We thank Li and colleagues for their insightful comments [1] on our recent work [2] regarding the association of acid suppression therapy with renal and survival outcomes in patients with chronic kidney disease (CKD). In response to their suggestions, we include here two important comorbidities (cerebrovascular disease and malignancy) into the multivariate analysis, which was considered as the leading causes of death among non-dialysis-dependent CKD patients followed in a large healthcare system [3]. We also considered proton pump inhibitor (PPI)–clopidogrel drug–drug interaction in the multivariate analysis because the use of concomitant PPI, which can inhibit cytochrome P450, may attenuate the effectiveness of clopidogrel and increase potential for adverse cardiovascular events [4].
Table 1 shows the percentage of cerebrovascular disease, malignancy, and clopidogrel. Table 2 shows sensitivity analysis when adjusting cerebrovascular disease, malignancy, and PPI–clopidogrel interaction in the original multivariate regression model. The association between H2RA and lower risks of ESRD and overall mortality, as well as between PPI and higher overall mortality, remained significantly consistent. We further compared the risk magnitude of overall mortality across different regression models in the PPI cohort (Table 3) and found the hazard magnitude remained consistent and seemed to be independent of PPI–clopidogrel interaction. This finding was consistent with previous two meta-analyses [5,6] of patients receiving clopidogrel, indicating that concomitant PPI use did not influence overall mortality. Another population-based cohort study in Denmark [4] of 13,001 patients with coronary stent implantation reported that PPI use did not modify the protective effect of clopidogrel, despite the production of a statistically non-significant interaction effect, and concomitant use was not associated with major adverse cardiovascular events. Moreover, two cohort studies [7,8] investigating risk of death among PPI users also did not yet consider PPI–clopidogrel interaction in the analysis. Nevertheless, caution is still warranted when using PPI and clopidogrel concomitantly.
Table 1.
Adding two comorbidities and one confounding drug in addition to baseline characteristics shown in the original Table 1 †.
| Overall CKD Patients (n = 102,802) | Propensity-Matched CKD Patients (n = 13,083) | |||||||
|---|---|---|---|---|---|---|---|---|
| PPI Cohort | H2RA Cohort | Control | PPI Cohort | H2RA Cohort | Control | |||
| Variables | (n = 7121) N (%) |
(n = 48,609) N (%) |
(n = 47,072) N (%) |
p-value | (n = 4361) N (%) |
(n = 4361) N (%) |
(n = 4361) N (%) |
p-value |
| Comorbidities | ||||||||
| Cerebrovascular disease | 708 (9.9) | 1957 (4) | 2198 (4.7) | <0.0001 | 269 (6.2) | 236 (5.4) | 234 (5.4) | 0.19 |
| Malignancy | 793 (11.1) | 4277 (8.8) | 3748 (8.0) | <0.0001 | 438 (10) | 291 (6.7) | 332 (7/6) | <0.0001 |
| Confounding drugs | ||||||||
| Clopidogrel | 985 (13.8) | 2655 (5.5) | 1349 (2.9) | <0.0001 | 433 (9.9) | 256 (5.9) | 164 (3.8) | <0.0001 |
Abbreviations: CKD, chronic kidney disease; PPI, proton pump inhibitor; H2RA, H2-receptor antagonist; NSAID, nonsteroid anti-inflammatory drug; ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. † Reference 2: J Clin Med, 2022, 11:5612.
Table 2.
Sensitivity analysis: Adjusted hazard ratio (aHR) for end-stage renal disease (ESRD) and overall mortality in three cohorts.
| Outcome | aHR | 95% Confidence Interval | p-Value |
|---|---|---|---|
| ESRD * | |||
| Control (n = 4361) | 1.00 | Reference | |
| PPI cohort (n = 4361) | 1.16 | 0.92–1.47 | 0.22 |
| H2RA cohort (n = 4361) | 0.40 | 0.30–0.53 | <0.0001 |
| Overall mortality # | |||
| Control (n = 4361) | 1.00 | Reference | |
| PPI cohort (n = 4361) | 1.83 | 1.64–2.03 | <0.0001 |
| H2RA cohort (n = 4361) | 0.64 | 0.57–0.72 | <0.0001 |
Abbreviations: the same as Table 1. * Adjusted for all covariates (age per year, sex, five original comorbidities [diabetes, coronary heart disease, hypertension, acid peptic disease, and chronic liver disease], two new comorbidities [cerebrovascular disease and malignancy], number of medical visits, NSAID, ACEI/ARB, and PPIxclopidogrel interaction term) and competing mortality. # Adjusted for all covariates (age per year, sex, five original comorbidities [diabetes, coronary heart disease, hypertension, acid peptic disease, and chronic liver disease], two new comorbidities [cerebrovascular disease and malignancy], number of medical visits, NSAID, ACEI/ARB, and clopidogrelxPPI interaction term).
Table 3.
Compare the risk magnitude of overall mortality across different regression models in the PPI cohort.
| PPI Cohort | |||
|---|---|---|---|
| aHR | 95% Confidence Interval | p-Value | |
| Model 1: original covariates (age per year, sex, five original comorbidities, number of medical visits, NSAID, and ACEI/ARB) |
1.83 | 1.65–2.03 | <0.0001 |
| Model 2: model 1 + adding two comorbidities (cerebrovascular disease, malignancy) | 1.81 | 1.63–2.01 | <0.0001 |
| Model 3: model 1 + adding PPIxclopidogrel interaction term | 1.84 | 1.65–2.04 | <0.0001 |
| Model 4: model 1 + model 2 + model 3 | 1.83 | 1.64–2.03 | <0.0001 |
| Model 5: model 1 + model 4 + clopidogrel | 1.87 | 1.68–2.08 | <0.0001 |
Author Contributions
Y.-C.C. designed the research; B.-H.Y. performed the statistical analysis; Y.-C.C. and B.-H.Y. wrote the paper; Y.-C.C., B.-H.Y. and W.-Y.C. analyzed the data; Y.-C.C. supervised the study. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
Funding Statement
This study was funded by the Buddhist Dalin Tzu Chi Hospital (DTCRD107(2)-E-02).
Footnotes
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