THIAZIDE DIURETICS













HCTZ vs Others for Hypertension in Male Veterans, NEJM (1993) [PubMed abstract]
  • The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
  • Male veteran
  • DBP 95 - 109 mmHg off medications
Baseline characteristics
  • Average age 59 years
  • Average BP 152/99 mmHg
  • Black race - 48%
  • Current smoker - 32%
Randomized treatment groups
  • Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
  • Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
  • Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
  • Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
  • Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Placebo
  • There was a washout period of 4 - 8 weeks before randomization
  • Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results

Average BP reduction at the end of the titration phase (SBP/DBP mmHg)
HCTZ Atenolol Captopril Clonidine Diltiazem Prazosin Placebo
14 / 10 11 / 12 9 / 10 16 / 12 13 / 14 12 / 11 3 / 5
  • Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
  • All medications were significantly better than placebo for blood pressure reduction
  • The incidence of side effects with HCTZ was similar to placebo

Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.


Average blood pressure reduction with thiazide diuretics compared to placebo (SBP/DBP)
HCTZ 6.25 mg/day HCTZ 12.5 mg/day HCTZ 25 mg/day HCTZ 50 mg/day Chlor 12.5 - 75 mg/day
4 / 2 6 / 3 8 / 3 11 / 5 12 / 4
  • HCTZ data based on 33 trials with an average baseline blood pressure of 155/100 mmHg
  • Chlorthalidone data based on 7 trials with an average baseline blood pressure of 163/88 mmHg. In the trials that were evaluated, chlorthalidone did not show a dose-dependent effect on blood pressure




ALLHAT study - Chlorthalidone vs Lisinopril vs Amlodipine for CVD, JAMA (2002) [PubMed abstract]
  • The ALLHAT study enrolled 33,357 patients with hypertension and either a history of CVD or risk factors for CVD
Main inclusion criteria
  • Age > 55 years
  • SBP ≥ 140 and/or DBP ≥ 90 or treated hypertension
  • One of the following: previous MI or stroke, left ventricular hypertrophy (LVH), type 2 diabetes, smoker, low HDL (< 35 mg/dl)
Main exclusion criteria
  • History of hospitalized or treated symptomatic heart failure
  • EF < 35%
Baseline characteristics
  • Average age 67 years
  • Women - 47%
  • Average BP - 146/84
  • Receiving treatment for hypertension - 90%
  • Race: White - 47% | Black - 32% | Hispanic - 16%
  • Qualifying risk factor: CVD - 52% | Diabetes - 36% | Smoker - 22% | LVH - 21% | Low HDL - 12%
Randomized treatment groups
  • Group 1 (15,255 patients) - Chlorthalidone 12.5 - 25 mg a day
  • Group 2 (9048 patients) - Amlodipine 2.5 - 10 mg/day
  • Group 3 (9054 patients) - Lisinopril 10 - 40 mg/day
  • Treatment was titrated to a BP goal of < 140/90
  • If BP goal was not met taking the maximum tolerated dosage of the initial medication, open-label Step 2 agent (atenolol, 25-100 mg/d, reserpine, 0.05-0.2 mg/d, or clonidine, 0.1-0.3 mg twice per day), or an open-label Step 3 agent (hydralazine, 25-100 mg twice per day) could be added
  • There was another arm of the study that used doxazosin. That arm was stopped early due to an increased risk of major CVD events. See ALLHAT doxazosin for more.
Primary outcome: Composite of fatal coronary heart disease or nonfatal myocardial infarction
Results

Duration: Average of 4.9 years
Outcome Chlor Aml Lis Comparisons
Primary outcome (6-year rate) 11.5% 11.3% 11.4% 1 vs 2 p=0.65 | 1 vs 3 p=0.81
Overall mortality (6-year rate) 17.3% 16.8% 17.2% 1 vs 2 p=0.20 | 1 vs 3 p=0.90
Stroke (6-year rate) 5.6% 5.4% 6.3% 1 vs 2 p=0.28 | 1 vs 3 p=0.02
Heart failure (6-year rate) 7.7% 10% 8.7% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
Achieved BP goal (< 140/90) at 1 year 57.8% 55.2% 50.6% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
Potassium < 3.5 mEq/L at 2 years 12.7% 2.6% 1.5% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
New-onset diabetes at 4 years 11.6% 9.8% 8.1% 1 vs 2 p=0.04 | 1 vs 3 p<0.001

Findings: Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.







Chlorthalidone vs Placebo in Patients with Hypertension and Stage 4 Kidney Disease, NEJM (2021) [PubMed abstract]
  • The study enrolled 160 patients with stage 4 kidney disease (GFR < 30 ml/min) and uncontrolled hypertension
Main inclusion criteria
  • Stage 4 CKD (GFR 15 to <30 ml/min)
  • Uncontrolled hypertension defined as 24-hour ambulatory SBP > 130 or DBP > 80 while receiving ≥ 1 antihypertensive
Main exclusion criteria
  • 24-hour ambulatory SBP > 160 or DBP > 100
  • History of stroke or MI
  • Receiving > 200 mg of furosemide or > 100 mg of torsemide
Baseline characteristics
  • Average age 66 years
  • Average GFR - 23 ml/min
  • Average BP - 140/68 mmHg
  • Median spot ACR - 830
  • Median NT-proBNP - 590 pg/ml
  • Diabetes - 76%
  • Receiving loop diuretic - 60%
  • Average # of antihypertensives - 3.4
Randomized treatment groups
  • Group 1 (81 patients): Chlorthalidone 12.5 - 50 mg once daily (average dose at 12 weeks was 23.1 mg)
  • Group 2 (79 patients): Placebo
  • The dose used in the assigned regimen was doubled every 4 weeks if, at that time, the patient had a home SBP of 135 mmHg or higher or DBP of 85 mmHg or higher: at week 4, the dose was doubled from 12.5 mg once daily to 25 mg once daily, and at week 8, the dose was doubled to 50 mg once daily (maximum dose). The dose was not increased if the patient had symptomatic orthostatic hypotension, hypercalcemia, moderate hypokalemia (potassium level < 3 mEq/L), acute gout, or recent hospitalization for poorly controlled diabetes. In these instances, the dose was either maintained or decreased, as determined by the investigator.
  • There was a 2-week run-in period where antihypertensive doses were standardized for all subjects
  • The patients were required to be receiving an ACE inhibitor or ARB or a beta-blocker at the time of randomization
Primary outcome: Change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks
Results

Duration: 12 weeks
Outcome Chlorthalidone Placebo Comparisons
Primary outcome (SBP mmHg) -11.0 -0.5 p<0.001
% change in ACR -52% -4% diff -50%, 95%CI [-60 to -37%]
% change in NT-proBNP -30% -11% diff -21%, 95%CI [-35 to -4%]
Change in GFR -2.7 ml/min -0.5 ml/min diff -2.2 ml, 95%CI [-3.3 to -1.0]
Increase in SCr > 25% 45% 13% N/A
Hypokalemia 10% 0% N/A
Hypomagnesemia 23% 16% N/A
Hyperuricemia 20% 9% N/A
Hyperglycemia 16% 5% N/A
Dizziness 25% 16% N/A
  • After the trial was over, patients were followed for 2 weeks off study meds. During this time, GFR reductions in the chlorthalidone group returned to baseline.
  • In subgroup analysis, loop diuretic use had no significant effect on SBP reduction

Findings: Among patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo.







HCTZ vs Placebo for Osteoporosis Prevention, Annals of Internal Medicine (2000) [PubMed abstract]
  • A study in the Annals of Internal Medicine enrolled healthy men and women aged 60 - 79 years
Main inclusion criteria
  • Age 60 - 79 years
  • Normotensive
  • Bone mineral density (BMD) within 2 standard deviations of normal for their age (Z-score ± 2)
Main exclusion criteria
  • Taking bisphosphonates or hormone replacement therapy
  • Serious heart disease
  • Proteinuria
  • Elevated serum creatinine
  • Hyponatremia
  • Hypokalemia
  • Gout
  • Use of any diuretics or BP medications
  • Risk factors for osteoporosis (e.g. corticosteroids, malabsorptive conditions, etc.)
Baseline characteristics
  • Average age 68 years
  • Average BMD women (total hip) - 0.768 g/cm²
  • Average BMD men (total hip) ∼ 0.945 g/cm²
  • Average calcium intake (women) - 1100 - 1400 mg/day
  • Average calcium intake (men) - 770 - 944 mg/day
Randomized treatment groups
  • Group 1 (105 patients) Placebo once daily
  • Group 2 (108 patients) HCTZ 12.5 mg once daily
  • Group 3 (107 patients) HCTZ 25 mg once daily
  • All subjects were given advice to consume 1000 - 1500 mg of calcium a day
  • BMD measurements were taken every 6 months
Primary outcome: Percent change in BMD at the total hip over 3 years
Results

Duration: 3 years
Outcome Placebo HCTZ 12.5 mg HCTZ 25 mg Comparisons
Primary outcome (% change in women) -0.81% -0.06% +0.62% 1 vs 2, diff 0.75, 95%CI [-0.43 to 1.92] | 1 vs 3, diff 1.43, 95%CI [0.25 to 2.60]
Primary outcome (% change in men) +0.54% +1.36% +0.58% 1 vs 2, diff 0.83, 95%CI [-0.60 to 2.25] | 1 vs 3, diff 0.04, 95%CI [-1.42 to 1.51]
Still taking assigned medication at 3 years (men) 81.6% 89.7% 60.5% N/A
  • Groups 2 and 3 had more hypokalemia requiring potassium supplements than Group 1 [27]

Findings: In healthy older adults, low-dose hydrochlorothiazide preserves bone mineral density at the hip and spine. The modest effects observed over 3 years, if accumulated over 10 to 20 years, may explain the one-third reduction in risk for hip fracture associated with thiazide in many epidemiologic studies.