Addition Of Hydrochlorothiazide Research Articles

Combining Loop and Thiazide DiureticsAcross the Left Ventricular Ejection Fraction Spectrum: The CLOROTIC Trial.

The addition of hydrochlorothiazide (HCTZ) to furosemide in the CLOROTIC (Combining Loop with Thiazide Diuretics for Decompensated HeartFailure) trial improved the diuretic response in patients with acute heart failure (AHF). This work aimed to evaluate if these results differ across the spectrum of left ventricular ejection fraction (LVEF). This post hoc analysis of the randomized, double-blind, placebo-controlled CLOROTIC trial enrolled 230patients with AHF to receive either HCTZ or a placebo in addition to an intravenous furosemide regimen. The influence of LVEF on primary and secondary outcomes was evaluated. The median LVEF was 55%: 166 (72%) patients had LVEF >40%, and 64 (28%) had LVEF≤40%. Patients with a lower LVEF were younger, more likely to be male, had a higher prevalence of ischemic heart disease, and had higher natriuretic peptide levels. The addition of HCTZ to furosemide was associated with the greatest weight loss at 72of 96 hours, better metrics of diuretic response, and greater 24-hour diuresis compared with placebo, with no significant differences according to the LVEF category (using 2 LVEF cutoff points: 40% and 50%) or LVEF as a continuous variable (all P values were insignificant). There were no significant differences observed with the addition of HCTZ in terms of mortality, rehospitalizations, or safety endpoints (impaired renal function, hyponatremia, and hypokalemia) among the 2 LVEF groups (all P values were insignificant). Adding HCTZ to intravenous furosemide seems to be effective strategy for improving diuretic response in AHF without treatment effect modification according to baseline LVEF. (Combining Loop with Thiazide Diuretics for Decompensated HeartFailure [CLOROTIC], NCT01647932; Randomized, double blinded, multicenter study, to asses Safety and Efficacy of the Combination of Loop With Thiazide-type Diuretics vs Loop diuretics with placebo in Patients With Decompensated, EudraCT Number 2013-001852-36).

HYDROchlorothiazide versus placebo to PROTECT polycystic kidney disease patients and improve their quality of life: study protocol and rationale for the HYDRO-PROTECT randomized controlled trial

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD.MethodsThe HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m2, and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care.OutcomesThe primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m2 per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume.ConclusionThe HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.

Sex differences in clinical characteristics and outcomes in the CLOROTIC (combining loop with thiazide diuretics for decompensated heart failure) trial

AimsThe addition of hydrochlorothiazide (HCTZ) to furosemide improved the diuretic response in patients with acute heart failure (AHF) in the CLOROTIC trial. Our aim was to evaluate if there were differences in clinical characteristics and outcomes according to sex. MethodsThis is a post-hoc analysis of the CLOROTIC trial, including 230 patients with AHF randomized to receive HCTZ or placebo in addition to an intravenous furosemide regimen. The primary and secondary outcomes included changes in weight and patient-reported dyspnoea 72 and 96 h after randomization, metrics of diuretic response and mortality/rehospitalizations at 30 and 90 days. The influence of sex on primary, secondary and safety outcomes was evaluated. ResultsOne hundred and eleven (48%) women were included in the study. Women were older and had higher values of left ventricular ejection fraction. Men had more ischemic cardiomyopathy and chronic obstructive pulmonary disease and higher values of natriuretic peptides. The addition of HCTZ to furosemide was associated to a greatest weight loss at 72/96 h, better metrics of diuretic response and higher 24-h diuresis compared to placebo without significant differences according to sex (all p-values for interaction were not significant). Worsening renal function occurred more frequently in women (OR [95%CI]: 8.68 [3.41−24.63]) than men (OR [95%CI]: 2.5 [0.99−4.87]), p = 0.027. There were no differences in mortality or rehospitalizations at 30/90 days. ConclusionAdding HCTZ to intravenous furosemide is an effective strategy to improve diuretic response in AHF with no difference according to sex, but worsening renal function was more frequent in women. Clinical trial registrationClinicaltrials.gov: NCT01647932; EudraCT Number: 2013-001852-36.

Combining loop and thiazide diuretics for acute heart failure across the estimated glomerular filtration rate spectrum: A post-hoc analysis of the CLOROTIC trial.

In patients with acute heart failure (AHF), the addition of hydrochlorothiazide (HCTZ) to furosemide improved diuretic response in the CLOROTIC trial. This work aimed to evaluate if these effects differ across the estimated glomerular filtration rate (eGFR) spectrum. This post-hoc analysis of the CLOROTIC trial analysed 230 patients with AHF and explored the influence of eGFR on primary and secondary endpoints. The median eGFR was 43 ml/min/1.73 m2 (range 14-109) and 23% had eGFR ≥60 ml/min/1.73 m2 (group 1), 24% from 45 to 59 ml/min/1.73 m2 (group 2), and 53% <45 ml/min/1.73 m2 (group 3). Patients treated with HCTZ had greatest weight loss at 72 h in all three groups, but patients in group 1 had a significantly greater response (-2.1 kg [-3.0 to 0.5]), compared to patients in groups 2 (-1.3 kg [-2.3 to 0.2]) and 3 (-0.1 kg [-1.3 to 0.4]) (p-value for interaction = 0.246). At 96 h, the differences in weight were -1.8 kg (-3.0 to -0.3), -1.4 kg (-2.6 to 0.3), and -0.5 kg (-1.3 to -0.1) in groups 1, 2, and 3, respectively (p-value for interaction = 0.256). There were no significant differences observed with the addition of HCTZ in terms of diuretic response, mortality or rehospitalizations, or safety endpoints (impaired renal function, hyponatraemia, and hypokalaemia) among the three eGFR groups (all p-values for interaction were no significant). The addition of eGFR-adjusted doses of oral HCTZ to loop diuretics in patients with AHF improved diuretic response across the eGFR spectrum. ClinicalTrials.gov: NCT01647932; EudraCT number: 2013-001852-36.

Heart failure: an update from the last years and a look at the near future.

In the last years, major progress occurred in heart failure (HF) management. Quadruple therapy is now mandatory for all the patients with HF with reduced ejection fraction. Whilst verciguat is becoming available across several countries, omecamtiv mecarbil is waiting to be released for clinical use. Concurrent use of potassium-lowering agents may counteract hyperkalaemia and facilitate renin-angiotensin-aldosterone system inhibitor implementations. The results of the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trial were confirmed by the Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER) trial, and we now have, for the first time, evidence for treatment of also patients with HF with preserved ejection fraction. In a pre-specified meta-analysis of major randomized controlled trials, sodium-glucose co-transporter-2 inhibitors reduced all-cause mortality, cardiovascular (CV) mortality, and HF hospitalization in the patients with HF regardless of left ventricular ejection fraction. Other steps forward have occurred in the treatment of decompensated HF. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR) trial showed that the addition of intravenous acetazolamide to loop diuretics leads to greater decongestion vs. placebo. The addition of hydrochlorothiazide to loop diuretics was evaluated in the CLOROTIC trial. Torasemide did not change outcomes, compared with furosemide, in TRANSFORM-HF. Ferric derisomaltose had an effect on the primary outcome of CV mortality or HF rehospitalizations in IRONMAN (rate ratio 0.82; 95% confidence interval 0.66-1.02; P=0.070). Further options for the treatment of HF, including device therapies, cardiac contractility modulation, and percutaneous treatment of valvulopathies, are summarized in this article.

Case report: a thiazide diuretic to treat polyuria induced by tolvaptan

BackgroundCurrently, the vasopressin V2 receptor antagonist tolvaptan is the only available treatment for autosomal dominant polycystic kidney disease (ADPKD), but there are tolerability issues due to aquaretic side-effects such as polyuria. A possible strategy to ameliorate these side-effects may be addition of a thiazide diuretic, this is an established treatment in nephrogenic diabetes insipidus, a condition where vasopressin V2 receptor function is absent.Case presentationWe describe a 46-year-old male ADPKD-patient, who was prescribed tolvaptan, which caused polyuria of around 5 l per day. Hydrochlorothiazide was added to treat hypertension, which resulted in a marked decrease in urine production. While using tolvaptan, rate of eGFR decline was − 1.35 mL/min/1.73m2 per year, whereas after hydrochlorothiazide was initiated this was − 3.97 mL/minute/1.73m2 per year.ConclusionsThis case report indicates that while addition of hydrochlorothiazide may improve tolerability of vasopressin V2 receptor antagonists, co-prescription should only be used with great scrutiny as it may decrease tolvaptan effect on rate of ADPKD disease progression.

Efficacy and safety of olmesartan and hydrochlorothiazide versus telmisartan and hydrochlorothiazide in newly diagnosed patients with mild-to-moderate hypertension

Background: Hypertension is one of the most prevalent noncommunicable diseases. The Joint National Commission VIII guidelines recommend angiotensin receptor blockers (ARBs) as the first‑line drug and addition of hydrochlorothiazide (HCTZ) increases their efficacy. Olmesartan medoxomil is recently introduced, whereas telmisartan is a relatively older ARB. This study was conducted to assess the efficacy and safety of olmesartan and HCTZ versus telmisartan and HCTZ in the treatment of mild‑to‑moderate hypertension. Materials and Methods: A total of 120 patients with mild‑to‑moderate hypertension were recruited and randomized to receive either olmesartan 20 mg+HCTZ 12.5 mg (Group O) or telmisartan 40 mg+HCTZ 12.5 mg (Group T) orally once daily for 8 weeks. Blood pressure (BP) and heart rate were recorded at baseline and at 4th and 8th weeks, but blood sugar and lipid profile were estimated at baseline and 8th week. Results: Forty‑six Group O and 44 Group T patients completed the study. Majority of patients were in the fifth decade of life (72.3%), 56% were males, and 35% had type II diabetes mellitus and received oral antidiabetics. The mean BP was 148.6 ± 5.9/89.2 ± 5.9 and 147.9 ± 5.2/88.1 ± 4.2 mmHg at baseline and decreased significantly at week 8 (131.0 ± 5.4/80.3 ± 2.9 and 136.8 ± 5.5/83.6 ± 3.9 mmHg) in Group O and Group T respectively. Patients in Group O had significant reduction in systolic BP (SBP) (P = 0.0001) and diastolic BP (P = 0.04) than that in Group T. More than 10 mmHg decrease in SBP was observed in 86.9% versus 65.9% of patients in Group O and Group T, respectively, which was statistically significant (P = 0.01). Diabetic patients in both groups had a significant decrease in blood sugar by week 8, but intergroup comparison was insignificant. Change in heart rate and lipid profile was negligible. Common adverse effects were dizziness, abdominal pain and pedal edema in both groups. Conclusion: Olmesartan + HCTZ was more effective than telmisartan + HCTZ in lowering BP.

Addition of hydrochlorothiazide to angiotensin receptor blocker therapy can achieve a lower sodium balance with no acceleration of intrarenal renin angiotensin system in patients with chronic kidney disease.

Objective:Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR).Methods:The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease.Results:Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (tNa), although 24-hour urinary Na excretion (UNaV) remained constant. Daily urinary angiotensinogen excretion (UAGTV, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r2=0.26) and tNa (r2=0.25) correlated with baseline 24-hour UAGTV. Changes in filtered Na load correlated with changes in nighttime systolic BP (r2=0.17), but not with changes in daytime systolic BP. The change in the tNa to filtered Na load ratio was influenced by the change in daytime UNaV (β=−0.67, F=16.8), rather than the change in nighttime UNaV.Conclusions:Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of UAGTV by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events.

Antihypertensive and metabolic effects of hydrochlorothiazide versus amlodipine when added to losartan in patients with type 2 diabetes.

We performed a prospective, randomized, multicenter, parallel-group, per-protocol study to compare the effects of hydrochlorothiazide (HCTZ) and amlodipine as add-on to losartan treatment in hypertensive type 2 diabetic patients. A total of 49 Japanese type 2 diabetic patients with inadequate control of blood pressure while receiving losartan 50mg were randomly allocated to receive a fixed-dose single-pill combination of HCTZ 12.5mg plus losartan (N=26) or a free combination of amlodipine 5mg plus losartan (N=23). During 8weeks of follow-up, changes in blood pressure and laboratory data including HbA1c, uric acid, and potassium were compared between the groups using analysis of covariance. Systolic and diastolic blood pressure decreased in both groups, the reductions of which were greater in the amlodipine group. However, the least square mean (95% CI) differences between groups were not statistically significant [2.3 (-6.8 to 11.4) mmHg, p=0.618 and 2.7 (-2.4-7.9) mmHg, p=0.293, respectively]. HbA1c increased in patients receiving HCTZ but not in the amlodipine group. Uric acid also increased in patients receiving HCTZ but decreased in patients receiving amlodipine, yielding a significant between-group difference of 1.0 (0.5-1.5) mg/dl (p<0.001). No intra- or intergroup change was observed in serum potassium levels. This pilot study suggests that HCTZ and amlodipine result in nonsignificant effects on systolic and diastolic blood pressure reduction when administrated as add-on therapy to losartan in hypertensive patients with type 2 diabetes; however, addition of HCTZ may be associated with less favorable effects on metabolic profiles than amlodipine.

Efficacy and Safety of Aliskiren/Amlodipine or Aliskiren/Amlodipine/Hydrochlorothiazide Combinations

Background: In stage II hypertensive patients, a combination antihypertensive therapy is required as in most of the cases the blood pressure (BP) -lowering goal is not achieved by monotherapy. Aliskiren [a first-in-class, orally active direct inhibitor of rennin] is effectively reduces the BP, both as monotherapy as well as in combination with other antihypertensive drugs. Although the safety of aliskiren in combination with amlodipine and hydrochlorothiazide is well established, a regional variation in response and safety of the combination may arise due to the genetic makeup of the study population and lifestyle choices. Objective: To evaluated the safety and efficacy of a combination of aliskiren and amlodipine with or without hydrochlorothiazide in stage II Hypertension in Thai patients population. Method: A 18-week, open-label non randomized study. Following a 2-week run-in period, 230 patients with stage II hypertension were enrolled treated to reach a target blood pressure (BP) < 130/80 mm Hg with treatment intensification sequence of aliskiren/amlodipine 150/5 mg, aliskiren/amlodipine 300/10 mg, aliskiren/amlodipine/hydrochlorothiazide 300/10/12.5 mg,andaliskiren/amlodipine/hydrochlorothiazide 300/10/25 mg for every 4 weeks. At each visit, patients achieving the BP goal (<130/80 mmHg) were excluded from further visits. The efficacy and safety were evaluated. Result: 88.2%(n = 195) patients achieved BP target with aliskiren/amlodipine 150/5 mg, whereas 10.4% (n = 23) required a treatment up-titration to aliskiren/amlodipine 300/10 mg, and only 1.3% (n = 3) patients required an addition of hydrochlorothiazide to the aliskiren/amlodipine combination. Subgroup analysis by age and diabetes status revealed similar treatment outcomes in this study. The combination was well tolerated, with only headache and vertigo as the most commonly occurring adverse events in 1.7% (n = 4) and 1.3% (n = 3) of the patients, respectively. Conclusion: Combinations of aliskiren and amlodipine or an addition of hydrochlorothiazide to the combination is effective and safe in the treatment of patients with stage II hypertension in Thailand.

Long-term safety of nebivolol and valsartan combination therapy in patients with hypertension: an open-label, single-arm, multicenter study

Long–term safety of a free–tablet combination of nebivolol and valsartan was assessed in a Phase III, open–label trial (NCT01415505). Adults with hypertension entered a 4–week placebo run–in phase, followed by a 52–week treatment phase. Initial dosage (Neb/Val 5/160 mg/d) was titrated up to 20/320 mg/d to achieve blood pressure (BP) goal (JNC7 criteria), with the addition of hydrochlorothiazide (up to 25 mg/d) if needed. Safety and tolerability parameters included adverse events. Efficacy assessments included baseline–to–endpoint change in diastolic BP and systolic BP and the percentage of patients who achieved BP goal. All analyses were performed using descriptive statistics. Study completion rate was 60.4% (489/810). The most frequent reason for discontinuation was insufficient therapeutic response (8.4%). Adverse events were experienced by 59.2% of patients, with the most common being headache (5.7%), nasopharyngitis (5.0%), and upper respiratory tract infection (4.6%). Three (0.4%) deaths occurred during the study; none was considered related to study medication. Mean ± standard deviation changes from baseline at week 52 (observed cases) were −25.5 ± 15.9 mm Hg (systolic BP) and −19.0 ± 8.7 mm Hg (diastolic BP). A total of 75.7% nebivolol/valsartan–treated and 57.8% nebivolol/valsartan/hydrochlorothiazide–treated completers achieved BP goal. Long–term treatment with nebivolol and valsartan in adults with hypertension was safe and well–tolerated.

Abstract 042: Effects of Diuretics on Sglt2 Inhibitor-induced Changes in Urinary Sodium Excretion Rate In Obese Metabolic Syndrome Rats

Proximal tubular sodium-glucose co-transporter 2 (SGLT2) transports glucose and sodium with a 1:1 stoichiometry. However, studies have indicated that treatment with SGLT2 inhibitors does not substantially increase the urinary excretion rate of sodium, while that of glucose is markedly increased. These data suggest that urinary sodium is reabsorbed by other mechanisms distal to the nephron during SGLT2 inhibition. Here, we aimed to investigate whether diuretics affect the SGLT2 inhibitor-induced changes in the urinary excretion rate of sodium in obese metabolic syndrome SHR/NDmcr-cp(+/+) (SHRcp) rats. Male 13-week-old SHRcp rats were treated with: 1) vehicle (0.5% carboxymethylcellulose), 2) a SGLT2 inhibitor, luseogliflozin (10 mg/kg/day, p.o.), 3) luseogliflozin + hydrochlorothiazide (10 mg/kg/day, p.o.) or 4) luseogliflozin + hydrochlorothiazide + furosemide (5 mg/kg/day, p.o.) for 5 weeks (n = 6-8 per group). Blood pressure and glucose metabolism were evaluated by telemetry and oral glucose tolerance test respectively. Vehicle-treated SHRcp rats developed non-dipper type hypertension (night and day time systolic blood pressure; 186 ± 2 and 185 ± 2 mmHg, respectively) and insulin resistance. As compared with vehicle-treated animals, luseogliflozin-treated rats showed an approximately 4,000-fold increase in urinary glucose excretion and improved glucose metabolism. Luseogliflozin also slightly decreased blood pressure, which was associated with an approximately 30% increase in urinary excretion of sodium. The addition of hydrochlorothiazide or hydrochlorothiazide + furosemide further decreased blood pressure and improved blood pressure circadian rhythm to a dipper profile in luseogliflozin-treated animals. In these animals, urinary sodium excretion tended to be increased by diuretics, although these changes were not statistically significant. These data indicate that SGLT2 inhibitor-induced natriuresis is not enhanced by diuretics. Thus, SGLT2 inhibitors may elicit their beneficial effects on glucose metabolism and hypertension in patients who are treated with diuretics.

Comparative effect of canrenone or hydrochlorothiazide addition to valsartan/amlodipine combination on urinary albumin excretion in well-controlled type 2 diabetic hypertensive patients with microalbuminuria

Objective: To compare the effect of adding canrenone or hydrochlorothiazide (HCTZ) to valsartan/amlodipine combination on urinary albumin excretion (UAE) in microalbuminuric type 2 diabetic hypertensives.Research design and methods: After a 2-week placebo period and after 4 weeks of valsartan 160 mg plus amlodipine 5 mg combination, 120 patients whose blood pressure (BP) was not controlled (> 130/80 mmHg) were randomized to canrenone 25 mg or HCTZ 12.5 mg in addition to the previous therapy for 24 weeks. After the first 6 weeks of triple therapy, canrenone or HCTZ doses were doubled in the patients whose BP was yet uncontrolled. At the end of each period (placebo, dual combination and triple combination therapy), clinic and ambulatory BP measurements were recorded and 24 h UAE was evaluated.Results: Both triple combinations produced greater clinical and ambulatory BP reduction than dual therapy, with no difference between the two groups. UAE was reduced by both regimens, but the decrease associated with canrenone add-on therapy was more pronounced. At week 24, UAE decreased by 45.3% in the canrenone group and by 20.3% in the HCTZ group (p < 0.01).Conclusions: These findings indicate that, despite similar BP-lowering effect, the addition of canrenone to valsartan/amlodipine combination was more effective in reducing UAE than HCTZ addition.

CHANGES IN THE PARAMETERS OF 24-HOUR BLOOD PRESSURE MONITORING AND ARTERIAL STIFFNESS IN PATIENTS WITH HYPERTENSION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE TREATED WITH VALSARTAN

Aim. To study changes in the parameters of the 24-hour blood pressure (BP) monitoring and arterial stiffness (AS) in patients with arterial hypertension (HT) and chronic obstructive pulmonary disease (COPD) treated with angiotensin II receptors blocker, valsartan. Material and methods. Men with HT and COPD (n=23), who have been receiving valsartan with starting dose 80 mg/day for 6 months as antihypertensive therapy were included into the study. If target BP was not achieved, correction of the valsartan dose was carried out with the hydrochlorothiazide addition when needed. Clinical examination, 24-hour BP and AS monitoring using BPLab MnSDP-2 monitor ("Petr TELEGIN",Russia), clinical evaluation of COPD were performed. Results. Abnormal circadian BP profile and the elastic properties of arteries were diagnosed in the majority of hypertensive patients with COPD. Valsartan therapy allowed to achieve target BP levels in 100% of patients, normalization of circadian BP profile in 56.5%, improvement in AS parameters: a significant increase in PTT2 (from 89.6±14.3 to 94.4±18.4 ms), reduction of (dP/dt)max (from 566.6±117.9 to 518.8±146.2 mmHg/s), AIx (from -4.0±15.2 to -11.6±20.8 %) as compared to the baseline. Circadian changes in daily parameters of AS in studied patients with the most obvious night-time abnormalities of the elastic properties of arteries were detected. Valsartan intake led to Alx reduction at night-time. Conclusion. Valsartan-based therapy in hypertensive patients with concomitant COPD demonstrated a high antihypertensive efficacy and favorable changes in the elastic properties of the vascular wall that confirm its organoprotective effect.

In vitro study of the interaction of cysteine with a thiazide diuretic (hydrochlorothiazide) at different ph by voltammetric and spectroscopic techniques

The interaction of cysteine (RSH) with a thiazide diuretic, hydrochlorothiazide (HCTZ) was characterized by UV-Vis absorption spectroscopy and square-wave voltammetry in Britton-Robinson (B-R) buffer solution (with pH 5, 7 and 9). On the square-wave voltamogram of cysteine, the reduction peak current of mercurous cysteine thiolate (Hg2(RS)2) decreased and its peak potential shifted to more positive values with the addition of HCTZ. This results showed that the RSH interacted with HCTZ. The stoichiometry of HCTZ-RSH molecular complex was determined by voltammetric data with the result of 1: 1. By using linear regression analysis of the voltammetric data at pH 5, 7 and 9, the apparent formation constants of HCTZ-RSH complex were calculated to be 9.54 × 103, 2.80 × 104 and 2.55 × 104 M−1, respectively. At the same time, this interaction was also supported by UV-Vis spectroscopic measurements. According to the voltammetric and spectroscopic results, it was suggested that the interaction mode between RSH and HCTZ molecules might be a combination of hydrophobic interactions and hydrogen bonds.

Aliskiren-based dual- and triple-combination therapies in high-risk US minority patients with Stage 2 hypertension

Previously, we reported the efficacy of aliskiren/amlodipine in US minority adults with stage 2 hypertension, with additional blood pressure (BP) lowering from the addition of hydrochlorothiazide (HCTZ). A subgroup analysis in patients with hypertension and comorbidities of diabetes, cardiometabolic syndrome, or obesity, and in black participants is reported. This 8-week, multicenter, double-blind study included 412 self-identified minority patients with mean sitting systolic BP (msSBP) ≥160 mm Hg and <200 mm Hg). Patients were randomized to receive either combination aliskiren/amlodipine 150/5 mg or amlodipine 5 mg. Doses were forced-titrated to a maximum of aliskiren/amlodipine/HCTZ 300/10/25 mg or aliskiren/amlodipine 300/10 mg, respectively. There were 256 black (62%), 118 diabetic (29%), 284 cardiometabolic syndrome (69%), and 249 obese (60%) randomized patients. Baseline msSBP was ∼167 mm Hg across all subgroups. Least-square mean reductions in msSBP, the primary efficacy outcome, from baseline to week 8 across all subgroups, ranged from 35 to 37 mm Hg with aliskiren/amlodipine/HCTZ and 28 to 30 mm Hg with aliskiren/amlodipine (P < .01 for all between-treatment comparisons). Both regimens were well tolerated. Among high-risk patients, such as diabetics or those with cardiometabolic syndrome, combination aliskiren/amlodipine is effective in lowering BP; the addition of HCTZ provided incremental BP-lowering efficacy while maintaining tolerability. However, because our subgroups were not mutually exclusive, the generalization of our findings to the population seen in clinical practice is limited.

Efficacy and tolerability of the single-pill combination of aliskiren 300 mg/amlodipine 10 mg in hypertensive patients not controlled by olmesartan 40 mg/amlodipine 10 mg

Objective:We aimed to investigate whether the single pill combination (SPC) of aliskiren 300 mg and amlodipine 10 mg (ALIS 300/AMLO 10) improves blood pressure (BP) reduction in hypertensive patients not adequately controlled by the SPC olmesartan 40 mg and amlodipine 10 mg (OLM 40/AMLO 10).Methods:Open-label, non-randomized single-arm study. Patients with stage 2 hypertension were titrated to the SPC OLM 40/AMLO 10 (4-week Phase 1). If hypertension was not controlled they were switched to the SPC ALIS 300/AMLO 10 (4-week Phase 2). In the optional 4-week study extension hydrochlorothiazide (HCT) 12.5 mg was added. EudraCT 2009-016693-33.Results:In the 342 patients treated, OLM 40/AMLO 10 reduced systolic BP (SBP)/diastolic BP (DBP) by 24.5/14.5 mmHg by end of Phase 1. Those 187 patients with uncontrolled hypertension at the end of Phase 1 switched to ALIS 300/AMLO 10 experienced a further SBP reduction of 5.1 mmHg (95% confidence interval [CI] 3.7 to 6.5, p < 0.0001) and a DBP reduction of 4.8 mmHg (95% CI 3.8 to 5.8; p < 0.0001) in Phase 2. DBP or SBP responder rates were achieved by 51.3% or 44.4%, respectively, SBP and DBP normalization by 36.4%. In 65 patients whose BP was not controlled in Phase 2, SPC ALIS 300/AMLO 10/HCT 12.5 mg decreased SBP/DBP by further 8.1/6.7 mmHg (p < 0.0001 each). No deaths or serious adverse events were noted. Significant adverse events leading to study discontinuation were reported in 2.6% (Phase 1), 2.7% (Phase 2), and 0% (extension). Limitations included the open-label, single-arm non-randomized design, and the relatively short duration.Conclusions:In this switch study reflecting clinical practice, patients with moderate hypertension not controlled by the SPC OLM 40/AMLO 10 achieved a clinically and statistically significant reduction of blood pressure from the SPC ALIS 300/AMLO 10 and the optional addition of HCT. All drug combinations were well tolerated.

Blood Pressure-Lowering Efficacy of an Olmesartan Medoxomil/Hydrochlorothiazide-Based Treatment Algorithm in Elderly Patients (Age ≥65 Years) Stratified by Age, Sex and Race

Hypertension is a leading risk factor for development of heart failure, stroke and renal disease in the elderly. The objective of this study was to evaluate, by means of a prespecified secondary analysis of a 12-week, open-label, single-arm, dose-titration study, the blood pressure (BP)-lowering efficacy and safety of an olmesartan medoxomil (OM)/hydrochlorothiazide (HCTZ)-based titration regimen in patients aged ≥65 years with hypertension. Subgroups were stratified by age (≥65 to ≤75 or >75 years), sex (male or female) and race (Black or non-Black). Following a 2- to 3-week placebo run-in phase, patients received OM 20 mg, uptitrated to OM 40 mg, followed by addition of HCTZ 12.5-25 mg step-wise at 3-week intervals if seated cuff BP (SeBP) was ≥120/70 mmHg. Patients below this target SeBP were maintained at their current dose but uptitrated to the next consecutive dose if mean seated cuff systolic BP (SBP) was ≥140 mmHg and/or mean seated cuff diastolic BP was ≥90 mmHg at follow-up visits. Efficacy was assessed by 24-hour ambulatory BP monitoring (ABPM) and SeBP measurements. The primary efficacy variable was the change from baseline in mean 24-hour ambulatory SBP after 12 weeks. Secondary efficacy endpoints included the change from baseline in mean 24-hour ambulatory SBP; change from baseline in ambulatory BP during the daytime (8:00 am-4:00 pm), nighttime (10:00 pm-6:00 am) and the last 6, 4 and 2 hours of the dosing interval; change from baseline in SeBP at each titration step and at study end; and the proportion of patients achieving mean 24-hour ambulatory BP targets and SeBP goals at week 12. The frequency and severity of treatment-emergent adverse events (TEAEs) were also documented. Baseline and week 12 ABPM data were available for 150 out of 178patients who entered the active treatment phase. Changes from baseline in mean 24-hour ambulatory BP were -26.0/-12.5 mmHg and -24.9/-12.0 mmHg in patients aged ≥65 to ≤75 years (n = 128) and >75 years (n = 48), respectively (all p < 0.0001 vs baseline). Changes from baseline in mean 24-hour ambulatory BP were -26.0/-13.0 mmHg and -25.4/-11.5 mmHg in male (n = 92) and female (n = 84) patients, respectively (all p < 0.0001 vs baseline) and -26.7/-11.8 mmHg and -25.6/-12.4 mmHg in Black (n = 28) and non-Black (n = 148) patients, respectively (all p < 0.0001 vs baseline). Clinically significant ambulatory BP reductions were observed during the daytime, nighttime and the last 6, 4 and 2 hours of the dosing interval in all subgroups. Changes from baseline at week 12 in mean SeBP were similar to 24-hour ambulatory BP changes reported previously. At week 12, the proportion of patients achieving the 24-hour ambulatory BP target of <130/80 mmHg ranged from 67.5% to 77.4% and achieving the SeBP goal of <140/90 mmHg ranged from 60.7% to 68.8% across the subgroups. Most TEAEs and drug-related TEAEs were mild or moderate in severity, and there were no trends across subgroups. In a subgroup analysis based upon age, sex and race in patients aged ≥65 years with hypertension, an OM/HCTZ-based algorithm was efficacious and well tolerated. ClinicalTrials.gov Identifier: NCT00412932.

Moderate versus intensive treatment of hypertension using amlodipine/valsartan and with the addition of hydrochlorothiazide for patients uncontrolled on angiotensin receptor blocker monotherapy: results in racial/ethnic subgroups

Combination therapy may reduce racial/ethnic differences in response to antihypertensives. In this post-hoc analysis, we evaluated treatment response by race/ethnicity among hypertensive adults enrolled in a 12-week, double-blind study in which patients previously uncontrolled (mean sitting systolic blood pressure [MSSBP] ≥150 and <200 mm Hg) on angiotensin receptor blocker (ARB) monotherapy (other than valsartan) for 28 days or more (n = 728) were randomized to amlodipine/valsartan 10/320 mg (intensive) or 5/160 mg (moderate). Treatment-naïve patients (in previous 28 days) or those who failed on a non-ARB first underwent a 28-day run-in period with olmesartan 20 mg or 40 mg, respectively. Hydrochlorothiazide (HCTZ) 12.5 mg was added to both arms at week 4; optional up-titration to 25 mg at week 8 (if MSSBP >140 mm Hg). Intensive treatment provided greater BP lowering versus moderate treatment throughout the study, regardless of race/ethnicity (474 white, 198 African American, 165 Hispanic individuals). Least-square mean reductions from baseline to week 4 in MSSBP (primary outcome) ranged from 20.4 to 23.5 mm Hg (intensive) versus 17.5 to 19.0 mm Hg (moderate), across racial/ethnic subgroups. Both regimens were well tolerated. Amlodipine/valsartan/HCTZ combination therapy was efficacious across racial/ethnic subgroups. Maximal efficacy was obtained with intensive treatment.

A Titrate-to-Goal Study of Switching Patients Uncontrolled on Antihypertensive Monotherapy to Fixed-Dose Combinations of Amlodipine and Olmesartan Medoxomil ± Hydrochlorothiazide

In the prospective, open-label, titrate-to-goal Blood Pressure Control in All Subgroups With Hypertension (BP-CRUSH) study, 999 patients with hypertension uncontrolled on monotherapy (mean age, 55.6 ± 11.4 years; baseline blood pressure [BP], 153.7 ± 9.2/91.9 ± 8.6 mm Hg) were switched to fixed-dose amlodipine/olmesartan medoxomil (AML/OM) 5/20 mg. Patients were uptitrated every 4 weeks to AML/OM 5/40 mg and 10/40 mg to achieve BP < 120/70 mm Hg. Patients were subsequently uptitrated every 4 weeks to AML/OM+hydrochlorothiazide (HCTZ) 10/40+12.5 mg and 10/40+25 mg to achieve BP <125/75 mm Hg. The primary end point, the cumulative percentage of patients achieving seated systolic BP < 140 mm Hg (< 130 mm Hg for patients with diabetes) by week 12, was 75.8%. The mean (± standard error) BP changes from baseline during the titration periods ranged from -14.2±0.4 mm Hg/-7.7 ± 0.3 mm Hg for AML/OM 5/20 mg to -25.1 ± 0.7 mm Hg/-13.7 ± 0.4 mm Hg for AML/OM+HCTZ 10/40+25 mg. By week 20, the cumulative BP threshold of <140/90 mm Hg was achieved by 90.3% of patients. An ambulatory BP monitoring substudy (n=243) showed that 24-hour efficacy was maintained. Treatment-emergent adverse events (TEAEs), mostly mild to moderate in severity, occurred in 529 patients (53.0%). Drug-related TEAEs occurred in 255 patients (25.5%). This well-tolerated, treat-to-goal algorithm enabled a large proportion of patients with uncontrolled hypertension on monotherapy to safely achieve BP control on single-pill AML/OM combination therapy or triple therapy with the addition of HCTZ. .