Association Between Preadmission Acid Suppressive Medication Exposure and Severity of Illness in Patients Hospitalized With COVID-19.

Recent studies have suggested that proton pump inhibitor (PPI) use may increase the risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and worsen the course COVID-19. , This observation is biologically plausible, as gastric acid is a well-established line of defense against microbial pathogens, including SARS-CoV-1. In addition, PPI use may worsen outcomes in patients with COVID-19 through alterations of the gut microbiome and intestinal immune apparatus. Conversely, recent data suggest that histamine 2 receptor antagonists (H2RAs), which are less potent than PPIs in terms of acid suppression, may be beneficial in SARS-CoV-2 , through direct antiviral effects.

Considering that acid suppressive medications are among the most commonly consumed drugs in the United States, an understanding of the impact of these agents on COVID-19 outcomes is of significant importance. In particular, data informing the public on whether there is an evidence-based rationale to modify the use of these chronic medications during the pandemic are necessary. We studied whether preadmission exposure to PPIs or H2RAs was associated with worse outcomes among patients hospitalized with COVID-19.

Methods

This was a secondary analysis of a retrospective cohort study aiming to better characterize digestive manifestations in patients hospitalized with COVID-19 across 36 medical centers in North America. The first 50 to 100 consecutive patients with a confirmed diagnosis of COVID-19 at each participating institution were included. Clinical data from the time of symptom onset until discharge, death, or the end of the study period were manually abstracted from electronic health records by study personnel under the oversight of a primary clinician-investigator. Conventional regression and propensity score matched analyses were performed to evaluate the association between preadmission acid suppressive medication exposure and mechanical ventilation or death. Sensitivity analyses were conducted to evaluate the validity of excluding patients with unknown PPI/H2RA status and of imputing missing data. More comprehensive methods are provided in the Supplementary Material.

Results

Between April 15 and June 5, 2020, data were collected from 1992 subjects. There were 146 patients excluded from the primary analysis because PPI or H2RA use within 1 month of admission was unknown. Characteristics of the final study cohort (1846 patients with COVID-19) are shown in the Supplementary Table 1. A total of 417 patients (22.6%) had recent PPI use, 167 (9.1%) had recent H2RA use, and 29 (1.6%) had both. The baseline variables included in the final regression models are listed in Supplementary Table 2.

Supplementary Table 1

Patient Characteristics

Patient Characteristic	Overall (N = 1846)
Demographics
Age, y, mean (SD)	59.9 (16.4)
Sex, male, n (%)	1044 (56.6)
Race, n (%)
White	680 (36.8)
Black	774 (41.9)
Other/Unknown	392 (21.2)
Body mass index, mean (SD)	31.5 (8.14)
PPI use, Yes, n (%)	417 (22.6)
H2 blocker use, Yes, n (%)	167 (9.1)
Patient health characteristics
Comorbidities, Yes, n (%)
Hypertension	1146 (62.1)
Coronary artery disease/myocardial infarction	284 (15.4)
Congestive heart failure	194 (10.5)
COPD	171 (9.26)
Asthma	240 (13.0)
Obstructive sleep apnea	197 (10.7)
Peripheral vascular disease	91 (4.93)
Cerebrovascular accident or TIA	170 (9.21)
Dementia	118 (6.39)
Diabetes Mellitus	658 (35.6)
ESRD	175 (9.48)
Current malignancy	117 (6.34)
Prior malignancy	171 (9.26)
Digestive disease	183 (9.91)
Other comorbidities	829 (44.9)
No comorbidities	203 (11.0)
No. Comorbidities, median (min-max; IQR)	2 (0-10; 3)
Chemotherapy or Immunosuppression, n (%)
Yes	219 (11.9)
No	1621 (87.8)
Unknown	6 (0.33)
Current or recent ACE or ARB use, Yes, n (%)	556 (30.1)
Current or recent NSAID use, n (%)
Yes	506 (27.4)
No	1100 (59.6)
Unknown	240 (13.0)
Current or recent antibiotic use, n (%)
Yes	560 (30.3)
No	1251 (67.8)
Unknown	35 (1.90)
Admission clinical lab measures
White blood cell count, mean (SD)	7.18 (4.00)
Hemoglobin, mean (SD)	12.9 (2.20)
Platelets. mean (SD)	207.5 (90.3)
Aspartate, mean (SD)	50.7 (54.1)
Alanine aminotransferase, mean (SD)	37.5 (34.5)
Alkaline phosphate, mean (SD)	82.3 (48.8)
Bilirubin, mean (SD)	0.64 (0.63)
Albumin, mean (SD)	3.63 (0.52)
Creatinine, mean (SD)	1.65 (2.76)
Outcomes
Mechanical ventilation required, Yes, n (%)	584 (31.6)
ICU admission, Yes, n (%)	795 (43.1)
In-hospital death, Yes, n (%)	327 (17.7)
HLOS, days, median (min-max, IQR)	8 (0.4-113; 13)

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease; HLOS, hospital length of stay; ICU, intensive care unit; IQR, interquartile range; NSAID, nonsteroidal anti-inflammatory drug; TIA, transient ischemic attack.

Supplementary Table 2

Variables Included in the Final Regression Models for Mechanical Ventilation or Death

Mechanical ventilation	Death
H2RA use	H2RA use
PPI use	PPI use
Age	Age
Body mass index
Sex	Sex
Race	Race
Dementia	Dementia
	Congestive heart failure
Number of comorbidities	Number of comorbidities
White blood cell count at admission	White blood cell count at admission
Platelets at admission	Platelets at admission
Aspartate aminotransferase at admission	Aspartate aminotransferase at admission
Alkaline phosphatase at admission
Albumin at admission	Albumin at admission
Creatinine at admission
Antibiotics before admission

DMC19 Registry Instructions 4_17_20

Please complete the below data collection form (DCF) in REDCap at the time of discharge or death. Data will appear in the DMC19 database once entry and verification are complete.

We aim to capture inpatients with a confirmed COVID-19 diagnosis, regardless of whether they have digestive manifestations. After prevalence is defined in hospitalized patients, and as the numbers grow, we may focus on patients who are known to have GI manifestations and/or include outpatients.

Please make all efforts to collect data on the first 50 to 100 consecutive patients at your hospital or health system.

Eligible patients can and should be identified by any means necessary, which may include, but is not limited to, institutional laboratory records, data warehouse queries, electronic health record research subject identification tools/dashboards, and discussions with the infectious disease or critical care services, etc. You may elect to use the emergency ICD-10 code of U07.1 – 2019-nCov acute respiratory disease – to help identify eligible patients.

Please triple-check data for accuracy before submission. Although we are performing central data monitoring, we cannot verify incoming data against source documents, nor are we performing on-site monitoring visits. Therefore, the overall quality of the data is assured primarily at the site level.

Along the lines of #5, coordinators should confer with a clinician during data collection to ensure that clinical context is accounted for as much as possible in the interpretation of questions that involve an element of subjectivity.

All data fields should have affirmative, negative, and unknown options. Therefore, missing data will be assumed to be inadvertent and this will generate a query.

Please maintain a secure key at your site that allows patient identification on the basis of subject ID#. This may be used in the future for to collect data pertaining to long-term outcomes.

After adjusting for measured baseline confounders, PPI use was not independently associated with the need for mechanical ventilation in the primary regression analysis (odds ratio [OR] 1.02; 95% confidence interval [CI] 0.73–1.43; P = .89) (Figure 1 ). In contrast, H2RA use was associated with 1.55 times the odds of requiring mechanical ventilation relative to patients not exposed to H2RA (OR 1.55; 95% CI 1.11–2.19; P = .01) (Figure 1). Propensity score matched analysis confirmed the lack of association between PPI use and mechanical ventilation and demonstrated a significant increase in the likelihood of mechanical ventilation among patients exposed to H2RA (risk difference 9.72%; 95% CI 1.26%–18.2%; P = .02). In sensitivity analyses, removal of patients with at least 1 missing covariate value (480 observations) or inclusion of patients with unknown PPI/H2RA use (139 additional observations) did not change the findings.

Figure 1

ORs (95% CIs) for mechanical ventilation (blue) or death (red) based on final regression models.

PPI use was not independently associated with increased death (OR 0.87; 95% CI 0.66–1.14; P = .31) (Figure 1). Similarly, H2RA exposure was not associated with increased death (OR 1.37; 95% CI 0.96–1.95; P = .08) (Figure 1). Propensity score matched analysis showed similar findings. In the sensitivity analyses, removal of patients with at least 1 missing covariate value (375 observations) did not change the findings pertaining to PPI use. However, this analysis did demonstrate a statistically significant association between H2RA exposure and in-hospital mortality (OR 1.48; 95% CI 1.04–2.12; P = .03). The sensitivity analysis that included patients with unknown PPI/H2RA status (139 additional observations) did not change the results.

Discussion

In this large-scale study of patients hospitalized with COVID-19 across 36 medical centers in North America, preadmission exposure to PPI and/or H2RA did not appear to strongly affect the likelihood of mechanical ventilation or death. Our findings do not support the putative deleterious effects of PPIs and in fact contradict the hypothesized benefits of H2RAs in SARS-CoV-2 infection. These observations suggest that modified use of these medications for the purpose of improving COVID-19 outcomes is not justified. Instead, the results reinforce the preexisting guidance of taking acid suppressive medications only when indicated and at the lowest dose that achieves the clinical objective for which they were recommended.

The observation that preadmission H2RA use increased the risk of mechanical ventilation in this cohort is noteworthy, as it opposes growing evidence of the beneficial effect of famotidine. The reasons for this finding are unclear and may not apply to famotidine specifically, as the exact H2RA consumed by patients in the cohort was not determined. However, since the estimated effect size was relatively small, there was no association between H2RA use and death, and residual confounding is always a risk in observational studies of this nature, the finding largely serves to caution against overuse of this medication and highlights the importance of additional research prior to clinical care or policy changes. It is also important to emphasize that recent studies showing the favorable effect of famotidine have evaluated active treatment rather than preadmission exposure, as we assessed in this study.

This study has several important limitations. First, PPI and H2RA exposure was not verified against pharmacy records and their consistent use could not be confirmed. However, these medications are commonly acquired over the counter, limiting the ability of prescription claims to confirm use. Furthermore, medication use in this study was collected manually by comprehensive review of electronic health records by clinicians or study coordinators under the oversight of a clinician-investigator, with likely increased accuracy compared with administrative data. Second, as noted previously, we did not specifically query the use of famotidine relative to the other H2RAs, and thus a beneficial effect of this medication may have been diluted by other drugs in this class. Third, we did not collect data on in-hospital acid suppressive medication administration, which may have been associated with preadmission exposure and could have confounded the analysis. Last, observations from this cohort reflect the earliest phase of the pandemic and may not apply to the current time.

In conclusion, we did not observe a strong deleterious effect of preadmission PPI use or a beneficial effect of preadmission H2RA use among patients hospitalized with COVID-19. These findings caution against the modified use of these medications to improve COVID-19–related outcomes.

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