The association between proton pump inhibitor prescription and QT interval prolongation in intensive care unit patients

DOI: https://doi.org/10.21203/rs.3.rs-2167911/v1

Abstract

Introduction: Drug-induced QT interval prolongation has been reported to be related tolife-threatening polymorphic ventricular tachycardia (torsade de pointes). Proton pump inhibitors (PPIs) are prescribed widelyfor hospitalized patients, the QT interval prolongation and torsade de pointes caused by PPIs were reported. We tried to explore whether PPIs can increase the risk of QT interval prolongation among intensive care unit (ICU) patients.

Methods: This study included patients with electrocardiography (ECG) reports from the Medical Information Mart for Intensive Care III database (MIMIC-III). Patients younger than 18 years and those with missing laboratory results were excluded. The end point was QT interval prolongation according to ECG reports.

Results:This study included 84,653 ECG reports of 25,426 ICU patients, 14,520 (57.1%) patients had been prescribed PPIs and 2,271 (8.93%) showed a prolonged QT interval. Patients treated with PPIs had a higher incidence of QT interval prolongation (11.17% vs. 5.95%; odd ratio [OR] 1.99, 95% CI: 1.81-2.19; P < 0.001) than those absent PPIs prescription. PPI treatment was associated with an increased risk of QT interval prolongation (OR 1.45, 95% CI: 1.30-1.62; P < 0.001) in adjusted logistic regression for serum potassium, serum magnesium, serum total calcium, estimated glomerular filtration rate (eGFR), comorbidities and known QT-prolonging drugs. In the matched population, patients treated with PPIs also had a higher risk of QT prolongation (8.74% vs. 6.29, OR 1.43, 95% CI: 1.23-1.66). Pantoprazole was associated with higher risk of QT interval prolongation compared with omeprazole and lansoprazole.

Conclusion: There was an association between PPI prescription and QT interval prolongation in ICU patients, independent on known QT-prolonging factors. Pantoprazole had thehighest risk among three PPIs.

1 Introduction

Drug-induced QT interval prolongation is associated with life-threatening polymorphic ventricular tachycardia (torsade de pointes, TdP), and electrocardiography (ECG) is an important method for assessing cardiac safety [1]. It is well known that the side effects of some non-antiarrhythmic agents can extend the ventricular action potential duration through several mechanisms, inhibit the rapidly activated delayed rectifier potassium current (Ikr) and cause electrolyte abnormalities (hypokalaemia, hypocalcaemia, and hypomagnesaemia). For instance, some gastrointestinal agents (cisapride and domperidone), antibiotics (moxifloxacin and azithromycin) and antidepressants (citalopram and escitalopram) are listed as known risk factors of TdP by the AriZona Center for Education and Research on Therapeutics in the QT drug lists (crediblemeds.org) [2]. To avoid in-hospital sudden cardiac death, it is necessary to understand the risk stratification of QT interval prolongation caused by drugs. In particular, commonly prescribed drugs among hospitalized patients, such as proton pump inhibitors (PPIs), might have the potential for fatal side effects.

Clinically, PPIs are effective medications for gastroesophageal reflux disease and peptic ulcer disease[3, 4], which are prescribed widely for treating or preventing gastrointestinal bleeding caused by serious illness (i.e., acute myocardial infarction) or medications (i.e., anti-inflammatory drugs and aspirin) in hospitalized patients. However, the overuse of PPIs for inappropriate indications is prevalent in hospitalized patients [5, 6].

PPI-related hypomagnesaemia raises concerns about their cardiac safety [7]. Some reports demonstrated that QT interval prolongation and TdP were caused by pantoprazole [79]. Moreover, three PPIs (omeprazole, lansoprazole and pantoprazole) that are considered as conditional risk factors of TdP should be discontinued when electrolyte abnormalities occur [2]. QT prolongation independent of electrolyte abnormalities is possible during PPI treatment, as shown in basic research and clinical reports. A recent study indicated that three kinds of PPIs (omeprazole, lansoprazole and pantoprazole) could directly reduce the Ikr and were related to a prolonged QT interval independent of hypomagnesemia in a large cohort [10]. In addition, the association between PPI treatment and increased long-term cardiovascular disease risk was also reported, regardless of hypomagnesemia [11].

Patients admitted to intensive care units (ICUs) have more risk factors and increased rates of drug-related QT prolongation [12], but it is unknown whether PPIs increase the risk of QT interval prolongation among critically ill patients. Therefore, we conducted a study with ICU patients to determine the association between PPI prescription and the risk of QT interval prolongation while searching for other risk factors.

2 Methods

2.1 Database source

The study data were obtained by an approved researcher Hualong Liu, certification number:43151599) from the Medical Information Mart for Intensive Care III (MIMIC-III) database v 1.4, which is a publicly available clinical database including ICU patients who stayed in the Beth Israel Deaconess Medical Center between 2001 and 2012 [13].

2.2 Data extraction

We extracted the study data using structured query syntax. Extracted data included sex, age, race, ICU category, simplified acute physiology score (SAPS), mean values of vital signs at admission, laboratory results during hospitalization and comorbidities from discharge diagnoses based on ICD-9 codes and medications. Medications included PPIs (omeprazole, lansoprazole, pantoprazole and others), antiemetics (metoclopramide and 5-hydroxytryptamine 3 receptor antagonists [5-HT3RAs]), quinidine, amiodarone, β blockers, digoxin, diuretics, antibiotics (quinolone and macrolide), antidepressants, antipsychotics, quinine/chloroquine (CQ)/hydroxychloroquine (HCQ), and opiates (supplemental table 1).

2.3 ECG reports

The end point of this study was QT interval prolongation according to ECG reports extracted from the note-events table of the MIMIC-III database. First, we investigated the relationship between PPI prescription during hospitalization and QT interval prolongation and possible risk factors. Furthermore, we matched each ECG report with drug prescriptions on the same date according to the report date, as well as electrolyte and estimated glomerular filtration rate (eGFR) values, and analysed the association with a higher temporal accuracy. We calculated the eGFR according to the chronic kidney disease epidemiology collaboration equation [14].

2.4 Study population

A total of 123,488 ECG reports charted in hospitals from 33,295 ICU patients were screened. Patients younger than 18 years and those with missing laboratory results were excluded (Fig. 1).

2.5 Statistical analysis

Continuous variables with a normal distribution are expressed as the mean ± standard deviation (SD), continuous variables with a nonnormal distribution are expressed as the median and interquartile range (IQR), and the difference between patients treated with PPIs and those not treated with PPIs was examined by t tests and Mann‒Whitney U tests, respectively. Categorical variables are expressed as numbers and percentages (%), and differences were examined by Fisher’s exact test.

Crude and adjusted logistic regression models were used to determine the association between PPI prescription and QT interval prolongation. Covariates included age, sex, race, heart rate, laboratory results (eGFR, potassium, calcium and magnesium), the SAPS, ICU category, comorbidities (heart failure, atrial fibrillation, valvular heart disease, hypertension, diabetes, chronic pulmonary disease, hypothyroidism, renal failure, liver disease, tumours) and medications (quinidine, amiodarone, β blockers, digoxin, diuretics, macrolide, quinolone, antidepressants, antipsychotics, methadone, opiates, quinine/CQ/HCQ, 5-HT3RAs and metoclopramide). Furthermore, we conducted 1:1 propensity scores matching (PSM) using nearest neighbour to determine a matched population to correct the differences between patients with PPIs and not treated with PPIs. The odds ratio (OR) and 95% confidence intervals (95% CIs) were reported. The differences among patients treated with omeprazole, lansoprazole and pantoprazole were compared. For each ECG report, the interactions of PPIs and serum potassium, calcium, magnesium, and eGFR values as continuous variables on QT interval prolongation were analysed. We identified the best linear or fractional polynomial models according to the minimum Akaike information criterion.

All statistical analyses were performed by Stata version 14 (Stata Corp., College Station, TX), and a P value of <​ 0.05 was considered statistically significant.

3 Results

This study included 84,653 ECG reports from 25,426 ICU patients (Fig. 1) according to the inclusion and exclusion criteria. Of these patients, 14,520 (57.1%) had been prescribed PPIs in the ICU. Patients who were treated with PPIs were older (66.40 ± 15.86 years vs. 63.91 ± 17.56 years, P = 0.001), were more likely to be female (45.07% vs. 43.03%, P = 0.001), were more likely to be white (73.61% vs. 69.78%, P < 0.001), had more comorbidities and medication use, were more likely to stay in the noncardiac ICU (71.45% vs. 63.03%, P < 0.001), had higher SAPS (18.93 ± 5.28 vs. 17.82 ± 5.33, P < 0.001) and had higher heart rates (86.49 ± 16.50 vs. 84.84 ± 16.08 beats/min, P < 0.001) than patients who were not treated with PPIs. Systolic BP (118.56 ± 17.36 vs. 119.47 ± 17.08 mmHg, P < 0.001), diastolic BP (60.12 ± 11.03 vs. 61.43 ± 11.0 mmHg, P < 0.001), total calcium (8.45 ± 0.69 vs. 8.55 ± 0.74 mg/dl, P < 0.001) and eGFR (median 59.1 vs. 65.8 ml/min/1.73 m2, P < 0.001) values were lower in patients who were treated with PPIs than in those who were not treated with PPIs, and potassium (4.18 ± 0.56 vs. 4.18 ± 0.61 mEq/L, P = 0.379) and magnesium (2.00 ± 0.29 vs. 2.00 ± 0.31 mg/dl, P = 0.089) levels were similar between the two groups (Table 1). After PSM, baseline characteristics did not differ between the two groups (Table 2).

Table 1

Characteristics of overall ICU patients according to PPI prescriptions.

Characteristics

Total

(n = 25,426)

Treated with PPIs

(n = 14,520)

Not treated with PPIs

(n = 10,906)

P value

Age, years

65.34 ± 16.66

66.40 ± 15.86

63.91 ± 17.56

0.001

Sex, female, n (%)

11,237 (44.19)

6,544 (45.07)

4,693 (43.03)

0.001

Weight, kg

80.72 ± 24.47

77 (65–92)

78 (66–92)

0.011

Simplified acute physiology score

18.45 ± 5.33

19 (15–22)

17 (14–21)

< 0.001

Race, n (%)

       

White

18,298 (71.97)

10,688 (73.61)

7,610 (69.78)

< 0.001

Other/unknown

7,128 (28.03)

3,832 (26.39)

3,296 (30.22)

 

ICU category, n (%)

       

Cardiac surgery recovery unit

3,351 (13.18)

1,474 (10.15)

1,877 (17.21)

< 0.001

Coronary care unit

4,827 (18.98)

2,672 (18.40)

2,155 (19.76)

 

Non cardiac ICU

17,248 (67.84)

10,374 (71.45)

6,874 (63.03)

 

Vital signs

       

Heart rate, beats/min

85.78 ± 16.34

86.49 ± 16.50

84.84 ± 16.08

< 0.001

Systolic BP, mmHg

118.95 ± 17.25

118.56 ± 17.36

119.47 ± 17.08

< 0.001

Diastolic BP, mmHg

60.68 ± 11.05

60.12 ± 11.03

61.43 ± 11.0

< 0.001

Laboratory examinations

       

Potassium, mEq/L

4.18 ± 0.58

4.18 ± 0.56

4.18 ± 0.61

0.379

Total calcium, mg/dL

8.50 ± 0.72

8.45 ± 0.69

8.55 ± 0.74

< 0.001

Magnesium, mg/dL

2.00 ± 0.30

2.00 ± 0.29

2.00 ± 0.31

0.089

Median eGFR, ml/min/1.73 m2

62.0 (37.9, 89.7)

59.1 (35.0, 87.1)

65.8 (42.3, 93.1)

< 0.001

Comorbidities

       

Atrial fibrillation, n (%)

7,052 (27.74)

4,297 (29.59)

2,755 (25.26)

< 0.001

Acute myocardial infarction, n (%)

1,548 (6.09)

784 (5.40)

764 (7.01)

< 0.001

Heart failure, n (%)

7,718 (30.35)

5,020 (34.57)

2,698 (24.74)

< 0.001

Hypertension, n (%)

14,105 (55.47)

8,263 (56.91)

5,842 (53.57)

< 0.001

Diabetes mellitus, n (%)

6,913 (27.18)

4,205 (28.96)

2,707 (24.82)

< 0.001

Chronic pulmonary disease, n (%)

5,652 (22.23)

3,579 (24.65)

2,073 (19.01)

< 0.001

Renal failure, n (%)

4,138 (16.27)

2,801 (19.29)

1,337 (12.26)

< 0.001

Liver disease, n (%)

2,764 (10.87)

1,978 (13.62)

786 (7.21)

< 0.001

Tumours, n (%)

2,716 (10.68)

1,696 (11.68)

1,020 (9.35)

< 0.001

Medications

       

Quinidine, n (%)

43 (0.17)

23 (0.16)

20 (0.18)

0.631

Amiodarone, n (%)

2,751 (10.82)

1,947 (13.41)

804 (7.37)

< 0.001

β blockers, n (%)

13,111 (51.57)

8,824 (60.77)

4,287 (39.31)

< 0.001

Digoxin, n (%)

1,541 (6.06)

1,144 (7.88)

397 (3.64)

< 0.001

Diuretics, n (%)

9,954 (39.15)

6,986 (48.11)

2,968 (27.21)

< 0.001

Quinolone, n (%)

7,376 (29.01)

5,628 (38.76)

1,748 (16.03)

< 0.001

Macrolide, n (%)

1,669 (6.56)

1,277 (8.79)

392 (3.59)

< 0.001

Antidepressants, n (%)

3,512 (13.81)

2,571 (17.71)

941 (8.63)

< 0.001

Antipsychotics, n (%)

3,646 (14.34)

2,639 (18.17)

1,007 (9.23)

< 0.001

Methadone, n (%)

381 (1.50)

277 (1.91)

104 (0.95)

< 0.001

Other opiates, n (%)

9,556 (37.58)

6,544 (45.07)

3,012 (27.62)

< 0.001

Quinine/CQ/HCQ, n (%)

194 (0.76)

154 (1.06)

40 (0.37)

< 0.001

5-HT3 receptor antagonists, n (%)

7,346 (28.89)

5,152 (35.48)

2.194 (20.12)

< 0.001

Metoclopramide, n (%)

7,895 (31.05)

3,152 (21.71)

4,743 (43.49)

< 0.001

QT prolongation, n (%)

2,271 (8.93)

1,622 (11.17)

649 (5.95)

< 0.001

BP: blood pressure; eGFR: estimate glomerular filtration rate; CQ: chloroquine; HCQ: hydroxychloroquine.

Table 2

Characteristics of propensity-matched ICU patients according to PPI prescriptions.

Characteristics

Treated with PPIs

(n = 4,964)

Not treated with PPIs

(n = 4,964)

P value

Age, years

65.33 ± 16.71

65.48 ± 17.39

0.658

Sex, female, n (%)

2,211 (44.54)

2,217 (44.66)

0.904

Median Weight, kg

77 (65–91)

78 (66–92)

0.113

Simplified acute physiology score

18 (14–21)

18 (14–21)

0.121

Race, n (%)

     

White

3,595 (72.42)

3,616 (72.84)

0.636

Other/unknown

1,369 (27.58)

1,348 (27.16)

 

ICU category, n (%)

     

Cardiac surgery recovery unit

676 (13.62)

626 (12..61)

0.274

Coronary care unit

1,048 (21.11)

1,085 (21.86)

 

Non cardiac ICU

3,240 (65.27)

3,253 (65.53)

 

Vital signs

     

Heart rate, beats/min

85.06 ± 16.19

84.99 ± 16.47

0.936

Systolic BP, mmHg

118.83 ± 16.94

119.43 ± 17.49

0.080

Diastolic BP, mmHg

60.70 ± 10.84

61.12 ± 11.11

0.054

Laboratory examinations

     

Potassium, mEq/L

4.19 ± 0.58

4.18 ± 0.62

0.563

Total calcium, mg/dL

8.52 ± 0.72

8.53 ± 0.73

0.653

Magnesium, mg/dL

2.00 ± 0.29

2.01 ± 0.31

0.446

Median eGFR, ml/min/1.73 m2

63.1 (36.7–90.6)

62.7 (38.3–90.7)

0.991

Comorbidities

     

Atrial fibrillation, n (%)

1,341 (27.01)

1,313 (26.45)

0.525

Acute myocardial infarction, n (%)

299 (6.02)

345 (6.95)

0.061

Heart failure, n (%)

1,433 (28.87)

1,428 (28.77)

0.912

Hypertension, n (%)

2,792 (56.24)

2,825 (56.91)

0.504

Diabetes mellitus, n (%)

1,321 (26.61)

1,322 (26.63)

0.982

Chronic pulmonary disease, n (%)

1,061 (21.37)

1,077 (21.70)

0.696

Renal failure, n (%)

806 (16.24)

808 (16.28)

0.957

Liver disease, n (%)

449 (9.05)

455 (9.17)

0.834

Tumours, n (%)

502 (10.11)

495 (9.97)

0.815

Medications

     

Quinidine, n (%)

8 (0.16)

6 (0.12)

0.593

Amiodarone, n (%)

458 (9.23)

440 (8.86)

0.529

β blockers, n (%)

2,363 (47.60)

2,381 (47.97)

0.718

Digoxin, n (%)

244 (4.92)

241 (4.85)

0.889

Diuretics, n (%)

1,704 (34.33)

1,709 (34.43)

0.916

Quinolone, n (%)

1,113 (22.42)

1,085 (21.86)

0.499

Macrolide, n (%)

282 (5.68)

269 (5.42)

0.569

Antidepressants, n (%)

587 (11.83)

601 (12.11)

0.665

Antipsychotics, n (%)

615 (12.39)

616 (12.41)

0.976

Methadone, n (%)

66 (1.33)

57 (1.15)

0.414

Other opiates, n (%)

1,664 (33.52)

1,636 (32.96)

0.551

Quinine/CQ/HCQ, n (%)

27 (0.54)

30 (0.6)

0.690

5-HT3 receptor antagonists, n (%)

1,213 (24.44)

1,230 (24.78)

0.692

Metoclopramide, n (%)

1,627 (32.78)

1,620 (32.63)

0.881

QT prolongation, n (%)

434 (8.74)

312 (6.29)

< 0.001

BP: blood pressure; eGFR: estimate glomerular filtration rate; CQ: chloroquine; HCQ: hydroxychloroquine.

3.1 PPI treatment increased the incidence of QT interval prolongation in ICU patients

Of the 25,426 ICU patients, 2,271 (8.93%) had at least one ECG report showing QT interval prolongation. The incidence of QT prolongation was 11.17% in patients who were treated with PPIs and 5.95% in those who were not treated with PPIs. PPI treatment was associated with an increased risk of QT interval prolongation (OR 1.99, 95% CI: 1.81–2.19). We performed three multivariable logistic regression models to identify the influence of confounding factors. Model I showed a correlation between PPI prescription and QT prolongation (OR: 1.93, 95% CI: 1.76–2.13) after adjustment for age, sex and race. Model II showed a similar result (OR 1.93, 95% CI: 1.75–2.13), even though the model was further adjusted for eGFR, heart rate, potassium, calcium and magnesium. Finally, Model III was fully adjusted for age, sex, race, eGFR values, electrolyte values, comorbidities and medications, and the association between PPI prescription and QT interval prolongation was consistent (OR 1.45, 95% CI: 1.30–1.62) (Table 3). In the matched population, patients treated with PPIs also had a higher risk of QT prolongation (8.74% vs. 6.29, OR 1.43, 95% CI: 1.23–1.66).

Table 3

Association between PPIs and QT interval prolongation (N = 25,426).

Model

OR (95% CI)

P value

Crude Model

1.99 (1.81–2.19)

< 0.001

Adjusted Model I

1.93 (1.76–2.13)

< 0.001

Adjusted Model II

1.93 (1.75–2.13)

< 0.001

Adjusted Model III

1.45 (1.30–1.62)

< 0.001

PSM population

1.43 (1.23–1.66)

< 0.001

Model I: adjusted for age, sex, and race
Model II: Model I plus eGFR, heart rate and electrolyte values (potassium, calcium, magnesium)
Model III: Model I plus SAPS, comorbidities (heart failure, atrial fibrillation, valvular heart disease, hypertension, diabetes, chronic pulmonary disease, hypothyroidism, renal failure, liver disease, tumours) and medications (quinidine, amiodarone, β blockers, digoxin, diuretics, macrolides, quinolones, antidepressants, antipsychotics, opiates, quinine/CQ/HCQ, 5-HT3 receptor antagonists, and metoclopramide)

3.2 Differences among three PPIs

We compared the incidences of three PPIs to determine their effect differences on QT prolongation. Pantoprazole was the most frequent (84.7%) PPI used, and the proportions of omeprazole and lansoprazole use were 7.9% and 6.8%, respectively. Pantoprazole showed a higher QT prolongation risk (OR 1.68, 95% CI: 1.31–2.18) than omeprazole. However, there was no significant difference between lansoprazole and omeprazole (OR 1.27, 95% CI: 0.90–1.77) (Fig. 2).

3.3 PPIs in combination with other drugs increase the risk of QT interval prolongation

We explored the impact of drug combinations on the risk of QT prolongation, including the combination of PPIs with 10 categories of drugs (Table 4). PPIs in combination with amiodarone lead to an almost 2.5-fold higher risk of QT prolongation (OR 2.52, 95% CI: 2.13–2.97). The prescriptions of diuretics (48.1%) and opiates (45.1%) were common in patients treated with PPIs, and patients treated with the combination of PPIs with diuretics (OR 2.19, 95% CI: 1.91–2.51) and opiates (OR 1.97, 95% CI: 1.62–2.39) showed a higher risk of QT prolongation. Furthermore, patients treated with quinolones (OR 2.19, 95% CI: 1.91–2.51), macrolides (OR 1.97, 95% CI: 1.62–2.39), antidepressants (OR 1.80, 95% CI: 1.54–2.10), antipsychotics (OR 2.04, 95% CI: 1.75–2.38), 5-HT3RAs (OR 1.65, 95% CI: 1.44–1.90) and metoclopramide (OR 1.71, 95% CI: 1.44–2.02) also showed an increased risk of QT prolongation if combined with PPIs. However, there was no increased risk of QT prolongation in patients treated with PPIs plus digoxin (OR 1.18, 95% CI: 0.95–1.47).

Table 4

The combination of PPIs and other drugs.

Drug combination

N

Adjusted OR

P

PPIs + amiodarone

1,947

2.52 (2.13–2.97)

< 0.001

PPIs + diuretics

6,986

1.65 (1.42–1.91)

< 0.001

PPIs + digoxin

1,144

1.18 (0.95–1.47)

0.126

PPIs + quinolones

5,628

2.19 (1.91–2.51)

< 0.001

PPIs + macrolides

1,277

1.97 (1.62–2.39)

< 0.001

PPIs + antidepressants

2,571

1.80 (1.54–2.10)

< 0.001

PPIs + antipsychotics

2,639

2.04 (1.75–2.38)

< 0.001

PPIs + opiates

6,544

1.65 (1.43–1.89)

< 0.001

PPIs + 5-HT3RAs

5.162

1.65 (1.44–1.90)

< 0.001

PPIs + metoclopramide

3,152

1.71 (1.44–2.02)

< 0.001

Adjusted for age, sex, race, eGFR, heart rate, electrolyte values, comorbidities and medications

3.4 The impact of PPI treatment on QT prolongation was independent of serum potassium, magnesium, calcium and eGFR values

We matched 84,653 ECG reports with PPI prescriptions and serum potassium, total calcium, magnesium and eGFR values on the same date according to the report date to determine and avoid the influence of electrolytes and renal function. Lower potassium, total calcium and eGFR values were related to an increased risk of QT prolongation, but a low magnesium value was not (Supplemental Table 2). The association between PPI prescription and QT prolongation was consistent (OR 1.12, 95% CI: 1.04–1.21) in the analysis for each ECG report, even though the model was adjusted for electrolyte and eGFR values. There were no significant interactions between PPI prescription and potassium (P for interaction = 0.286), total calcium (P for interaction = 0.282), magnesium (P for interaction = 0.344), or eGFR values (P for interaction = 0.718) (Fig. 3).

4 Discussion

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.

5 Conclusion

This retrospective study indicated that PPI treatment was associated with an increased risk of QT interval prolongation in ICU patients, even after adjustment for electrolyte values, eGFR values and known QT-prolonging drugs. Pantoprazole had the highest risk compared with omeprazole and lansoprazole. The combination of PPIs and other QT-prolonging drugs should be avoided.

Declarations

Funding: This study was supported by the National Natural Science Foundation of China (Grant Nos.82030018, 31971041) and Scientific Foundation of Jiangxi Province (20203AEI91005).

Competing Interests: The authors declare have no relevant conflicts of interests. 

Ethic approvalEthic approval for this study was no required since all data was obtained from A public database, MIMIC-III project was approved by Institutional Review Boards of Beth Israel Deaconess Medical Center (Boston, MA) and the Massachusetts Institute of Technology (Cambridge, MA).  

Informed Consent and Consent for Publication: Not applicable.     

Author contributions: All authors contribute to design of this study and approved the manuscript. Weiguo Fan and Hualong Liu extracted data and performed statistical analyses, Weiguo Fan, Yang Shen, and Kui Hong wrote and reviewed the manuscript.

Data Availability: MIMIC-III database v1.4 is freely-available on PhysioNet (https://doi.org/10.13026/C2XW26). The code for data query and extraction is available from the MIMIC Code Repository (https://github.com/MIT-LCP/mimic-code).

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