Patient safety tip of the week archive

In our June 29, 2010 Patient Safety Tip of the Wee we discussed the risks of this potentially fatal syndrome in
hospitalized patients. Torsade de Pointes is a form of ventricular tachycardia, often fatal,
in which the QRS complexes become “twisted” (changing in amplitude and morphology)
but is best known for its occurrence in patients with long QT intervals. Though cases of
the long QT interval syndrome (LQTS) may be congenital, many are acquired and due to
a variety of drugs that we prescribe. The syndrome is more common in females and many
have a genetic predisposition. And there are a number of reasons why this syndrome is
more likely to both occur and result in death in hospitalized patients. Hospitalized
patients have a whole host of other factors that may help precipitate malignant
arrhythmias in vulnerable patients. They tend to have underlying heart disease,
electrolyte abnormalities (eg. hypokalemia, hypomagnesemia, hypocalcemia), renal or
hepatic impairment, and bradycardia, all of which may be precipitating factors. More
importantly they may have the sorts of conditions for which we prescribe the drugs that
are primarily responsible for prolonging the QT interval (eg. haloperidol, antiarrhythmic
agents, etc.). And many of those drugs are given intravenously and in high doses in the
hospital as compared to the outpatient arena. Rapid intravenous infusion of such drugs
may be more likely to precipitate Torsade de Pointes than slow infusion.
But, of course, the syndrome is not limited to hospitalized patients and we must remain
vigilant for prolongation of the QT interval in outpatients as well. That is especially the
case when dose escalations occur.
In our prior column we discussed the many drugs potentially implicated in prolonging the
QT interval and potentially leading to Torsade de Pointes. But one class of drugs that had
been relatively unrepresented was the antidepressant class. Then, in 2011 the FDA issued
a warning about QT interval prolongation for citalopram (Celexa), later updated to
restrict the dosage of citalopram to 20 mg. in patients older than 60 years and patients
taking other drugs inhibiting cytochrome P450 2Che FDA also
recommends discontinuation of citalopram in patients found to have persistent QTc
measurements greater than 500 msec.
Antidepressants, of course, are used not only in the treatment of depression but are also
sometimes used for a wide variety of other clinical problems (eg. chronic pain, migraine,
etc.).
Now a new study from the Partners HealthCare System has used innovative electronic
health record technologies to assess the risk in patients taking both newer and older
antideprehe approach (see below) also has tremendous potential
for other studies and for development of clinical decision support systems.
The authors were able to examine medical records for over 4 million unique patients
within their system of hospitals and outpatient practices. They identified over 240,000
adult patients given at least one antidepressant.prescription and were then able to assess
corrected QT intervals (QTc) from the electronic medical records in those patients who
had electrocardiograms done. In many cases they had the opportunity to see the impact of
dose escalations on the QTc. Plus they were able to assess a whole host of comorbidities
and potentially confounding variables from the clinical records on these patients. They
were able to identify a dose-response association of QTc prolongation for citalopram,
escitalopram, and amitriptyline. This was not seen for other antidepressants. On the
other hand, they found an association with QTc shortening for buproprion, a drug
sometimes used in patients in whom first line antidepressants fail to produce anticipated
result.
The authors, in discussing the implications of their findings, are quick to point out that
QTc prolongation is only a surrogate measure for potential Torsade de Pointes and that
the reported incidence of torsade in patients taking antidepressants is low. Nevertheless,
they found that almost one in every five patients taking antidepressants had prolongation
of the QTc interval and might be potentially at risk. Their findings might help in selection
of individual drugs in certain patients. Importantly, it emphasizes the need for periodic
monitoring in such patients, particularly when dose escalation is considered.
In our June 29, 2010 Patient Safety Tip of the Wee we referenced the AHA/ACCF statement on Torsade de Pointes
he drugs most commonly associated with Torsade de Pointes are
haloperidol, methadone, thioridazine, amiodarone, quinidine, sotalol, procainamide,
erythromycin, azithromycin, the antihistamine terfenadine and certain antifungals. For a
full list of drugs that commonly cause prolongation of the QT interval and may lead to
Torsade de Pointes, go tot site also has a list of drugs
that prolong the QT interval and might possibly cause Torsade de Pointes and another list
of drugs that have conditional risk (eg. only when combined with other drugs). Some
drugs (eg. cisapride/Propulsid, a drug formerly used to promote GI motility) have
actually been withdrawn from the market because of serious cardiac side effects,
including prolongation of the QT interval and torsade de pointes.
Our June 29, 2010 Patient Safety Tip of the Week also discussed not only inpatient issues but also issues related to QTc prolongation and the emergency department, psychiatry, anesthesia, and surgery and the nuances of measuring the QT interval and the QTc (corrected QT). In all settings it is important to consider not only the potential effect of various drugs but also underlying conditions and other contributing factors such as electrolyte disturbances. We had recommendations on what your hospital facilities should be doing:  Define how you will measure and monitor the QT/ QTc in your organization  Decide how you will identify at-risk patients and monitoring frequencies for each  If a pre-op EKG is done, make sure someone pays attention to the baseline QTc  When starting drugs known to prolong the QT (eg. psychotropic drugs, methadone) make sure a baseline EKG is obtained and do reminders for when the QT should be remeasured  Develop CPOE and decision support rules and surveillance to generate reminders  Take appropriate actions as soon as you identify QT prolongation  Establish patient educational materials to give at-risk patients at time of discharge To those we obviously now would add appropriate attention to those patients in outpatient settings who are begun on any of the drugs noted or have dose escalations of such drugs. One must keep in mind that the incidence of Torsade de Pointes and fatal arrhythmias is still quite low overall. Prolongation of the QTc interval is only a surrogate measure of the potential for such serious events. The potential benefits of many of these psychotropic agents may outweigh the risks of Torsade. But identifying the risk factors should at least flag such patients for closer monitoring during treatment with psychotropic drugs. As we mentioned, the approach used by Castro and colleaguelso has tremendous potential for other studies and for development of clinical decision support systems. They examined electronic health records using natural language processing (NLP) and machine-learning algorithms. Their article discusses the difficulties in identifying serious, but rare, adverse medication effects in the randomized controlled trials done prior to FDA approval or in the post-marketing surveillance studies done after approval. While results of studies using the techniques they used can really only demonstrate associations rather than determining definite cause-effect they really have unlimited potential to raise red flags that otherwise would take many years to appear. They also have great potential for clinical decision support systems. Though we always need to keep in mind the risks of “alert fatigue”, such systems could be used to prompt ordering of electrocardiograms in those patients on one of the higher risk drugs when a dose escalation occurs or when additional drugs are ordered. Or they could provide reminders when serum potassium or magnesium levels should be considered in patients
on such drugs. We described potential rules logic for some of those alerts in our June 29,
2010 Patient Safety Tip of the Wee
This is really great work. Kudos to Castro and colleagues at Partners HealthCare not just
for the messages in the specific study conducted but also for highlighting the potential
use of such pharmacovigilance techniques for many other potential purposes.
References:
Castro VM, Clements CC, Murphy SN, et al. QT interval and antidepressant use: a cross
sectional study of electronic health records. BMJ 2013; 346: f288 (Published 29 January
2013)

FDA. FDA Drug Safety Communication: Revised recommendations for Celexa
(citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high
doses. 3/28/12

Drew BJ, Ackerman MJ, Funk M on behalf of the American Heart Association Acute
Cardiac Care Committee of the Council on Clinical Cardiology, the Council on
Cardiovascular Nursing, and the American College of Cardiology Foundation
Prevention of Torsade de Pointes in Hospital Settings: A Scientific Statement From the
American Heart Association and the American College of Cardiology Foundation
Circulation 2010;121;1047-1060; originally published online Feb 8, 2010

CredibleMeds™ website.

Source: http://www.patientsafetysolutions.com/docs/February_5_2013_Antidepressants_and_QT_Interval_Prolongation.pdf