Droperidol, QT prolongation, and sudden death – what is the evidence – Part I

Also posted over at Rogue Medic (now at EMS Blogs).

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I am continuing to look for evidence that droperidol deserves to be given a scarlet letter black box warning. The authors of this literature review take a look at several articles and some case studies.

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Because the outcome of interest, sudden death caused by torsades de pointes, is uncommon and difficult to assess, QT prolongation has become a surrogate marker for potential arrhythmogenicity and is therefore commonly used in research and by regulatory agencies.^18[1]

Surrogate endpoints are great for making it seem that we know more than we actually do know. When there is not enough information, surrogate end points are a way of saying, If this belief is true, and this other belief is also true, then Treatment Z is safe (or dangerous), or saves X number of lives per year (or kills X number of patients who otherwise would have been expected to live).

The example that I repeatedly use is the Cardiac Arrhythmia Suppression Trial,^[2] which ended up demonstrating that treatment based on the surrogate endpoint of eliminating PVCs (Premature Ventricular Contractions) because they are associated with a higher rate of death actually resulted in tens of thousands of extra deaths.^[3] That is the difference between looking at surrogate endpoints (making assumptions about death rates) and looking at actual death rates.

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a consistent relationship between the length of the QT interval and the risk of torsades de pointes or sudden death is not clearly established and might vary from drug to drug and from individual to individual. Hundreds of drugs are known to prolong the QT interval, with widely variable degrees of evidence for clinical dysrhythmias.^{16,17 [1]}

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What did the authors find?

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Because of the small number of studies and articles identified, we were unable to perform a true systematic review (ie, meta-analysis)^{22 [1]}

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First, what does the FDA (Food and Drug Administration) label recommend as the dosage of droperidol?

Adult Dosage: The maximum recommended initial dose of droperidol is 2.5 mg I.M. or slow I.V. Additional 1.25 mg doses of droperidol may be administered to achieve the desired effect. However, additional doses should be administered with caution, and only if the potential benefit outweighs the potential risk.^[4]

As if that caution does not apply to the use of every medication.

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In one surgical study of 40 patients receiving three weight-based doses of droperidaol, which if given to a 70 kg adult, would be doses of 7 mg, 12.25 mg, and 17.5 mg. Much higher than 2.5 mg. Yes, this is surgery, so what does the FDA recommend about surgical dosing?

Dosage should be individualized. Some of the factors to be considered in determining dose are age, body weight, physical status, underlying pathological condition, use of other drugs, the type of anesthesia to be used, and the surgical procedure involved.^[4]

They certainly were not excluding surgery from their dosing recommendation.

QTc interval prolongation occurred within 1 minute of injection and did not increase with time. Prolongation of the median QTc interval occurred by 37, 44, and 59 ms, respectively, in a dose-dependent fashion; this was also statistically significant (P<.003). ^[1]

Of these patients receiving very high doses, how many died?

No dysrhythmias developed. ^[1]

There was a lower dose surgical study and a long-term psychiatric study. Again, there was QT prolongation, but no arrhythmia (dysrhythmia and arrhythmia are synonyms).

And there is one ED (Emergency Department) retrospective study –

Over a 4-year period, 15,374 patients received 18,020 doses of droperidol. Of the 682 patients who had an ECG performed after droperidol administration, 14 (3.1%) had prolonged QT intervals (defined as >480 ms) without evidence of any bundle branch block. Four of the 14 patients had previously documented prolonged QT intervals not associated with droperidol use. A control group (n=100) who had ECGs performed without the administration of droperidol had a similar incidence of prolonged QT intervals (4.0%). ^[1]

The patients who received droperidol appear to have been less likely to develop QT segment prolongation. With droperidol – 3.1% had QT prolongation. Without droperidol – 4.0% had QT prolongation.

The control group only had 100 patients, so each patient represents 1.0%, but if droperidol is so dangerous there should be more QT prolongation in the droperidol group. Maybe there is something about the way that droperidol is used in the ED that decreases the supposed danger.

These studies do not mean that droperidol is safe, but they do raise questions about the rush to add a black box warning to the droperidol label.

With the black box warning, the FDA essentially says, Lawyers, look here. You don’t have to demonstrate that droperidol is dangerous – we did that for you. Go sue some doctors.

These studies do not support the claim by the FDA that droperidol is dangerous. In Part II, I will continue with the case studies reviewed by the authors.

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Footnotes:

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^[1] Droperidol, QT prolongation, and sudden death: what is the evidence?
Kao LW, Kirk MA, Evers SJ, Rosenfeld SH.
Ann Emerg Med. 2003 Apr;41(4):546-58. Review.
PMID: 12658255 [PubMed - indexed for MEDLINE]

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^[2] Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial.
Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al.
N Engl J Med. 1991 Mar 21;324(12):781-8.
PMID: 1900101 [PubMed - indexed for MEDLINE]

Free Full Text Article from N Engl J Med with links to Free Full Text PDF download

CONCLUSIONS. There was an excess of deaths due to arrhythmia and deaths due to shock after acute recurrent myocardial infarction in patients treated with encainide or flecainide. Nonlethal events, however, were equally distributed between the active-drug and placebo groups. The mechanisms underlying the excess mortality during treatment with encainide or flecainide remain unknown.

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^[3] C A S T and Narrative Fallacy
Rogue Medic
Article

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^[4] DROPERIDOL injection, solution
[Hospira, Inc.]
FDA label
DailyMed
Dosage and administration

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