The results from a 2016 study that utilized data mining and laboratory experimentation indicated that the combination of ceftriaxone and lansoprazole was associated with an increased risk of long QT syndrome.

Recently, a multicenter, retrospective cohort study involving 13 hospitals in Ontario, Canada, and over 31,000 patients sought to answer the question of whether adult medical inpatients receiving ceftriaxone treatment concomitant lansoprazole compared with other proton pump inhibitors (PPIs) were associated with an increased risk of ventricular arrhythmias, cardiac arrest, or death.

To be included in the study, participants had to be consecutive adult patients admitted to a medical service in one of the 13 Canadian facilities between January 1, 2015, and December 31, 2021. Inclusion criteria involved the administration of at least one dose of parenteral ceftriaxone during the hospital stay and an order for a PPI during the period between the first and last dose of ceftriaxone. Data were obtained from the GEMINI database on hospitalizations and the Canadian Institute for Health Information Discharge Abstract Database and the National Ambulatory Care Reporting System.

Investigators examined exposures of interest, which referred to concomitant lansoprazole during the period between the first and last dose of ceftriaxone. The comparison group included patients who received a different PPI other than lansoprazole and who also received ceftriaxone during the same timeframe as the lansoprazole group. Patients who received lansoprazole in addition to another PPI were included in the lansoprazole group.

The primary outcome was a composite of ventricular arrhythmia or cardiac arrest that developed during the hospital stay and postadmission based on ICD-10 codes. The secondary outcome was all cause in-hospital mortality. Patients with a history of ventricular premature depolarization, other premature depolarization, and unspecified cardiac arrhythmias were excluded.

Covariants for ventricular arrhythmia that were predetermined included coronary artery disease, prior myocardial infarction, heart failure, cardiomyopathy, prior history of ventricular arrhythmia or cardiac arrest, chronic kidney disease, and abnormal serum potassium levels.

Another covariant examined was systemic medication classes prescribed before the first dose of ceftriaxone that may increase the risk of ventricular arrhythmias based on the American Heart Association scientific statement. Among these agents were fluoroquinolones (ciprofloxacin, moxifloxacin, and levofloxacin), macrolides (azithromycin, erythromycin, and clarithromycin), cardiac medications (amiodarone, disopyramide, dofetilide, dronedarone, hydroquinidine, flecainide, ibutilide, niferidil, procainamide, propafenone, quinidine, sotalol, digoxin, dobutamine, milrinone, epinephrine, norepinephrine, dopamine, isoprenaline, ephedrine), and other medications (bupropion, escitalopram, citalopram, desipramine, imipramine, trazodone, venlafaxine, lithium, chlorpromazine, thioridazine, haloperidol, levomeprazin, levosulpride, pimozide, ulpiride, sultopride, domperidone, ondansetron, metoclopramide, diphenhydramine, fluconazole, itraconazole, ketoconazole, methadone, donepezil, hydroxychloroquine, and chloroquine).

There were 3,747 patients (12%) in the lansoprazole group and 27,405 patients in the other PPI group (88%). The mean age of the total population was 71.7 years. The lansoprazole group was older, was from a long-term care facility, had higher acuity, was admitted to the ICU for COVID-19 or aspiration, and was receiving arrhythmogenic medications.

Ventricular arrhythmias or cardiac arrest occurred in 445 patients of which 3.4% (126 patients) were in the lansoprazole group and 1.2% (319 patients) were in the other PPI group (P < .001). All-cause in-hospital mortality occurred in 746 patients (19.9%) in the lansoprazole group and 2762 patients (10.1%) in the other PPI group.

Following propensity score adjustment, the lansoprazole group still had a statistically significantly higher risk of ventricular arrhythmia or cardiac arrest and in-hospital mortality. The lansoprazole had an adjusted risk difference of 1.7%, which was statistically significant for ventricular arrhythmias or cardiac arrest and correlated with a number needed-to-harm of 58.8. For inpatient-mortality, the adjusted risk difference between the groups was 7.4%. Both subgroup and sensitivity analyses demonstrated a higher risk of ventricular arrhythmia, cardiac arrest, and mortality in the lansoprazole group.

Limitations of the study included that this study design was retrospective and used administrative data; investigators could not determine if the two drugs were administered concomitantly; and the exact date of a cardiac event included in the primary outcome was not recorded. When another PPI was used in addition to lansoprazole during the study period, lansoprazole accounted for a median of 50% of the total duration of PPI use and in 77% of cases, lansoprazole accounted for the majority of the total duration of PPI use.

Nonetheless, this study complements previous retrospective studies and case reports that have demonstrated potential adverse cardiovascular events when ceftriaxone is administered along with lansoprazole. Given the availability of a multitude of other PPI agents to choose from, pharmacists should educate on this potential risk and recommend alterative therapy until more definitive data are available to disprove this potential for harm. Pharmacists should also be familiar with the website www.crediblemeds.org, which provides data on the risk of drug-induced QTc (corrected QT) prolongation.

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