Precedex Takes Step Toward FDA Indication for Longer-Term Use
Precedex (dexmedetomidine) only has existing FDA indications for short-term sedation (< 24 hours) in both mechanically ventilated and non-intubated patients. That short leash is because of dexmedetomidine's tendency to produce hypotension and bradycardia, and has limited Precedex's approved uses mainly to elective surgeries and other invasive procedures. Many intensivists use Precedex off-label for critically ill patients undergoing longer periods of mechanical ventilation; an indication here would create a much larger market for Precedex, since >300,000 patients experience prolonged mechanical ventilation each year, and many receive continuous sedative infusions for days or weeks.
With the results of 2 randomized Phase III/IV trials reported by Stephan Jakob, Esko Ruokonen, and Jukka Tukala in the March 21 JAMA, Precedex marketer Hospira may eventually get their wish -- though probably with strings attached.
What They Did:
Investigators randomized 1,000 patients at 44 European and Russian ICUs who were mechanically ventilated for > 24 hours to receive either dexmedetomidine (Precedex), midazolam (Versed), or propofol (Diprivan) as sedation (the MIDEX and PRODEX trials). The exclusion criteria were relatively narrow and reasonable (e.g., pregnancy, shock, pre-existing bradycardia). Precedex dosing was 0.2-1.4 µg/kg/hr -- up to twice the maximum 0.7 µcg/kg/hr Precedex dosing approved by the FDA in the U.S.
They measured the duration of time spent at the desired level of sedation on the Richmond Agitation-Sedation Scale and duration of mechanical ventilation (primary outcomes), as well as numerous secondary outcomes.
The trials were designed and controlled by Orion Pharma (Finland), patent holders of Precedex, based on the primary authors' original idea. Orion also performed the statistical analyses, which the authors independently verified, reporting they had full access to all the data. Only one author (not a lead author) disclosed a personal consulting payment from Orion/Hospira; all authors' institutions received grants and payments for recruiting patients, as is customary. Authors report writing the manuscript cooperatively with Orion's team, who are listed as co-authors (no ghostwriter/medical communications agency is mentioned).
What They Found:
Patients receiving Precedex spent virtually the same amount of time at the target level of sedation as did patients receiving either Versed or propofol. I.E., dexmedetomidine was as effective as either midazolam or propofol at sedating mechanically ventilated patients for extended periods (more than half the patients were on ventilators for longer than 4 days).
Precedex also appeared to reduce the total time spent on mechanical ventilation (invasive + non-invasive), compared to midazolam (Versed). Those getting Precedex were extubated almost 2 days sooner, and required a median of 123 hours total assisted ventilation vs. 164 hours for midazolam (p=0.03).
Precedex also reduced ventilator days by 1 day compared to propofol (p=0.04); however, they reported this as "no difference" because after considering the patients requiring non-invasive ventilation after extubation, the difference in total assisted ventilation time was no longer statistically significant (I thought this was too conservative).
There were no differences in length of stay in the ICU or hospital between groups. There was an excess of deaths in the Precedex group in MIDEX; a slight excess of deaths in the propofol group (favoring Precedex) in PRODEX; neither were statistically significant differences in mortality. The overall mortality of Precedex-treated patients was 22%; for standard-care (midazolam or propofol), 20% (p=0.49).
Patients were more alert and communicative while receiving Precedex than either midazolam or propofol, and better able to communicate pain (this was determined and reported by the nurses caring for them, using a Visual Analogue Scale).
Cardiovascular Adverse Events from Precedex?
Dexmedetomidine is a centrally-acting alpha-2 agonist. If that sounds a lot like the antihypertensive drug clonidine, that's because it is: dexmedetomidine is a slightly altered version of clonidine, but has an 8-fold higher affinity for receptors in the CNS. Despite the molecular tweak, dexmedetomidine still has some cardiovascular effects. In one of the trials (the MIDEX trial),
- Hypotension was reported in 21% (51 of 247) patients receiving Precedex, but only 12% (29 of 250) in those receiving midazolam.
- Bradycardia was reported in 14% (35 of 247) patients receiving Precedex, and only 5% (13 of 250) patients receiving midazolam.
In the other trial (PRODEX), no differences in the incidence of hypotension and bradycardia between Precedex and propofol were noted, (about 13% for all arms for both hypotension and bradycardia).
In an earlier multicenter randomized trial published in JAMA in 2009 (n=375), Precedex also reduced ventilator days by 2 compared to midazolam. In that trial, they used more liberal definitions of hypotension and bradycardia. The incidence of bradycardia was 42% in the Precedex-treated patients and 19% in the Versed patients. There was no excess hypotension in the Precedex-treated patients (56% in both arms).
In a 2011 summary of Precedex safety data from RCTs analyzed by the the EMA (European FDA), the drug was found to be discontinued about 2% of the time for bradycardia and 1.5% of the time for hypotension, slightly more than propofol (0.4% brady and 1.1% hypotension) and significantly more than midazolam (0.3% and 0.3%).
Precedex annual sales have been estimated at $200 million. Hospira faces the prospect of generic competition against Precedex soon, as its patents begin to expire beginning in July 2013. Precedex costs about $100-300 / day per patient, about the same as brand name propofol, but much less than midazolam.
Clinical Takeaway: This adds to previous evidence that Precedex probably works for longer periods of sedation, without obvious excess of harm over alternative agents, and with possible benefits of reducing the time of mechanical ventilation (but not in the ICU). Dexmedetomidine has been approved and used in Japan for extended episodes of mechanical ventilation since 2010, after a postmarketing phase IV study suggested safety; postmarketing surveillance has so far identified no safety concerns that have been made public. Hypotension or conduction disease should be absolute barriers to using it, to me. Watch for a full-court press from Hospira to get this new FDA indication, as their patent window is narrowing and their stock price has been stagnant, reportedly from problems in their other product lines.
Jakob SM et al. Dexmedetomidine vs Midazolam or Propofol for Sedation During Prolonged Mechanical Ventilation. JAMA 2012;307:1151-1160.