Aprocitentan Effective in CKD Patients With Resistant Hypertension: PRECISION

Aprocitentan (Tryvio; Idorsia Pharmaceuticals), which targets the endothelin pathway, can safely lower blood pressure in patients with chronic kidney disease (CKD) and resistant hypertension, according to a post hoc analysis of the PRECISION trial.

On top of standardized antihypertensive therapy, the endothelin receptor antagonist (ERA) reduced both office and ambulatory BP, with greater effects at night versus during the day, as well as urine albumin-to-creatinine ratio (UACR).

Researchers led by Patrick Rossignol, MD, PhD (Princess Grace Hospital, Monaco), report their findings in a paper published online recently in Hypertension.

The drug was well-tolerated in this high-risk subgroup, with a safety profile similar to what was seen in the overall trial population. There were no major changes in potassium or sodium levels or in estimated glomerular filtration rate (eGFR), although a risk of edema, largely confined to the first month of treatment, was observed.

“When you have resistant hypertension, you’re more likely to have CKD, and when you have CKD, you’re more likely to have resistant hypertension. This is a very difficult group to treat,” study co-author John Flack, MD (Southern Illinois University School of Medicine, Springfield), told TCTMD, adding that “trying to get their blood pressure controlled is an important part of reducing their cardiovascular risk.”

Based on these results, “very strong consideration” should be given to using aprocitentan to treat patients with CKD and resistant hypertension, he said. Edema is an issue hypertension specialists deal with frequently and it’s manageable, he added. “I don’t really view the edema as a major problem because, one, it’s fairly straightforward to select patients who already have significant problems with edema [and avoid giving them the drug] and, two, to prevent the emergence of edema, you’re definitely going to have them on a diuretic anyway, and hopefully one that is appropriate to their level of kidney function.”

Digging Into PRECISION

Based on the results of the PRECISION trial, aprocitentan was approved by the US Food and Drug Administration in March 2024 for use in patients with hypertension inadequately controlled by other agents. The drug significantly reduced office and ambulatory BP versus placebo in patients with resistant hypertension on a fixed-dose combination of amlodipine, valsartan, and hydrochlorothiazide.

The current post hoc analysis zeroed in on the 147 trial participants (20% of the total population) considered to be at high or very high risk according to Kidney Disease Improving Global Outcomes (KDIGO) criteria, reflecting a low eGFR and/or significant proteinuria. Compared with the rest of the trial participants, these patients were older (average age 66.1 vs 60.6 years) and were more likely to be male (70.7% vs 56.6%), Black (17.0% vs 9.8%), and on at least four antihypertensive medications (71.4% vs 60.9%). They also had higher rates of diabetes and sleep apnea syndrome and a lower rate of congestive heart failure.

Within the KDIGO high-risk group, reductions in office systolic BP within the first 4 weeks of treatment were higher with the 12.5- and 25-mg doses of aprocitentan (13.5 and 16.6 mm Hg, respectively) than with placebo (4.4 mm Hg). The reduction with aprocitentan 25 mg was maintained during a subsequent 32-week single-blind period.

Aprocitentan also lowered daytime and nighttime ambulatory systolic BP, with greater reductions seen at night. After the first 4 weeks, for instance, nighttime ambulatory systolic BP fell by 9.6 and 13.8 mm Hg with the 12.5- and 25-mg doses, respectively, versus 2.5 mm Hg with placebo.

Additionally, UACR was reduced by 47.1% and 59.6% with the lower and higher doses of aprocitentan, respectively, after 4 weeks, with a nonsignificant decline of 2.4% in the placebo group. The impact of the 25-mg dose of aprocitentan was maintained throughout the 32-week single-blind period.

Both BP and UACR increased in patients randomized to placebo versus continued aprocitentan in a withdrawal phase that followed the single-blind treatment period.

These effects were consistent in other subgroups, such as those with stage 3 or 4 CKD or micro- or macroalbuminuria.

The most common adverse event in KDIGO high-risk patients, as in the overall trial population, was edema, mostly mild or moderate peripheral leg edema that was managed with or without additional diuretic therapy. Among patients in this subgroup who received any dose of aprocitentan, 37.9% had at least one edema event, higher than the 25.4% rate seen in the overall PRECISION trial.

Edema risk was concentrated in the initial 4 weeks of treatment, in which 16.3% of those treated with the 12.5-mg dose of aprocitentan, 15.1% of those treated with the 25-mg dose, and 4.4% of those treated with placebo had new or recurrent edema.

Heart failure events occurred in 11 participants, with seven requiring hospitalization. None of these events, however, were considered related to study treatment or led to discontinuation.

‘A Promising Drug’

George Thomas, MD (Cleveland Clinic, OH), a nephrologist specializing in hypertension, said patients with CKD and resistant hypertension encompass one of the hardest populations to manage. The challenge is “trying to use agents that do not have a negative impact on their kidney function and also avoid certain other issues like hyperkalemia,” he explained.

In this high-risk subgroup, aprocitentan provided a meaningful and durable reduction in BP, with no changes in kidney function and no increase in hyperkalemia, Thomas emphasized.

On the other hand, he added, “the main concern that I would have obviously is the edema,” particularly in patients with more advanced CKD or heart failure. That issue, he said, has contributed to the low use of aprocitentan in his practice because many patients have concomitant cardiac issues or heart failure.

In addition, “as the GFR goes down, in my mind, I would be a little bit more careful, a little bit more wary, of potential edema effects because those are the patients who are more likely to have volume-related problems with or without a history of heart failure.”

Nonetheless, aprocitentan is “a promising drug with a mechanism of action that is unique,” Thomas said, adding that this paper “should prompt clinicians to consider using it more.”

The main issue that had been holding back adoption of aprocitentan, Flack said, was not edema but rather the risk evaluation and mitigation strategy (REMS) that was put in place by the FDA when it approved the drug. That requirement was lifted in April.

When using aprocitentan, physicians should avoid treating patients with heart failure and those with massive lower-extremity edema, Flack advised. “But in most of the patients who fit the criteria that this study enrolled (resistant hypertension and various levels of chronic kidney disease),” he said, “it’s going to be a pretty acceptable and attractive drug to add to their regimen.”