Precedex as good as Versed or Propofol (JAMA) - PulmCCM Central
Jan 062013
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).

Other Info

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.

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  5 Responses to “Precedex as good as Versed or Propofol, but with cardiovascular effects (RCT)”

  1. This was discussed at our journal club last week: Consider that length of mechanical ventilation (midazolam vs. dexmedetomidine) was assessed using Cox models. Subjects were censored at death. The excess mortality in the dexmedetomidine arm may have provided enough shorter length of stays to eke out the p of 0.03.

    Because death is a competing endpoint for length of mechanical ventilation, models reflecting this are used, such as the composite endpoint of the 28-day ventilator free days (as used by NHLBI ARDSNet) or a Cox model with death as a competing risk.

    When I look at MIDEX and PRODEX, it’s my interpretation that the investigators failed to reject the null hypothesis, though not for lack of trying.

    • Thanks for making this insightful point Dr Netzer.

      Ventilator-free days are indeed one of the accepted ways to resolve the competing effects of death and duration of mechanical ventilation. It’s interesting that they didn’t use that endpoint here, and I’m glad you pointed it out. Unfortunately, authors don’t address the issue in their comments section. In the end I’m forced to admit my limitations in my ability to evaluate statistical methodologies with any sophistication; I (like 99% of physicians) rely on the people I’d hope JAMA would pay well to do this, and to require explanation for any potential funny business. And of course, people like you always help to help keep things honest.

      This kind of thing is why I am always skeptical when the industry sponsor actually designs the study and has their statistician perform the analyses. Maybe we can entice the authors to explain this better to us, here — I emailed Dr. Takala (corresponding author) to invite a response.

      • Thank you for these comments. Ventilator-free days is one approach to avoid the impact of mortality. We chose another approach in our primary analyses, namely worst-ranking the patients who died – this has been described in detail in the electronic supplement (“Imputation rules”). We also performed a number of sensitivity analyses – please see the electronic supplement eTables 5-9

        eTable 5: Length of mechanical ventilation, including observed data only
        eTable 6: Time to extubation, including observed data only
        eTable 7: Length of mechanical ventilation; patients who die during ventilation were censored at time of death
        eTable 8: Time to extubation; patients who die while intubated were censored at time of death
        eTable 9: Duration of mechanical ventilation, including survivors only

        All these sensitivity analyses support the primary analysis, indicating that the primary analysis is robust, and the conclusions remain the same regardless of the approach chosen. Our (very) conservative imputation rules basically do the same thing as ventilator-free days: worst ranking to 45 days is equivalent to zero ventilator-free days.

        I would also like to emphasize that there was not only the analyses of the study statistician employed by the sponsor – there were in fact TWO independent analyses, as described in detail in the paper.

        • Dr Takala, thanks for your helpful and informative response. This helps to make things more clear.

  2. I just want to ask if we can give boluses of precedex, and if can be, how much is the maximum acceptable dose for bolus as in to give for less than a minute. Isnt safe if we can give 10 mcg as bolus. please, I need your clarifications.