Superior antihypertensive and cardioprotective effects of chlorthalidone compared with hydrochlorothiazide.

Diuretics are the most commonly used drugs for the treatment of hypertension, either alone or in combination with other antihypertensive drugs. Of all diuretics, hydrochlorothiazide (HCTZ) and chlorthalidone (CTD) are the most commonly used, with HCTZ being the most widely prescribed diuretic. Recent studies have shown that CTD is a better diuretic with superior antihypertensive effectiveness and cardiovascular protection. Although these diuretics are chemically, pharmacokinetically and pharmacodynamically different, CTD continues to be called a "thiazide-like" diuretic. The only common features they both share are a sulfhydryl group in their molecules and their common mechanism and site of diuretic action. In order to get a better understanding of the true pharmacologic actions as well as the benefits and risks of these diuretics, a MEDLINE search of the English language literature between 1964 and January 2021 was conducted, using the terms "diuretics", "hydrochlorothiazide", "chlorthalidone", "hypertension", "cardiovascular disease" and "treatment". From this search, 28 pertinent papers were selected and they will be discussed in this review together with collateral literature. The analysis of results revealed that CTD is superior to HCTZ in antihypertensive effectiveness and cardioprotection and should be the preferred diuretic for the treatment of hypertension.

Unintended consequences of the new ACC/AHA blood pressure treatment guidelines.

Hypertension is a major risk factor for cardiovascular disease, heart failure, chronic kidney disease and stroke. Therefore, its early detection and treatment are very important according to blood pressure (BP) treatment guidelines issued by the various scientific societies. Over the years, BP treatment guidelines have changed from strict control of BP to more relaxed control, and lately to a strict BP control influenced by the results of the SPRINT trial. The recently published BP treatment guidelines by the American College of Cardiology/American Heart Association (ACC/AHA) recommend a systolic BP (SBP) and diastolic BP reduction to less than 130 mmHg and less than 80 mmHg, respectively, for all ages, and have also changed the classification of hypertension by changing the term "prehypertension" of the JNC 7 (7th Joint National Committee) guidelines to "stage 1 hypertension". These changes could have significant social and economic consequences for the patients. In order to get a better perspective of the current status of SBP control, we conducted a MEDLINE search of the English language literature from 2014 to 2018 in connection with recent (2014-2018) BP treatment guidelines, using the terms 'hypertension', 'blood pressure control', 'intensive blood pressure control', 'blood pressure treatment guidelines', and 'benefits and risks of intensive blood pressure control', and 26 pertinent papers were retrieved. These papers together with collateral literature, which goes beyond the year 2014, will be discussed in this review.

Controversies regarding the cardiovascular effects of testosterone replacement therapy in older men.

Testosterone (T) levels decline with the advancement of age and have been associated with increased incidence of cardiovascular disease (CVD). Indeed, several epidemiologic and prospective cohort studies have suggested that low T levels (lower tertile or quartile) are associated with increased incidence of CVD, type 2 diabetes mellitus (T2DM), obesity and dyslipidemia. In contrast, correction of low T levels with testosterone replacement therapy (TRT) is associated with a decrease in the incidence of CVD, T2DM and dyslipidemia as has been demonstrated by several randomized, controlled trials as well as prospective cohort studies. However, recent studies have shown that TRT is associated with an increased incidence of adverse CV events and these studies have created a great controversy regarding the CV benefits of TRT. In order to get a better perspective on the current status of TRT, a focused MEDLINE and Cochrane database search of the recent English language literature between 2010 and 2017 was conducted and 29 pertinent papers were retrieved. The studies reviewed could not definitely confirm the beneficial or adverse CV effects of TRT. Therefore, on the basis of the current stage of knowledge, older male subjects with low T levels could continue to receive TRT, but this decision should be discussed with their physicians.

Promising cardiovascular and blood pressure effects of the SGLT2 inhibitors: a new class of antidiabetic drugs.

Patients with type 2 diabetes mellitus (T2DM) exhibit an increased risk of cardiovascular (CV) events. Treatment of these patients with traditional as well as newer glucose-lowering drugs has not demonstrated superiority in CV outcomes compared to placebo, despite effective control of diabetes. However, the recently FDA-approved sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of T2DM have demonstrated promising CV-protecting and blood pressure-lowering effects in addition to their effectiveness in glucose lowering, making them a novel class of drugs for the treatment of T2DM. So far, there are three SGLT2 inhibitors approved by the FDA and EMA for the treatment of T2DM: canagliflozin, dapagliflozin and empagliflozin. They exert their antihyperglycemic effect through inhibition of SGLT2 in the kidney and significantly reduce glucose reabsorption from the proximal renal tubule. By blocking glucose reabsorption, they lead to loss of calories, weight, abdominal and total body fat, blood pressure and CV complications. One CV outcomes randomized trial and several short-term studies have shown reductions in CV events and blood pressure in patients with T2DM. It is the hope that large ongoing long-term outcome studies will provide further much-needed information, when they are completed.

The impact of SPRINT on the future treatment of hypertension: a mini review.

Blood pressure (BP) control is associated with a significant decrease in the risk of coronary artery disease (CAD), stroke and chronic kidney disease (CKD), and U.S. treatment guidelines in 2003 and 2007 recommended a BP reduction to <140/90 mmHg for uncomplicated hypertension and to <130/80 mmHg for hypertension complicated by CAD, diabetes mellitus (DM) or CKD. In hopes of further decreasing the adverse effects of hypertension, more aggressive lowering of systolic blood pressure (SBP) was tested. However, this aggressive control of SBP did not materialize in additional cardiac benefits, and in fact resulted in worsening of cardiovascular and renal complications with the exception of stroke. These findings led national committees in 2014 and 2015 to draw up new guidelines recommending a relaxation of BP control based on recent clinical evidence, until publication of SPRINT. This National Institutes of Health (NIH)-sponsored study showed that aggressive SBP lowering to <120 mmHg was beneficial in further decreasing the risk of CVD, CVD mortality and strokes. The results of this study will most likely lead to the revision of current guidelines and to the recommendation of stricter BP control. However, the results of SPRINT are not final and still are in contrast with other recent studies. Until new guidelines become available, we should follow the current ones, or move closer to older guidelines depending on the clinical situation. A return to BP <140/90 mmHg for older subjects or uncomplicated hypertension and to <130/80 mmHg for hypertension complicated by CAD, DM and CKD may be appropriate.

The clinical significance and costs of herbs and food supplements used by complementary and alternative medicine for the treatment of cardiovascular diseases and hypertension.

Complementary and alternative medicine (CAM) is widely used by people in the United States and other countries for the treatment of health conditions that include hypertension (HTN), cardiovascular disease (CVD), heart failure, hyperlipidemia and other condtions. The visits to CAM practitioners result in significant out-of-pocket expenses, as CAM is not covered by health insurance in the majority of cases. The reasons for this are that the products used are not closely regulated by governmental regulatory agencies and lack scientific evidence about their effectiveness and safety. The people regard these products as being 'natural' and, consequently, safe. However, there is evidence that these products can be contaminated and adulterated with other substances and could cause harm to the persons who take them. The responsibility falls on the health professionals, who should become familiar with the various CAM products, inquire their patients whether they taking any of these products and advise them accordingly. This review is based on a recent statement issued by the American Medical for the use of CAM for the treatment of HTN. For its preparation, a Medline search of the English language literature was performed between 2010 and 2014 restricted in the use of CAM for CVD and HTN, and from the 88 abstracts reviewed, 23 pertinent papers were selected. These papers together with collateral literature will be discussed in this review regarding CAM and CAM products on their effectiveness and safety for the treatment of CVD and HTN.

Cardiovascular complications from consumption of high energy drinks: recent evidence.

The energy drinks (ED) are caffeinated beverages that are popular among teenagers and young adults. They are aggressively marketed as providing alertness, energy and sex prowess. The EDs in addition to caffeine contain several plant stimulants and simple sugars, which increase their caloric content. The caffeine concentration in these drinks is high and their overconsumption could lead to insomnia, agitation, tremors and cardiovascular complications including sudden death. Alcohol is often mixed with EDs (AMEDs) in the wrong perception that the caffeine in the EDs will prevent the drowsiness and sleepiness from alcohol and allow the person to consume more alcohol. This false perception, could lead to alcohol intoxication and the taking of risky decisions, like driving under the influence of alcohol and the risk of serious physical harm to themselves and others. To prevent the problem of consumption of EDs and AMEDs, the caring physician could help by advising the parents and his young patients about the serious health risks from the consumption of these drinks. In order to grasp the extend of the problem of ED and AMED consumption, we did a Medline search of the English language literature from January 2010 to December 2013, using the terms EDs and alcohol-mixed EDs. All the findings from the recent studies regarding the cardiovascular complications from the consumption of EDs and AMEDs together with collateral literature will be discussed in this review.

Current status of ß-blockers for the treatment of hypertension: an update.

ß-Adrenoceptor blockers (ß-blockers) are one of the oldest classes of cardiovascular drugs still in use. Several short- and long-term clinical outcomes studies have demonstrated their effectiveness and safety for the treatment of hypertension, coronary artery disease, myocardial infarction, heart failure and sudden cardiac death. Due to their safety and efficacy, ß-blockers have been recommended by several national and international committees as first-line therapy of hypertension. However, despite their proven benefits, their use as first-line treatment for hypertension has come under criticism lately. Because of these recent developments, several authors have recommended that ß-blockers no longer be used as first-line therapy for hypertension. In this review, evidence-based information will be presented, which will demonstrate that ß-blockers are an effective and safe class of antihypertensive and cardiovascular drugs for most patients with the exception of black and elderly hypertensive patients in whom the ß-blockers are less effective compared to other classes of drugs. In addition, evidence will be presented from several major meta-analyses that ß-blockers are equally effective in reducing blood pressure and cardiovascular complications. This review will also discuss differences in the mechanism of action of older and newer (third-generation) ß-blockers and provide evidence that newer agents should be preferred over the older ones in the treatment of hypertensive patients with certain comorbidities.

A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina.

Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.

A new paradigm in the treatment of the cardiovascular disease continuum: focus on prevention.

The cardiovascular disease continuum (CVDC) is a sequence of cardiovascular events, which begins from a cluster of cardiovascular risk factors consisting of diabetes mellitus, dyslipidemia, hypertension, smoking and visceral obesity. If these factors are not intervened with early, they will, inexorably, progress to atherosclerosis, coronary artery disease, myocardial infarction, left ventricular hypertrophy, left ventricular dilatation leading to left ventricular diastolic or systolic dysfunction and eventually end stage heart failure and death. For this concise review, a Medline search of the English language literature between the years 2000 and 2009 was conducted and 33 pertinent publications were selected. Based on the evidence contained in these publications, it is possible that early intervention and treatment of the various cardiovascular risk factors, which initiate and perpetuate the CVDC, could prevent it or arrest its further progress. Therefore, this concise review will emphasize the early detection and treatment of the various cardiovascular risk factors, which initiate and perpetuate the CVDC.

Triple-drug, fixed-dose combinations for the treatment of hypertension: focus on olmesartan/amlodipine/hydrochlorothiazide combination.

Hypertension is a major risk factor for cardiovascular, renal and stroke complications. Its incidence continues to rise worldwide, and it is projected that by the year 2025, 1 billion people will be hypertensive. Despite the enormity of the high blood pressure burden, its control to < 140/90 mmHg for uncomplicated hypertensives and < 130/80 mmHg for patients with diabetes mellitus, chronic kidney disease or coronary artery disease remains poor and currently stands at approximately 50%. Reasons for this poor control include physician inertia and poor patient compliance and adherence due mostly to complicated drug regimens. Since hypertension is a multifactorial condition, its control will require the administration of multiple drugs with complimentary mechanisms of action. Several studies have shown that the patient's compliance and adherence to treatment is inversely related with the number of drugs administered. It is, therefore, important to combine different drugs with complimentary mechanisms of action into a single pill. Recent studies have shown that triple-drug combinations are very effective, safe and well tolerated by the patients. Three different triple-drug, fixed-dose combinations have recently been approved by the FDA for the treatment of hypertension, including, olmesartan medoxomil/amlodipine besylate/hydrochlorothiazide. These studies with collateral literature will be discussed in this concise review.

Long-term efficacy of a combination of amlodipine and olmesartan medoxomil ± hydrochlorothiazide in patients with hypertension stratified by age, race and diabetes status: a substudy of the COACH trial.

A prespecified subgroup analysis of a 44-week open-label extension study is presented. The efficacy and safety of the combination of amlodipine (AML) + olmesartan medoxomil (OM), with and without the addition of hydrochlorothiazide (HCTZ), were investigated in patients aged ≥65 and <65 years, Blacks and non-Blacks and patients with and without type 2 diabetes. After an 8-week double-blind, placebo-controlled portion of the study, patients initiated therapy on AML 5 + OM 40 mg per day, were uptitrated stepwise to AML 10 + OM 40 mg per day, with the addition of HCTZ 12.5 mg, and 25 mg if blood pressure (BP) goal was not achieved (<140/90 or <130/80 mm Hg for patients with diabetes). Endpoints included the change from baseline in mean seated systolic BP, mean seated diastolic BP and achievement of BP goal. BP decreased from baseline for all treatments in each prespecified subgroup. By the end of the study, BP goal was achieved in 61.0% of patients aged ≥65 years, 68.1% of patients aged <65 years, 63.3% of Blacks, 67.8% of non-Blacks, 26.9% of patients with diabetes and 72.9% of patients without diabetes. The combination of AML + OM ± HCTZ was efficacious, safe and well tolerated by these subgroups.

Efficacy and tolerability of amlodipine plus olmesartan medoxomil in patients with difficult-to-treat hypertension.

Hypertension is particularly prevalent in patients aged ≥65 years, those with a body mass index ≥30 kg m(-2), Blacks and those with type II diabetes. Here we report a prespecified secondary analysis of the efficacy of amlodipine (10 mg day(-1)), olmesartan medoxomil (40 mg day(-1)), a combination of the two and placebo in these subgroups. Patients were randomized to treatment for 8 weeks. The primary efficacy endpoint was the change from baseline in mean seated diastolic blood pressure (DBP). Secondary efficacy endpoints included the change from baseline in mean seated systolic BP (SBP), proportions of patients achieving BP goal (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes), and the number and percentage of patients achieving a range of BP targets. Safety and tolerability of amlodipine 5 and 10 mg, olmesartan medoxomil 10, 20 and 40 mg, and all possible combinations of the two were also assessed. For each prespecified subgroup, all active treatments resulted in significant BP reductions from baseline (P<0.05). The antihypertensive effect of the combination of amlodipine+olmesartan medoxomil was generally greater than the constituent amlodipine or olmesartan medoxomil monotherapies, regardless of subgroup. In general, more patients receiving combination therapy achieved BP goal than those treated with monotherapies. The safety and tolerability of combinations were similar to monotherapies across the subgroups. These results suggest that the combination of amlodipine+olmesartan medoxomil provides a safe and effective option for the treatment of hypertension in challenging patient populations.

Treatment of hypertension with olmesartan medoxomil, alone and in combination with a diuretic: an update.

Olmesartan medoxomil is an angiotensin II (Ang II) receptor blocker (ARB) that has been approved by the US Food and Drug Administration (FDA) for the treatment of hypertension. It is a prodrug that is hydrolysed in the gut into its active metabolite, olmesartan (RNH-6270). Olmesartan is highly selective for the Ang II type 1 receptor (AT1) to which it binds completely and insurmountably and has very little affinity for the other receptor subtypes AT2 and AT4. After oral administration, in animals and humans, it achieves a maximal blood drug concentration within a maximal time of approximately 2 h. It is then slowly eliminated in the urine and faeces. His half-life is approximately 13 h, which makes it suitable for once-daily administration. Olmesartan medoxomil given orally in single daily doses of 20-40 mg has demonstrated significant blood pressure (BP) lowering effects in hypertensive patients. A medline search for the preparation of this manuscript was conducted and revealed 128 references, from 2000 to 2007. Of these, only 16 well-designed prospective clinical trials were selected. The remaining were either animal studies, reviews or studies in progress. In well-designed clinical trials, olmesartan medoxomil has demonstrated similar antihypertensive actions to the other antihypertensive drugs, as well as other members of its class given the highest recommended doses. In addition, the BP lowering effect of olmesartan, like the other members of its class, is greatly enhanced in combination with a diuretic. Its safety profile is similar to the other ARBs and no different than placebo.

Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence.

Stroke is a major cause of death and disability and its incidence increases linearly with age and the level of systolic and diastolic blood pressure. Stroke, besides being a cause of long-term disability for the affected person, also imposes a significant burden on society and healthcare costs. Although good blood pressure control is very critical for stroke prevention, angiotensin receptor blockers (ARBs) may be superior to angiotensin-converting enzyme inhibitors (ACEIs) for the same degree of blood pressure control. This hypothesis has clinical and experimental support. ARBs prevent stroke incidence by blocking the angiotensin II (AII), AT1 receptors preventing brain ischaemia and allowing AII to stimulate the unoccupied AT2 receptors, which improve brain ischaemia. ACEIs, by reducing AII generation, are less effective in preventing stroke. This hypothesis provides evidence that AII plays an important role in the prevention of stroke. Certain ARBs like losartan, and telmisartan, irbesartan and candesartan possess additional properties which may play a role in stroke prevention, which is independent of AII. These include antiplatelet aggregating, hypouricemic, antidiabetic and atrial antifibrillatory effects. However, the most critical factor in stroke prevention is good blood pressure control irrespective of drug used.

Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan.

Poorly controlled hypertension is a major risk for cardiovascular morbidity and mortality, strokes, heart failure and renal failure. Despite these devastating complications, blood pressure control of

Antihypertensive efficacy and safety of olmesartan medoxomil compared with amlodipine for mild-to-moderate hypertension.

The antihypertensive efficacy of the angiotensin II receptor blocker olmesartan medoxomil has been shown to compare favourably with that of other antihypertensive agents. This randomized, double-blind study compared the antihypertensive efficacy of the starting dose of olmesartan medoxomil with that of the calcium channel blocker amlodipine besylate (amlodipine) in subjects with mild-to-moderate hypertension. Following a 4-week, single-blind, placebo run-in period, 440 subjects aged >/=18 years were randomized to the starting dose of olmesartan medoxomil (20 mg/day), amlodipine (5 mg/day), or placebo for 8 weeks. Subjects were evaluated by 24-h ambulatory blood pressure monitoring (ABPM) and by seated cuff blood pressure (BP) measurements at trough. The primary end point was the change from baseline in mean 24-h diastolic blood pressure (DBP) by ABPM at Week 8. Secondary end points included change from baseline in mean 24-h ambulatory systolic blood pressure (SBP) at 8 weeks, change from baseline in mean seated trough cuff DBP and SBP measurements, and response and control rates for DBP <90 and <85 mmHg. Control rates for SBP <140 and <130 mmHg were also calculated. Olmesartan medoxomil and amlodipine produced significantly greater reductions in ambulatory and seated DBP and SBP compared with placebo. Mean reductions in ambulatory and seated BP were similar between the two active agents; however, in the olmesartan medoxomil group, significantly more patients achieved the SBP goal of <130 mmHg and the DBP goal of <85 mmHg. Both drugs were well tolerated at the recommended starting dose. Although amlodipine was associated with a higher incidence of oedema, this did not reach statistical significance. Olmesartan medoxomil is an effective antihypertensive agent, with BP-lowering efficacy at the starting dose similar to that of amlodipine, and is associated with more patients achieving the rigorous BP goals of SBP <130 mmHg and DBP <85 mmHg.

Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension.

In a multicenter, randomized, double-blind trial, the authors compared the antihypertensive efficacy of once-daily treatment with the new angiotensin II type 1 receptor blocker (ARB) olmesartan (20 mg) with recommended starting doses of losartan (50 mg), valsartan (80 mg), and irbesartan (150 mg) in 588 patients with a cuff diastolic blood pressure (DBP) of greater than or equal to 100 and less than or equal to 115 mm Hg and a mean daytime DBP of greater than or equal to 90 mm Hg and less than 120 mm Hg, as measured by ambulatory blood pressure monitoring. Cuff and ambulatory blood pressures were monitored at baseline and after 8 weeks of treatment. All groups were predominantly white and approximately 62% male, and their mean age was approximately 52 years. In all groups, mean baseline DBP and systolic blood pressure (SBP) were approximately 104 and 157 mm Hg, respectively. The reduction of sitting cuff DBP with olmesartan (11.5 mm Hg), the primary efficacy variable of this study, was significantly greater than with losartan, valsartan, and irbesartan (8.2, 7.9, and 9.9 mm Hg, respectively). Reductions of cuff SBP with the four ARBs ranged from 8.4-11.3 mm Hg and were not significantly different. The reduction in mean 24-hour DBP with olmesartan (8.5 mm Hg) was significantly greater than reductions with losartan and valsartan (6.2 and 5.6 mm Hg, respectively) and showed a trend toward significance when compared to the reduction in DBP with irbesartan (7.4 mm Hg; p=0.087). The reduction in mean 24-hour SBP with olmesartan (12.5 mm Hg) was significantly greater than the reductions with losartan and valsartan (9.0 and 8.1 mm Hg, respectively) and equivalent to the reduction with irbesartan (11.3 mm Hg). All drugs were well tolerated. The authors conclude that olmesartan, at its starting dose, is more effective than the starting doses of the other ARBs tested in reducing cuff DBP in patients with essential hypertension.

Similar effects of isolated systolic and combined hypertension on left ventricular geometry and function: the LIFE Study.

Echocardiograms of 143 patients with isolated systolic hypertension were compared to 808 patients with combined (systolic and diastolic) hypertension. All patients met electrocardiographic criteria for left ventricular hypertrophy and were evaluated off medication. Patients with isolated systolic hypertension were older, shorter, weighed less, and were mostly women, but body mass index (BMI) was similar in both groups. Systolic blood pressure (SBP) was 172 mm Hg in isolated systolic hypertension, 174 mm Hg in combined (P = not significant). Diastolic blood pressure was 83 and 101 mm Hg, respectively (P < .001). Despite having mean arterial pressure 12 mm Hg lower than patients with combined hypertension, the group with isolated systolic hypertension had equally severe abnormalities of left ventricular mass, left ventricular geometric patterns, and measures of systolic and diastolic function. Peripheral resistance was lower and pulse pressure/stroke volume ratio (arterial stiffness index) was higher and the isovolumic relaxation time shorter in isolated systolic hypertension. Multiple regression analyses identified age, height, BMI, stress-corrected mid wall shortening, stroke volume, male gender, and systolic or mean blood pressure (but not isolated systolic hypertension) as independent correlates of left ventricular mass. Relative wall thickness was independently associated with isolated systolic hypertension (P = .001) in addition to mean pressure and other covariates. The present results add support to the concept that systolic blood pressure (SBP) is a stronger determinant than diastolic pressure of cardiac target organ damage in hypertension.