A population-based study on the association between acute renal failure (ARF) and the duration of polypharmacy

Polypharmacy has become an emerging public health issue in recent years. Polypharmacy has been correlated with adverse drug reactions (ADRs), increased risk of hospitalization, reduced adherence to medication, and unnecessary expenses [1, 2]. In addition, several studies have indicated that polypharmacy is directly or indirectly associated with acute renal failure (ARF) [3–7]. Because the mortality rate of patients hospitalized for ARF is approximately 45 %, and almost 30 % of patients with ARF require renal transplantation [8], further assessments of the association between ARF and polypharmacy would be important in clinical practice.

Methodological problems are present in studies of the relationship between polypharmacy and ARF. First, the definition and measurement of polypharmacy are inconsistent [9–13], making comparisons among studies difficult. For example, polypharmacy has been defined as the concomitant use of five or more drugs, or as the number of unnecessary or inappropriate medications [14–16], with the former definition more widely used by physicians because of its clinical convenience [17]. Second, most previous studies of the association between polypharmacy and ARF have focused only on elderly people, not on the general population [3, 5, 8, 11, 14, 15, 17], thus making the results of these studies difficult to compare across different ages. Third, the involvement of managed care has resulted in fewer patients with polypharmacy, because drug benefit plans of managed care programs vary greatly [17]. Therefore, assessments of the association between polypharmacy and ARF require better health care environments to minimize these interfering factors.

Our aim of this study is to assess the association between the duration of polypharnacy and the development of ARF by analyzing the Taiwan National Health Insurance Research Database (NHIRD). The National Health Insurance (NHI) of Taiwan, first established in 1995, the NHI is a nationwide, compulsory, uniform and comprehensive health insurance system, in which every citizen (beneficiary) is covered by the same health benefits, including a full drug benefit package, excluded over-the-counter (OTC) drugs, in western and Chinese traditional medicine, regardless of the premium paid. Each citizen has access to any doctor or healthcare institution throughout the country, with same and low cost-sharing and/or deductibles. In addition, the NHI has contracts with over 92 % of all clinics and almost 100 % of all hospitals and other healthcare institutions, which have been accredited by standards very similar to those of the Joint Commission International (JCI). The low cost-sharing, similar quality and high accessibility of medical care have resulted in an average of 15.1 outpatient visits per person per year. Each individual receives about 3.35 medications per prescription, much higher than in European countries or the United States. These characteristics make possible a determination of the association between duration of polypharmacy and ARF [18, 19]. In addition, the NHIRD contains aggregated utilization records on all individuals throughout the country, including reasons for utilization in ICD-9-CM diagnostic codes and the medication details of each enrollee. This information allowed a determination of the factors influencing ARF, including gender, age, comorbidities, stay in intensive units (ICUs) and major site of operation one month prior to ARF admission, while assessing the association between duration of polypharmacy and ARF.

Statistical analyses showed that all comorbidities tested were significantly correlated with ARF (p<0.001), with all odds ratios being >1.00. A higher percentage of patients in the case group stayed in the ICU during hospitalization (46.98 % vs. 11.37 %). Site of operation was significantly correlated with ARF (p<0.001), except for operations on the ears (p<0.736). The case group had significantly longer days in taking NSAID or Triamterene drugs than the control group (8.10 ± 22.61 days vs. 4.78 ± 17.23 days, p<0.001).

All comorbidities, except for atherosclerotic heart disease, dysarrhythmia and chronic obstructive pulmonary disease, were associated with higher risks of ARF (OR >1.00 each; p<0.001). Only surgical operations on the cardiovascular system, digestive system, integumentary system and miscellaneous diagnostic and therapeutic procedures showed ORs >1.00 and with statistical significant (p<0.05 each). In contrast, operations on the nervous system, endocrine system, nose, mouth and pharynx, respiratory system, urinary system, male genital organs, female genital organs and musculoskeletal system had a negative coefficient (between −2.63 and −0.15) compared with other sites of operation. Number of NSAID or Triamterene days was not selected to be included in the stepwise logistic regression model.

Our analysis of a dataset from the population-based NHIRD revealed a positive association between the duration of polypharmacy and the occurrence of ARF. Even after controlling for other factors, a longer duration of polypharmacy was associated with a higher risk of ARF.

The adoption of managed care systems by more countries has made research focusing on polypharmacy [17, 28], especially duration of polypharmacy, more difficult to perform. Usually the medications prescribed to enrollees in managed care programs are highly controlled, whereas non-prescription medications are not. The lack of information about non-prescription medications makes it very difficult to trace polypharmacy under managed care environments. The actual occurrence of polypharmacy may be higher than that reported, since many people do not inform their doctors about taking non-prescription drugs regularly. This situation, however, is rare in Taiwan, because the NHI pays for most drugs for acute and chronic diseases, and enrollees seldom spend their own money to buy nonprescription drugs regularly. It has made it easier to assess polypharmacy in Taiwan than in other countries. Moreover, since we defined polypharmacy as the concomitant use of more than five medications and we assessed the cumulative days of polypharmacy, we were better able to assess the duration of polypharmacy and the association of duration with ARF (or adverse drug events leading to ARF) than previous studies, which assessed only the correlation between polypharmacy and ARF [1, 2, 4, 7, 10, 29–31]. Indeed, we found that patients with a longer duration of polypharmacy were at higher risk for ARF hospitalization, consistent with previous findings reporting that excessive medication intake can cause renal damage and ARF [32–34]. Although we did not observe any significant differences between our case and control groups in the reasons for medication, we found that the average duration of polypharmacy was longer in the case than in the control group (191 days vs. 146 days). Therefore, the main cause of ARF may not be the medication itself, but rather the cumulative effects of polypharmacy. After controlling for confounding factors, including comorbidities, stay in the ICU during ARF hospitalization or site of operation within one month prior to ARF hospitalization, we still found that the risk of ARF was associated with duration of polypharmacy.

Consistent with previous reports, we found that polypharmacy was more likely to occur in elderly people [3, 9, 12]. The cumulative duration of polypharmacy in elderly people was likely higher because many of these individuals may take more than 5 medications per day due to multiple chronic diseases, including gastrointestinal bleeding, diabetes, chronic obstructive pulmonary disease and atherosclerotic heart disease. The optimal strategy to prevent ARF in elderly people may be to encourage doctors to avoid prescribing multiple medications or medications with renal toxicity to elderly people, or to prescribe medications at minimal doses [35]. This, however, may become more unrealistic since the elderly population in many countries is growing rapidly. Therefore, more research is necessary to reduce inappropriate medications in elderly patients requiring long duration of polypharmacy.

We also found that comorbidities, ICU stay during hospitalization for ARF and site of operation within one month prior to ARF hospitalization were associated with higher risks of ARF, findings consistent with previous reports [36, 37]. Our finding, however, that dysrhythmia was not associated with a risk of ARF, differed from those showing associations between cardiac diseases and ARF [38–40]. Our result may have been because of the inclusion of too many cardiac comorbidities in our logistic regression analysis. Although the number of days taking NSAID or Triamterene drugs was found significantly different between two groups, it was not selected in stepwise logistic regression model. It was probably because the number of days taking NSAID or triamterene drug was highly correlated with the duration of polyphamacy.

This study had two main limitations. First, we relied on medication claims in the NHIRD database to define polypharmacy. In reality, some patients may have purchased or taken medications on their own, thus underestimating the actual occurrence and duration of polypharmacy. However, due to the high accessibility of Taiwan’s universal health insurance and the wide coverage for medications, few people would purchase medications on their own. Therefore, the influence of this underestimation on our results were likely minimal. Second, this study was limited by the use of this database, in that our case group included patients without a history of ARF for the previous three years, minimizing the effects of previous ARF on current ARF.

We observed statistically significant associations between the duration of polypharmacy and the occurrence of ARF in this study. However, this association needs further study to ensure a causal relationship. In addition, the study of duration of polypharmacy also needs further attentions to specific group of people, such as elderly patients with multiple chronic diseases, since the society of many developed countries age very soon.