What is an appropriate antiemetic for an elderly patient with a risk of QT prolongation?

Comment by InpharmD Researcher

When used as a single antiemetic agent, dexamethasone, diphenhydramine, scopolamine do not appear to elicit clinically significant QT prolongation risk. Certain regimens used in cancer patients, such as aprepitant, fosaprepitant, and palonosetron are not associated with prolonged QT intervals. If ondansetron is considered, the initial IV dose should be limited to ≤ 8 mg in patients > 75 years.

Background

A recent review on the management of postoperative nausea and vomiting (PONV) for patients at risk of prolonged QT interval or for patients who routinely receive neurotransmitter-modulating therapy examined eight commonly used antiemetic medications (ondansetron, dexamethasone, diphenhydramine, scopolamine, metoclopramide, promethazine, prochlorperazine, and fosaprepitant) in these selected high-risk project groups. The expert panel formulated an antiemetic decision tool for high-risk anesthesia patients (presented in Table 1) with cost valuation at the time of publication assigned to each medication. The number of cardiac risk factors (bradycardia, atrioventricular block, cardiac pauses, takotsubo cardiomyopathy, heart disease, congenital long QT syndrome) and potential other risk factors (pheochromocytoma, hypokalemia, hypomagnesemia, hypocalcemia, female gender, hypothyroidism, hypothermia, hemodialysis) may pose an increased risk of QT prolongation. [1]

A 2016 review assessed cardiac complications after the use of antiemetic drugs in cancer patients. Many antiemetic agents have limited or conflicting data regarding effects on QTc prolongation (presented in Table 2). There were some agents mentioned by the authors that were not typically associated with QTc prolongation. Granisetron was stated as having conflicting data, but some studies, including a randomized controlled trial, have shown no significant effect on QTc prolongation at the approved dose. Palonosetron was also listed as an agent that does not seem to cause significant changes in QTc interval, as shown in many studies, including a randomized controlled trial. The authors stated that palonosetron might be the ideal drug of choice to prevent nausea and vomiting for cancer patients undergoing chemotherapy. Aprepitant and fosaprepitant were also included as options that have not been associated with QTc prolongation. [2]

Antipsychotic medications with antiemetic effects such as chlorpromazine, droperidol, and haloperidol, are noted to be the most likely to cause QTc prolongation and increase the risk of torsades. Additionally, the serotonin receptor antagonists ondansetron, granisetron, and dolasetron, also have a possible risk, however less so than the antipsychotics. Diphenhydramine has less risk but there have been reports of QT prolongation. Palonosetron is a notable serotonin receptor antagonist that has not been shown to cause QTc prolongation. Other agents such as dexamethasone, metoclopramide, and neurokinin-1 antagonists, including aprepitant (contraindicated with pimozide, terfenadine, astemizole, and/or cisapride due to ventricular arrhythmias) have been used without reports of QTc prolongation. [3]

A 2017 meta-analysis comparing the effects of haloperidol to serotonin receptor antagonists included eight randomized controlled trials. The mean dose of haloperidol used in the identified trials was 1.34 mg without any extrapyramidal side effects. Seven trials reported the number of patients with a QTc interval of more than 470 ms, comparable to serotonin receptor antagonists. The estimated incidence of QTc prolongation in the haloperidol group was 18.82% (95% confidence interval [CI] 15.17% to 23.10%) and 15.82% (95% CI 12.47% to 19.87%). Based on the equivalent pooled Mantel Haenszel odds ratio for QTc prolongation in both groups (fixed effects, p= 0.23, I2= 0%), the authors concluded that the randomized controlled trials included in this analysis could not establish an increased risk of QTc prolongation or any cardiac arrhythmia with haloperidol versus serotonin receptor antagonists. [4]

References:

[1] Hymel N, Davies M. Evidence-based antiemetic decision tool for management of postoperative nausea and vomiting in patients at high risk of QT prolongation and patients receiving neurotransmitter-modulating medications. AANA J. 2020;88(4):312-318.
[2] Barni S, Petrelli F, Cabiddu M. Cardiotoxicity of antiemetic drugs in oncology: An overview of the current state of the art. Crit Rev Oncol Hematol. 2016;102:125-134. doi:10.1016/j.critrevonc.2016.04.012
[3] Hendren, G., Aponte-Feliciano, A., & Kovac, A. (2015). Safety and efficacy of commonly used antiemetics. Expert Opinion on Drug Metabolism & Toxicology, 11(11), 1753–1767. doi:10.1517/17425255.2015.1080688
[4] Singh PM, Borle A, Makkar JK, Trikha A, Fish D, Sinha A. Haloperidol Versus 5-HT3 Receptor Antagonists for Postoperative Vomiting and QTc Prolongation: A Noninferiority Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials. J Clin Pharmacol. 2018;58(2):131-143. doi:10.1002/jcph.999
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is an appropriate antiemetic for an elderly patient with a risk of QT prolongation?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-5 for your response.

 

Antiemetic Decision Tool for High-Risk Anesthesia Patients 
Antiemetic agent QT prolongation risk Use with SSRI/SNRI Use with MAOI Costa
Ondansetron potential risksb potential risksb potential risksb $
Comments: Avoid in CLQTS. Use caution in patients with hypokalemia/hypomagnesemia/other electrolyte disturbances, bradycardia/ bradyarrhythmias/patients receiving medications that cause bradycardia, underlying heart disease/CHF, and patients receiving other QT-prolonging medications (especially chemotherapeutic agents). Ondansetron plus promethazine may increase the risk of prolonged QT interval; consider obtaining baseline ECG and monitor for ECG changes during use.
Dexamethasone no clinically significant risk no clinically significant risk no clinically significant risk $
Comments: Reduce dose of dexamethasone in concomitant use of NK1 agents due to risk of high serum dexamethasone levels (apparent for 8 d after NK1 use).
Diphenhydramine no clinically significant risk no clinically significant risk no clinically significant risk  $ 
Comments: Avoid in CLQTS. Avoid excessive dose.
Scopolamine no clinically significant risk potential risksb potential risksb $$ 
Comments: Scopolamine plus SSRI/SNRI/MAOI may increase patient’s risk of development of central anticholinergic syndrome, especially in patients receiving multiple agents that affect neurotransmitters or in patients over age 65 y. Observe for mental status changes and central anticholinergic syndrome when scopolamine is given with antidepressants. Avoid use in patients with narrow-angle glaucoma and patients receiving aclidinium, azelastine, cimetropium, eluxadoline, glucagon, glycopyrrolate, ipratropium, levosulpiride, orphenadrine, paraldehyde, potassium chloride, thalidomide, tiotropium, and umeclidinium.
Promethazine potential risksb potential risksb  potential risksb  $ 
Comments: Avoid in CLQTS. Best to avoid concomitant use of metoclopramide and promethazine. This combination may increase risk of QT prolongation. Consider obtaining baseline ECG and monitor for ECG changes during coadministration. Coadministration of promethazine and metoclopramide may increase the risk of CNS depression and extrapyramidal effects. Best to avoid use with other potentially QT-prolonging medications.
Prochlorperazine potential risksb potential risksb  potential risksb  $$ 
Comments: Combination of metoclopramide and prochlorperazine can result in extrapyramidal effects and neuroleptic malignant syndrome. Prochlorperazine may increase the risk of QT interval prolongation. Best to avoid use with other potentially QT-prolonging medications. Combination of prochlorperazine with SSRI/SNRI, ondansetron, metoclopramide, promethazine, isoflurane, and sevoflurane may increase the risk of QT prolongation.
Metoclopramide potential risksb  choose an alternative therapyc choose an alternative therapyc $ 
Comments: Avoid in CLQTS, avoid in patients with low/high serum potassium ions or magnesium or other electrolyte disturbances. Use with caution in elderly, patients with cardiac conduction disturbances/bradycardia, or patients receiving other QT-prolonging drugs. Avoid in any serotonin-modulating agents, including tramadol, due to risk of extrapyramidal activity and neuroleptic malignant syndrome. Combination of metoclopramide and prochlorperazine can result in extrapyramidal effects and neuroleptic malignant syndrome.
Fosaprepitant no clinically significant risk no clinically significant risk no clinically significant risk $$$$ 
Comments: Reduce dose of dexamethasone in concomitant use of NK1 agents due to risk of high serum dexamethasone levels (apparent for 8 d after NK1 use).

Abbreviations: CHF, congestive heart failure; CLQTS, congenital long QT syndrome; CNS, central nervous system; ECG, electrocardiogram; MAOI, monoamine oxidase inhibitor; NK, neurokinin; SSRI/SNRI, selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor

a $ indicates $0.10-$5; $$, $5.01-$49.99; and $$$$, $400.01-$499.99. None listed here cost $50.01 to $400, the third cost category.

b Literature finds potential risks, and additional monitoring or observation for interactions may be beneficial

c Literature reports known or observed drug interactions or side effects or a higher risk of drug interactions or side effects, so it is optimal to choose an alternative therapy
References:

Adopted from:
Hymel N, Davies M. Evidence-based antiemetic decision tool for management of postoperative nausea and vomiting in patients at high risk of QT prolongation and patients receiving neurotransmitter-modulating medications. AANA J. 2020;88(4):312-318.

Antiemetic drugs and cardiotoxicity

Class

 Drug  Cardiotoxicity  Notes 

5-HT3-RAs

 

Dolasetron

 QT prolongation

Contraindicated in children and adolescents; correction of electrolyte imbalances (K+, Mg+); concomitant administration with potentially QT-prolonging drugs should be avoided

Ondansetron

 QT prolongation

Dose-dependent QT change; Infuse within at least 15 seconds diluted in 50 to 100 mL of saline solution; do not exceed a dose of 8 mg in patients > 75 years;
use with caution in case of electrolyte imbalance, congestive heart failure, and bradyarrhythmias

Granisetron

 Arrhythmias; ECG changes Data are limited and inconsistent

Tropisetron

 Heart rate reduction Limited data 

Palonosetron

 -- Cardiotoxic effects are currently not known

Dopamine receptor antagonists

Metoclopramide 

QT prolongation, hypotension, shock, syncope, bradycardia or atrioventricular block, and cardiac arrest

 The maximum dose in 24 hours is 30 mg (or 0.5 mg/kg of body weight); maximum length of treatment: 5 days

Haloperidol 

 QT prolongation and TdP Risk associated more with intravenous and repeated doses

Olanzapine 

 QTc prolongation Risk associated with combination with other antipsychotics or antidepressants

Steroids 

 Dexamethasone  Cardiac arrhythmias Data for a causative effect with high dose steroids only

5-HT3-RAs = 5HT3 receptor antagonists; ECG = electrocardiogram; TdP = Torsades de pointes 
References:

Adopted from:
Barni S, Petrelli F, Cabiddu M. Cardiotoxicity of antiemetic drugs in oncology: An overview of the current state of the art. Crit Rev Oncol Hematol. 2016;102:125-134. doi:10.1016/j.critrevonc.2016.04.012

 

Drug-drug interactions contributing to QT prolongation in cardiac intensive care units

Design

Retrospective chart review

N= 187

Objective

To determine the most common drug-drug interaction (DDI) pairs contributing to QTc prolongation in cardiac intensive care units (ICUs)

Study Groups

Pharmacokinetic drug-drug interactions (PK-DDIs) (n= 78)

Pharmacodynamic drug-drug interactions (PD-DDIs) (n= 65)

Inclusion Criteria

Admitted to cardiac ICU, age ≥ 18, ECG showed evidence of QTc ≥ 500 ms

Exclusion Criteria

Prior history of long QT syndromes

Methods

Data were obtained from medical records utilizing 12-lead ECGs, typically evaluated daily or every other day depending on need. The medication lists were also obtained from medical records. Pharmacokinetic drug-drug interactions were defined as those that occurred due to alterations in the CYP-mediated metabolism of medications known to prolong the QTc interval. Pharmacodynamic interactions were defined as those that occurred due to the additive effects of two medications either identified as contributing to or directly causing prolongation of the QTc interval.

Duration

January 2009 to July 2009

Outcome Measures

Occurrence of DDIs contributing to QTc prolongation

Baseline Characteristics

  

PK-DDIs (n= 78)

PD-DDIs (n= 65)

  

Age, years

 63 62  

Male

 48 (61.5%) 40 (61.5%)  

Results

PK-DDIs occurring more than once

PD-DDIs occurring more than once

Medication combination

  N Medication combination  N 

Ondansetron + acetaminophen

 11 Amiodarone + ondansetron 8

Tacrolimus + metronidazole

 9

Tacrolimus + voriconazole

 7

Amiodarone + metronidazole

 8 

Amiodarone + risperidone

 4 

Ondansetron + amiodarone

 7 

Diphenhydramine + tacrolimus

 4 

Ondansetron + famotidine

 6 

Amiodarone + diphenhydramine

 4 

Risperidone + amiodarone

 5 

Amiodarone + haloperidol

 3 

Haloperidol + famotidine

 5 

Amiodarone + nicardipine

 3 

Ondansetron + lidocaine

 5 

Diphenhydramine + ondansetron

 3 

Voriconazole + metronidazole

 5 

Nicardipine + ondansetron

 3 

Tacrolimus + voriconazole

 5 

Ondansetron + risperidone

 3 

Haloperidol + acetaminophen

 3 

Amiodarone + azithromycin

 2 

Diphenhydramine + amiodarone

 3 

Amiodarone + perflutren

 2 

Haloperidol + amiodarone

 3 

Amiodarone + sulfamethoxazole/trimethoprim

 2 

Citalopram + pantoprazole

 3 

Diphenhydramine + venlafaxine

 2 

Ondansetron + diltiazem

 3 

Diphenhydramine + voriconazole

 2 

Risperidone + haloperidol

 3 

Fluoxetine + moxifloxacin

 2 

Amiodarone + diltiazem

 2 

Haloperidol + ondansetron

 2 

Nicardipine + amiodarone

 2 

Haloperidol + risperidone

 2 

Trazodone + amiodarone

 2 

Ondansetron + sulfamethoxazole/trimethoprim

 2 

Verapamil + amiodarone

 2 

Ondansetron + venlafaxine

 2 

Diphenhydramine + venlafaxine

 2     

Ondansetron + escitalopram

 2     

Ondansetron + haloperidol

 2     

Ondansetron + venlafaxine

 2     

Adverse Events

 N/A

Study Author Conclusions

Drug-drug interactions may be a significant cause of QT prolongation in cardiac ICUs. These data can be used to educate clinicians on safe medication use. Computerized clinical decision support could be applied to aid in the detection of these events.

InpharmD Researcher Critique

 A limitation of this study includes its dependency on accurately logged patient medical records, as it was a retrospective trial from a single cardiac ICU. This study found drug-drug interactions to be a common risk factor for torsades de pointes; however, this may be due to the selection bias of including patients with drug-drug interactions.



References:

Armahizer MJ, Seybert AL, Smithburger PL, Kane-Gill SL. Drug-drug interactions contributing to QT prolongation in cardiac intensive care units. J Crit Care. 2013;28(3):243-249. doi:10.1016/j.jcrc.2012.10.014

 

Effect of Single Doses of IV Palonosetron, up to 2.25 mg, on the QTc Interval Duration: a Double-blind, Randomized, Parallel Group Study in Healthy Volunteers

Design

Double-blind, randomized, parallel group study; N= 221

Objective

To investigate the effects of clinical and supratherapeutic doses of palonosetron on the electrocardiogram (ECG) profile compared to placebo

Study Groups

Placebo intravenous (IV) + placebo oral

Palonosetron 0.25 mg IV + placebo oral

Palonosetron 0.75 mg IV + placebo oral

Palonosetron 2.25 mg IV + placebo oral

Placebo IV + moxifloxacin 400 mg oral

(n) not reported

Inclusion Criteria

Healthy patients ages 18-65 with body weight between 20% of ideal weight according to the 1983 Metropolitan Height/Weight Tables

Exclusion Criteria

Cardiovascular disorder or family history of sudden cardiac death at age <50 years, any condition known to increase the possibility of QT interval prolongation, baseline 12-lead ECG interval abnormality

Methods

Out of the initial 230 healthy subjects, 221 were ultimately randomized into five study groups. Moxifloxacin group was used as a positive control to assess assay sensitivity. The exact number of subjects in each group was not reported, however the goal was to have at least 42 subjects per group. 

Three digital 12-lead ECGs (one minute apart) were recorded for 24 hours (h) prior to dosing (at −23 h 45 min, −23 h 30 min, −23 h, −22 h, −20 h, −18 h, −16 h, −14 h, −12 h, −10 h, −8 h, and at 0 h) and through 48 hours post-dose at 18-time points. 

Duration

48 hours

Outcome Measures

Placebo time-matched and baseline-subtracted individual QTc interval prolongation (QTcI) 

Baseline Characteristics

  

Study subjects (N= 221)

Mean age, years

 41.4

Male (%)

 120 (54)

White (%)

 211 (96)

Results

Data not reported.

Mean change in QTcI was reported to be less than 10 ms for all time points across all palonosetron treatment groups. Mean change in QTcI in Moxifloxacin group reported to have exceeded 10 ms at five consecutive time points.

 

Adverse Events

Common Adverse Events: headache (n= 33), constipation/abdominal pain (n= 27), infections (n= 10), backpain (n= 8), cardiac palpitation (n= 1, placebo group)

Adverse events were similar across treatment groups (21, 15, 23, and 20 treatment emergent adverse events [TEAEs] in placebo, palonosetron 0.25 mg, palonosetron 0.75 mg, and palonosetron 2.25 mg groups, respectively).

19 TEAEs were reported in the moxifloxacin positive-control group

Serious Adverse Events: headache (n= 1, palonosentron 0.75 mg)

Percentage that Discontinued due to Adverse Events: none reported

Study Author Conclusions

Palonosetron caused neither significant clinical prolongation of the QTc interval or adverse cardiac events in this study, indicating, based on ICH E14 guideline principles, that its risk of cardiotoxicity is low and that its use in the prevention of CINV in patients receiving MEC and HEC is apparently safe for cardiac function.

InpharmD Researcher Critique

Despite a longer half life and supratherapeutic doses, palonosetron showed no cardiotoxicity.  

 

References:

Morganroth J, Flaharty KK, Parisi S, Moresino C. Effect of single doses of IV palonosetron, up to 2.25 mg, on the QTc interval duration: a double-blind, randomized, parallel group study in healthy volunteers. Support Care Cancer. 2016;24(2):621-627. doi:10.1007/s00520-015-2822-6

 

The interaction of antiemetic dose of droperidol with propofol on QT interval during anesthetic induction

Design

Prospective randomized controlled trial

N= 72

Objective

To investigate the dose-dependency of low-dose droperidol on the heart-rate corrected QT (QTc) interval and the interaction between low-dose droperidol and propofol during anesthetic induction

Study Groups

0 mg droperidol/saline (n= 24)

1.25 mg droperidol (n= 24)

2.5 mg droperidol (n= 24)

Inclusion Criteria

Aged 20 to 80 years, American Society of Anesthesiologists (ASA) status of 1 or 2, underwent elective upper limb surgery under general anesthesia 

Exclusion Criteria

Preoperative electrocardiogram (ECG) abnormalities, medical history of ischemic heart disease, and diabetes, or had received preoperative medications such as beta-blockers or antiarrhythmic drugs

Methods

Patients were randomized to one of three study groups, receiving a bolus injection of 1 mL of drug followed one minute later by fentanyl (3 μg/kg). Two minutes after fentanyl, patients were induced for anesthesia using propofol 1.5 mg/kg. Immediately after the loss of consciousness, patients were given 0.15 mg/kg bolus of vecuronium. 

Heart rate, mean arterial pressure, bispectral index (BIS), and 12-lead ECG were recorded at baseline (T1), 3 minutes after injection of study drug (T2), 3 minutes after propofol (T3), and 2 minutes after tracheal intubation (T4). 

Duration

N/A

Outcome Measures

QTc interval prolongation

Baseline Characteristics

  

0 mg droperidol/saline (n= 24)

1.25 mg droperidol (n= 24)

2.5 mg droperidol (n= 24)

Age, years (interquartile range [IQR])

 51 (33 to 66) 52 (32 to 59) 60 (32 to 69)

Male

 10 (42%) 10 (42%) 13 (54%)

ASA (IQR)

  1 (1 to 1) 1 (1 to 2) 1 (1 to 2)

Results

The QTc interval in the 0 mg droperidol/saline group and 1.25 mg droperidol group was significantly shorter after propofol but recovered after intubation. In the 2.5 mg droperidol group, the QTc interval was significantly prolonged after droperidol injection, but recovered after propofol injection, and was again significantly prolonged after intubation (p< 0.05). The significance of data was shown in graphs, and exact values were not present.  

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

The results showed that 1.25 mg droperidol does not prolong the QTc interval, whereas 2.5 mg droperidol prolongs it significantly. This finding suggests that at antiemetic doses the effect of droperidol on the QTc interval is dose-dependent. Propofol furthermore counteracted the QTc interval that had been prolonged by 2.5 mg droperidol. Propofol would be suitable for inducing anesthesia in patients needing droperidol for preventing PONV.

InpharmD Researcher Critique

The majority of patients in this study were middle-aged adults, not the elderly. However, given the potential risk of increased QTc interval with 2.5 mg droperidol, use should be cautious in the elderly population. 

 

References:

Toyoda T, Terao Y, Oji M, Okada M, Fukusaki M, Sumikawa K. The interaction of antiemetic dose of droperidol with propofol on QT interval during anesthetic induction. J Anesth. 2013;27(6):885-889. doi:10.1007/s00540-013-1625-5