Chlorthalidone vs Hydrochlorothiazide for Hypertension-CV Events: Did the Design Influence the Outcome?

The Diuretic Comparison Project (DCP)1 was a real world study planned to evaluate in a pragmatic manner whether Chlorthalidone (CTD), as compared with Hydrochlorothiazide (HCTZ), would reduce the risk of major nonfatal cardiovascular disease outcomes in elderly hypertensive participants (≥65 years) who were receiving HCTZ (25 or 50 mg) at baseline. This study being a real world study lacks the robustness of a randomized controlled trial. The principle limitation being unequal exposure of the two diuretics, prolonged unknown duration of exposure to HCTZ vs a short exposure to CTD (Median 2.4 years). In the high risk population with history of MI/Stroke, CTD conferred a lower risk of primary outcome as compared to low risk population where no significant difference in outcome was seen in both diuretics. Other factors included, lack of established dose equivalency of the two diuretics and absence of use of 12.5 mg HCTZ in older hypertensives. How to cite this article: Pareek A, Messerli FH, Ram CVS. Chlorthalidone vs Hydrochlorothiazide for Hypertension-CV Events: Did the Design Influence the Outcome? J Assoc Physicians India 2023;71(10):93-93.

Comparative evaluation of efficacy and safety of artesunate-lumefantrine vs. artemether-lumefantrine fixed-dose combination in the treatment of uncomplicated Plasmodium falciparum malaria.

OBJECTIVE: To establish efficacy and safety of artesunate/lumefantrine fixed-dose combination (FDC) in comparison with artemether/lumefantrine FDC in treatment of uncomplicated Plasmodium falciparum malaria. METHODS: Confirmed cases of uncomplicated P. falciparum malaria were randomly assigned to receive artesunate (100 mg)/lumefantrine (480 mg) (ASLF FDC) or artemether (80 mg)/lumefantrine (480 mg) (AMLF FDC) tablets for 3 days. Patients were followed up on Day 7, 14, 21 and 28. RESULTS: Of the 158 enrolled patients, 144 completed the study. Seventy-three patients (94.8%) from the ASLF group and 71 patients (94.7%) from the AMLF group showed parasite clearance within 48 h. The mean parasite clearance time was 25.40 ± 14.82 h in the ASLF group and 24 ± 13.32 h in the AMLF group (P = 0.542). All patients showed gametocyte clearance by Day 7 and remained gametocyte free till Day 28. Sixty-five patients (84.4%) from the ASLF group and 56 patients (74.7%) from the AMLF group were afebrile within 24 h. The mean fever clearance time was 17.38 ± 12.33 h in the ASLF group and 17.2 ± 12.01 h in the AMLF group (P = 0.929). There was one early treatment failure in the AMLF group as per WHO criteria. Improvement in haemoglobin and haematocrit was comparable in both the treatment groups. In the ASLF group, of the 25 (32.47%) patients anaemic at baseline, only seven (9.09%) reported anaemia on Day 28, while in the AMLF group, of the 14 (18.67%) patients anaemic at baseline, only four (5.33%) reported anaemia on Day 28. Both study medications were well tolerated. CONCLUSION: Artesunate (100 mg)/lumefantrine (480 mg) fixed-dose combination could add one more option to currently available artemisinin combinations in treatment of uncomplicated P. falciparum malaria.

Evaluation of efficacy and tolerability of glimepiride and metformin combination: a multicentric study in patients with type-2 diabetes mellitus, uncontrolled on monotherapy with sulfonylurea or metformin.

The objectives of this study were to evaluate the efficacy and tolerability of glimepiride plus extended release metformin (MET) on glycemic control in patients with type-2 diabetes mellitus uncontrolled on monotherapy with sulfonylurea or MET. This was a prospective, open-labeled, multicentric study over 12 weeks. Patients who were diagnosed with type-2 diabetes and were uncontrolled on monotherapy with single oral hypoglycemic agents such as glimepiride or MET and characterized by glycosylated hemoglobin (HbA1c) ≥7% and ≤10% and fasting plasma glucose (FPG) ≥ 140 mg/dL were enrolled in this study. Treatment regimen was started at 1 mg of glimepiride plus 500 mg of MET once a day and was titrated to next dose level depending on the clinician's judgment, not exceeding a total daily dose of 8 mg of glimepiride and 2000 mg of MET. After 12-weektreatment, glimepiride plus MET combination showed improvement in metabolic control as assessed by changes in HbA1c, FPG, and post prandial glucose (PPG). Primary efficacy parameter, HbA1c, was significantly reduced to (7.65 ± 1.70) at the end of the treatment from the baseline value (8.35 ± 0.93) (P < 0.001). Of the patients, 65.79% showed ≥0.5% reduction in HbA1c and or HbA1c <7% at the end of the therapy. FPG and PPG were significantly reduced at the end of the therapy as compared with baseline values (P < 0.001). Moreover, the lipid profile was also improved during the treatment period. The addition of glimepiride to MET is an effective treatment for patients inadequately controlled on sulfonylurea or Met alone. A combination of glimepiride with MET achieves good glycemic control with better tolerability profile.

Evaluation of efficacy and tolerability of gliclazide and metformin combination: a multicentric study in patients with type 2 diabetes mellitus uncontrolled on monotherapy with sulfonylurea or metformin.

The objective of this study was to compare the effects of gliclazide/metformin on glycemic control in patients with Type 2 diabetes mellitus uncontrolled on monotherapy with sulfonylurea or metformin. This was a prospective, open-labeled, multicentric study over 12 weeks. Patients who were diagnosed of Type 2 diabetes and were uncontrolled on monotherapy with oral hypoglycemic agents, including gliclazide and metformin, characterized by HbA1c 7% or greater and 10% or less and fasting plasma glucose (FPG) 140 mg/dL or greater were enrolled in this study. The treatment regimen was started at 80 mg gliclazide plus 500 mg metformin once a day and was titrated to the next dose level depending on the clinician's judgment, not exceeding a total daily dose of 320 mg gliclazide and 2000 mg metformin. Changes from baseline HbA1c, FPG, and postprandial glucose were examined. After 12-weeks treatment, the gliclazide + metformin combination showed improvement in metabolic control as assessed by changes in HbA1c, FPG, and postprandial glucose. The primary efficacy parameter, HbA1c, was significantly reduced to 7.35 ± 1.10 at the end of treatment from the baseline value (8.51 ± 0.77) (P < 0.001). A total of 84.35% of patients showed a 0.5% or greater reduction in HbA1c and 37.39% of patients reported less than 7% HbA1c at the end of therapy. FPG and postprandial glucose were significantly reduced at the end of therapy as compared with baseline values (P < 0.001). Moreover, the lipid profile was also improved during the treatment period. The addition of gliclazide to metformin is an effective treatment for patients inadequately controlled on sulfonylurea or metformin alone. A combination of gliclazide with metformin achieves good glycemic control and improves lipid levels with better tolerability profile.

A randomized, comparative, multicentric evaluation of atenolol/amlodipine combination with atenolol alone in essential hypertensive patients.

As there is a strong, positive, and continuous correlation between blood pressure and risk of cardiovascular diseases; improved control of blood pressure is necessary to produce maximum reduction in clinical cardiovascular endpoints. The primary objective was to demonstrate that atenolol/amlodipine combination therapy is superior to atenolol monotherapy with respect to mean fall in systolic blood pressure and diastolic blood pressure. The secondary objective was to compare the response rate and to evaluate the tolerability of study medications. This randomized, comparative, multicentric, 12-week study consisted of screening visit followed by baseline visit 48-hours postscreening. All enrolled patients received 7-day placebo washout. Eligible patients were randomized to receive either atenolol 25 mg/amlodipine 2.5 mg or atenolol 25 mg alone. Nonresponders after 4 weeks of therapy were escalated to atenolol 50 mg/amlodipine 5 mg or atenolol 50 mg, respectively. Out of 190 enrolled patients (94: combination group; 96: monotherapy group), 174 patients (84: combination therapy, 90: monotherapy) completed the study. After 4 weeks of therapy, low-dose combination group was superior to low-dose monotherapy with respect to mean fall in SBP (P = 0.008) and DBP (P = 0.021) and response rate (P = 0.012). Also high-dose combination therapy was superior to high-dose monotherapy with respect to mean SBP (P = 0.001), DBP (P = 0.011), and response rate (P = 0.035) at the end of 12 weeks of therapy. At the end of therapy, significantly more number of patients from combination group achieved normalization of BP (SBP < 120 mmHg and DBP < 80 mmHg) (P = 0.009). Thus, once daily treatment with atenolol/amlodipine fixed-dose combination offers superior antihypertensive efficacy over atenolol monotherapy in patients with mild-to-moderate essential hypertension.

Efficacy and tolerability of a fixed-dose combination of metoprolol extended release/amlodipine in patients with mild-to-moderate hypertension: a randomized, parallel-group, multicentre comparison with losartan plus amlodipine.

BACKGROUND: Epidemiological studies and clinical trials have shown that prevention of cardiovascular disease, the ultimate goal of hypertension treatment, requires a sufficient reduction in blood pressure. OBJECTIVE: The primary objective of this study was to compare the mean decrease in systolic (SBP) and diastolic (DBP) blood pressure between metoprolol extended release (XL)/amlodipine fixed-dose combination and losartan plus amlodipine combination in patients with mild-to-moderate essential hypertension. The secondary objectives of this study were to compare the proportion of responders in the two treatment groups and to evaluate the tolerability of the study medications. METHODS: This was a randomized, parallel-group, multicentre comparative study conducted at the outpatient departments of three teaching hospitals in India. Patients with mild-to-moderate hypertension (defined as DBP 90-109 mmHg) aged between 18 and 75 years were enrolled in this study and followed up for 12 weeks. Response to study treatments was evaluated in terms of mean decrease in SBP and DBP and the response rate (reduction to SBP <140 mmHg and DBP <90 mmHg). RESULTS: Out of 152 patients who underwent a 1-week placebo washout, 148 eligible patients were randomized to receive either metoprolol XL 25 mg/amlodipine 2.5 mg fixed-dose combination (76 patients) or losartan 25 mg plus amlodipine 2.5 mg (72 patients). The two treatment groups were similar with respect to demographic and baseline characteristics. Non-responders after 4 weeks of therapy were escalated to metoprolol XL 50 mg/amlodipine 5 mg fixed-dose combination or losartan 50 mg plus amlodipine 5 mg, respectively. The study was completed by 66 patients in each group, of whom 43 patients in each group responded to the starting doses. After 4 weeks' therapy, both treatments were associated with significant decreases in SBP and DBP from baseline (p < 0.001) and were comparable with respect to mean decrease in SBP (p = 0.304), mean decrease in DBP (p = 0.630) and response rate (p = 1.0). Also, both the step-up therapies were comparable with respect to mean decrease in SBP (p = 0.484), mean decrease in DBP (p = 0.650) and response rate (p = 0.134) at week 12. Both treatments were well tolerated in the studied population. CONCLUSION: Metoprolol XL/amlodipine fixed-dose combination was found to be as effective and well tolerated as losartan plus amlodipine in the treatment of essential hypertension.

Interamerican Society of Cardiology (IASC) position statement: Chlorthalidone vs. thiazide-type diuretics.

The Interamerican Society of Cardiology (IASC) Position Statement for hypertension management in Latin America is a practical and useful review of five different hypertension guidelines. Though, thiazide diuretics have been recommended as firstline option, the position statement needs to highlight differences within the thiazide class. Chlorthalidone is structurally and pharmacokinetically distinct from thiazide-type iuretics like hydrochlorothiazide with a longer half-life and 24-h anti-hypertensive effect. It has been shown to reduce cardiovascular morbidity and mortality in several landmark studies evaluating anti-hypertensives.

Aceclofenac-tizanidine in the treatment of acute low back pain: a double-blind, double-dummy, randomized, multicentric, comparative study against aceclofenac alone.

Tizanidine and aceclofenac individually have shown efficacy in the treatment of low back pain. The efficacy and tolerability of the combination have not yet been established. The objective of the study was to evaluate the efficacy and safety of aceclofenac-tizanidine fixed dose combination against aceclofenac alone in patients with acute low back pain. This double-blind, double-dummy, randomized, comparative, multicentric, parallel group study enrolled 197 patients of either sex in the age range of 18-70 years with acute low back pain. The patients were randomized to receive either aceclofenac (100 mg)-tizanidine (2 mg) b.i.d or aceclofenac (100 mg) alone b.i.d for 7 days. The primary efficacy outcomes were pain intensity (on movement, at rest and at night; on VAS scale) and pain relief (on a 5-point verbal rating scale). The secondary efficacy outcomes measures included functional impairment (modified Schober's test and lateral body bending test) and patient's and investigator's global efficacy assessment. aceclofenac-tizanidine was significantly superior to aceclofenac for pain intensity (on movement, at rest and at night; P < 0.05) and pain relief (P = 0.00) on days 3 and 7. There was significant increase in spinal flexion in both the groups from baseline on days 3 and 7 with significant difference in favour of the combination group (P < 0.05). There were significantly more number of patients with excellent to good response for the aceclofenac-tizanidine treatment as compared to aceclofenac alone (P = 0.00). Both the treatments were well tolerated. In this study, aceclofenac-tizanidine combination was more effective than aceclofenac alone and had a favourable safety profile in the treatment of acute low back pain.

Compelling therapy of LVH: straight (and not-so-straight) inferences from evidence.

We have read with interest the Korean Society of Hypertension guidelines for the management of hypertension and congratulate the Society for an extensive review of literature while drafting the guidelines. The guidelines indicate preferring ACE-I and CCB over diuretics in patients with left ventricle hypertrophy. However, in landmark head-to-head comparison trials, the thiazide-like diuretic chlorthalidone has been shown to be superior to ACE-I and CCB in decreasing left ventricle mass and preventing heart failure in hypertensive patients. Also, we put forth the paradoxical finding that mere regression of LVH may not always translate into reduction in risk of HF; and that the pleiotropic effects of chlorthalidone may be the explanation behind its beneficial action in HF.

Chlorthalidone, not hydrochlorothiazide, is the right diuretic for comparison.

We have read the study design "Comparison of effects between calcium channel blocker and diuretics in combination with angiotensin II receptor blocker on 24-h central blood pressure and vascular hemodynamic parameters in hypertensive patients: study design for a multicenter, double-blinded, active controlled, phase 4, randomized trial" by Oh GC, et al. with interest. The authors aim to compare the efficacy of amlodipine or hydrochlorothiazide (HCTZ) with an ARB. However, we wish to highlight that chlorthalidone (CTD) is the evidence-based and recommended anti-hypertensive diuretic, and should replace HCTZ in the trial to effectively compare efficacy against the CCB amlodipine.

Aceclofenac: Species-Dependent Metabolism and Newer Paradigm Shift from Oral to Non-oral Delivery.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the group of drugs prescribed in various pain related disorders and inflammatory conditions. Diclofenac (DI) is widely prescribed drug for chronic inflammatory conditions like osteoarthritis (OA), a highly prevalent musculoskeletal disorder of adults, projected to affect about 60 million people of total world population by 2020. The chronic oral administration of diclofenac is linked with many gastrointestinal complications like ulceration, bleeding and perforation. These issues paved the way for the development of a structurally similar drug Aceclofenac, which proved to be a safer and more efficient alternative. In spite of better tolerability of Aceclofenac, the oral use of it is not completely free from typical NSAID like side effects. Thus in this context, it becomes mandatory to explore the potential of newer delivery approaches. Amongst the varied newer carrier-systems, microemulsion systems, lipidic colloidal carrier systems and many other supramolecular systems promise to improve the delivery. They tend to place the molecules to the desired target site or in the vicinity without disturbing the unaffected normal surrounding tissues and also ensure enhanced permeation into the skin. The current investigation highlights and deals with the different conventional and novel approaches used thus far in oral delivery of Aceclofenac, their limitations and recent shift towards non oral routes.

Aceclofenac cocrystal nanoliposomes for rheumatoid arthritis with better dermatokinetic attributes: a preclinical study.

AIM: The aim of present research was to complex aceclofenac with lysine (LYS) and the developed aceclofenac-LYS cocrystal was encapsulated in lipid bilayers of liposomes by employing dual carrier approach for the treatment of pain-related disorders in rheumatoid arthritis (RA). MATERIALS & METHODS: The developed carriers were characterized for particle size, drug release, ex vivo and in vivo studies, dermatokinetic modeling, complete freund's adjuvant (CFA)-induced RA rat model, radiant heat tail-flick method, formalin-induced paw-licking model, paw edema model and xylene-induced ear edema model in mice. RESULTS: The developed nanoliposomes offered nanometric size, controlled drug release and enhanced drug permeation. Further, hydrogel incorporated nanoproduct was found to be rheologically acceptable and substantially compatible with rodent skin. CONCLUSION: The studies indicated the superiority of LYS-conjugated liposome-entrapped nanocarriers for improved management of conditions like RA over the marketed product.

Efficacy and safety of beta-arteether and alpha/beta-arteether for treatment of acute Plasmodium falciparum malaria.

One hundred thirty-eight adult patients with acute Plasmodium falciparum malaria were randomized to receive either beta-arteether or alpha/beta-arteether. The drugs were administered in the dose of 150 mg once a day intramuscularly for three consecutive days in hospitalized patients. After one week of hospitalization, patients were followed-up for three weeks after release from the hospital. There was no statistically significant difference between cure rates, mean fever clearance time (FCT), mean parasite clearance time (PCT), and occurrence of side effects in either group. The cure rate was 97.14% for beta-arteether and 97.01 for alpha/beta-arteether (P = 0.9660). The mean PCT was 38.49 hours for beta-arteether and 36.90 hours for alpha/beta-arteether (P = 0.6054), and the mean FCT was 37.27 hours for beta-arteether and 37.9 hours for alpha/beta-arteether (P = 0.8718). Both arteether formulations were safe and efficacious in reducing the clinical symptoms of acute falciparum malaria. There was also rapid clearance of parasitemia with both formulations. Thus, either beta-arteether or alpha/beta-arteether can be used in the treatment of acute falciparum malaria.

Congestive heart failure: More common as well as an important cardiovascular outcome.

Hydroxychloroquine, due to its multifaceted pleiotropic benefits including anti-inflammatory effects has great potential in reducing cardiovascular (CV) morbidity and mortality. CV outcome data of hydroxychloroquine is available through 2 retrospective studies in rheumatoid arthritis patients, both of which have not considered congestive heart failure (CHF) as an outcome measure. CHF is an important CV outcome and is more common than myocardial infarction and stroke; and increased age is associated with increased risk of CHF. Hydroxychloroquine has potential in exerting beneficial effects on CHF because of it's effect of mild bradycardia. Hence, we request authors to include CHF as one of the outcome measure in the event driven protocol of the OXI trial.