A suggestion of benefit from chlorthalidone in patients with prior stroke/MI is difficult to interpret, Areef Ishani says.
CHICAGO, IL—Chlorothalidone does not reduce major adverse cardiovascular events compared with hydrochlorothiazide in older, predominantly male military veterans with hypertension, according to the randomized Diuretic Comparison Program (DCP). Through a median follow-up of 2.4 years, the primary outcome MACE—complex stroke, MI, hospitalization for heart failure, unstable angina leading to urgent coronary revascularization, or noncancer death—occurred in approximately 10% of patients in each arm study (HR 1.04; 95% CI 0.94-1.16), Areef Ishani, MD (Minneapolis VA Health Care System and University of Minnesota), reported here at the 2022 American Heart Association Scientific Sessions. A subgroup analysis showed that chlorthalidone was beneficial in patients with a history of myocardial infarction or stroke, about 11% of the total study population, although Ishani said “it’s hard to understand how to place this in the context of an overall negative trial.” . Ishani said he and his colleagues wrestle with the question of what these results mean for choosing between these two diuretics in practice, noting that worldwide, many more patients receive hydrochlorothiazide versus chlorthalidone. “I believe that any of the drugs are suitable for use in the treatment of hypertension,” he added. What should be given for the signal of benefit for chlorthalidone in patients with a history of myocardial infarction or stroke is unclear and requires additional study, but may influence clinical decision making, Ishani said. “I think that’s a conversation with your patient about how they want to hedge their bets. Because the drugs are so similar, if they were to say, ‘I want to stay with one drug or the other because of this subgroup,’ I think that’s a conversation that needs to be had.” Diuretic comparison program Chlorthalidone and hydrochlorothiazide have been used to treat hypertension for decades. Some studies have suggested that chloralidone provides better cardiovascular effects than hydrochlorothiazide, accompanied by improved 24-hour blood pressure control and other pleiotropic effects, Ishani said. But more recent observational research has shown similar CVD risks with each, with the potential for more adverse effects such as hypokalemia, acute kidney injury, and chronic kidney disease with chloralidone. At DCP, researchers set out to investigate potential differences among agents within the US Veterans Health Administration’s integrated health care system. Using a pragmatic design, they utilized the electronic medical record (EMR) to identify physicians and patients to participate and then obtained consent by both mail and telephone. The trial included 13,523 patients (mean age 72 years, 97% men) who were older than 65 years, were already taking hydrochlorothiazide at a dose of 25 or 50 mg/day, and had a most recent systolic BP of 120 mm Hg or higher. They were randomized to either remain on their regular dose of hydrochlorothiazide or switch to an equivalent dose of chlorthalidone (12.5 or 25 mg/day). After this point, all patients were treated with usual care and had no further contact with the trial investigators. Results were collected through the EMR system, Medicare and VA claims databases, and the National Death Index. Most patients (94.5%) were receiving the lowest dose of hydrochlorothiazide before enrollment, so a similar proportion was placed on the lowest dose of chlorthalidone after randomization. Throughout the trial, mean systolic BP and mean potassium remained similar in both groups, although over time, there was a slight increase in the proportion of patients receiving potassium supplementation in the chlorthalidone arm. The MACE rate during follow-up was 10.4% in the chlorthalidone group and 10.0% in the hydrochlorothiazide group. There were no differences for any of the individual components of this endpoint or for all-cause mortality, any revascularization, and erectile dysfunction. Treatment outcome appeared to vary based on history of MI or stroke. In patients with such a history, chlorthalidone had a lower risk of MACE (HR 0.73, 95% CI 0.57-0.94), but in those without such a history, chlorthalidone had a higher risk (HR 1.12, 95% CI 1.00-1.26). Ishani cautioned that this could be a switch finding and called for future studies to investigate this. Regarding expected adverse events, chlorthalidone was associated with higher rates of new allergic or adverse events to a thiazide-type diuretic (1.6% vs. 0.3%) and hypokalemia (6.0% vs. 4.4%), with latter difference to be due to an increase in potassium levels measured in the laboratory below 3.1 mEq/L (5.0% vs. 3.6%). Hospitalization for acute kidney injury occurred at comparable rates in the two arms of the trial. “Intensive results,” but questions remain Discussing the results after Ishani’s presentation, Daniel Levy, MD (National Heart, Lung, and Blood Institute, Framingham, MA), noted that previous trials, including SHEP and ALLHAT, had demonstrated the positive cardiovascular effect of using chloralidone. The DCP trial, he said, addressed a major knowledge gap about the relative effects of these two antihypertensives by using a rational, pragmatic design. Levy highlighted a number of issues to consider when interpreting the trial. First, it questioned whether the results were biased in favor of hydrochlorothiazide, since all participants were already taking the drug before randomization. This would serve to select patients who already had good BP control and few diuretic side effects. And second, he wondered if the results could be generalized to women and younger patients. Ultimately, however, the trial “provides compelling results, although some questions remain,” Levy said. Consider that everyone is getting their blood pressure checked in the country and the world—that’s an important answer that tells us they’re similar. Manesh Patel Biykem Bozkurt, MD, PhD (Baylor College of Medicine, Houston, TX), during a press conference, also raised some issues to consider, including the open-label design, the potential impact of prolonged effects of hydrochlorothiazide on patients randomized to chlorthalidone, and the lack of information on the efficacy of decongestion with each agent. He said he would like to see additional subgroup analyses, particularly after detecting the signal in the earlier MI/stroke subset, and questioned whether the results would be different among patients with more advanced disease, such as those with heart failure. Referring to TRANSFORM-HF, another pragmatic trial with neutral results presented at the meeting, Bozkurt said: “Both of these studies demonstrate the same efficacy of diuretic options in the target populations, but the patient subgroups for which we use these diuretics , the more so – Potents with better bioavailability and longer half-life, I think, remain unanswered, which means we’re likely to continue to use them in clinical practice for such patients.” For Manesh Patel, MD (Duke University, Durham, NC), chair of the program committee for this year’s meeting, DCP highlights the “gift of randomization. Running large, randomized trials still gives us answers, and especially when you do them realistically, it gives us important answers. And consider that everyone in the country and in the world is getting their blood pressure checked—that’s an important response that tells us they’re similar.” Confronted with the choice between the agents in practice, Patel told TCTMD that he is not sure the difference in hypokalemia is significant and that, overall, the two diuretics are similar. “In some respects, if you’re treating someone with one of those two drugs, it probably makes sense to stay. I don’t know you’re going to shift,” he said.
