Patient Safety Tip of the Week
October 10, 2017 More on Torsade
de Pointes
Torsade de pointes is a relatively uncommon cause of sudden
unexpected death but one that is potentially preventable (see our June 29, 2010 Patient Safety Tip of
the Week “Torsade
de Pointes: Are Your Patients At Risk?”).
It 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.
The 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 to the CredibleMeds® website. That site provides
frequent updates when new information becomes available about drugs that may
prolong the QT interval.
But one matter of
real concern is prolongation of the QT interval by combinations of drugs.
The FDA (FDA 2016) issued a
warning last year about the commonly used anti-diarrheal loperamide
(Imodium and numerous OTC formulations) as a possible cause of unexplained
cardiac events including QT interval prolongation, Torsade de Pointes or other
ventricular arrhythmias, syncope, and cardiac arrest. Apparently, the majority
of reported serious heart problems occurred in individuals who were
intentionally misusing and abusing high doses of loperamide
in attempts to self-treat opioid withdrawal symptoms or to achieve a feeling of
euphoria. “In cases of abuse, individuals often use other drugs together with loperamide in attempts to increase its absorption and
penetration across the blood-brain barrier, inhibit loperamide
metabolism, and enhance its euphoric effects.” The FDA lists the following
drugs (noting the list is incomplete) as commonly interacting with loperamide: cimetidine, ranitidine, clarithromycin,
erythromycin, gemfibrozil, quinidine, quinine, ritonavir, itraconazole
and ketoconazole.
The latter two drugs are antifungal agents in the azole
category. Researchers at Duke
University School of Medicine recently presented at IDWeek
2017 data about interaction in patients receiving azole antifungals and
amiodarone, a commonly used anti-arrhythmic drug (Cook
2017). Senior author PharmD Melissa Johnson presented results of a study
of inpatients who were given systemic azoles (fluconazole, voriconazole,
posaconazole, itraconazole)
and amiodarone concomitantly. Of 252 patients with EKG results there was a mean
maximal change in QTc of +32.4ms from baseline from
471.6 ms at baseline (monotherapy) to 504.0 ms (concomitant therapy). The commonly used danger parameter
of QTc≥500ms was seen in 25.4% of patients at baseline and a follow-up QTc ≥500ms was seen in 48.8% of patients. Though
no cardiac events were apparent in relation to concomitant azole-amiodarone
therapy in the study, Dr. Johnson noted that more studies are needed to better
understand the safety of azoles given in the context of other QTc prolonging drugs.
Another study (Lorberbaum
2016) used data mining and laboratory investigation to uncover some
potential QT interval-prolonging
drug-drug interactions (QT-DDIs). They found both direct and indirect signals
in the adverse event reports that the combination of ceftriaxone
(a cephalosporin antibiotic) and lansoprazole (a proton-pump inhibitor)
will prolong the QT interval.
The major risk factors for Torsade de Pointes are
potentially modifiable. Since the electrolyte disturbances may be corrected and
medications may be switched there is significant opportunity to reduce the risk
of torsade de pointes when prolonged QTc intervals
are recognized early. But it’s pretty clear that it is beyond the capacity of
the human brain to remember not only all the individual drugs that may prolong
the QT interval but also all the drug-drug combinations that increase the risk.
Add to that a general unawareness of the risks for Torsade de Pointes. So we
really need to rely upon technology to help us. Clinical decision support
systems (CDSS) are the logical answer. We discussed these in our Patient Safety
Tips of the Week for April 9, 2013 “Mayo
Clinic System Alerts for QT Interval Prolongation”and June 10, 2014 “Another
Clinical Decision Support Tool to Avoid Torsade de Pointes”.
In our April 9, 2013
Patient Safety Tip of the Week “Mayo
Clinic System Alerts for QT Interval Prolongation” we discussed one such
CDSS tool that had been implemented at the Mayo Clinic (Haugaa
2013). In November 2010 the Mayo Clinic developed and implemented a
system-wide QT alert system, called the pro-QTc
system (see the prior column or the Haugaa article
itself for details of the pro-QTc formula and scoring
system). With some variation based on factors such as heart rate, a corrected
QT interval (QTc) 500 msec
or greater would trigger a notification alert to the ordering physician as a
“semi-urgent finding” with a link to a Mayo website with guidance on management
of such cases. They sent alerts to clinicians regarding about 2% of patients. For
the population as a whole the QTc was a significant
predictor of mortality. For each 10 msec increment in
QTc there as a 13% increase in mortality, independent
of age and sex. The pro-QTc score was also a
significant predictor of death and did so in a “dose-dependent” manner (i.e.
each one-point increment in the pro-QTc score further
increased mortality by a factor of 17%). On multivariable analysis only the number
of QT-prolonging medications and electrolyte abnormalities were significant
independent predictors of death. This again emphasizes the importance of
recognizing drug combinations that may contribute to QT prolongation.
Then in our June 10,
2014 Patient Safety Tip of the Week “Another
Clinical Decision Support Tool to Avoid Torsade de Pointes” we discussed
another study which demonstrated that use of CDSS and computerized alerts can
reduce the risk of QT interval prolongation (Tisdale
2014). One of the most important considerations is developing a system in
which the risk of alert fatigue is minimized. We know from multiple studies
done in the past that physicians override over 90% of computer alerts during
CPOE (computerized physician order entry). To minimize the risk of alert
fatigue and still accomplish your goal of reducing the risk to patients it is
important to (1) deliver the alert to the right person (2) deliver alerts only
for the most potentially serious events and (3) provide alternative options for
the physician’s response.
They system developed and implemented by Tisdale and
colleagues did all three. First, the alerts first went to the pharmacist, who
would then evaluate the situation and decide whether discussion with and
recommendations for the physician were appropriate. Second, the thresholds to
trigger the alerts were set at levels expected to minimize alert fatigue. And,
third, the pharmacist responding to the alert would present the physician with
some options for actions.
Their system would trigger an alert when the QTc interval was >500 ms
or there was an increase in QTc of ≥60 ms from baseline. Their system also identified through the
electronic medical record multiple other conditions or laboratory results that
identified patients at higher risk for QT interval prolongation.
After implementation
of the CDSS system the found a significant reduction in the risk of QT
prolongation (odds ratio 0.65). In addition, they found a significant reduction
in the prescription of non-cardiac drugs known to prolong the QT interval
(especially fluoroquinolone antibiotics and intravenous haloperidol). Overall,
82% of alerts were overridden. That still compares favorably to the frequency
with which other alerts are overridden. Most of the overrides were for cardiac
drugs (eg. amiodarone or other anti-arrythmic drugs). The authors point out that overriding the
computer alert did not mean that nothing was done. For example, even though the
order for the drug may have been overridden the pharmacist and physician may
have modified some other risk factor (eg. corrected
an electrolyte disturbance or stopped another medication) or increased the
frequency of QTc surveillance.
So what should your hospital or healthcare organization
should be doing? We recommend the following:
- 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
risk category
- If a
pre-op EKG is done, make sure someone pays attention to the baseline QTc interval
- When
starting drugs known to prolong the QT (eg.
psychotropic drugs, methadone, amiodarone, etc.) 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 to
appropriate staff like those in the studies by Haugaa
and Tisdale
- Consider
sending the alerts to a clinical pharmacologist rather than directly to
physicians; the clinical pharmacologist may then interact with the
physician with suggestions for interventions
- Take
appropriate actions as soon as you identify QT prolongation
- Establish
patient educational materials to give at-risk patients at time of
discharge
- Appropriate
attention to those patients in outpatient settings who are begun on any of
the drugs noted or have dose escalations of such drugs
Torsade de pointes is a relatively uncommon cause of sudden
unexpected death but one that is potentially preventable. Being aware of the
risk factors and having systems that identify when potentially dangerous drugs
are being given to at-risk patients may potentially save lives.
Some of our prior
columns on QT interval prolongation and Torsade de Pointes:
June 29, 2010 “Torsade
de Pointes: Are Your Patients At Risk?”
February 5, 2013 “Antidepressants
and QT Interval Prolongation”
April 9, 2013 “Mayo
Clinic System Alerts for QT Interval Prolongation”
June 10, 2014 “Another
Clinical Decision Support Tool to Avoid Torsade de Pointes”
April 2015 “Anesthesia
and QTc Prolongation”
References:
CredibleMeds® website
FDA (US Food and Drug Administration). FDA Drug Safety
Communication: FDA warns about serious heart problems with high doses of the
antidiarrheal medicine loperamide (Imodium), including
from abuse and misuse. FDA Safety Announcement June 7, 2016
http://www.fda.gov/Drugs/DrugSafety/ucm504617.htm
Lorberbaum T. Sampson KJ, Chang
JB, et al. Coupling Data Mining and Laboratory Experiments to Discover Drug
Interactions Causing QT Prolongation. J
Am Coll Cardiol
2016; 68(16): 1756-1764
http://content.onlinejacc.org/article.aspx?articleID=2565914
Cook K, Sraubol T, Bova K, et al. QTc Prolongation
in Patients Receiving Triazoles and Amiodarone. IDWeek 2017 Poster 173
As discussed in:
Han DH. QTc Prolongation With
Concomitant Amiodarone, Azoles Examined. MPR 2017; October 6, 2017
Haugaa KH, Bos
JM, Tarrell RF, et al. Institution-Wide QT Alert
System Identifies Patients With a High Risk of Mortality. Mayo Clin Proc 2013; 88(4): 315-325
http://download.journals.elsevierhealth.com/pdfs/journals/0025-6196/PIIS0025619613000712.pdf
Tisdale JE, Jaynes HA, Kingery J,
et al. Effectiveness of a Clinical Decision Support System for Reducing the
Risk of QT Interval Prolongation in Hospitalized Patients. Circulation:
Cardiovascular Quality and Outcomes 2014; published online before print May 6,
2014
http://circoutcomes.ahajournals.org/content/early/2014/05/06/CIRCOUTCOMES.113.000651.abstract
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