Clevidipine in the ER: A new option for severe, acute hypertension?

November 01, 2007

Chicago, IL - An investigational new calcium channel blocker with an ultrashort half-life, clevidipine (Cleviprex, The Medicines Company), has shown promise in a study in patients presenting to the emergency room with an episode of severe acute hypertension[1]. Dr Joseph Varon (University of Texas Health Science Center, Houston) presented the findings of VELOCITY at the American College of Chest Physicians meeting last week, noting that this is the first trial ever to deal with this issue.

Varon told heart wire there are 35 million people with hypertension in the US, and at least a million of these will have one or more acute episodes of high blood pressure at some point, necessitating a visit to the emergency room. Current drugs used for this purpose, such as sodium nitroprusside, labetalol, and nicardipine, "are not easy to titrate, and we tend to overshoot with the blood-pressure management. As a result, people get strokes, heart attacks, all sorts of nasty things," he explained. There has been no new therapy for this indication for 10 years, he added.

Clevidipine's advantage is in its ultrashort half-life of less than one minute, he said, adding, "If I were to put it in a simple way, I would say that clevidipine is 'supernicardipine.' The beauty of clevidipine is in the short on-off, and the way we performed the study meant that if we overdid it, we just stopped the infusion and then the blood pressure came back to normal. It was an amazing finding. Most of our patients were able to have their blood pressure controlled within 10 minutes. When you are dealing with a situation such as emergency care, that's a big advantage."

Clevidipine safe and effective
Clevidipine is 'supernicardipine.'

In the open-label, single-arm study performed at 11 centers across the US, patients presenting to the emergency room with persistent systolic blood pressure (SBP) >180 mm Hg or diastolic BP >115 mm Hg were eligible. The BP had to be measured twice, 15 minutes apart, to make sure it was not a false-positive value. In the efficacy analysis, 117 patients were included—mean age was 53 years, 51% were female, and 77% were black. Almost all patients (97%) had a history of hypertension.

Mean baseline SBP was 203 mm Hg. After clevidipine was initiated, infused peripherally with a non-weight-based dosing regimen, the mean SBP rapidly decreased during the titration period: -12 mm Hg at three minutes, -34 mm Hg at 15 minutes, and -45 mm Hg at 30 minutes. Median time to patients achieving a 15% reduction in SBP was 9.5 minutes, with 89% (104 of 117 patients) achieving their target within half an hour. At 18 hours, the BP reduction was -55 mm Hg (-27%) from baseline.

The study also looked at prolonged infusion of clevidipine, Varon explained. "There was a safety component to VELOCITY looking at what happens if we give this medication for a long period of time, and the longest time we gave it was 18 hours continuously, and all the patients did quite well." Throughout 18 hours, target SBP was maintained at a steady clevidipine infusion rate. Oral antihypertensive therapy was begun one hour before anticipated cessation of clevidipine.

"The rapid control achieved with clevidipine in this study is an important finding, because every minute counts when treating acute hypertension," says Varon. "Maintaining target blood pressure can prevent potentially irreversible damage to the brain, heart, kidneys, and blood vessels," he added. Most of the patients in the study (81%) had evidence of end-organ injury, including renal disease and coronary artery disease, he noted.

No AF seen with clevidipine in VELOCITY

No hypotensive events were reported in VELOCITY, but there was a modest increase in heart rate (9 bpm) at 30 minutes; however, after this time and up to 18 hours, heart rate tended back to baseline.

A previous set of trials—ECLIPSE, comparing clevidipine with conventional treatments in the setting of perioperative blood-pressure management—were temporarily halted in 2005 because of a higher incidence of atrial fibrillation (AF) seen in patients randomized to clevidipine. The trials were, however, restarted, and the results presented earlier this year at the ACC meeting, as reported by heart wire . AF did not appear related to clevidipine, the ECLIPSE lead investigator said at the time.

Varon told heart wire there wasn't a single case of AF in VELOCITY, nor was the tachycardia noted excessive. Although adverse events (AEs) were reported in 10% of patients, he said: "I truly do not believe they were related to the drug itself, but we had to record AEs as part of the trial. For example, someone had low potassium, and it was recorded, but that patient was receiving a diuretic."

Approval for clevidipine by year-end?
For many years we have been treating BP [in an acute setting] without really knowing how.

"The important thing about VELOCITY is that it's the very first study ever to deal with acute hypertension in the emergency department; that is probably the most groundbreaking part of this presentation," Varon told heart wire . "For many years, we have been treating BP [in an acute setting] without really knowing how. So clevidipine not only helps us to do this in a controlled way but actually allows us to bring a new medication into the ER."

Clevidipine is currently under review by the FDA, and the company is hoping the drug will be approved by the end of this year, Varon said.

Varon says his next project is a trial comparing clevidipine with nicardipine and with labetalol in the same acute setting. The exact details of the study are yet to be finalized, however.

Varon is a consultant and advisor to The Medicines Company.


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