May 11, 2009 (San Francisco, California) — Stage 1 and stage 2 hypertensive patients treated with a novel antihypertensive agent designed to block the endothelin and angiotensin receptors significantly reduced systolic and diastolic blood pressure when compared with the angiotensin receptor blocker irbesartan, a new study has shown.
In addition, after 12 weeks of treatment with the dual-acting receptor antagonist, approximately 60% of patients treated with the highest dose of the agent achieved blood-pressure control outlined by the clinical guidelines, whereas just 32% of patients treated with irbesartan achieved the same degree of control.
"There are a significant proportion of patients we can't control with modern monotherapy agents," lead investigator Dr Joel Neutel (University of California, Irvine) told heartwire ."If the goal is less than 140 mm Hg and the patient is starting out with anything higher than 150 mm Hg, they are not likely going to get to goal with one drug. This is an opportunity for somebody with stage 1 hypertension or even early stage 2 hypertension, where you might be able to get them to goal with one drug. If not, then it's a very easy addition of a second agent to get to goal."
The results of the study were presented here last week at the American Society of Hypertension 2009 Scientific Sessions.
Inhibiting Both Systems Would Be Complementary
The compound, a dual-acting receptor antagonist known at the moment as PS433540 (Ligand Pharmaceuticals, San Diego, CA), blocks the angiotensin and endothelin receptors. Both angiotensin and endothelin are powerful vasoconstrictors and appear to work hand in hand, with one stimulating the other to contribute to high blood pressure in patients. Speaking with the media, Neutel said that inhibition of both systems would also be complementary and result in a greater reduction in blood pressure than by blocking either receptor alone.
In this phase 2b study, patients were randomized to placebo, PS433540 200 mg, 400 mg, and 800 mg, or irbesartan 300 mg. Approximately 60% of patients were stage 1 hypertensive, and the mean systolic and diastolic blood pressures at baseline were approximately 155 mm Hg and 97 mm Hg, respectively.
At 12 weeks, all doses of PS433540 lowered systolic and diastolic blood pressure significantly more than placebo. In a comparison with high-dose irbesartan, the 800-mg dose of PS433540 significantly reduced systolic and diastolic blood pressures to a greater extent, while there were only trends toward lower blood pressures with 400-mg dose.
Mean Blood Pressure Change From Baseline at 12 Weeks
|Blood pressure measure||Placebo (n=59)||PS433540 200 mg (n=58)||PS433540 400 mg(n=58)||PS433540 800 mg (n=28)||Irbesartan 300 mg (n=58)|
|Change in systolic blood pressure from baseline (%)||1.8||-13.2a||-14.2b||-23.4c||-10.7|
|Change in diastolic blood pressure from baseline (%)||0.2||-7.2a||-9.2a||-14.3c||-7.1|
b. p=0.08 vs irbesartan
c. p<0.003 vs irbesartan
During the course of the study, data from an earlier phase 2a study showed that dosages beyond 500 mg did not alter the blood pressure further. As a result, enrollment in the 800-mg arm of the trial was halted, although investigators suggest this might have been a mistake, given the significant reductions observed in the 28 patients treated with the 800-mg dose.
In terms of blood-pressure control, defined as <140/90 mm Hg, 62% of patients treated with the 800-mg dose achieved control, while 52% and 36% achieved control with the 400-mg and 200-mg doses, respectively. Overall, just 32% of patients treated with irbesartan achieved ideal blood-pressure levels.
"When you look at control rates for hypertension in this country as well as in the rest of the world, we know and are acutely aware that we haven't done nearly as well as we would have hoped," said Neutel. "Even with all the wonderful drugs we have for the management of hypertension, we're still not doing it. If we can come up with something that is more effective and more likely to get patients to goal, it would be a very important addition to what we have for the management of hypertension."
Neutel said the drug was safe and well tolerated but that there was an excess of peripheral edema with the 800-mg dose. There was no effect on liver enzymes, and no significant effect on hematocrit and hemoglobin levels.
Press-conference moderator Dr George Bakris (University of Chicago Medical Center, IL) told heartwire that an ideal use for the dual-acting receptor antagonist would be in the posttransplant setting. Drugs used to prevent rejection significantly increase endothelin levels, and as a result, calcium-channel blockers are typically prescribed.
"Here you have a pure way of using a combination drug that would protect the kidney and at the same time dilate it with probably less edema than you would see with the calcium-channel blocker," said Bakris.
For "garden-variety" hypertension, Bakris told heartwire that studies are still needed to see how the drug stacks up against the combination of amlodipine and benazepril, a combination that now has hard clinical-end-point data from the ACCOMPLISH study. Based on the current guidelines, these combination agents would be used only in patients with stage 2 hypertension, he noted.
Ligand Pharmaceuticals, maker of PS433540, sponsored the trial.
Heartwire from Medscape © 2009 Medscape, LLC
Cite this: Dual-Acting Receptor Antagonist Superior to ARB for Treatment of Hypertension - Medscape - May 11, 2009.