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Polypharmacy among COVID-19 patients: A systematic review

      Abstract

      Background

      Polypharmacy, the concomitant use of 5 or more medications, is highly prevalent among older adults and individuals with multimorbid conditions and has been linked to suboptimal clinical outcomes in various diseases. However, little is known about the impact of polypharmacy on clinical outcomes among coronavirus disease 2019 (COVID-19) patients.

      Objective

      This systematic review summarizes the available literature on the association between polypharmacy and specific drug classes, and clinical outcomes among COVID-19 patients.

      Methods

      We conducted an electronic database search on Embase, Medline, Cochrane, Scopus, Google Scholar, clinicaltrials.gov, LITCOVID, PubMed, PubMed Central (PMC), and China national knowledge infrastructure for studies on Polypharmacy among COVID-19 patients using relevant combinations of the keywords. Only studies published between November 2019 to September 2020 were included. Seven articles out of 1502 unique articles met the inclusion criteria and were used for the current study. We adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline in conducting and reporting this systematic review.

      Results

      The total sample size of all studies was 474,342, out of which 10,519 patients were COVID-19 positive, and 4818 COVID-19 positive patients experienced polypharmacy. Five out of the 7 included studies found associations between polypharmacy and negative clinical outcomes among COVID-19 patients. Polypharmacy was associated with increase in the relative risk of a positive COVID-19 test result (P < 0.01), death among male COVID-19 patients (P < 0.001), increase in the rate of acute kidney injury (P = 0.003), and adverse drug reactions (P < 0.001). Antipsychotic drugs were associated with severe COVID-19 morbidity (OR = 2.79; 95% CI 2.23–3.49) and increased risk of death among COVID-19 infected men (OR = 1.71; 95% CI 1.18–2.48) and women (OR = 1.96; 95% CI 1.41–2.73).

      Conclusion

      Polypharmacy and selected drug classes are associated with increased risk of adverse clinical outcomes among COVID-19 patients. Understanding these relationships can enhance risk stratification and evidence-based decision-making that may improve care and clinical outcomes of COVID-19 patients.

       Background

      • Little is known about the impact of polypharmacy on coronavirus disease 2019 (COVID-19) clinical outcomes.
      • We summarized the available literature on the association between polypharmacy and specific drug classes, and clinical outcomes among COVID-19 patients.

       Findings

      • Polypharmacy is associated with increased risk of adverse clinical outcomes among COVID-19 patients.
      • Antipsychotics, non-tricyclic antidepressants, opioid analgesics and drugs for peptic ulcer and gastroesophageal reflux disease were among drug classes associated with adverse clinical outcomes among COVID-19 patients.
      Since coronavirus disease 2019 (COVID-19) was first discovered in Wuhan, China, in November 2019, it has infected nearly 132 million persons and caused over 2.9 million deaths.
      World Health Organization (WHO)
      Coronavirus disease (COVID-19) sashboad.
      Older adults and individuals with pre-existing multimorbidities, the presence of 2 or more chronic diseases, remain by far the most vulnerable to severe COVID-19 infection, which can result in hospitalization, admission to the intensive care units, or death.
      • Atkins J.L.
      • Masoli J.A.H.
      • Delgado J.
      • et al.
      Preexisting comorbidities predicting COVID-19 and mortality in the UK Biobank community cohort.
      ,
      • Iaccarino G.
      • Grassi G.
      • Borghi C.
      • et al.
      Age and multimorbidity predict death among COVID-19 patients: results of the SARS-RAS Study of the Italian Society of Hypertension.
      For instance, of the 1.7 billion people with underlying conditions who are estimated to be at an elevated risk of severe COVID-19 infection globally, 66% were adults aged 70 years and above.
      • Clark A.
      • Jit M.
      • Warren-Gash C.
      • et al.
      Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study.
      In addition to being vulnerable to severe COVID-19 infection, older adults and individuals with pre-existing multimorbidities are also predisposed to or experiencing polypharmacy. Although some have argued that polypharmacy should be determined by the context of the clinical appropriateness, polypharmacy is most commonly defined as the concomitant use of 5 or more medications.
      • Masnoon N.
      • Shakib S.
      • Kalisch-Ellett L.
      • Caughey G.E.
      What is polypharmacy? A systematic review of definitions.
      The true global magnitude of polypharmacy is hard to estimate. Evidence shows that it is highly prevalent globally and will keep increasing as the population ages.
      • Khezrian M.
      • McNeil C.J.
      • Murray A.D.
      • Myint P.K.
      An overview of prevalence, determinants and health outcomes of polypharmacy.
      The high prevalence of polypharmacy in long-term-care (LTC) facilities was noted in a systematic review that reported a polypharmacy prevalence of up to 91.2%.
      • Jokanovic N.
      • Tan E.C.
      • Dooley M.J.
      • Kirkpatrick C.M.
      • Bell J.S.
      Prevalence and factors associated with polypharmacy in long-term care facilities: a systematic review.
      In addition, vulnerable groups, especially older persons, are disproportionately affected by severe COVID-19 infection, as evidenced in the ravaging effect of the disease in LTC facilities and among community-dwelling of older adults worldwide.
      • Atkins J.L.
      • Masoli J.A.H.
      • Delgado J.
      • et al.
      Preexisting comorbidities predicting COVID-19 and mortality in the UK Biobank community cohort.
      ,
      • Iaccarino G.
      • Grassi G.
      • Borghi C.
      • et al.
      Age and multimorbidity predict death among COVID-19 patients: results of the SARS-RAS Study of the Italian Society of Hypertension.
      The dual threat of COVID-19 infection and polypharmacy to the same vulnerable group—older adults and individuals with pre-existing multimorbidities—is particularly problematic because polypharmacy has been shown to lead to suboptimal treatment outcomes in various diseases.
      • Fried T.R.
      • O’Leary J.
      • Towle V.
      • Goldstein M.K.
      • Trentalange M.
      • Martin D.K.
      Health outcomes associated with polypharmacy in community-dwelling older adults: a systematic review.
      During the influenza epidemic of 1996-1997, polypharmacy was found to be an independent prognostic risk factor for influenza-associated hospitalization and death.
      • Hak E.
      • Verheij T.J.
      • van Essen G.A.
      • Lafeber A.B.
      • Grobbee D.E.
      • Hoes A.W.
      Prognostic factors for influenza-associated hospitalization and death during an epidemic.
      In addition, evidence suggests that among patients undergoing polypharmacy, certain drug classes can explain the variability in the occurrence of adverse outcomes.
      • Lee E.A.
      • Brettler J.W.
      • Kanter M.H.
      • et al.
      Refining the definition of polypharmacy and its link to disability in older adults: conceptualizing necessary polypharmacy, unnecessary polypharmacy, and polypharmacy of unclear benefit.
      For instance, whereas cardiovascular polypharmacy was not associated with unplanned noncardiovascular hospitalization,
      • Appleton S.C.
      • Abel G.A.
      • Payne R.A.
      Cardiovascular polypharmacy is not associated with unplanned hospitalisation: evidence from a retrospective cohort study.
      antipsychotics were associated with severe clinical outcomes among older patients with pneumonia.
      • Knol W.
      • van Marum R.J.
      • Jansen P.A.
      • Souverein P.C.
      • Schobben A.F.
      • Egberts A.C.
      Antipsychotic drug use and risk of pneumonia in elderly people.
      The overwhelming evidence on the high prevalence of polypharmacy among groups vulnerable to severe COVID-19 infection and its independent negative impact on other respiratory diseases such as influenza
      • Hak E.
      • Verheij T.J.
      • van Essen G.A.
      • Lafeber A.B.
      • Grobbee D.E.
      • Hoes A.W.
      Prognostic factors for influenza-associated hospitalization and death during an epidemic.
      necessitates an investigation into the role of polypharmacy in COVID-19 clinical outcomes. Currently, little is known in this area because of the novel nature of the disease and hence a paucity of research on polypharmacy among COVID-19 patients.
      Understanding the impact of polypharmacy on COVID-19 clinical outcomes can help to inform better pharmacotherapeutic management for the most vulnerable to severe COVID-19 infection and lead to improvement in their health outcomes. This systematic review explores the state of science on polypharmacy among patients with COVID-19. We aimed to assess the association between polypharmacy and specific drug classes on clinical outcomes among patients with COVID-19.

      Methods

       Search strategy and data sources

      The Preferred Reporting Items for Systematic Reviews and Meta-Analyses was followed in conducting and reporting this systematic review.
      • Shamseer L.
      • Moher D.
      • Clarke M.
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation [published correction appears in BMJ. 2016;354:i4086].
      Medical subject headings and different combinations of key words relevant to COVID-19 and polypharmacy were used to carry out an electronic search on Embase, Medline, Cochrane, Scopus, Google Scholar, clinicaltrials.gov, LITCOVID, PubMed, PubMed Central, and China national knowledge infrastructure from November 2019 to September 2020 (Appendix 1). In addition, the references of the studies that met the inclusion criteria were searched to identify additional articles for inclusion.

       Study selection criteria and process

      Only primary research articles involving individuals of any age who tested positive for COVID-19 and had data on polypharmacy (5 or more medications dispensed concurrently) and published between November 2019 and September 2020 were included in this systematic review. No language restriction was applied in the selection of articles. However, all the studies that met eligibility criteria for inclusion were originally published in English language. Studies with insufficient information on the number of medications or incomplete data were excluded. A protocol was developed in collaboration with all authors and registered prospectively on PROSPERO systematic review database (CRD42020205380).
      The study selection process and management were conducted using the Rayyan QCRI (Rayyan Systems).
      • Ouzzani M.
      • Hammady H.
      • Fedorowicz Z.
      • Elmagarmid A.
      Rayyan-a web and mobile app for systematic reviews.
      All identified abstracts and articles were independently screened by 2 of the authors (S.I. and O.M.) for eligibility on the basis of the Rayyan QCRI categorization as “include” (eligible), “exclude” (irrelevant), and “maybe” (unsure). The articles classified as “maybe” were resolved by consensus after a detailed review of the articles by all authors (S.I., O.M., E.J.E.). The initial comprehensive search of the aforementioned databases yielded a total of 1502 unduplicated potentially relevant abstracts and articles. During the preliminary screening of the abstracts, 1400 items were excluded on the basis of the exclusion criteria and relevance. From the remaining 102 items, 94 more items were excluded after reviewing the full articles. After this, 8 articles were found eligible for further evaluation. However, one article was further excluded because of the absence of any measurable clinical outcome. Therefore, only 7 articles met the inclusion criteria and were used for the current study. Figure 1 displays the Preferred Reporting Items for Systematic Review and Meta-Analysis–based flowchart of the studies selection process.
      Figure thumbnail gr1
      Figure 1PRISMA-based flow chart of study selection. Abbreviation used: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

       Study data management and extraction

      A predefined data extraction form developed and approved by all authors was used to extract the relevant data from all the articles included. The data items extracted included the publication information, study sample size, number of COVID-19 patients, definition of polypharmacy, number of COVID-19 patients undergoing polypharmacy (taking 5 or more medications), number of medications categorized, class of medications, the associated clinical outcomes (death, adverse drug reactions [ADRs], COVID-19 morbidity, etc.). After the data extraction, all authors reviewed the content of the data extraction form to check for accuracy and determine the suitability of the categorization.

       Assessment of the risk of bias

      To assess the methodological quality of the studies included, the risk of bias of each article was assessed independently by 2 reviewers (S.I. and O.M.) using the Joanna Briggs Institute (JBI) critical appraisal tool specific for case-control studies, cohort studies, and studies containing prevalence data.
      University of Adelaide
      JBI: critical appraisal tools.
      Generally, studies were evaluated on the basis of clarity of eligibility criteria, sample size, validity of outcome measurement, statistical analysis, and measures to reduce confounding and bias. There were 10 items in the checklist for case-control studies, 12 items in the checklist for cohort studies, and 9 items in the checklist for prevalence studies. Each reviewer independently rated studies by selecting the appropriate response for each item (“Yes,” “No,” “Unclear,” or “Not applicable”). These responses were adapted into numeric scores. All items checked as “Yes” in the checklist were assigned a score of 1, whereas items in the checklist marked as “No,” “Unclear,” or “Not Applicable” were assigned a score of 0 (Appendix 2). The total score for each study was then summed up and calculated as a proportion (%) of the total items to indicate the quality of the study (Table 1).
      Table 1Characteristics of studies included and main clinical findings
      Article author(s), dateStudy designStudy countryStudy periodTotal sample size [N = 474,342]No. COVID-19 positive patients [n = 10,519]No. Patients with COVID-19 with polypharmacy [n = 4818]Mean age (y)Age range (y)Drug classification methodClinical outcome(s)Methodological quality assessment
      Based on Joanna Briggs Institute critical appraisal tool (Assessment of the Risk of Bias) specific for each respective study design.15
      Taher et al.,
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.


      July, 2020
      Retrospective cohort studyBahrainApril 1–May 31, 202073 (hospitalized patients with COVID-19)734354 ± 13.5N/APolypharmacy (increasing No. of medications) for COVID-19 pneumonia was associated with having AKI (n = 24, [82.8%], P < 0.003).

      Polypharmacy was associated with severe AKI (stage 3) (90%, P < 0.031)
      6/12 (50%)
      Poblador-Plou et al.,
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.


      July, 2020
      Retrospective cohort studySpain(Follow-up period = at least 30 d from cohort entry) 4 March 2020 (i.e., date of the first confirmed infection in the region) to 17 April 2020 (enrolment period). The researchers followed patients from the date of inclusion in the cohort to 17 May 2020, or to the date of death4412 (All COVID-19 positive patients in the Spanish Region of Aragon)441240267.7 (± 20.7)Anatomical-Therapeutic-Chemical (ATC) classification system at the third level was used to classify drugs
      • A higher No. of mean medications was associated with poorer outcomes.
      • Polypharmacy was associated with death among male patients with COVID-19 (n = 242 [59.5%], P < 0.001).
      • Some of the most frequently dispensed drugs among individuals of both sexes (men vs. women) who died were on drugs for:
      • 1.
        Peptic ulcer and GERD (49.6% vs. 58.5%).
      • 2.
        Antithrombotic agents (36.9% vs. 39.0%).
      • 3.
        Other analgesics and antipyretics (31.0% vs. 37.4%).
      • 4.
        High-ceiling diuretics (24.6% vs. 34.6%).
      • 5.
        Antidepressants (20.4% vs. 38.7%).
      8/12 (66.7%)
      McKeigue et al.,
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      July 23, 2020
      Matched case control studyScotlandDispensed prescriptions issued in primary care during the last 240 d41,220 (all individuals who were tested for COVID-19 in Scotland. 36,948 controls, 4272 cases)42723452N/A0–75 y

      ≥ 75y
      Examined noncardiovascular drugs separately from cardiovascular drugs.

      The Laporte and Healy review was used to classify drug classes postulated to increase the risk of severe COVID-19.

      The BNF chapter 2 (cardiovascular) and chapter 13 (NSAIDs) was also used to operationalize drug classes
      Severe COVID-19 is strongly associated with polypharmacy, with increased rate ratio as the number of noncardiovascular drugs increased among those not residing in care homes (P < 0.001).

      No. meds: rate ratio (95% CI)

      4–6: 2.97 (2.47–3.57)

      7–9: 4.38 (3.61–5.32)

      10–12: 6.5 (5.3–8.0)

      >12: 10.8 (8.7–13.2)
      8/10 (80%)
      Gavin et al.,
      • Gavin W.
      • Campbell E.
      • Zaidi S.A.
      • et al.
      Clinical characteristics, outcomes and prognosticators in adult patients hospitalized with COVID-19.
      July 2020
      Retrospective chart reviewUnited StatesMarch 1–31, 2020140 (hospitalized patients with COVID-19)14014060 y42–81 yN/AThere was no statistically significant difference in the mean No. of medications between the different groups of patients with COVID-19 (those who did not receive MV, those who received MV and survived, and those who received MV and died)9/9 (100%)
      De Smet et al.,
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: retrospective observational study.
      June 2020
      A retrospective, single-center observational studyBelgiumMarch 12 and April 30, 202081 (hospitalized patients with COVID-19)815265–97 yN/AThere was no statistically significant difference in polypharmacy between COVID-19 survivors and nonsurvivors (P = 0.52)8/9 (88.9%)
      Sun et al.,
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      April 2020
      A retrospective studyChinaJanuary 17 to February 29, 2020217 (hospitalized patients with COVID-19)21721745.7 ± 16.6 yThe WHO-UMC system was used to assess causality for all suspected ADRsPolypharmacy was associated with having adverse drug reactions (P < 0.001)9/9 (100%)
      McQueenie et al.,
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      August 20, 2020
      Retrospective cohort studyUnited KingdomMarch 16, 2020–May 18, 2020428,199 (data obtained from United Kingdom biobank)132450048–86 yN/AThere is a clear dose response relationship in the risk of a COVID-19 positive test result (P < 0.01) as the No. of medications increased no medications: RR (95% CI)

      4–6: 1.58 (1.34–1.87)

      7–9: 2.24 (1.81–2.77)

      ≥10: 3.09 (2.37–4.01)
      11/12 (91.7%)
      Abbreviations used: AKI, acute kidney injury; COVID-19, coronavirus disease 2019; GERD, gastroesophageal reflux disease; N/A, not applicable; BNF, British National Formulary; NSAIDs, nonsteroidal anti-inflammatory drugs; RR, relative risk; MV, mechanical ventilation; WHO, World Health Organization; UMC, Uppsala Monitoring Centre; ADRs, adverse drug reactions.
      a Based on Joanna Briggs Institute critical appraisal tool (Assessment of the Risk of Bias) specific for each respective study design.
      University of Adelaide
      JBI: critical appraisal tools.

       Statistical analysis

      The interventions, settings, study designs, and outcome measures of the included studies were heterogenous; hence, a statistical synthesis or meta-analysis was not performed. We conducted a qualitative synthesis of the included studies where possible using descriptive statistics. Mean, standard deviation, and range were used to synthesize and report continuous variables, whereas frequencies and percentages were used to describe categorical variables.

      Results

       Characteristics of studies

      The characteristics of the 7 unique articles from the United States, United Kingdom, China, Spain, and Bahrain, published between April and August 2020, were included in this review (Table 1). All the included studies were originally published in English language. Of the 7 studies included, 3 were retrospective cohort studies,
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      2 were retrospective review of health records,
      • Gavin W.
      • Campbell E.
      • Zaidi S.A.
      • et al.
      Clinical characteristics, outcomes and prognosticators in adult patients hospitalized with COVID-19.
      ,
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      1 study was a matched case-control study,
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      and the final study was a retrospective observational study.
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: retrospective observational study.
      The total sample size of all studies was 474,342, with wide variation noted in the sample sizes across studies. The smallest sample size of the included studies was 73,
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      and the largest sample size was 428,199.
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      The study participants’ age across all studies ranged from 0 to 97 years, with the minimum age in 6 of the 7 studies included being 42 years.
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      • Gavin W.
      • Campbell E.
      • Zaidi S.A.
      • et al.
      Clinical characteristics, outcomes and prognosticators in adult patients hospitalized with COVID-19.
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      ,
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: retrospective observational study.
      In 5 of the 7 included studies, all patients were COVID-19 positive,
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      ,
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      ,
      • Gavin W.
      • Campbell E.
      • Zaidi S.A.
      • et al.
      Clinical characteristics, outcomes and prognosticators in adult patients hospitalized with COVID-19.
      ,
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      ,
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: retrospective observational study.
      as were the 4272 cases matched to 36,948 controls in the sixth study,
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      and 1324 of the 428,199 patients in the seventh study.
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      Across all studies, a total of 10,519 patients were COVID-19 positive. On the basis of the JBI assessment criteria,
      University of Adelaide
      JBI: critical appraisal tools.
      the quality scores for the included studies ranged from 50%-100%.

       Description of polypharmacy

      Six of the 7 included studies reported on the number of medications used by patients, including those for other comorbid conditions.
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      ,
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      • Gavin W.
      • Campbell E.
      • Zaidi S.A.
      • et al.
      Clinical characteristics, outcomes and prognosticators in adult patients hospitalized with COVID-19.
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: retrospective observational study.
      One of the above 6 studies reported on the number of cardiovascular and noncardiovascular medications separately.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      The final study reported only the number of medications used to treat COVID-19 pneumonia specifically.
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      Three of the 7 included studies categorized the number of medications used by COVID-19 patients ranging from 0 to 12 or more,
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      ,
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      ,
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      and 2 studies defined polypharmacy generally as concurrently taking 5 or more medications without giving a breakdown of the exact number of medications (Table 1).
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      ,
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: retrospective observational study.
      The remaining 2 studies reported the mean number of medications among patients with COVID-19 ranging from 5.40 ± 2.10 to 8.57 ± 3.34.
      • Gavin W.
      • Campbell E.
      • Zaidi S.A.
      • et al.
      Clinical characteristics, outcomes and prognosticators in adult patients hospitalized with COVID-19.
      ,
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      Across all studies, 4818 COVID-19 positive patients experienced polypharmacy.

       Polypharmacy and clinical outcomes among COVID-19 patients

      The association between polypharmacy and clinical outcomes among patients with COVID-19 extracted from the included studies is summarized in Table 1. Majority (71%) of the studies found statistically significant association between polypharmacy and negative clinical outcomes (Table 1).
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      ,
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      ,
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      In contrast, 2 studies (29%) reported no statistically significant differences in the mean number of medications between comparison groups (COVID-19 survivors and nonsurvivors with or without mechanical ventilation).
      • Gavin W.
      • Campbell E.
      • Zaidi S.A.
      • et al.
      Clinical characteristics, outcomes and prognosticators in adult patients hospitalized with COVID-19.
      ,
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: retrospective observational study.

       Morbidity and mortality

      A higher mean number of medications was associated with severe COVID-19 morbidity and increased mortality among patients with COVID-19 (Table 1). Poblador-Plou et al.
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      found that there was a statistically significant difference in the mean number of drugs between male (P < 0.001) and female (P = 0.006) survivors of COVID-19 compared with their deceased counterparts. Polypharmacy was significantly associated with death among male patients with COVID-19 (n = 242 (59.5%), P < 0.001).
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      McKeigue et al.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      reported an association (P < 0.001) between noncardiovascular polypharmacy and severe COVID-19 infection among noncare home residents. This association was strongest in those without any diagnosed comorbidity.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      The study by Taher et al.
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      reported that a relationship exists between polypharmacy and acute kidney injury (AKI) among patients with COVID-19. Increase in the number of medications administered for COVID-19 management was strongly associated with increase in the rate of AKI (P = 0.003) and the severity of AKI (P = 0.031).
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.

       ADRs

      Patients with COVID-19 who experienced ADR had a higher mean number of medications than patients with COVID-19 with no ADRs (P < 0.001).
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      Furthermore, number of medications administered to patients with COVID-19 was found to be an independent risk factor for the occurrence of ADRs, because patients with higher mean number of medications (9 drugs vs. 5 drugs) were 4 times more likely to experience ADRs than patients with an average of 5 (odds ratio [OR] = 3.99, [95% CI 2.23–7.13]).
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.

       Risk of COVID-19 infection

      Polypharmacy is associated with increased risk of contracting COVID-19 infection. In the study by McQueenie et al.,
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      a clear dose-response relationship between polypharmacy and an increased risk of a positive COVID-19 test result was discovered (P < 0.01). As the degree of polypharmacy increased, the rate ratio of a positive COVID-19 test result increased (P < 0.01) (4-6 medications rate ratio = 1.58, [95% CI 1.34–1.87] and ≥10 medications 3.09 [2.37–4.03]).
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      This association remained statistically significant (P < 0.01) even after adjusting for demographic factors, Townsend score, location of assessment centers, smoking status, alcohol intake frequency, body mass index, and physical activity.
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.

       Class of comedications associated with negative clinical outcomes among COVID-19 patients with polypharmacy

      The specific class of comedications associated with clinical outcomes among COVID-19 patients is summarized in Table 2. Four of the 7 included studies reported on the class of medications or specific drugs suspected of or linked to negative clinical outcomes.
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      ,
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      ,
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      ,
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      Among these 4 articles, 2 noted anassociation between some class of medications and specific drugs with adverse clinical outcomes among the cohort.
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      ,
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      A third article documented a list of drugs suspected in adverse reactions among the study sample.
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      The fourth article reported no statistically significant association between the selected medications and the adverse outcome investigated.
      Table 2Association of specific drug classes with COVID-19 clinical outcomes
      Drugs associated with death (ATC classification system code)
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      OR (95% CI)
      Drugs associated with severe COVID-19
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      Adjusted Rate Ratio (95% CI); P value
      Drugs suspected in ADRs
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      n (%)
      Men vs women:

      Potassium-sparing agents (C03D): 2.52 (1.27–4.97) vs. 2.86 (1.50–5.44)

      high-ceiling diuretics (C03C): 1.79 (1.30–2.49) vs. 1.71 (1.29–2.27)

      Antipsychotics (N05A): 1.71 (1.18–2.48) vs. 1.96 (1.41–2.73)

      Drugs for peptic ulcer and GERD (A02B): 1.45 (1.13–1.86) vs. 1.32 (1.02–1.71)

      Among women:

      Other beta-lactam antibacterials (J01D): 2.17 (1.00–4.71)

      Antigout preparations (M04A): 2.06 (1.05–4.04)

      Antiepileptics (N03A): 1.94 (1.31–2.88)

      Antithrombotic agents (B01A): 1.51 (1.16–1.97)

      Antidepressants (N06A): 1.33 (1.02–1.73)

      Among Men:

      Corticosteroids (D07A): 3.83 (1.43–10.3)

      Vasodilators for cardiac diseases (C01D): 3.15 (1.55–6.41)

      Immunosuppressants (L04A): 2.49 (1.08–5.76)

      Insulins and analogs (A10A): 2.33 (1.21–4.48)

      Vitamin B12 and folic acid (B03B): 1.88 (1.20–2.97)

      Other drugs for obstructive airway diseases, inhalants (R03B): 1.83 (1.10–3.05)

      Beta-blocking agents (C07A): 1.53 (1.11–2.11)

      Anxiolytics (N05B): 1.52 (1.05–2.22)
      Antipsychotic drugs: 2.79 (2.23–3.49)

      Opioid analgesics: 1.83 (1.61–2.07)

      Antidepressant drugs (not Tricyclic antidepressants): 1.76 (1.50–2.07)

      Proton pump inhibitors: 1.44 (1.31–1.58)

      Drugs used in nausea and vertigo: 1.43 (1.21–1.69)

      Gabapentinoids: 1.37 (1.16–1.60)

      Other drugs for Epilepsy 1.34 (1.06–1.69)

      Antihistamine: 1.30 (1.12–1.50)

      Tricyclic and related antidepressant drugs: 1.18 (1.03–1.36)
      Suspected drugs

      Lopinavir and ritonavir (All ADRs: 60 [63.8]; Severe ADRs: 10 [10.6])

      Umifenovir (All ADRs: 17 [18.1]; Severe ADRs: 6 [6.38])

      Chloroquine (All ADRs: 5 [5.31]; Severe ADRs: 0)

      Xuebijing injection (All ADRs: 3 [3.19]; Severe ADRs: 1)

      Antibacterial drugs (All ADRs: 4 [4.25]; Severe ADRs: 0)

      Other drugs 5 (All ADRs: [5.31]; Severe ADRs: 0)

      Causality assessment

      Lopinavir and ritonavir: (Probable: 35 (37.2); Possible: 25 (26.6))

      Umifenovir (Probable: 5 [5.31]; Possible: 12 [12.8])

      Chloroquine (Probable: 4 [4.25]; Possible: 1 [1.06])

      Xuebijing injection: (Probable: 2 [2.13]; Possible: 1 [1.06])

      Antibacterial drugs: (Probable: 2 [2.13]; Possible: 2 [2.13])

      Other drugs 5 (Probable: 4 [4.25]; Possible: 1 [1.06])
      Abbreviations used: COVID-19; coronavirus disease 2019; ATC, anatomical therapeutic chemical; OR, odds ratio; ADRs, adverse drug reactions; GERD, gastroesophageal reflux disease.
      The most frequently used class of medications among patients with COVID-19 (men vs. women) in the cohort who died were drugs for peptic ulcer and gastro-esophageal reflux disease (GERD) (49.6% vs. 58.5%), antithrombotic agents (36.9% vs. 39.0%), and other analgesics and antipyretics (31.0% vs. 37.4%).
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      Proton pump inhibitors were associated with a higher risk of severe COVID-19 (RR = 1.44; [95% CI 1.31–1.58]).
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      Drugs for peptic ulcer and GERD were associated with greater odds of death in men (OR = 1.45, [95% CI 1.13–1.86]) and women (OR = 1.32, [95% CI 1.02–1.71]).
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      Among male patients with COVID-19, corticosteroids (OR = 3.83, [95% CI 1.43–10.3]), vasodilators for cardiac diseases (OR = 3.15, [95% CI 1.55–6.41]), and immunosuppressants (OR = 2.49, [95% CI 1.08–5.76]) were strongly associated with death.
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      In contrast, among female patients with COVID-19, other beta-lactam antibacterial (OR = 2.17, [95% CI 1.00–4.71]), antigout preparations (OR = 2.06, [95% CI 1.05–4.04]), and antiepileptic medication (OR = 1.94, [95% CI 1.31–2.88) were most strongly associated with death.
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      Two studies reported an association between antipsychotics and adverse clinical outcomes among patients with COVID-19.
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      ,
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      Antipsychotic drugs were associated with nearly 3 times (RR = 2.79, [95% CI 2.23–3.49]) more risk of severe COVID-19 morbidity
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      and nearly 2 times the risk of death in men (OR = 1.71, [95% CI 1.18–2.48]) and women (OR = 1.96, [95% CI 1.41–2.73]).
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      A statistically significant association was reported between antidepressants (nontricyclic antidepressants: RR = 1.76, [95% CI 1.50–2.07], tricyclic antidepressants RR = 1.76, [95% CI 1.50–2.07]) and severe COVID-19 infection.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      However, one study noted an association between antidepressants and death (OR = 1.33, [95% CI 1.02–1.73]) in women but not in men.
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      One study identified several medications suspected to cause ADRs among patients with COVID-19 in the study group.
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      In particular, lopinavir and ritonavir were suspected in 63.8% of all the ADRs and 10.6% of severe ADRs among patients with COVID-19 in the study.
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.

      Discussion

      The findings from this systematic review of the available evidence suggest that polypharmacy is associated with adverse clinical outcomes among patients with COVID-19. The adverse clinical outcomes reported include ADRs, AKI, increased risk of COVID-19 infection, severe COVID-19, and mortality. This is consistent with the result of other studies that have reported the negative clinical impact of polypharmacy on different viral and respiratory diseases such as pneumonia and influenza.
      • Fried T.R.
      • O’Leary J.
      • Towle V.
      • Goldstein M.K.
      • Trentalange M.
      • Martin D.K.
      Health outcomes associated with polypharmacy in community-dwelling older adults: a systematic review.
      ,
      • Hak E.
      • Verheij T.J.
      • van Essen G.A.
      • Lafeber A.B.
      • Grobbee D.E.
      • Hoes A.W.
      Prognostic factors for influenza-associated hospitalization and death during an epidemic.
      ,
      • Hakozaki T.
      • Hosomi Y.
      • Shimizu A.
      • Kitadai R.
      • Mirokuji K.
      • Okuma Y.
      Polypharmacy as a prognostic factor in older patients with advanced non-small-cell lung cancer treated with anti-PD-1/PD-L1 antibody-based immunotherapy.
      ,
      • Greene M.
      • Steinman M.A.
      • McNicholl I.R.
      • Valcour V.
      Polypharmacy, drug-drug interactions, and potentially inappropriate medications in older adults with human immunodeficiency virus infection.
      The findings from our systematic review provide further evidence for the argument in favor of deprescribing, especially among older patients with COVID-19 for whom drug clearance is altered because of age-associated physiological changes.
      • Ross S.B.
      • Wilson M.G.
      • Papillon-Ferland L.
      • et al.
      COVID-SAFER: deprescribing guidance for hydroxychloroquine drug interactions in older adults.
      Deprescribing refers to a patient-tailored intervention to prevent inappropriate polypharmacy through medication simplification and optimization.
      • Scott I.A.
      • Hilmer S.N.
      • Reeve E.
      • et al.
      Reducing inappropriate polypharmacy: the process of deprescribing.
      Because deprescribing has been shown to prevent medication harm in patients,
      • Scott I.A.
      • Hilmer S.N.
      • Reeve E.
      • et al.
      Reducing inappropriate polypharmacy: the process of deprescribing.
      there is a need to incorporate it in the pharmacotherapeutic management of COVID-19 patients undergoing polypharmacy.
      • IUPHAR SamerC.
      • Webb D.
      • et al.
      International union for basic and clinical pharmacology (IUPHAR) clinical division considerations in the context of COVID-19 pandemics.
      Incorporating this intervention early-on in the management of patients with COVID-19 may prevent further exacerbation of the disease. In addition, because increasing level of polypharmacy has been found to increase the risk of getting infected with COVID-19, prophylactically optimizing medication regimens for older adults and individuals with multimorbid conditions might help to lower their risk of getting infected with COVID-19.
      • Brandt N.
      • Steinman M.A.
      Optimizing medication management during the COVID-19 pandemic: an implementation guide for post-acute and long-term care.
      To achieve this, prescribers and pharmacists must collaborate to review patient medications and ensure that the benefit of the medications outweighs the risk in the context of the specific patient.
      Our findings also linked specific drug classes to adverse outcomes in COVID-19 patients. Generally, medications with anticholinergic properties, sedative effect, respiratory depression, and some medications acting on the gastrointestinal tracts were more likely to increase the risk of adverse outcomes among patients with COVID-19. This is understandable because COVID-19 compromises several other organs in the body
      • Zaim S.
      • Chong J.H.
      • Sankaranarayanan V.
      • Harky A.
      COVID-19 and multiorgan response.
      and, hence, may alter the physiological levels of certain drugs, leading to pharmacodynamic and pharmacokinetic interactions often marked by ADRs and other negative clinical outcomes. Evidence from our systematic review revealed that antipsychotics, proton pump inhibitors, antihistamines, and opioid analgesics were among the drug classes with the strongest association with negative clinical outcomes among patients with COVID-19. The aforementioned drug classes have also been implicated in adverse clinical outcomes in other disease states.
      • Nosè M.
      • Recla E.
      • Trifirò G.
      • Barbui C.
      Antipsychotic drug exposure and risk of pneumonia: a systematic review and meta-analysis of observational studies.
      • Wiese A.D.
      • Griffin M.R.
      • Schaffner W.
      • et al.
      Long-acting opioid use and the risk of serious infections: a retrospective cohort study.
      • Deshpande A.
      • Pant C.
      • Pasupuleti V.
      • et al.
      Association between proton pump inhibitor therapy and Clostridium difficile infection in a meta-analysis.
      A systematic review of observational studies concluded that exposure to antipsychotics is associated with an increased risk of pneumonia.
      • Nosè M.
      • Recla E.
      • Trifirò G.
      • Barbui C.
      Antipsychotic drug exposure and risk of pneumonia: a systematic review and meta-analysis of observational studies.
      Similarly, proton pump inhibitors and opioid analgesics have also been linked to increased risk of serious infections including pneumonia, endocarditis, and enteric infection.
      • Wiese A.D.
      • Griffin M.R.
      • Schaffner W.
      • et al.
      Long-acting opioid use and the risk of serious infections: a retrospective cohort study.
      ,
      • Deshpande A.
      • Pant C.
      • Pasupuleti V.
      • et al.
      Association between proton pump inhibitor therapy and Clostridium difficile infection in a meta-analysis.
      Furthermore, antipsychotics, antihistamine, opioid analgesics, and proton pump inhibitors are often implicated in adverse effects such as infection, falls, hospitalization, emergency department visits, and death,
      • Knol W.
      • van Marum R.J.
      • Jansen P.A.
      • Souverein P.C.
      • Schobben A.F.
      • Egberts A.C.
      Antipsychotic drug use and risk of pneumonia in elderly people.
      ,
      • Alvarez C.A.
      • Mortensen E.M.
      • Makris U.E.
      • et al.
      Association of skeletal muscle relaxers and antihistamines on mortality, hospitalizations, and emergency department visits in elderly patients: a nationwide retrospective cohort study.
      • Machado-Duque M.E.
      • Castaño-Montoya J.P.
      • Medina-Morales D.A.
      • Castro-Rodríguez A.
      • González-Montoya A.
      • Machado-Alba J.E.
      Drugs with anticholinergic potential and risk of falls with hip fracture in the elderly patients: a case–control study.
      • Rolita L.
      • Spegman A.
      • Tang X.
      • Cronstein B.N.
      Greater number of narcotic analgesic prescriptions for osteoarthritis is associated with falls and fractures in elderly adults.
      yet these drug classes are commonly used among older patients, especially those dwelling in LTC facilities.
      • Phillips L.J.
      • Birtley N.M.
      • Petroski G.F.
      • Siem C.
      • Rantz M.
      An observational study of antipsychotic medication use among long-stay nursing home residents without qualifying diagnoses.
      ,
      • Bain K.T.
      • Schwartz E.J.
      • Chan-Ting R.
      Reducing off-label antipsychotic use in older community-dwelling adults with dementia: a narrative review.
      For instance, there have been reports of off-label use of antipsychotics in long-stay nursing homes without qualifying diagnoses
      • Phillips L.J.
      • Birtley N.M.
      • Petroski G.F.
      • Siem C.
      • Rantz M.
      An observational study of antipsychotic medication use among long-stay nursing home residents without qualifying diagnoses.
      and in older community-dwelling adults with dementia,
      • Bain K.T.
      • Schwartz E.J.
      • Chan-Ting R.
      Reducing off-label antipsychotic use in older community-dwelling adults with dementia: a narrative review.
      despite modest benefit and high risk of harm. Findings from this systematic review provide additional evidence against such practices as it predisposes older persons to an increased risk of severe COVID-19 infection and mortality.
      Lopinavir/ritonavir and chloroquine are among drugs undergoing clinical trial with the aim of repurposing them for COVID-19 treatment.
      • Giovane R.A.
      • Rezai S.
      • Cleland E.
      • Henderson C.E.
      Current pharmacological modalities for management of novel coronavirus disease 2019 (COVID-19) and the rationale for their utilization: a review.
      However, the study that identified several medications suspected in ADRs among patients with COVID-19 linked lopinavir/ritonavir and chloroquine to a high proportion of ADRs investigated.
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      This finding has implications for policy and research, especially because there has been heated scholarly and political debates surrounding the use of these repurposed medications and their analogs in managing patients with COVID-19. Several expert recommendations have advocated for caution in the use of these drugs among patients with COVID-19 because of conflicting and controversial evidence about their benefits and harm.
      • Laporte J.-R.
      • Healy D.
      Medications compromising Covid infections: in the midst of the SARS-CoV-2 pandemia, caution is needed with commonly used drugs that increase the risk of pneumonia.
      • Ailabouni N.J.
      • Hilmer S.N.
      • Kalisch L.
      • Braund R.
      • Reeve E.
      COVID-19 pandemic: considerations for safe medication use in older adults with multimorbidity and polypharmacy.
      • Lemaitre F.
      • Solas C.
      • Grégoire M.
      • et al.
      Potential drug-drug interactions associated with drugs currently proposed for COVID-19 treatment in patients receiving other treatments.
      Concerns have also been raised as to whether pharmacists should dispense or not dispense prescriptions for these medications for the management of COVID-19 outside of a clinical trial setting, especially for older persons for whom clinical trial data are nonexistent.
      • Cox S.
      To dispense or not to dispense: lessons to be learnt from ethical challenges faced by pharmacists in the COVID-19 pandemic.
      The consensus is that as drug experts, gatekeepers and patient advocates, and pharmacists are encouraged to use their professional judgment in such situations.
      • Cox S.
      To dispense or not to dispense: lessons to be learnt from ethical challenges faced by pharmacists in the COVID-19 pandemic.
      Although a number of COVID-19 vaccines are currently available for immunization against the disease, several countries still struggle with access to COVID-19 vaccines.
      • Li Y.
      • Tenchov R.
      • Smoot J.
      • Liu C.
      • Watkins S.
      • Zhou Q.
      A comprehensive review of the global efforts on COVID-19 vaccine development.
      This situation is made complex by the emergence of new variants for which the available COVID-19 vaccines have reduced efficacy
      • Mahase E.
      Covid-19: where are we on vaccines and variants?.
      and the increase in new COVID-19 cases and deaths globally.
      World Health Organization (WHO)
      Weekly epidemiological update on COVID-19- 6 April 2021.
      Therefore, clinicians are still faced with situations where they must exercise their clinical judgment in administering certain medications to patients with COVID-19. This systematic review provides evidence for medication optimization for patients with COVID-19 undergoing polypharmacy to improve their health outcomes.
      The heterogeneity of the included studies is worth mentioning because it impacts the strength of the evidence presented. There were variations in the study design, population characteristics, sample size, definition of polypharmacy, and outcome measurements across the included studies. The study sample of most
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      ,
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      ,
      • Gavin W.
      • Campbell E.
      • Zaidi S.A.
      • et al.
      Clinical characteristics, outcomes and prognosticators in adult patients hospitalized with COVID-19.
      ,
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      ,
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: retrospective observational study.
      of the included articles consisted entirely of patients with COVID-19 with differing disease severity from asymptomatic to critical, and 2 of the included studies
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      ,
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      whose combined sample size made up 98% of the total sample size consisted of both COVID-19 negative and positive patients. Importantly, individual studies differed in whether and how they controlled for confounding factors as it relates to polypharmacy. The presence of comorbidities is one of the strongest confounders for the observed effect of polypharmacy in various disease states, hence the necessity to control for it to improve the strength of evidence.
      • Schöttker B.
      • Saum K.U.
      • Muhlack D.C.
      • Hoppe L.K.
      • Holleczek B.
      • Brenner H.
      Polypharmacy and mortality: new insights from a large cohort of older adults by detection of effect modification by multi-morbidity and comprehensive correction of confounding by indication.
      We noted that only 1 of the included studies controlled for the presence of comorbidities as it pertains to the effect of polypharmacy on the clinical outcomes in patients with COVID-19.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      The study by McKeigue et al.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      found a statistically significant association between noncardiovascular polypharmacy and severe COVID-19 which remained after adjusting for potential confounders including presence of other comorbidities. This may serve as evidence that polypharmacy presents an independent risk for adverse COVID-19 outcomes, which cannot be fully explained by presence of comorbidities. Similar studies have also noted the independent association between polypharmacy and adverse clinical outcomes in various disease states such as influenza,
      • Hak E.
      • Verheij T.J.
      • van Essen G.A.
      • Lafeber A.B.
      • Grobbee D.E.
      • Hoes A.W.
      Prognostic factors for influenza-associated hospitalization and death during an epidemic.
      HIV,
      • Justice A.C.
      • Gordon K.S.
      • Skanderson M.
      • et al.
      Nonantiretroviral polypharmacy and adverse health outcomes among HIV-infected and uninfected individuals.
      and dementia.
      • Hein C.
      • Forgues A.
      • Piau A.
      • Sommet A.
      • Vellas B.
      • Nourhashémi F.
      Impact of polypharmacy on occurrence of delirium in elderly emergency patients.
      Another interesting point to note is that despite robust evidence that cardiovascular diseases worsen COVID-19 severity,
      • Pranata R.
      • Huang I.
      • Lim M.A.
      • Wahjoepramono E.J.
      • July J.
      Impact of cerebrovascular and cardiovascular diseases on mortality and severity of COVID-19–systematic review, meta-analysis, and meta-regression.
      ,
      • Matsushita K.
      • Ding N.
      • Kou M.
      • et al.
      The relationship of COVID-19 severity with cardiovascular disease and its traditional risk factors: a systematic review and meta-analysis.
      the study by McKeigue et al.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      found no statistically significant association between cardiovascular polypharmacy and severe COVID-19.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      This further suggests that the COVID-19 related risk conferred by polypharmacy may be independent of the risk from comorbidities. A previous study also noted no association between cardiovascular polypharmacy and worsening severity of noncardiovascular conditions.
      • Appleton S.C.
      • Abel G.A.
      • Payne R.A.
      Cardiovascular polypharmacy is not associated with unplanned hospitalisation: evidence from a retrospective cohort study.
      More rigorous studies are needed to better understand this phenomenon in the context of COVID-19.
      In view of the negative impact of polypharmacy and specific drug classes on COVID-19 clinical outcomes, it suffices to say that pharmaceutical care is critical now more than ever before. Pharmacists, as highly trained drug experts and the most accessible health care providers,
      • Mohiuddin A.K.
      The Role of the Pharmacist in Patient Care: Achieving High Quality, Cost-Effective and Accessible Healthcare Through a Team-Based, Patient-Centered Approach.
      are therefore strategically placed to improve COVID-19 clinical outcomes of patients through optimized medication management, virtual patient counseling, and medication stewardship, among other services.
      • Gross A.E.
      • MacDougall C.
      Roles of the clinical pharmacist during the COVID-19 pandemic.
      ,
      • Bhat S.
      • Kehasse A.
      Additional clinical pharmacists roles during COVID-19.
      Recognizing their strategic position in the fight against COVID-19 infection, several countries have extended and expanded the legal role of pharmacists to fully explore their potential during this pandemic.
      • Cox S.
      To dispense or not to dispense: lessons to be learnt from ethical challenges faced by pharmacists in the COVID-19 pandemic.
      The role of pharmacist in other epidemics
      • Isenor J.E.
      • Edwards N.T.
      • Alia T.A.
      • et al.
      Impact of pharmacists as immunizers on vaccination rates: a systematic review and meta-analysis.
      and chronic disease care is well documented;
      • Mohiuddin A.K.
      The Role of the Pharmacist in Patient Care: Achieving High Quality, Cost-Effective and Accessible Healthcare Through a Team-Based, Patient-Centered Approach.
      ,
      • Swaden L.
      The role of the HIV pharmacist in managing complex polypharmacy has never been more important.
      hence, it is pertinent to ensure that they are fully incorporated in COVID-19 infection management. Furthermore, pharmacists are drug information experts and hence play a vital role in evaluating and interpreting the rapidly evolving literature on COVID-19 pharmacotherapy to support other clinicians’ decision-making and inform population-level policy-making. In addition, they also serve as drug information resource for the public who might be confused about inaccurate claims about COVID-19 vaccine or the effects of drugs being repurposed for COVID-19 treatment. To that end, pharmacists must continue to collaborate with other members of the health care team to ensure that patients with COVID-19 and vulnerable groups get the best quality pharmaceutical care to improve their health outcomes.

       Study strengths and limitations

      Our systematic review has limitations that deserves to be noted. First, all the studies reviewed were observational studies, which may have significant risk of bias due to lack of randomization and a negative impact on the overall quality of the evidence documented in our systematic review.
      • Colditz G.A.
      Overview of the epidemiology methods and applications: strengths and limitations of observational study designs.
      In addition, presence of comorbidities is a potential confounder for the observed adverse effects associated with polypharmacy, because patients included in the studies may be experiencing other baseline comorbidities that can independently worsen their COVID-19 outcomes. Consequently, direct causality cannot be inferred from these studies. Second, because of the paucity of literature on the subject matter, one of the studies we included was a preprint article that had not been peer-reviewed at the time of data extraction.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Associations of severe COVID-19 with polypharmacy in the REACT-SCOT case-control study.
      However, we decided to include it because the valuable information contained in the article outweighed the risk of excluding it. This article has since been published in a peer-reviewed journal, and the information extracted at the time of the review remained unchanged.
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      Third, it was not possible to conduct a meta-analysis because the included studies did not meet the criteria for a quantitative/statistical synthesis owing to their heterogenous nature related to the interventions, settings, study designs, and outcome measures. Finally, the potential effect of polypharmacy on patients with COVID-19 is still not fully understood because this requires more rigorous studies and, perhaps, a longer follow-up period. However, because of the novel and rapidly spreading nature of the pandemic, it was necessary to synthesize the available evidence to aid clinical decision-making for vulnerable patients with COVID-19. On the basis of the above limitations, we recommend that the findings of this systematic review be interpreted with utmost caution.
      Notwithstanding its limitations, our study is valuable in assessing and presenting the current evidence on polypharmacy among patients with COVID-19. The information synthesized in this study can help lay a strong foundation for further studies in this area and provide clinicians and policymakers with the most relevant and recent information to make evidence-based and informed decisions that will improve care and health outcomes of patients with COVID-19. In addition, we highlighted the knowledge gaps present on the subject matter and provided a resounding case on the strong need for further research on polypharmacy and COVID-19 infection.

      Conclusion

      Polypharmacy is associated with increased risk of adverse health outcomes among patients with COVID-19. Some drug classes frequently used in older adults are associated with elevated susceptibility to adverse COVID-19 clinical outcomes. In view of this, pharmacists and health care providers need to collaborate to optimize medication management to reduce harm among vulnerable groups, especially the older adults who are more prone to multimorbidity and polypharmacy. The findings from this systematic review can aid informed COVID-19 related decision-making to improve the clinical outcomes in patients with COVID-19. However, further research is needed in this area to provide more evidence on the association between polypharmacy and COVID-19 infection and modes of action across different classes of medication, especially for patients at higher risk of adverse clinical outcomes.

      Acknowledgments

      The authors would like to thank the authors of the articles used for this systematic review for their scientific contributions, which lay the foundation for understanding the roles of polypharmacy and drug classes on clinical outcomes among patients with COVID-19.

      Appendix

      Tabled 1Appendix 1 Search strategy
      A Combination of key words and MeSH terms was used on different electronic databases (Embase, Medline, Cochrane, Scopus, Google Scholar, clinicaltrials.gov, LITCOVID, PubMed, PubMed Central [PMC], and China national Knowledge infrastructure [CNKI]) with necessary adaptations to each database.
      • [1.] Coronavirus[[MeSH]
      • [2.] “COVID-19” OR “2019-nCoV” OR “2019nCoV” OR “SARS-CoV-2” OR “Severe acute respiratory syndrome-coronavirus-2” OR “Coronavirus disease” OR “Coronavirus disease 2019” OR “novel coronavirus”
      • [3.] Polypharmacy [MeSH]
      • [4.] “polypharmacy” OR “multiple drugs” OR “Multiple Medications” OR “Potentially inappropriate medications”
      • [5.] “Outcomes” OR “outcome” OR “Mortality” OR “death” OR “hospitalization” OR “complications” OR “complication” OR “recovery” OR “drug-drug interactions” OR “adverse drug events”
      • [6.] 1 AND 3
      • [7.] 1 AND 3 AND 5
      • [8.] 1 OR 2 AND 3 OR 4 AND 5
      Tabled 1Appendix 2 Methodological quality of studies included
      Joanna Briggs Institute ChecklistMcKeigue et al.4
      • McKeigue P.M.
      • Kennedy S.
      • Weir A.
      • et al.
      Relation of severe COVID-19 to polypharmacy and prescribing of psychotropic drugs: the REACT-SCOT case-control study.
      Taher et al.1
      • Taher A.
      • Alalwan A.A.
      • Naser N.
      • Alsegai O.
      • Alaradi A.
      Acute kidney injury in COVID-19 pneumonia: a single-center experience in Bahrain.
      Poblador-Plou et al.2
      • Poblador-Plou B.
      • Carmona-Pírez J.
      • Ioakeim-Skoufa I.
      • et al.
      Baseline chronic comorbidity and mortality in laboratory-confirmed COVID-19 cases: results from the PRECOVID study in Spain.
      McQueenie et al. 2020
      • McQueenie R.
      • Foster H.M.E.
      • Jani B.D.
      • et al.
      Multimorbidity, Polypharmacy, and COVID-19 infection within the UK Biobank cohort.
      Gavin et al 2020
      • Gavin W.
      • Campbell E.
      • Zaidi S.A.
      • et al.
      Clinical characteristics, outcomes and prognosticators in adult patients hospitalized with COVID-19.
      De Smet et al.3
      • De Smet R.
      • Mellaerts B.
      • Vandewinckele H.
      • et al.
      Frailty and mortality in hospitalized older adults with COVID-19: retrospective observational study.
      Sun et al. 2020
      • Sun J.
      • Deng X.
      • Chen X.
      • et al.
      Incidence of adverse drug reactions in COVID-19 patients in China: an active monitoring study by hospital pharmacovigilance System.
      Case Control Studies
      Maximum Attainable Score for Case Control Studies is 10.
      • 1.
        Were the groups comparable other than the presence of disease in cases or the absence of disease in controls?
      Yes
      • 2.
        Were cases and controls matched appropriately?
      Yes
      • 3.
        Were the same criteria used for identification of cases and controls?
      No
      • 4.
        Was exposure measured in a standard, valid and reliable way?
      Yes
      • 5.
        Was exposure measured in the same way for cases and controls?
      Yes
      • 6.
        Were confounding factors identified?
      Unclear
      • 7.
        Were strategies to deal with confounding factors stated?
      Yes
      • 8.
        Were outcomes assessed in a standard, valid, and reliable way for cases and controls?
      Yes
      • 9.
        Was the exposure period of interest long enough to be meaningful?
      Yes
      • 10.
        Was appropriate statistical analysis used?
      Yes
      Total Score8
      Cohort Studies
      Maximum Attainable Score for cohort Studies is 12.
      • 1.
        Were the 2 groups similar and recruited from the same population?
      YesYesYes
      • 2.
        Were the exposures measured similarly to assign people
      YesYesYes
      • 3.
        to both exposed and unexposed groups?
      NoNoYes
      • 4.
        Was the exposure measured in a valid and reliable way?
      YesYesYes
      • 5.
        Were confounding factors identified?
      NoNoYes
      • 6.
        Were strategies to deal with confounding factors stated?
      NoNoYes
      • 7.
        Were the groups/participants free of the outcome at the start of the study (or at the moment of exposure)?
      NoNoNo
      • 8.
        Were the outcomes measured in a valid and reliable way?
      YesYesYes
      • 9.
        Was the follow-up time reported and sufficient to be long enough for outcomes to occur?
      NoYesYes
      • 10.
        Was follow-up complete, and if not, were the reasons for loss to follow-up described and explored?
      YesYesYes
      • 11.
        Were strategies to address incomplete follow-up utilized?
      NoYesYes
      • 12.
        Was appropriate statistical analysis used?
      YesYesYes
      Total Score6811
      Prevalence Data
      Maximum Attainable Score for prevalence Studies is 9.
      • 1.
        Was the sample frame appropriate to address the target population?
      YesYesYes
      • 2.
        Were study participants sampled in an appropriate way?
      YesYesYes
      • 3.
        Was the sample size adequate?
      YesYesYes
      • 4.
        Were the study subjects and the setting described in detail?
      YesNoYes
      • 5.
        Was the data analysis conducted with sufficient coverage of the identified sample?
      YesYesYes
      • 6.
        Were valid methods used for the identification of the condition?
      YesYesYes
      • 7.
        Was the condition measured in a standard, reliable way for all participants?
      YesYesYes
      • 8.
        Was there appropriate statistical analysis?
      YesYesYes
      • 9.
        Was the response rate adequate, and if not, was the low response rate managed appropriately?
      YesYesYes
      Total Score989
      £ Maximum Attainable Score for Case Control Studies is 10.
      # Maximum Attainable Score for cohort Studies is 12.
      π Maximum Attainable Score for prevalence Studies is 9.

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      Biography

      Sorochi Iloanusi, BSPharm, Doctoral Candidate, Department of Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Houston, TX
      Osaro Mgbere, PhD, MS, MPH, Adjunct Professor, Department of Pharmaceutical Health Outcomes and Policy; and Research Scientist, Institute of Community Health, College of Pharmacy, University of Houston, Houston, TX
      Ekere J. Essien, MD, DrPH, Professor, Department of Pharmaceutical Health Outcomes and Policy; and Director, Institute of Community Health, College of Pharmacy, University of Houston, Houston, TX