Ever since the publication of ALLHAT1 which used chlorthalidone as the preferred diuretic, there has been concern that other thiazides may be either less effective or not as safe as this agent. The LEGEND observational study of 730 000 individuals2 showed no cardiovascular risk advantages, and a higher risk of hypokalaemia (HR 2.72,95%CI2.38-3.12), reflecting that in the doses conventionally used, it is arguably a slightly more effective diuretic but not more effective at reducing cardiovascular risk.
The 2022 publication of DCP (the Diuretic Comparison Project)3 provides further clarity. This pragmatic, multi-centre open label trial randomised 13 500 individuals to either of the two agents and found no difference in the primary composite cardiovascular endpoint (1.04 95% CI 0.94–1.16) or in any of its components. Hypokalaemia was more common in the chlorthalidone group (1.38 95% CI 1.19–1.60), although as expected this was not as dramatic as in LEGEND. The finding of a tiny subgroup in whom chlorthalidone seemed to perform better should be regarded as either hypothesis generating or should just be ignored. It is perhaps worth noting that at the start of the trial only 13% of patients were on a diuretic alone – one third needed one other agent, and one third needed two other agents (and 15% needed 3 agents plus a diuretic…)
And then furosemide for hypertension…
A Cochrane review4 found that less than 120 patients have been placed in placebo controlled trials of furosemide for hypertension, and that a dose of 40 mg per day was no more effective than placebo. There wasn’t enough information to comment on side effects.
If there is an effect on systolic blood pressure, it is probably no more than a 7 mmHg drop. Furosemide makes sense in the presence of established chronic kidney disease,5 but in its absence seems to generate a self-fulfilling prophesy – patients who shouldn’t be on it become pre-renal, and then the dose of furosemide is increased because of this, and they become more pre-renal. In any such patient, ask about postural dizziness, and formally test for postural hypotension.
The ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group: Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs. Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).JAMA2002;288:2981–97 ↩
JAMA Intern Med. doi:10.1001/jamainternmed.2019.7454 ↩
N Engl J Med 2022;387:2401-10. DOI: 10.1056/NEJMoa2212270 ↩
Musini VM, Rezapour P, Wright JM, Bassett K, Jauca CD. Blood pressure-lowering efficacy of loop diuretics for primary hypertension. Cochrane Database Syst Rev. 2015 May 22;2015(5):CD003825. doi: 10.1002/14651858.CD003825.pub4. PMID: 26000442; PMCID: PMC7156893. ↩
Pugh, D., Gallacher, P.J. & Dhaun, N. Management of Hypertension in Chronic Kidney Disease. Drugs 79, 365–379 (2019). https://doi.org/10.1007/s40265-019-1064-1 ↩