key: cord-0982524-xgx3bf9u
authors: Iloanusi, Sorochi; Mgbere, Osaro; Essien, Ekere J.
title: Polypharmacy Among COVID-19 Patients: A Systematic Review
date: 2021-05-26
journal: J Am Pharm Assoc (2003)
DOI: 10.1016/j.japh.2021.05.006
sha: 8b0cda5b5faceb85227a9af73cb73403aaf3c1e2
doc_id: 982524
cord_uid: xgx3bf9u

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.

Since 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 1 . Older adults and individuals with pre-existing multimorbidities, the presence of two 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 (ICU) or death 2, 3 . For instance, out 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 4 . 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 5 . 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 6 . 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% 7 . Additionally, vulnerable groups especially older persons are disproportionately affected by severe COVID-19 infection as evidenced in the ravaging effect of the disease in long-term-care facilities and among community dwelling of older adults worldwide 2,3 .

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 8 . During the influenza epidemic of 1996/7, polypharmacy was found to be an independent prognostic risk factor for influenzaassociated hospitalization and death 9 . In addition, evidence suggests that among patients undergoing polypharmacy, certain drug classes can explain the variability in the occurrence of adverse outcomes 10 .

For instance, while cardiovascular polypharmacy was not associated with unplanned non-cardiovascular hospitalization 11 , antipsychotics were associated with severe clinical outcomes among older patients with pneumonia 12 . The overwhelming evidence on the high prevalence of polypharmacy among vulnerable groups to severe COVID-19 infection and its independent negative impact on other respiratory diseases such as influenza 9 necessitates an investigation into the role of polypharmacy in COVID-19 clinical outcomes. Currently, little is known in this area due to 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 COVID-19 patients. We aimed to assess the association between polypharmacy and specific drug classes on clinical outcomes among COVID-19 patients.

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis was followed in conducting and reporting this systematic review 13 Table 1 ). In addition, the references of the studies that met the inclusion criteria were searched to identify additional articles for inclusion.

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® 14 . All identified abstracts and articles were independently screened by two of the authors (SI and OM) for eligibility based on 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 (SI, OM, EJE). The initial comprehensive search of the above-named databases yielded a total of 1502 unduplicated potentially relevant abstracts and articles. During the preliminary screening of the abstracts, 1400 items were excluded based on the exclusion criteria and relevance.

From the remaining 102 items, 94 more items were excluded after reviewing the full articles. Following J o u r n a l P r e -p r o o f 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 seven articles met the inclusion criteria and were used for the current study. Figure 1 displays the PRISMA-based flowchart of the studies selection process.

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) and 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.

To assess the methodological quality of the studies included, the risk of bias of each article was assessed independently by two reviewers (SI and OM) using the Joanna Briggs Institute (JBI) critical appraisal tool specific for case control studies, cohort studies and studies containing prevalence data respectively 15 .

Generally, studies were evaluated based on 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 was assigned a score of 1, while Items in the checklist marked as "No", "Unclear" or "Not Applicable" was assigned a score of 0 (Supplemental Table 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) .

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 J o u r n a l P r e -p r o o f deviation, and range was used to synthesize and report continuous variables, while frequencies and percentages was used to describe categorical variables.

The characteristics of the seven unique articles from the United States, United Kingdom, China, Spain, and Bahrain, and published between April and August 2020 were included in this review ( Table 1) . All the included studies were originally published in English Language. Out of the seven studies included, three were retrospective cohort studies [16] [17] [18] , two were retrospective review of health records 19, 20 , one study was a matched case-control study 21 and the final study was a retrospective observational study 22 .

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 17 , while the largest sample size was 428,199 18 . The study participants' age across all studies ranged from 0 -97 years, with the minimum age in six of the seven studies included being 42 years [16] [17] [18] [19] [20] 22 .

In five out of the seven included studies, all patients were COVID-19 positive 16, 17, 19, 20, 22 , as were the 4,272 cases matched to 36,948 controls in the sixth study 21 , and 1,324 out of the 428,199 patients in the seventh study 18 . Across all studies, a total of 10,519 patients were COVID-19 positive. Based on the JBI assessment criteria 15 , the quality scores for the included studies ranged from 50% to 100%.

Six out of the seven included studies reported on the number of medications used by patients including those for other comorbid conditions 16, [18] [19] [20] [21] [22] . One of the above six studies reported on the number of cardiovascular medications and the number of non-cardiovascular medications separately 21 . The final study reported only the number of medications used to treat COVID-19 pneumonia specifically 17 . Three out of the seven included studies categorized the number of medications used by COVID-19 patients ranging from 0 to >12 17, 18, 21 , while two studies defined polypharmacy generally as concurrently taking five or more medications without giving a breakdown of the exact number of medications (Table 1) 16, 22 .

The remaining two studies reported the mean number of medications among COVID-19 patients ranging from 5.40±2.10 to 8.57±3.34 19, 20 . Across all studies, 4,818 COVID-19 positive patients experienced polypharmacy.

The association between polypharmacy and clinical outcomes among COVID-19 patients extracted from the included studies is summarized in Table 1 . Majority (71%) of the studies found polypharmacy to be significantly associated with negative clinical outcomes (Table 1) [16] [17] [18] 20, 21 . In contrast, two studies (29%) reported no significant differences in the mean number of medications between comparison groups (COVID-19 survivors and non-survivors with or without mechanical ventilation) 19,22 . a. Morbidity and Mortality: A higher mean number of medications was significantly associated with severe COVID-19 morbidity and increased mortality among COVID-19 patients (Table 1) 18 . This association remained significant (p<0.01) even J o u r n a l P r e -p r o o f after adjusting for demographic factors, Townsend score, location of assessment centers, smoking status, alcohol intake frequency, BMI and physical activity 18 .

The specific class of comedications associated with clinical outcomes among COVID-19 patients is summarized in Table 2 . Four out of the seven included studies reported on the class of medications and/or specific drugs suspected or linked to negative clinical outcomes 16, 17, 20, 21 . Among these four articles, two noted a significant association between some class of medications and specific drugs with adverse clinical outcomes among the cohort 16, 21 . A third article documented a list of drugs suspected in adverse reactions among the study sample 20 . The fourth article reported no significant association between the selected medications and the adverse outcome investigated 17 .

The most frequently used class of medications among COVID-19 patients (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%) 16 .

Proton pump inhibitors were significantly associated with a higher risk of severe COVID-19 (RR=1.44; 95% CI: 1.31-1.58) 21 . 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) 16 J o u r n a l P r e -p r o o f women but not in men 16 . One study identified several medications suspected to cause ADRs among COVID-19 patients in the study group 20 . In particular, lopinavir and ritonavir was suspected in 63.8% of all the ADRs and 10.6% of severe ADRs among COVID-19 patients in the study 20 .

The findings from this systematic review of the available evidence suggests that polypharmacy is significantly associated with adverse clinical outcomes among COVID-19 patients. 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 8, 9, 23, 24 . The findings from our systematic review provides further evidence for the argument in favor of deprescribing especially among older COVID-19 patients for which drug clearance is altered due to age-associated physiologic changes 25 . Deprescribing refers to a patient-tailored intervention to prevent inappropriate polypharmacy through medication simplification and optimization 26 . Since deprescribing has been shown to prevent medication harm in patients 26 , there is a need to incorporate it in the pharmacotherapeutic management of COVID-19 patients undergoing polypharmacy 27 .

Incorporating this intervention early-on in the management of COVID-19 patients may prevent further exacerbation of the disease. In addition, since 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 28 . 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 COVID-19 patients. This is understandable because COVID-19 compromises several other organs in the body 29 and hence may alter the physiological levels of certain drugs, leading to pharmacodynamic and pharmacokinetic interactions often marked by ADRs, and other negative clinical J o u r n a l P r e -p r o o f 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 COVID-19 patients. The aforementioned drug classes have also been implicated in adverse clinical outcomes in other disease states [30] [31] [32] . A systematic review of observational studies concluded that exposure to antipsychotics is associated with an increased risk of pneumonia 30 .

Similarly, proton pump inhibitors and opioid analgesics have also been linked to increased risk of serious infections including pneumonia, endocarditis and enteric infection 31, 32 . Furthermore, antipsychotics, antihistamine, opioid analgesics and proton pump inhibitors are often implicated in adverse effects such as infection, falls, hospitalization, emergency room visits, and death 12,33-35 , yet these drug classes are commonly used among older patients especially those dwelling in long term care facilities 36, 37 . For instance, there have been reports of off-label use of antipsychotics in long-stay nursing homes without qualifying diagnoses 36 21 . This further suggests that the COVID-19 related risk conferred by polypharmacy may be independent from the risk from comorbidities. A previous study also noted no significant association between cardiovascular polypharmacy and worsening severity of noncardiovascular conditions 11 . 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 51 are therefore strategically placed to improve COVID-19 clinical outcomes of patients through optimized medication management, virtual J o u r n a l P r e -p r o o f patient counselling, medication stewardship, among other services 52, 53 . 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 42 . The role of pharmacist in other epidemics 54 and chronic disease care is well documented 51, 55 , 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 policymaking. 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 healthcare team to ensure that COVID-19 patients and vulnerable groups get the best quality pharmaceutical care to improve their health outcomes.

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 56 . In addition, presence of comorbidities is a potential confounder for the observed adverse effects associated with polypharmacy, as 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. Secondly, due to 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 57 . 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 21 . Thirdly, it was not possible to conduct a meta-analysis because the included studies did not meet the criteria for a quantitative/statistical synthesis due to their heterogenous nature related to the interventions, settings, study designs and outcome measures. Finally, the potential effect of polypharmacy on COVID-19 patients is still not fully understood as this require more rigorous studies and perhaps, a longer follow up period. However, due to the novel and rapidly spreading nature of the pandemic, it was necessary to synthesize the available evidence to aid clinical decision making for vulnerable COVID-19 patients. Based J o u r n a l P r e -p r o o f on 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 COVID-19 patients. 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 COVID-19 patients. 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.

Polypharmacy is associated with increased risk of adverse health outcomes among COVID-19 patients.

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 elderly 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 of COVID-19 patients.

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 indication, especially for patients at higher risk of adverse clinical outcomes.

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 COVID-19 patients.

J o u r n a l P r e -p r o o f 

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OR "multiple drugs' OR "Multiple Medications" OR "Potentially inappropriate medications

not, was the low response rate managed appropriately? Total Score 9 8 9 J o u r n a l P r e -p r o o f