This retrospective study indicated that PPIs increased the risk of QT prolongation in ICU patients. In addition, several drugs caused higher QT prolongation risk when used in combination with PPIs, including amiodarone, diuretics, quinolones, macrolides, antidepressants, antipsychotics, opiates, 5-HT3RAs and metoclopramide.
A prolonged QT interval is an independent predictor of ventricular arrhythmia and is associated with hospital adverse outcomes (including death and discharge against medical advice) among critically ill patients [15, 16]. In a retrospective study, acquired QT prolongation was often found in ICU patients, with a high prevalence up to 27.9%, because of the use of drugs and comorbidities [12]. In the past twenty years, QT interval prolongation has been the main cause of the withdrawal or restricted use of non-antiarrhythmic agents [17, 18].
PPIs are commonly prescribed in ICU patients, but their risk related to ventricular arrhythmia is not fully recognized. According to several case reports, omeprazole, lansoprazole and pantoprazole have been listed as conditional risks by the website crediblemeds.org [2], and small sample studies have shown the risk of torsade de pointes when long-term PPI treatment causes hypomagnesemia [7, 9, 19]. However, QT prolongation independent of electrolyte abnormalities is possible during PPI treatment, as shown in several basic research and clinical reports. Although low magnesium is common in PPI-related TdP, approximately one-third (5/14) of patients have serum magnesium levels of 1.8 mg/dL or above [7]. Data from electronic health records also indicate that the combination of ceftriaxone and lansoprazole increases the risk of QT prolongation [20]. In a large cohort of US veterans, PPIs were independently associated with a 20% − 40% increased risk of QT interval prolongation [10]. Our study performed with 25,426 ICU patients also found that the impact of PPI treatment on QT prolongation was independent of serum potassium, magnesium, calcium and eGFR values. However, a small sample cohort study of children with dyspepsia found no impact of PPI treatment on QT interval prolongation or other ventricular repolarization parameters [21]. We considered that the low-risk population and small sample size may not have sufficient statistical power to draw significant results.
Ikr inhibition is the most common mechanism of QT prolongation drugs, and whether PPIs directly affect cardiomyocyte action potential and QT interval prolongation is controversial. Lorberbaum et al [20] found that the combination of lansoprazole and ceftriaxone blocked the Ikr at clinical concentrations. In contrast, another experimental study with isolated rabbit hearts reported that lansoprazole alone or in combination with ceftriaxone did not prolong the QT interval or action potential duration [22]. Lazzerini et al [10] explored more details of the mechanism of PPI-related QT prolongation, and whole-cell path-clamp recording identified four PPIs at clinically relevant concentrations that inhibited the Ikr due to the PPIs directly binding to the channel pore cavity.
Our results indicated that pantoprazole increased the highest risk of QT prolongation among three PPIs, which may be attributed to the varying inhibition capacity of the Ikr among the three PPIs. Pantoprazole induced a higher inhibitory effect (82.8%) on the Ikr at a concentration of 100 µmol/L than lansoprazole (51.2%) and omeprazole (32.3%) [10]. Pantoprazole is the most frequent PPI related to TdP. In a series of cases, pantoprazole was used in 64% (18/28) of the patients with TdP, while lansoprazole did not show prolongation of the action potential duration in animal models [22] or prolongation of the QT interval in a healthy population [23]. These results indicated a difference among PPIs; pantoprazole is the PPI that is most likely to increase TdP risk.
In this study, more than half of ICU patients were treated with PPIs, and combinations of PPIs and diuretics (48.11%), quinolones (38.76%), opiates (45.07%), and 5-HT3RAs (35.48%) were common. PPI treatment was associated with a higher risk of QT prolongation if combined with diuretics, amiodarone, antibiotics, antidepressant agents, antipsychotic agents, 5-HT3RAs, and metoclopramide. These drugs are known to increase the QT risk of TdP or the conditional risk of TdP and may affect the QT interval synergistically with PPIs through two mechanisms. Diuretics also induce electrolyte abnormalities, and amiodarone is a classic antiarrhythmic drug. The Ikr inhibition of these drugs has also been reported, including quinolones [24], macrolides [25], antidepressants [26], antipsychotics [27], opiates [28], 5-HT3RAs [29] and metoclopramide [30]. In fact, several reports showed that QT prolongation and torsade de pointes related to the use of PPIs were induced by combination with other drugs, such as disopyramide [31], ceftriaxone [20] and escitalopram [32]. In the hospital setting, polypharmacy is common. One observational study found that PPIs were prescribed for 40.1% of hospitalized patients and in combination with up to 153 drugs affecting the QT interval [33]. Therefore, the risk of drug combinations between PPIs and other QT-prolonging drugs should not be overlooked.
To our knowledge, this is the first study to determine the association between PPI treatment and the risk of QT prolongation in ICU patients. This association was consistent after adjustment for electrolyte values matched with ECG reports on the same day, and there was no significant interaction, which confirmed that PPIs were related to an increased risk of QT prolongation independent of electrolyte values. The current recommendation about PPI use (monitoring for electrolytes alone) is possibly not enough to avoid TdP for ICU patients, and ECG should be recommended to detect prolonged QT intervals in a timely manner. Strict use according to indications, prescribing lansoprazole or omeprazole instead of pantoprazole and avoiding the combination of PPIs with other QT-prolonging drugs may reduce exposure to unnecessary arrhythmia risk, given the current status of the wide misuse of PPIs.
This study has several limitations. First, an observational and retrospective study design cannot determine a causal relationship, and prospective controlled trials are needed to determine whether PPI treatment prolongs the QT interval in a high-risk population. Moreover, PPI prescriptions before hospitalization were unable to be acquired, and it is unknown whether the association depends on long-term treatment. Finally, the endpoint of this study was extracted from ECG text reports, and QT interval values and other ECG repolarization parameters were absent.