New Orleans, LA - The investigational intravenous antihypertensive clevidipine is as safe as conventional treatments—including nitroglycerin (NTG), sodium nitroprusside (SNP), and nicardipine (NIC)—when used in the pre-, peri-, and postoperative period of cardiac surgery, new data show. The novel drug might also give better blood-pressure (BP) control than the comparators, according to anesthesiologist Dr Solomon Aronson (Duke University Medical Center, Durham, NC), who reported the findings of the Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events (ECLIPSE) trials in two late-breaking clinical-trials sessions, one today and one yesterday.

Aronson told heartwire: "This is the first time we are really defining this phenomenon of acute blood-pressure control, which is clearly different from chronic hypertension. This suggests that great attention should be given to precise perioperative blood-pressure control. This is a whole new paradigm."

"More research is needed to confirm the benefits of clevidipine," said Aronson, "but these initial results against three very commonly used therapies demonstrate a new potentially valuable alternative, which is very encouraging."

No increase in AF seen with clevidipine

Aronson explained that more than 50% of patients undergoing cardiac surgery, such as bypass or valve repair/replacement, would experience perioperative hypertension requiring the use of an intravenous agent. But the agents that are conventionally used—NIC, SNP, and NIC—have limitations, he noted.

Clevidipine, an intravenous dihydropyridine calcium-channel antagonist with an ultrashort half-life of less than one minute, is under development by The Medicines Company, which says it plans to file a new drug application for the drug by the end of June. The higher incidence of atrial fibrillation (AF) seen in patients randomized to clevidipine in the ECLIPSE studies, which resulted in the trials being temporarily halted, does not appear to be related to the drug, Aronson said.

ECLIPSE consisted of three studies in a total of 1964 patients—ECLIPSE-NTG, ECLIPSE-SNP, and ECLIPSE-NIC. Beginning just before surgery, investigators monitored patients' BP and administered the assigned agent at their discretion if BP became too high. Clevidipine was initiated at an infusion rate of 2 mg/h, and the dose could be doubled every 90 seconds up to a maximum of 16 mg/h. Comparator drugs were given as per the protocol in each participating institution.

The primary end points in the studies—which were mandated by the FDA as safety trials—were death, MI, stroke, and renal dysfunction, Aronson explained.

Primary end point by treatment comparison

Outcome	Clevidipine	NTG	Clevidipine	SNP	Clevidipine	NIC
Death, %	2.8	3.4	1.7	4.7*	4.4	3.2
MI, %	3.3	3.5	1.4	2.3	2.3	1.1
Stroke, %	1.6	2.3	1.1	1.5	0.6	1.1
Renal dysfunction, %	6.9	8.1	8.5	9.1	8.3	5.9

Secondary end points included serious adverse events and BP control for the first 24 hours. "We looked at serious adverse events, including AF, as a secondary end point, and there was no difference between AF in the clevidipine groups compared with the other agents," Aronson told heartwire.

Serious adverse events

Event	Clevidipine (n=752)	Comparators (n=754)
Total, %	17.7	20.0
Atrial fibrillation, %	2.4	2.4
Respiratory failure, %	1.1	2.5
Renal failure, %	2.3	1.7
Ventricular fibrillation, %	0.9	1.5
Cardiac arrest, %	0.5	1.1
Cerebrovascular accident, %	0.5	1.1
Postprocedural hemorrhage, %	0.5	1.1

BP excursions associated with 30-day mortality

Based on each patients' BP response during the 24 hours after initiating therapy, investigators also determined "BP excursions"—how much and how long systolic BP went above or below predefined acceptable perioperative ranges. There was greater excursion outside the prespecified target BP range with nitroglycerin and sodium nitroprusside in the pre- and perioperative period compared with clevidipine, but no difference in this outcome between clevidipine and nicardipine (the latter can only be used in the postoperative period, Aronson explained). "We found that clevidipine allowed a much better control of BP," he commented to heartwire.

A significant association was found between BP excursions and 30-day mortality risk. The risk of death increased by 20% with an average excursion of 1 mm Hg for 60 minutes and rose rapidly for each additional 1 mm Hg. An excursion of 5 mm Hg for 60 minutes was associated with an almost 2.5-fold risk of death at 30 days.

Panelist Dr Bernard J Gersh (Mayo Clinic, Rochester, MN) commented that he was "surprised at how strong that relationship is. The next step will be to look mechanistically at why that relationship is so strong."

Therapeutic neglect?

Aronson told heartwire that the way that acute fluctuations of BP during surgery are currently treated varies from institution to institution. "I like to use the expression 'therapeutic neglect.' We have for years just tolerated, more than we should have, these sorts of acute fluctuations, and I think these data begin to teach us that this is not a good way to practice."

"With a better understanding of how to effectively control blood pressure during cardiac surgery, we believe we can significantly improve the outcomes of those operations, all while ensuring patient safety," he concluded.