Study: Blood pressure med combo cuts vEDS arterial events in half
Phase 3 ARCADE study tested irbesartan in patients taking celiprolol
Two years of daily irbesartan, a long-acting oral blood pressure medication, reduced the risk of severe arterial events by 50% in adults with vascular Ehlers-Danlos syndrome (vEDS).
That’s according to the results of the Phase 3 ARCADE (NCT02597361) trial, which tested the medicine on a background of celiprolol, a blood pressure medication with a different mechanism of action.
“The results of this first randomized controlled trial are expected to have a direct and important impact on the medical management of this life-threatening condition,” the researchers wrote. Details about ARCADE were published in Circulation in the study, “Efficacy of Irbesartan in Celiprolol-Treated Patients With Vascular Ehlers-Danlos Syndrome.”
Along with EDS symptoms such as overly mobile joints and soft, stretchy skin, vEDS is marked by fragile blood vessels, which are prone to aneurysms, that is, bulging, or ruptures that can lead to serious bleeding.
Blood pressure medications, like beta blockers and/or angiotensin II receptor blockers (ARBs), have been shown to lower the risk of vEDS progression and death.
Celiprolol is a beta blocker that lowered the risk of blood vessel rupture or tear in a Phase 4 clinical trial (NCT00190411). Last year, Zevra Therapeutics began dosing patients in the Phase 3 trial DiSCOVER (NCT05432466) to test if celiprolol can reduce the time to a medical emergency versus a placebo.
Combining medicines in treating vEDS
People “with [vEDS] continue to develop new symptomatic and asymptomatic arterial lesions, a persistent disease process that justifies the investigation of additional therapeutic approaches,” wrote researchers in France who designed the proof-of-concept ARCADE trial to evaluate the efficacy and safety of ARB irbesartan in vEDS patients on background therapy with celiprolol. The study was sponsored by Assistance Publique – Hôpitaux de Paris in France. Irbesartan is available as the brand name drugs Avalide, Avapro, and as generics.
“Irbesartan is not only known for its safety profile, but is also available as a low-cost generic drug, making it an advantageous option for the treatment of this rare disease,” they wrote.
Along with daily celiprolol, 57 adults, ages 18-70, with vEDS were randomly assigned to a placebo or irbesartan tablets, starting at 150 mg daily and increasing to 300 mg over eight weeks. At the study’s start (baseline), most patients (84.2%) had arterial lesions (injury).
The primary outcome measure was a composite of several vEDS-related events over two years. The events included cardiovascular death, or any vEDS-related fatal or nonfatal event and either new asymptomatic arterial aneurysms or dissections (tearing on the inside), or worsening of a preexisting lesion.
Analyzing the results
According to the analysis, the incidence of the primary composite outcome was 51% lower in the irbesartan group than in the placebo group. Eight symptomatic arterial events were arterial dissections, and one was an aneurysm rupture, all occurring later with irbesartan than with a placebo (mean 21.8 vs. 14.2 months).
The total number of new arterial asymptomatic lesions, either a new lesion or progression of a preexisting lesion, was significantly reduced by irbesartan over a placebo at both one and two years. An increase in the number of lesions in all arterial sites was seen solely in the placebo group.
Over two years, fewer symptomatic and asymptomatic events per patient occurred in the irbesartan group than the placebo group (13 vs. 35).
Blood pressure during a heartbeat (systolic) and between heartbeats (diastolic) dropped from baseline with irbesartan and remained significantly lower than with the placebo until the study’s end. No significant changes in heart rate occurred in either group, however.
In a subgroup analysis, the primary composite outcome was consistent across ages, mutation type, family genetic status, and arterial lesion severity, with a trend toward greater efficacy for irbesartan in men.
Four women in the irbesartan group had symptomatic hypotension, or abnormally low blood pressure, with a dose reduction in three. Nine patients (37%) had a systolic blood pressure fall below 100 mm Hg at least once over the two-year study, with no discontinuations.
Four patients with preexisting varicose veins (three on irbesartan, one on placebo) developed venous blood clots at baseline or during follow-up. Two reversible episodes of mildly elevated potassium occurred in both groups. Four episodes of temporary improvements in kidney function happened in the irbesartan group versus two in the placebo group.
“Irbesartan was associated with a lower risk of the composite outcome of severe symptomatic and asymptomatic arterial events over [two] years in adult patients with VEDS receiving celiprolol as background treatment,” the researchers wrote. “Unless contraindicated, the systematic use of an ARB such as irbesartan is recommended in the medical therapeutic management of this rare life-threatening condition.”
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