Drug interaction between ceftriaxone and lansoprazole tied to fatal arrhythmia, reveals big data
Taking a combination of ceftriaxone and lansoprazole is associated with prolonged QT interval, which can lead to a form of life-threatening polymorphic ventricular tachycardia known as Torsades de pointes (TdP), reveals a recent study.
“Acquired long QT syndrome [LQTS] is of particular concern when it is not anticipated and occurs as the result of a QT interval-prolonging drug-drug interaction [QT-DDI],” said the researchers. “QT-DDIs are not routinely evaluated preclinically and can go undiscovered for years.”
Mining the FAERS* database for adverse event reports, the researchers corroborated the evidence of QT-DDI with clinical data from the CUMC-EHR** which contains 1.6 million electrocardiograms (ECGs) of 382,221 patients treated between 1996 and 2014. The patients were categorized into the exposed cohort, which had been administered with both of the candidate drugs for DDI within a 7-day window, or the control cohorts, which had been exposed to either one of the drugs only in their records. [J Am Coll Cardiol 2016;68:1756-1764]
Out of the 889 putative signals detected from the FAERS, eight combinations remained after corroboration of data from the CUMC-EHR and elimination of confounders. The combination of the cephalosporin antibiotic ceftriaxone and the proton pump inhibitor lansoprazole was prioritized for experimental validation as lansoprazole was available over the counter besides being one of the top 150 most-prescribed drugs in the US in 2010, according to the authors.
“Because [the analyses] are in situ, they focus on drug combinations that are actually used together in clinical practice,” said the researchers.
Patients taking the combination of ceftriaxone and lansoprazole had significantly prolonged heart-rate corrected QT (QTc) intervals than those taking either drug alone (12 ms longer for male; p<0.001 and 9 ms longer for female; p<0.001).
Also, male patients taking both drugs were 1.4 times more likely to have a QTc interval ≥500 ms compared with the control cohorts (19.27 percent vs 14.21 percent or 12.84 percent for ceftriaxone alone or lansoprazole alone, respectively; p<0.001).
Among 603 patients who had their ECGs taken before and after taking both drugs, a significant increase in QTc interval was observed for both men and women after the combination treatment (14.0 ms; p=6.56x10-4 and 12.9 ms; p=1.03x10-4, respectively).
Results from electrophysiology experiments in the laboratory showed that ceftriaxone led to a dose-dependent reduction in current across the hERG# channel in the presence of lansoprazole (p=1.07x10-4 to <3.45x10-5), but not with ceftriaxone alone, indicating a block in the channel which has been known as a primary mechanism for prolonging QT interval.
Importantly, combining another cephalosporin antibiotic cefuroxime with lansoprazole showed no significant effects on both the QTc interval from clinical data and the dose-dependent blockage of hERG channel from experimental data, suggesting that the interaction was specific to the ceftriaxone-lansoprazole pair.
Nonetheless, the findings were still inconclusive enough for doctors to avoid prescribing this drug combination for all patients, or even patients who were at risk of prolonged QT interval, according to Drs Dan Roden, Jonathan Mosley, and Joshua Denny of the Vanderbilt University Medical Center in Nashville, Tennessee, US, in a separate editorial. [J Am Coll Cardiol 2016;68:1765-1768]
“What would really add value would be a well-controlled study [which need not be large] in human subjects, examining the effects of the drugs individually and in combination on the QT interval,” they said.