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Guest blogger Marisa has written up an expert review of our recent Journal Club discussion of clevidipine, as presented by Dr. Joshua Kosowsky of Brigham & Women’s Hospital:

Just last week, Clevidipine (Cleviprex) was approved by the FDA, making it the first new IV drug approved for high blood pressure in the past 10 years. Dr Joshua Kosowsky introduced us to Clevidipine when he discussed the VELOCITY (The evaluation of the effect of ultra-short-acting clevidipine in the treatment of patients with severe hypertension) trial as published in the June 2008 Annals of Emergency Medicine (PMID: 18534716), “Clevidipine, an Intravenous Dihydropyridine Calcium Channel Blocker, Is Safe and Effective for the Treatment of Patients With Acute Severe Hypertension” (residents: the PDF of this journal is online). More below:

Clevidipine previously received media attention in 2007 after the ECLIPSE (Evaluation of Clevidipine in the Postoperative Treatment of Hypertension Assessing Safety Events) trial, looking at its perioperative use in heart surgery, where it was shown to provide acute blood-pressure control with fewer blood pressure excursions than nitroglycerine, nitroprusside, or nicardapine with no increase in side effects. Although this study was temporarily halted in 2005 for a seemingly increase in atrial fibrillation among the clevidipine patients, by study end the A Fib did not appear linked to the study drug.

The VELOCITY trial was a safety and efficacy trial of IV clevidipine in the ED and ICU settings, in patients with severe hypertension defined as systolic blood pressure greater than 180mm Hg and/or diastolic blood pressure over 115mmg Hg. Patients were treated with clevidipine at a standardized dose of 2mg/hour, and titrated up until they reached target blood pressure (somewhat arbitrarily decided by the treating physician based on presenting condition, baseline blood pressure, and presence of comorbidities). Clevidipine was continued for a total duration of 18 to 96 hours to allow for study of long-term use of the drug. Additional antihypertensives were allowed to be used in the study per discretion of treating physician if the target blood pressure was not obtained within the initial 30 minutes, however 88.9% of patients achieved target range within 30 minutes of starting clevidipine, and 92% of patients were treated without the need for additional antihypertensive medications.

Clevidipine has a half-life less than one minute, and is degraded by plasma esterases, thus elimination is independent of the liver and kidney. Its rapid onset and offset, as well as its metabolic degradation makes it an ideal candidate for use in the Emergency Department, where treatment of patients is often made without full characterization of the patient, and patient conditions can change rapidly. It can be administered through peripheral IV, and all but one patient in the study was monitored with non-invasive blood pressure monitoring.

This prospective, open-label, single-arm study was conducted at 12 sites in the United States, and enrolled 131 patients. Patients were eligible for inclusion if they were older than 18 years and had persistent severe hypertension (SBP >180 and/or DBP >115 on 2 successive readings at least 15 minutes apart), and excluded if they did not meet blood pressure requirements, were likely to be intolerant of at least 18 hours of intravenous antihypertensive therapy, known or suspected aortic dissection, known liver failure or cirrhosis, likely withdrawal from alcohol, illicit drugs, or intentional overdose, positive pregnancy test result, intolerance or allergy to calcium channel blockers, soybean oil, or egg lecithin, receipt of any antihypertensive drug within 2 hours before enrollment, or participation in a drug or device research study in the previous 30 days. It is important to note that this inclusion/exclusion criteria omitted patients with true hypertensive emergencies such as dissection and eclampsia, in addition to those who were unable to provide written consent (possible stroke or hypertensive encephalopathy patients?), and many patients with true hypertensive urgencies with evidence of end-organ damage such as stroke, acute coronary syndrome, but may not have met blood pressure criteria.

Patients were then screened for end-organ injury, which 81% had at baseline, but only approximately 1/3 of patients had evidence of acute end-organ injury (focal neurologic signs, acute congestive heart failure, ischemic ECG changes, unstable angina, positive cardiac enzymes). This raises a question of who exactly was included in this study, and who was being treated with Clevidipine — if only 1/3 of patients had hypertensive emergencies, then the other 2/3 had hypertensive urgency or episodes, which ACEP guidelines state that rapid lowering of blood pressure in asymptomatic patients in the ED is unnecessary and may be harmful in some patients. It is unclear what these patients presented for and why they were admitted for that allowed for 18-96 hours of IV antihypertensive therapy.

Primary endpoints were the percentage of patients in whom SBP decreased below the lower limit of the initial target range within 3 minutes of initiating infusion (safety), and percentage of patients in whom SBP decreased to within the initial target range within 30 minutes of initiating infusion (efficacy). Secondary measures included change in pulse rate, proportion of patient successfully transitioned to oral antihypertensive therapy, and time to achievement of target range within the initial 30-minute treatment period. Only one patient had a significant increase in pulse rate (not mentioned in this paper, but in other reports on-line, the study investigators claim that there was not a single case of atrial fibrillation in this study, which was important in relation to the ECLIPSE trial).

Overall, clevidipine appeared to be safe and effective, with a rapid lowering of blood pressure with a median time to a 15% reduction in SBP of 9.5 minutes, and 90% of patients achieving target blood pressure range; however, at any point in time only 57-80% of patients were within the target blood pressure range. Only 2 patients experienced a decrease in blood pressure below the lower limit of the pre-specified initial target range within 3 minutes after the start of clevidipine infusion (although no data was given on episodes beyond the initial 3 minutes). Side effects experienced were headache, nausea, vomiting, pruritis. Serious adverse events were reported by 8.7% of patients, however these were all assessed as unrelated or unlikely related to clevidipine.

This was not a well-designed study – in fact, it even states that “sample size was determined by clinical judgment without formal power calculation. No formal statistical hypothesis testing was included as part of study design”, which almost has the feel of saying “let’s just put some people on clevidipine and see what happens, then we’ll write a paper”. But as astute clinician and well-respected researcher Dr. Lynne Richardson noted, this study looked at the safety and efficacy of clevidipine in the undifferentiated patient, and treated severe hypertension in patients with a variety of comorbidites regardless of presenting symptoms (as many practitioners do), although this practice clearly does not follow the guidelines. So while from an academic perspective this study may be treating patients with IV antihypertensive medications unnecessarily, in the real-world perspective, this study looks at the use of antihypertensives in the way in which many physicians would use it.

Clevidipine is now FDA approved, and is also currently in trials for traumatic intracerebral hemorrhage in patients with SBP > 160mm Hg, so it will be a matter of time before we see it in our Emergency Departments. So to reinforce what we should be doing with our hypertensive patients, according to JNC7, ACEP, and EMCREG:

JNC 7 (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) classification of hypertension:

Normal: below 120 mmHg systolic and below 80 mmHg diastolic
Pre-hypertension: Between 120-139 systolic or 80-89 diastolic
Stage 1:  Between 140-159 mmHg systolic or 90-99 diastolic
Stage 2: Greater than or equal to 160 mmHg systolic or 100 diastolic

Patients with marked BP elevations and acute target-organ damage (eg encephalopathy, MI, UA, pulmonary edema, eclampsia, stroke, head trauma, life-threatening arterial bleeding, or aortic dissection) require hospitalization and IV drug therapy.

Patients with markedly elevated BP but without acute target organ damage usually do not require hospitalization, but they should receive immediate combination oral antihypertensive therapy. They should be carefully evaluated and monitored for hypertension-induced heart and kidney damage and for identifiable causes of hypertension.

ACEP Guidelines:

Asymptomatic patients with pre-hypertension or Stage 1 Hypertension and normal physical exam should be referred for a blood pressure re-check
For asymptomatic patients, ACEP does not recommend using IV agents to acutely lower BP, and the goal should not be to normalize BP during the ED visit

EMCREG: Emergency Medicine Cardiac Research and Education Group

Stepped approach to referral time period and treatment initiation
Recommended referral time for repeat evaluation is 1-2 months unless SBP >=180 or the DBP >=110
-if BP above these levels, recommended follow-up within 1 wk

If SBP >210 or DBP >120, is reasonable to initiate oral anti-hypertensive medications and recommend earlier follow-up.
-If pt is to be started on anti-hypertensive, MD should obtain electrolytes and a creatinine prior to starting medication and refer patient for timely outpatient follow-up.
-consider comorbidities when prescribing medications
ALLHAT: thiazide superior to ACE-I, CCB, a-blockers
ANBP2: ACE-I superior to diuretics
**either excellent choice for most otherwise healthy patients
**thiazide if female child-bearing potential
**JNC-7 recommends thiazide

Stepped recommendations for treatment of asymptomatic hypertension without End Organ Damage:

140-159/90-99 observe and confirm within 2 months
160-179/100-109 confirm and treat within 1 month
180-209/110-119 confirm and treat within 1 week
210+/120+ confirm, evaluate, initial oral outpatient treatment, and refer for followup

Posted on Thursday, July 24th, 2008 at 12:36 pm by Nick. Filed under Monitoring, Journal Club, Blog.
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