether myocardial function, insulin sensitivity, and insulin secretion were affected by these treatments.ResultsHepatic TG levels increased by 57% post HCTZ treatment: ∆hTG HCTZ = 4.12% and remained unchanged post Valsartan treatment: ∆hTG V = 0.06%. The elevation of hepatic TG levels after HCTZ treatment was additionally accompanied by a reduction in insulin sensitivity: ∆SI HCTZ = -1.14. Treatment with Valsartan resulted in improved insulin sensitivity: ∆SI V = 1.24. Treatment-induced changes in hepatic TG levels and insulin sensitivity were statistically significant between groups (phTG = 0.0098 and pSI = 0.0345 respectively). Disposition index, DI, remained unchanged after HCTZ treatment: ∆DI HCTZ = -141 but it was increased by a factor of 2 after treatment with Valsartan: ∆DI V =1018). However, the change between groups was not statistically significant. Both therapies did not modify abdominal visceral and subcutaneous fat mass as well as myocardial structure and function. Additionally, myocardial, pancreatic, and skeletal muscle triglyceride deposits remained unchanged in both therapeutic arms.ConclusionsOur findings are two-fold and relate to hepatic steatosis and insulin sensitivity. HCTZ treatment worsened hepatic steatosis measured as hepatic triglyceride content and reduced insulin sensitivity. Valsartan treatment did not affect hepatic triglyceride levels and improved insulin sensitivity. The results of this study reinforce the message that in patients at risk for type 2 diabetes it is particularly important to choose an antihypertensive regimen that lowers blood pressure without exacerbating patient’s metabolic profile.

Stroke Progress Review Group

The Stroke Progress Review Group (PRG) was formed in 2001 to produce research recommendations to the National Institute of Neurological Disorders and Stroke (NINDS) for the next 10 years. The PRG produced a progress report in 2006, and a final report in 2012. The PRG process used expert study groups covering 16 areas of research. Each group was tasked to summarize progress in their field and then come up with research priorities. The proceedings were published in the journal Stroke and online.1,2 For planning the next decade, NINDS has reconfigured the PRG process with the intention of identifying a narrowed focus on the most critically important priorities, and obtaining more input from the wider community of healthcare workers involved with stroke and from the public using a dedicated web page: http://www.ninds.nih.gov/strokerfi Eventually, work-groups will be configured on stroke treatment, stroke prevention, and stroke recovery with the intention to narrow down priorities to 2 to 3 per area. I will describe progress on the basis of current decision to of NINDS to divide the field into 3 broad topics: acute stroke treatment, stroke prevention, and stroke repair/recovery/rehabilitation. Other aspects of stroke research that were considered priorities by the PRG between 2001 and 2012 will be covered in a fourth category (Other). ### Acute Stroke Treatment 1. Improve reperfusion therapy: the first priority in the area of acute stroke treatment that was identified in the reports of 2001, 2006, and 2012 was to improve reperfusion therapy. The following is a list of research progress in this area: 1. Enhanced thrombolysis—randomized trials: Study of Tenecteplase in Acute Ischemic Stroke (TNK), Ancrod, …

Recent Clinical Trials of Hypertension Management

The scene for clinical trials of hypertension management is in transition. The era of mega trials may not be over but is certainly in decline, and in the past 2 years there have been no studies reporting primary outcome data the scale of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and other major studies that marked clinical trial activity and informed guideline committees during the past 2 to 3 decades. This reflects in part the view that the present benchmark pharmacological agents for treating hypertension are difficult to improve, some systemic issues affecting the pharmaceutical industry influencing the ability to make the large investment required to perform mega trials and the quality of the antihypertensive drug pipeline. Together these considerations have tended to drive interest toward equivalence rather than efficacy studies (ie, trials designed to show an investigational agent is as good as, not better than, existing treatment), surrogate end points, including new blood pressure (BP) variables, and studies of combinations and algorithms rather than single interventions. Population studies around the world, however, continue to show that large numbers of people have hypertension that is not treated satisfactorily and are not achieving the goals set by the major national guidelines. These guidelines themselves are under continual scrutiny on the basis of recent data casting doubt on the validity of present BP goals. Guideline committees also face the issue that evidence based on expensive large-scale clinical trials is more often funded by the pharmaceutical or device industries than by government, leaving large evidence gaps in areas of public importance but no direct interest to industry funders. The purpose of the present article is to briefly review clinical trials of …

Mortality and Morbidity During and After Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

To determine whether an angiotensin-converting enzyme inhibitor (lisinopril) or calcium channel blocker (amlodipine) is superior to a diuretic (chlorthalidone) in reducing cardiovascular disease incidence in sex subgroups, we carried out a prespecified subgroup analysis of 15 638 women and 17 719 men in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Total follow-up (active treatment + passive surveillance using national administrative databases to ascertain deaths and hospitalizations) was 8 to 13 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease. In-trial rates of HF, stroke, and combined cardiovascular disease were significantly higher for lisinopril compared with chlorthalidone, and rates of HF were significantly higher for amlodipine compared with chlorthalidone in both men and women. There were no significant treatment sex interactions. These findings did not persist through the extension period with the exception of the HF result for amlodipine versus chlorthalidone, which did not differ significantly by sex. For both women and men, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary coronary heart disease outcome or any other cardiovascular disease outcome, and chlorthalidone-based treatment resulted in the lowest risk of HF. Neither lisinopril nor amlodipine is superior to chlorthalidone for initial treatment of hypertension in either women or men. Clinical Trial Registration— clinicaltrials.gov ; Identifier: NCT00000542.

Clinical Implications

HomeHypertensionVol. 61, No. 4Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 Apr 2013https://doi.org/10.1161/HYP.0b013e31828e0de3Hypertension. 2013;61:745Aldosterone Physiology and Cardiometabolic Risk (page 886)Normal aldosterone regulation is dynamic and responsive. Therefore, single cross-sectional aldosterone measurements capture only a limited range of aldosterone physiology. Quantifying the dynamic nature of aldosterone physiology may improve the understanding of the relationship between aldosterone and cardiometabolic diseases. In this issue of Hypertension, Vaidya et al hypothesized that progressive cardiometabolic abnormalities would predict a blunted dynamic range of aldosterone. Novel indices of aldosterone responses to dietary sodium manipulation were developed, the Sodium-modulated Aldosterone Suppression-Stimulation Index (for serum and SAUSSI for urine), and tested with risk factors in 539 human participants. These indices were calculated as the ratio of aldosterone on a high dietary sodium balance (maximally suppressed aldosterone) to aldosterone on restricted dietary sodium balance (stimulated aldosterone), thereby reflecting the full dynamic range of aldosterone to dietary sodium modulation. Individual cardiometabolic risk factors and components of the metabolic syndrome strongly predicted higher Sodium-modulated Aldosterone Suppression-Stimulation Index and SAUSSI and captured more predictive power than cross-sectional aldosterone measurements alone. These results suggest that abnormal aldosterone physiology, an impaired ability to appropriately stimulate and suppress aldosterone, may contribute to, and result from, progressive cardiometabolic abnormalities.Download figureDownload PowerPointAntihypertensive Therapy and Insulin Action (page 800)Meta-analysis of studies in hypertensive patients using β-blockers and thiazide diuretics indicates that although lowering blood pressure is associated with significantly fewer coronary heart disease events, the benefit is less than that expected from prospective observational data. One explanation is that these older drugs adversely affect cardiovascular risk factors through deleterious effects on insulin action, thereby reducing the impact of blood pressure lowering. This has led to increasing use of newer antihypertensive agents such as angiotensin-converting enzyme inhibitors and calcium channel blockers known to have neutral metabolic effects. Despite this, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the largest antihypertensive study to date, has shown diuretics to be superior to these newer agents in lowering some cardiovascular outcomes. In this issue of Hypertension, McHenry et al report results from a small study of carefully selected nondiabetic hypertensive patients. In a randomized double-blind crossover protocol, the authors find that sensitive measures of insulin action assessed by the euglycemic hyperinsulinemic clamp technique are no different after treatment with an angiotensin-converting enzyme inhibitor combined with low-dose thiazide compared with an angiotensin-converting enzyme inhibitor alone. These results contrast with the authors’ previous studies in diabetic hypertensive patients, where even low doses of thiazides had a negative impact on glucose metabolism. Overall, the current study is reassuring and should encourage physicians to include low-dose thiazide diuretics in treatment regimens for essential hypertension.Left Ventricular Global Function Index: Predictive Value (page 770)Current indices of left ventricular (LV) function are adequate at reflecting the heart’s actual functional state with respect to the vascular system and the body’s needs. However, they do not take into account how much structural remodeling has occurred and the lifetime evolution of the cardiovascular (CV) system for 1 specific individual. Our intent with proposing this novel approach was to integrate information on ventricular remodeling into the functional capacity of the heart for a given vascular system of an individual.By assessing stroke volume with respect to size of LV cavity and myocardium, the LV global function index combines LV mass, volume, and stroke volume into 1 index. In a multiethnic population free of symptomatic CV disease at baseline, the LV global function index was strongly and consistently associated with adverse CV events during follow-up, whereas LV ejection fraction was not associated with hard CV events beyond heart failure. LV global function index’s predictive power was better and more consistent than LV mass-to-volume ratio and LV ejection fraction and was comparable with indexed LV mass.By conventional indices, the impact of long-standing increased workload, such as hypertension, is manifested on LV structure before LV function. It is, therefore, essential to have a reliable and reproducible assessment of both LV structure as well as LV function in the risk stratification of cardiac patients. Therefore, LV global function index may provide unique information in the CV risk assessment and therapeutic follow-up of hypertensive patients.Download figureDownload PowerPoint Previous Back to top Next FiguresReferencesRelatedDetails April 2013Vol 61, Issue 4 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/HYP.0b013e31828e0de3 Originally publishedApril 1, 2013 PDF download Advertisement

Treatment of Hypertension

A method of treating hypertension by oral administration of the ethyl ester of L- alpha -methyl-3,4-dihydroxyphenylalanine or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions are disclosed.

Hypertension Control Among Newly Treated Patients Before and After Publication of the Main ALLHAT Results and JNC 7 Guidelines

Medication prescribing practice changed following the publications of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in 2002 and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) in 2003. Few data are available on changes in hypertension control rates for patients initiating antihypertensive treatment before and after these publications. The authors compared systolic and diastolic blood pressure (SBP and DBP) levels and hypertension control (SBP <140 mm Hg and DBP <90 mm Hg) rates in patients initiating antihypertensive treatment in a large managed care organization during 2 time periods: July 1, 2001, to June 30, 2002 (n=322); and July 1, 2003, to June 30, 2004 (n=323). The blood pressure reduction associated with antihypertensive medication initiation was similar in 2001-2002 and 2003-2004 (-11.9 and -10.5 mm Hg, respectively, P=.251 for SBP; -6.9 and -5.9 mm Hg, respectively, P=.160 for DBP). The mean SBP and DBP prior to treatment were significantly lower in 2003-2004 vs 2001-2002 (145.4 vs 151.3 mm Hg, P<.001 for SBP; 87.6 vs 90.1 mm Hg, P<.002 for DBP). Hypertension control rates increased from 38.0% to 50.2% (P=.005) from 2001-2002 to 2003-2004. Lower pretreatment SBP and DBP explained hypertension control improvement over time. In this real-world clinic population, antihypertensive treatment was initiated at lower blood pressure levels following publication of ALLHAT and JNC 7, resulting in substantial improvements in hypertension control rates.

Long-Term Effects of Incident Diabetes Mellitus on Cardiovascular Outcomes in People Treated for Hypertension

Thiazide-type diuretics are associated with an increased incidence of diabetes compared with other antihypertensive medications. In this study, we determined the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use. A total of 22 418 participants from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years posttrial) through the use of national databases. The primary outcome was CVD mortality (death from coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction or fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, nonsignificant risk for CVD mortality (hazard ratio [HR], 1.04; 95% CI, 0.74-1.47), all-cause mortality (HR, 1.04; 95% CI, 0.82-1.30), and non-CVD mortality (HR, 1.05; 95% CI, 0.77-1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range, 1.22-1.53). Participants with incident diabetes had elevated CHD risk compared with those with no diabetes (HR, 1.46; 95% CI, 1.09-1.96), but those on chlorthalidone had significantly lower risk than those on lisinopril (HR, 1.18 versus 2.57; P=0.04 for interaction). The findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops while on other antihypertensive medications.

Above Which Blood Pressure Level Does the Risk of Atrial Fibrillation Increase?

See related article, pp 198–204 Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, occurs in 1% to 2% of the general population,1 and its incidence is growing. Mostly because of the progressive aging of the population, the prevalence of AF is expected to double over the next 50 years.1 AF is a potentially devastating condition for several reasons. It portends a 5-fold risk of stroke,2 and ischemic strokes that occur in people with AF are often fatal or leave surviving patients generally more disabled and at higher risk of recurrences compared with other causes of stroke. AF triples the risk of heart failure,3 doubles the risk of dementia, and markedly increases the risk of all-cause mortality.4 For the above reasons, prevention of AF through appropriate control of its modifiable risk factors is a public health priority. Unfortunately, despite numerous experimental and clinical studies, the individual risk of developing AF in a given time frame is still difficult to estimate.5 Hypertension is a well-known modifiable risk factor for AF,3,4 although it is unclear above which blood pressure (BP) level the risk of AF definitely increases and, even more important, which target BP level should be pursued to reduce the risk of AF in treated hypertensive patients. In a population based, case-control study of 433 patients with incident AF and 899 controls, the risk of AF doubled in participants with systolic BP ≥150 …

Long-Term Follow-Up of Participants With Heart Failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Long-Term Follow-Up of Participants With Heart Failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Long-Term Follow-Up of Participants With Heart Failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participants, risk of new-onset heart failure (HF) was higher in the amlodipine (2.5-10 mg/d) and lisinopril (10-40 mg/d) arms compared with the chlorthalidone (12.5-25 mg/d) arm. Similar to other studies, mortality rates following new-onset HF were very high (≥50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases. With the use of national databases, posttrial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups, with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81-1.12) and 1.05 (0.89-1.25), respectively, for amlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fractions (84%) and preserved ejection fractions (81%), with no significant differences by randomized treatment arm. Once HF develops, risk of death is high and consistent across randomized treatment groups. Measures to prevent the development of HF, especially blood pressure control, must be a priority if mortality associated with the development of HF is to be addressed. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

The Best Medicine

In this article the author discusses how comparative effectiveness research may help reduce rising medical care costs in the U.S. She presents a brief overview of a clinical trial investigating treatments for hypertension (high blood pressure) in the U.S., called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), conducted by the U.S. National Heart, Lung, and Blood Institute (NHLBI). Topics include the NHLBI's rationale for the cost of the trial, which found that cheap diuretics worked better than more expensive drugs to rid the body of excess fluid, the cost of randomized control trials, and a solution for finding effective treatments without the costs of a standard clinical trial. INSET: Are We Getting Our Money's Worth?.

Resistant Hypertension

See related article, pp 1076–1080 Resistant hypertension (RHTN) is most simply defined as high blood pressure (BP) requiring ≥4 antihypertensive medications, whether controlled or uncontrolled.1 The true prevalence of RHNT is unknown and is likely to remain so, because determining an accurate estimation of prevalence would require a large prospective study of a diverse hypertensive cohort in which subjects' medications are force titrated if the BP remains above goal, adherence is closely monitored, and ambulatory BP monitoring is done to exclude white-coat RHTN. Given the cost and logistical challenges, such a study has not been done and is not likely to ever be done. In the absence of a definitive study, clinical trials have been largely relied on to serve as surrogate opportunities to estimate the prevalence of RHTN. In that regard, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is probably the most relevant in that it included a large and diverse cohort, and, per protocol, subjects were to have continued escalation of their treatment regimen as long as the BP remained elevated.2 At the end of the 5-year treatment period, uncontrolled hypertension was common in ALLHAT, with 34% of subjects never having achieved BP control and with 27% of subjects receiving ≥3 antihypertensive medications.3 These data, as well as control rates from other clinical trials, have been interpreted to suggest a prevalence of RHTN of 20% to 30% of general hypertensive cohorts.1 The problem, of course, is that ALLHAT and other clinical trials …

Time to re-appraise the role of alpha-1 adrenoceptor antagonists in the management of hypertension?

The role of alpha-1 adrenoceptor antagonists (alpha-blockers) in the management of hypertension continues to evolve. Recent data support their use as add-on therapy in uncontrolled hypertension when used in combination with all other major classes of antihypertensive drug and there is increasing evidence suggesting that they have modest but significant beneficial effects on lipid and glucose metabolism. The availability of extended-release formulations has contributed to an excellent tolerability profile. New data from an observational analysis of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) suggest that doxazosin gastrointestinal therapeutic system (GITS) used as a third-line antihypertensive agent lowered blood pressure and caused modest reductions in plasma lipids. Furthermore, use of doxazosin in ASCOT was not associated with an increased risk of heart failure, in contrast to the earlier finding of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Overall, currently available data support the use of alpha-blockers as safe, well tolerated and effective add-on antihypertensive drugs, which have additional favourable metabolic effects.

ALLHAT: still providing correct answers after 7 years

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is re-evaluated considering information from recent subgroup and exploratory analyses, other new clinical trials, and meta-analyses. The ALLHAT analyses specifically emphasize heart failure findings, results in Black participants and those with chronic kidney disease, selection and doses of thiazide and similar diuretics, and the association of antihypertensive drug use with new-onset diabetes and its cardiovascular consequences. The initial ALLHAT conclusion, that thiazide diuretics are superior to angiotensin-converting enzyme inhibitors (ACEIs), calcium antagonists (CCBs) and alpha-blockers in preventing one or more major clinical outcomes, including heart failure and stroke, and unsurpassed in significantly preventing any cardiovascular or renal outcome, has been further validated for patients with diabetes, renal disease, and/or metabolic syndrome. The evidence is even more compelling for Black patients. New-onset diabetes associated with thiazides did not increase cardiovascular outcomes. The diuretic was superior to all in preventing heart failure with preserved left-ventricular ejection fraction (LVEF) and similar to the ACEI in preventing heart failure with impaired LVEF. It was also unsurpassed in preventing atrial fibrillation. The totality of evidence re-affirms the initial ALLHAT conclusion that thiazide and similar diuretics (at evidence-based doses) are the preferred first-step therapy in most patients with hypertension.