Combination of loop diuretics with thiazide-type diuretics in heart failure

Volume overload is an important clinical target in heart failure management, typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via "sequential nephron blockade," first described more than 40 years ago. Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. We summarize the existing literature evaluating the combination of loop and thiazide diuretics in patients with heart failure in order to describe the possible benefits and hazards associated with this therapy. Combination diuretic therapy using any of several thiazide-type diuretics can more than double daily urine sodium excretion to induce weight loss and edema resolution, at the risk of inducing severe hypokalemia in addition to hyponatremia, hypotension, and worsening renal function. We provide considerations about prudent use of this therapy and review potential misconceptions about this long-used diuretic approach. Finally, we seek to highlight the need for pragmatic clinical trials for this commonly used therapy.     

Hydrochlorothiazide vs chlorthalidone,indapamide, and potassium‐sparing/hydrochlorothiazide diuretics for reducing left ventricular hypertrophy: A systematic review and meta‐analysis

Left ventricular hypertrophy develops in 36%‐41% of hypertensive patients and independently predicts cardiovascular events and total mortality. Moreover, drug‐induced reduction in left ventricular mass (LVM) correlates with improved prognosis. The optimal thiazide‐type diuretic for reducing LVM is unknown. Evidence regarding potency, cardiovascular events, sodium, and potassium suggested the hypothesis that “CHIP” diuretics (CHlorthalidone, Indapamide, and Potassium‐sparing diuretic/hydrochlorothiazide [PSD/HCTZ]) would reduce LVM more than HCTZ. Systematic searches of five databases were conducted. Among the 38 randomized trials, a 1% reduction in systolic blood pressure (SBP) predicted a 1% reduction in LVM, P = 0.00001. CHIP‐HCTZ differences in reducing LVM differed across trials (ie, heterogeneity), making interpretation uncertain. However, among the 28 double‐blind trials, heterogeneity was undetectable, and HCTZ reduced LVM (percent reduction [95% CI]) by −7.3 (−10.4, −4.2), P < 0.0001. CHIP diuretics surpassed HCTZ in reducing LVM: chlorthalidone −8.2 (−14.7, −1.6), P = 0.015; indapamide −7.5 (−12.7, −2.3), P = 0.005; and all CHIP diuretics combined −7.7 (−12.2, −3.1), P < 0.001. The comparison of PSD/HCTZ with HCTZ had low statistical power but favored PSD/HCTZ: −6.0 (−14.1, +2.1), P = 0.149. Thus, compared to HCTZ, CHIP diuretics had twice the effect on LVM. CHIP diuretics did not surpass HCTZ in reducing systolic or diastolic blood pressure: −0.3 (−5.0, +4.3) and −1.6 (−5.6, +2.4), respectively. The strength of evidence that CHIP diuretics surpass HCTZ for reducing LVM was high (GRADE criteria). In conclusion, these novel results have demonstrated that CHIP diuretics reduce LVM 2‐fold more than HCTZ among hypertensive patients. Although generally related to LVM, blood pressure fails to explain the superiority of CHIP diuretics for reducing LVM.