We’ve been using chlorthalidone and hydrochlarothiazide for decades – but no one has looked at which is the better diuretic. Why actually?
Some things just need to be clarified. This includes the question of whether the thiazide diuretic Hydrochlorothiazid (HCT) or the thiazide analogue chlorthalidone the better diuretic for patients with arterial hypertension is. Chlorthalidone was approved in the US as early as 1960 and has been there for a long time Thiazid-Diuretikum of choice. It was not until 1977 that HCT was approved by the FDA, initially without major consequences. In recent years, HCT has slowly come to the fore. Today, HCT is prescribed more frequently in the USA.
Potency isn’t everything
It’s different in Germany, or it’s always been like that: Germany is a passionate HCT country. Chlorthalidone was and is available, has some ardent supporters, but by and large ekes a rather precarious existence on the fringes of antihypertensive society.
The differences have often been described: chlorthalidone has a longer half-life of around two days, while HCT only has 6 to 12 hours. Chlorthalidone is also more potent in the key mechanism of action of all thiazides, namely inhibition of sodium return transport in the early distal tubule and, to some extent, inhibition of the Carboanhydrase. It was therefore hypothesized that chlorthalidone might be more effective in lowering blood pressure. At the same time, more potassium is lost due to the higher potency. Safety fans were therefore traditionally in the HCT camp.
DCP study: Academics do itn
Since there is no significant money to be made with either chlorthalidone or HCT, the question of all hypertension questions – which is better: chlorthalidone or HCT? – never answered by industry-sponsored studies. Academics, on the other hand, either did not have the necessary money for a randomized study. Or they weren’t really interested in the results for two substances anyway, which stem from times when the concept of randomized trials didn’t really exist yet.
Anyway, the Diuretic Comparison Project (DCP) has taken care of it. The ones that were briefly introduced in the summer Results were now in New England Journal published – in the form of a large, comparative, randomized, but not blinded study, in which 13,523 hypertensive patients aged over 65 years participated. The design was such that they were all patients who had initially taken HCT, either 25 mg or (rarely) 50 mg per day. After randomization, the therapy was then either continued or the patients were switched to 12.5 mg or 25 mg chlorthalidone.
The primary endpoint was a composite of nonfatal myocardial infarction or stroke, heart failure episode with hospitalization, emergency revascularization for unstable Angina pectoris or non-cancer-related death. Mean systolic blood pressure at baseline was 139 mmHg in both groups. After a median of 2.4 years, 10.4% of patients in the chlorthalidone group and 10% of patients in the HCT group had an endpoint event. That was as insignificant as it sounds. There were also no relevant subgroups that would have benefited more from one or the other. HCT alone performed significantly better for hypokalemia: it occurred in 4.4% of patients compared to 6% with chlorthalidone therapy (p<0.001). Hospital admissions due to hypokalemia were also slightly more frequent at 1.5% versus 1.1%, although this just failed to reach significance.
Exemplary evidence generation in the digital age
The DCP study was a pragmatic study with recruitment based on electronic medical records. This has advantages because it makes randomized studies without external financiers comparatively cheap. However, it also has disadvantages: In addition to the lack of blinding, one could argue that chlorthalidone was structurally disadvantaged because a well-functioning HCT therapy was the inclusion criterion, so to speak. The authors of the study therefore do not choose a winner, but rather evaluate the results as a draw. In any case, the DCP study does not provide a reason to switch patients with functioning HCT therapy to chlorthalidone. The reverse is probably also true, but the study does not allow this conclusion due to its design.
in one accompanying editorial the nephrologist Julie Ingelfinger from Massachusetts General Hospital points out that from her point of view the results are not surprising and that the significance of the DCP study lies more in the fact that it shows how randomized studies can be carried out so inexpensively and with little organizational effort in the digital age that they are affordable and feasible even if there is no sponsor.
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According to Ingelfinger, the amazing thing about the DCP project is that 62 years after the first approval of chlorthalidone and 45 years after the first approval of HCT, it was the first direct, randomized comparison between these two diuretics. Ingelfinger does not want to overinterpret the slight advantages that chlorthalidone had in the DCP study in patients with a history of a heart attack or stroke. According to the nephrologist, this could also be a coincidence.
Image source: Chris Sabor, Unsplash