The Diuretic Comparison Program (DCP), conducted in more than 13,500 US veterans aged 65 years and older, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, non-cancer death, hospitalization for acute heart failure. , or urgent revascularization, after a median follow-up of 2.4 years. There was also no difference in any of the individual endpoints or other secondary cardiovascular outcomes. However, in the subgroup of patients with a history of myocardial infarction or stroke (who comprised approximately 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk of primary effects while taking chlorthalidone compared with those taking hydrochlorothiazide. The DCP trial was presented today at the American Heart Association (AHA) 2022 Scientific Sessions by Areef Ishani, MD, director of the Minneapolis Integrated Care Community Primary Care and Specialty Care and director of the Veterans Affairs (VA) Midwest Health Care Network. Asked how to interpret the result for clinical practice, Ishani said: “I think we can now say that either of these two drugs is suitable for use in the treatment of hypertension.” But he added that deciding what to do with the subgroup of patients with a previous heart attack or stroke was more “challenging”. “We saw a very significant benefit in this subgroup, but that was in the context of an overall negative trial,” he noted. “I think that’s a conversation with patients about how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup outcome, I think it’s a conversation which needs to be done, but I think now we need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone is really beneficial in this group.” Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have shown no greater benefit from chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse effects, such as hypokalemia, acute kidney injury, and chronic kidney disease.

Real Study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and healthcare professionals to know which drug was being prescribed and to administer the drug in a real-world setting. “Patients can continue their normal care with their usual care team because we have integrated this trial into primary care clinics,” Ishani said. “We followed participants’ outcomes using their electronic health record. This study was non-invasive, cost-effective and inexpensive. In addition, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we typically rely on large academic medical centers”. Using VA electronic medical records, researchers recruited primary care physicians who identified patients over age 65 who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomized to continue receiving hydrochlorothiazide or switch to an equivalent dose of chlorthalidone. Patients were tracked through the electronic medical record as well as Medicare claims and the National Death Index. Results after a mean follow-up of 2.4 years showed no difference in blood pressure control between the two groups. For clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or emergency revascularization occurred in 10.4% of the chlorthalidone group and 10.0% of the hydrochlorothiazide (hazard ratio [HR]1.04; 95% CI, 0.94 – 1.16; P = .4). There was also no difference in any of the individual primary endpoints or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction. Regarding adverse effects, chloralidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.

Benefit in MI, Stroke Subgroup;

In the subgroup analysis, patients with a history of MI or stroke receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57 – 0.94). In contrast, patients without a history of myocardial infarction or stroke appeared to do worse when taking chlorthalidone (HR, 1.12; 95% CI, 1.00 – 1.26). “We were surprised by these results,” Ishani said. “We expected chlorthalidone to be more effective overall. However, learning these differences in patients who have a history of cardiovascular disease may affect patient care. It is best for people to talk to their health care physicians about which of these drugs are best for the individual’s needs.” He added: “More research is needed to further explore these effects because we don’t know how they might fit into the treatment of the general population.” Ishani noted that a limitation of this study was that most patients received the low dose of chlorthalidone, and previous studies that suggested benefits of chlorthalidone used the higher dose. “But the people voted – we had 4000 clinicians participating in this study, and the vast majority are using low-dose hydrochlorothiazide. And this is a conclusively negative study,” he said. “People also voted that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.” Commenting on the study at an AHA news conference, Biykem Bozkurt, Baylor College of Medicine, Houston, Texas, noted that in all of the National Institutes of Health’s landmark hypertension trials, there was a message of benefit for chlorthalidone compared with other antihypertensives. “We’ve always had this idea that chlorthalidone is better,” he said. “But this study shows no difference in primary cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable because chlorthalidone is a more potent diuretic.” Other limitations of the DCP trial are its open design, which could introduce some bias. the lasting effects of hydrochlorothiazide — most of these patients were receiving this agent as background therapy. and an inability to see the effectiveness of decongesting factors in such a pragmatic study, Bozkurt noted. He said he would like to see more analysis in the subgroup of patients with a previous heart attack or stroke. “Does this result mean that chlorthalidone is better for sicker patients, or is this result just due to chance?” asked. “While this study demonstrates equal efficacy of these two diuretics in the target population, the question of patient subgroups for whom we use a more potent diuretic I think remains unanswered,” he concluded. A designated DCP trial discussant at the final trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chloralidone had shown impressive results in previous major hypertension studies, including SHEEP and ALL . He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been undertaken by industry”. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although some questions remain. These include a possible bias towards hydrochlorothiazide – patients were selected who were already taking this drug and thus would already have a favorable response to it. Additionally, because the trial was conducted in a larger male population, it questioned whether the results could be generalized to women and younger patients. The DCP study was funded by the VA Cooperative Studies Program. Ishani reports no disclosures.
American Heart Association (AHA) Scientific Sessions 2022. Presentation 19443. Presented November 5, 2022. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.