Review

Authors: Panagiotis I Georgianos, Rajiv Agarwal

Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood pressure (BP) measurement is the essential first step in the diagnosis and management of hypertension. Dietary sodium restriction is often overlooked, but can improve BP control, especially among patients treated with an agent to block the renin-angiotensin system. In the presence of very high albuminuria, international guidelines consistently and strongly recommend the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as the antihypertensive agent of first choice. Long-acting dihydropyridine calcium channel blockers and diuretics are reasonable second- and third-line therapeutic options. For patients with treatment-resistant hypertension, guidelines recommend the addition of spironolactone to the baseline antihypertensive regimen. However, the associated risk of hyperkalemia restricts the broad utilization of spironolactone in patients with moderate-to-advanced CKD. Evidence from the CLICK (Chlorthalidone in Chronic Kidney Disease) trial indicates that the thiazide-like diuretic chlorthalidone is effective and serves as an alternative therapeutic opportunity for patients with stage 4 CKD and uncontrolled hypertension, including those with treatment-resistant hypertension. Chlorthalidone can also mitigate the risk of hyperkalemia to enable the concomitant use of spironolactone, but this combination requires careful monitoring of BP and kidney function for the prevention of adverse events. Emerging agents, such as the non-steroidal mineralocorticoid receptor antagonist ocedurenone, dual endothelin receptor antagonist aprocitentan and the aldosterone synthase inhibitor baxdrostat offer novel targets and strategies to control BP better. Larger and longer term clinical trials are needed to demonstrate the safety and efficacy of these novel therapies in the future. In this article, we review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of hypertension in patients with CKD.

Topics: Humans; Spironolactone; Hyperkalemia; Chlorthalidone; Hypertension; Antihypertensive Agents; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Blood Pressure

PubMed: 37355779
DOI: 10.1093/ndt/gfad118

Randomized Controlled Trial

Authors: Rajiv Agarwal, Arjun D Sinha, Andrew E Cramer...

BACKGROUND

Little evidence has been available to support the use of thiazide diuretics to treat hypertension in patients with advanced chronic kidney disease.

METHODS

We randomly assigned patients with stage 4 chronic kidney disease and poorly controlled hypertension, as confirmed by 24-hour ambulatory blood-pressure monitoring, in a 1:1 ratio to receive chlorthalidone at an initial dose of 12.5 mg per day, with increases every 4 weeks if needed to a maximum dose of 50 mg per day, or placebo; randomization was stratified according to previous use of loop diuretics. The primary outcome was the change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks. Secondary outcomes were the change from baseline to 12 weeks in the urinary albumin-to-creatinine ratio, N-terminal pro-B-type natriuretic peptide level, plasma renin and aldosterone levels, and total body volume. Safety was also assessed.

RESULTS

A total of 160 patients underwent randomization, of whom 121 (76%) had diabetes mellitus and 96 (60%) were receiving loop diuretics. At baseline, the mean (±SD) estimated glomerular filtration rate was 23.2±4.2 ml per minute per 1.73 m of body-surface area and the mean number of antihypertensive medications prescribed was 3.4±1.4. At randomization, the mean 24-hour ambulatory systolic blood pressure was 142.6±8.1 mm Hg in the chlorthalidone group and 140.1±8.1 mm Hg in the placebo group and the mean 24-hour ambulatory diastolic blood pressure was 74.6±10.1 mm Hg and 72.8±9.3 mm Hg, respectively. The adjusted change in 24-hour systolic blood pressure from baseline to 12 weeks was -11.0 mm Hg (95% confidence interval [CI], -13.9 to -8.1) in the chlorthalidone group and -0.5 mm Hg (95% CI, -3.5 to 2.5) in the placebo group. The between-group difference was -10.5 mm Hg (95% CI, -14.6 to -6.4) (P<0.001). The percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks was lower in the chlorthalidone group than in the placebo group by 50 percentage points (95% CI, 37 to 60). Hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia occurred more frequently in the chlorthalidone group than in the placebo group.

CONCLUSIONS

Among patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo. (Funded by the National Heart, Lung, and Blood Institute and the Indiana Institute of Medical Research; CLICK ClinicalTrials.gov number, NCT02841280.).

Topics: Aged; Albuminuria; Blood Pressure; Chlorthalidone; Creatinine; Diuretics; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Renal Insufficiency, Chronic; Severity of Illness Index; Sodium Chloride Symporter Inhibitors

PubMed: 34739197
DOI: 10.1056/NEJMoa2110730

Review

Authors: Franz H Messerli, Stefano F Rimoldi, Sripal Bangalore...

Longstanding hypertension ultimately leads to heart failure (HF), and, as a consequence most patients with HF have a history of hypertension. Conversely, absence of hypertension in middle age is associated with lower risks for incident HF across the remaining life course. Cardiac remodeling to a predominant pressure overload consists of diastolic dysfunction and concentric left ventricular (LV) hypertrophy. When pressure overload is sustained, diastolic dysfunction progresses, filling of the concentric remodeled LV decreases, and HF with preserved ejection fraction ensues. Diastolic dysfunction and HF with preserved ejection fraction are the most common cardiac complications of hypertension. The end stage of hypertensive heart disease results from pressure and volume overload and consists of dilated cardiomyopathy with both diastolic dysfunction and reduced ejection fraction. "Decapitated hypertension" is a term used to describe the decrease in blood pressure resulting from reduced pump function in HF. Progressive renal failure, another complication of longstanding hypertension, gives rise to the cardiorenal syndrome (HF and renal failure). The so-called Pickering syndrome, a clinical entity consisting of flash pulmonary edema and bilateral atheromatous renovascular disease, is a special form of the cardiorenal syndrome. Revascularization of renal arteries is the treatment of choice. Most antihypertensive drug classes when used as initial therapy decelerate the transition from hypertension to HF, although not all of them are equally efficacious. Low-dose, once-daily hydrochlorothiazide should be avoided, but long-acting thiazide-like diuretics chlorthalidone and indapamide seem to have an edge over other antihypertensive drugs in preventing HF.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cardio-Renal Syndrome; Chronic Disease; Heart Failure; Humans; Hypertension; Pulmonary Edema; Ventricular Dysfunction, Left

PubMed: 28711447
DOI: 10.1016/j.jchf.2017.04.012

Review

Authors: Domenic A Sica, Barry Carter, William Cushman...

KEY POINTS AND PRACTICAL RECOMMENDATIONS: •  Although chlorthalidone and hydrochlorothiazide are structurally similar, they are very different pharmacokinetically, with chlorthalidone having both an extremely long half-life (approximately 40 to 60 hours) and a large volume of distribution, with gradual elimination from the plasma compartment by tubular secretion. •  Furosemide usage, the most widely used diuretic in the loop diuretic class, can be complicated by extremely erratic absorption, with a bioavailability range of 12% to 112%. •  Chlorthalidone, at a dose of 25 mg, is comparatively more potent than 50 mg of hydrochlorothiazide, particularly as related to overnight blood pressure reduction. •  In ALLHAT, there was no difference among chlorthalidone, amlodipine, lisinopril, and doxazosin for the primary outcome or mortality. •  Secondary outcomes were similar except for a 38% higher rate of heart failure with amlodipine; a 10% higher rate of combined cardiovascular disease, a 15% higher rate of stroke, and a 19% higher rate of heart failure with lisinopril; and a 20% higher rate of cardiovascular disease, a 20% higher rate of stroke (40% higher rate in blacks), and an 80% higher rate of heart failure with doxazosin, compared with chlorthalidone. •  The ACCOMPLISH study may affect future practice guidelines as a result of its findings favoring the amlodipine/benazepril combination; however, the generalizability to patient populations with a lesser cardiovascular risk profile remains in question and the dose of hydrochlorothiazide was only 12.5 mg to 25 mg daily, which was a dose lower than that used in placebo-controlled trials using hydrochlorothiazide. •  Certain low-renin patient groups (eg, blacks, the elderly, and diabetics) as well as those who manifest the metabolic syndrome are commonly more responsive to thiazide-type diuretic therapy. •  Diuretics can be successfully combined with β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, centrally acting agents, and even calcium channel blockers. •  Although thiazide-type diuretics are among the best-tolerated antihypertensive agents in terms of symptomatic adverse effects, diuretic-related adverse side effects include those with established mechanisms (eg, such as electrolyte changes and/or metabolic abnormalities) and other side effects, which are less well understood mechanistically (eg, impotence), although the latter is not universally accepted as a diuretic-related side effect. •  Thiazide-induced hypokalemia is associated with increased blood glucose, and treatment of thiazide-induced hypokalemia may reverse glucose intolerance and possibly prevent diabetes. •  Thiazide-induced hyperuricemia occurs as a result of volume contraction and competition with uric acid for renal tubular secretion, but does not necessarily contraindicate using a thiazide, especially if a uric acid-lowering drug such as allopurinol is being used. •  Adverse interactions include the blunting of thiazide effects by nonsteroidal anti-inflammatory drugs and the potential to increase fatigue, lethargy, and increase in glucose when combined with β-blockers. •  Thiazide-type diuretics are useful first-line agents in the treatment of hypertension because they have been proven to reduce cardiovascular mortality and morbidity in systolic and diastolic forms of hypertension and do so at low cost. •  Loop diuretics should not be used as first-line therapy in hypertension since there are no outcome data with them. They should be reserved for conditions of clinically significant fluid overload (eg, heart failure and significant fluid retention with vasodilator drugs, such as minoxidil) or with advanced renal failure and can be combined with thiazide-type diuretics.

Topics: Antihypertensive Agents; Humans; Hypertension; Hyperuricemia; Hypokalemia; Risk Management; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Treatment Outcome

PubMed: 21896142
DOI: 10.1111/j.1751-7176.2011.00512.x

Review

Authors: Maria Czarina Acelajado, Zachary H Hughes, Suzanne Oparil...

Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting calcium channel blocker, and a blocker of the renin- angiotensin system, either an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin receptor blocker), at maximal or maximally tolerated doses. Antihypertensive medication nonadherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. RHTN is a high-risk phenotype, leading to increased all-cause mortality and cardiovascular disease outcomes. Healthy lifestyle habits are associated with reduced cardiovascular risk in patients with RHTN. Aldosterone excess is common in patients with RHTN, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of ≥5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic and an MR (mineralocorticoid receptor) antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying RHTN, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.

Topics: Aldosterone; Animals; Antihypertensive Agents; Blood Pressure; Drug Resistance; Drug Therapy, Combination; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Risk Factors; Sodium Chloride Symporter Inhibitors; Sympathetic Nervous System; Sympatholytics; Treatment Outcome; Water-Electrolyte Balance

PubMed: 30920924
DOI: 10.1161/CIRCRESAHA.118.312156

Comparative Study Observational Study

Authors: George Hripcsak, Marc A Suchard, Steven Shea...

IMPORTANCE

Chlorthalidone is currently recommended as the preferred thiazide diuretic to treat hypertension, but no trials have directly compared risks and benefits.

OBJECTIVE

To compare the effectiveness and safety of chlorthalidone and hydrochlorothiazide as first-line therapies for hypertension in real-world practice.

DESIGN, SETTING, AND PARTICIPANTS

This is a Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) observational comparative cohort study with large-scale propensity score stratification and negative-control and synthetic positive-control calibration on databases spanning January 2001 through December 2018. Outpatient and inpatient care episodes of first-time users of antihypertensive monotherapy in the United States based on 2 administrative claims databases and 1 collection of electronic health records were analyzed. Analysis began June 2018.

EXPOSURES

Chlorthalidone and hydrochlorothiazide.

MAIN OUTCOMES AND MEASURES

The primary outcomes were acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease outcome including the first 3 outcomes and sudden cardiac death. Fifty-one safety outcomes were measured.

RESULTS

Of 730 225 individuals (mean [SD] age, 51.5 [13.3] years; 450 100 women [61.6%]), 36 918 were dispensed or prescribed chlorthalidone and had 149 composite outcome events, and 693 337 were dispensed or prescribed hydrochlorothiazide and had 3089 composite outcome events. No significant difference was found in the associated risk of myocardial infarction, hospitalized heart failure, or stroke, with a calibrated hazard ratio for the composite cardiovascular outcome of 1.00 for chlorthalidone compared with hydrochlorothiazide (95% CI, 0.85-1.17). Chlorthalidone was associated with a significantly higher risk of hypokalemia (hazard ratio [HR], 2.72; 95% CI, 2.38-3.12), hyponatremia (HR, 1.31; 95% CI, 1.16-1.47), acute renal failure (HR, 1.37; 95% CI, 1.15-1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30). Chlorthalidone was associated with a significantly lower risk of diagnosed abnormal weight gain (HR, 0.73; 95% CI, 0.61-0.86).

CONCLUSIONS AND RELEVANCE

This study found that chlorthalidone use was not associated with significant cardiovascular benefits when compared with hydrochlorothiazide, while its use was associated with greater risk of renal and electrolyte abnormalities. These findings do not support current recommendations to prefer chlorthalidone vs hydrochlorothiazide for hypertension treatment in first-time users was found. We used advanced methods, sensitivity analyses, and diagnostics, but given the possibility of residual confounding and the limited length of observation periods, further study is warranted.

Topics: Antihypertensive Agents; Chlorthalidone; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Retrospective Studies

PubMed: 32065600
DOI: 10.1001/jamainternmed.2019.7454

Authors: Robert M Carey, David A Calhoun, George L Bakris...

Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. The diagnosis of RH requires assurance of antihypertensive medication adherence and exclusion of the "white-coat effect" (office BP above goal but out-of-office BP at or below target). The importance of RH is underscored by the associated risk of adverse outcomes compared with non-RH. This article is an updated American Heart Association scientific statement on the detection, evaluation, and management of RH. Once antihypertensive medication adherence is confirmed and out-of-office BP recordings exclude a white-coat effect, evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised.

Topics: American Heart Association; Antihypertensive Agents; Blood Pressure; Disease Management; Humans; Hypertension; United States

PubMed: 30354828
DOI: 10.1161/HYP.0000000000000084

Review

Authors: Ben J Wilson, Duane Bates

BACKGROUND

Heart failure is a common condition with considerable associated costs, morbidity, and mortality. Patients often present to hospital with dyspnea and edema. Inadequate inpatient decongestion is an important contributor to high readmission rates. There is little evidence concerning diuresis to guide clinicians in caring for patients with acute decompensated heart failure. Contemporary diuretic strategies have been defined by expert opinion and older landmark clinical trials.

OBJECTIVE

To present a narrative review of contemporary recommendations, along with their underlying evidence and pharmacologic rationale, for diuretic strategies in inpatients with acute decompensated heart failure.

DATA SOURCES

PubMed, OVID, and Embase databases were searched from inception to December 22, 2022, with the following search terms: heart failure, acute heart failure, decompensated heart failure, furosemide, bumetanide, ethacrynic acid, hydrochlorothiazide, indapamide, metolazone, chlorthalidone, spironolactone, eplerenone, and acetazolamide.

STUDY SELECTION

Randomized controlled trials and systematic reviews involving at least 100 adult patients (> 18 years) were included. Trials involving torsemide, chlorothiazide, and tolvaptan were excluded.

DATA SYNTHESIS

Early, aggressive administration of a loop diuretic has been associated with expedited symptom resolution, shorter length of stay, and possibly reduced mortality. Guidelines make recommendations about dose and frequency but do not recommend any particular loop diuretic over another; however, furosemide is most commonly used. Guidelines recommend that the initial furosemide dose (on admission) be 2-2.5 times the patient's home dose. A satisfactory diuretic response can be defined as spot urine sodium content greater than 50-70 mmol/L at 2 hours; urine output greater than 100-150 mL/h in the first 6 hours or 3-5 L in 24 hours; or a change in weight of 0.5-1.5 kg in 24 hours. If congestion persists after the maximization of loop diuretic therapy over the first 24-48 hours, an adjunctive diuretic such as thiazide or acetazolamide should be added. If decongestion targets are not met, continuous infusion of furosemide may be considered.

CONCLUSIONS

Heart failure with congestion can be managed with careful administration of high-dose loop diuretics, supported by thiazides and acetazolamide when necessary. Clinical trials are underway to further evaluate this strategy.

PubMed: 38204501
DOI: 10.4212/cjhp.3323