First stage of the study: A cross-sectional analysis was made of the 8,029 hospital admissions in the study period (January 2011 to March 2012) in order to identify drug-related AKI cases secondary to ACEI/ARB-II, diuretics and/or NSAIDs, and to describe the clinical characteristics of the admitted patients and their previous medications. Drug-related acute kidney injury secondary to the use of Triple Whammy drugs (AKITW) was defined as hospital admission with a discharge code of AKI (ICD-9-CM 584.9) in a patient who had been receiving any of those drugs prior to admission and where, following an audit of the medical record by a nephrologist, the possible cause of AKI is attributed to the use of ACEI/ARB-II, diuretics and/or NSAIDs, either alone or in combination (a prerenal situation may be involved based on the presence of fever, vomiting or diarrhea). In addition, the patient's baseline creatinine value was 1.3 mg/dL or lower at least one month before admission, which increased to more than 1.4 mg/dL on admission.

Excluded from the study were cases of hospital-acquired AKI (defined as patients who are admitted with a creatinine value below 1.3 mg/dL that increases to more than 1.4 mg/dL during hospitalization), obstructive AKI, glomerulonephritis, hepatorenal syndrome, decompensated heart failure, multiple organ failure, infection, ischemia, poisoning, end-stage cancer, exposure to radiocontrast agents or known nephrotoxic drugs, and multifactorial cases

Second stage of the study: Four basic health care areas (BHA) share an information system of computerized medical files with our hospital. As the prescription records of the 87,160 patients belonging to the BHA were available to us, we followed up a cohort of the 15,307 outpatients who had been prescribed one or more ACEI/ARB-II, diuretics or NSAIDs in February 2011. Our goal was to analyze the prevalence of use and incidence of drug-related AKI of this population for each type of drug and their combinations. The data from this cohort were cross-referenced with the data from hospital admissions due to AKITW that had been identified in the first stage. Out of the 85 cases of AKITW detected in stage 1 (15 months of follow-up), we selected the 65 cases belonging to the population of the four BHA with available computerized medical records and drug prescription data.

Third stage of the study: A cohort study was used to assess the impact of AKITW on hospital stays, costs and mortality. The study population was limited to hospitalization episodes in 2011 (12 months) of residents of the four BHA for whom prescription data pharmacy costs were available. All the hospitalization episodes due to AKITW belonging to the 4 BHA were considered cases (62 patients). The control group was made up of 62 randomly selected hospital admissions of patients without AKI, paired by medical specialty, sex, age and comorbidities according to Clinical Risk Group (CRG).9,10

Data for the selection and analysis of the hospitalizations were obtained from the Palamós Hospital computerized hospital admission files. The medical records were reviewed thoroughly by a nephrologist, who compiled detailed information about patient characteristics and progression. The variables collected on hospitalization episodes for AKITW were: age, sex, use of ACEI/ARB-II, diuretics and NSAIDs before admission except for ASA 100-300 mg (drug, mean daily dose and treatment duration in weeks), history of hypertension (HTN) (defined by antihypertensive medication use), chronic kidney disease (CKD) prior to admission (defined as any patient admitted under code ICD-9: 585), chronic heart failure (CHF) (defined as any patient admitted under code ICD-9: 428), prior rheumatic disease (previous diagnosis of rheumatic disease with follow-up by a rheumatologist), associated prerenal cause (depletion due to fever, vomiting or diarrhea), signs of dehydration (admitting physician recorded dehydration on the ER report, or patient was admitted with hypotension and the examination revealed dry skin or mucosae), edema, pain and cause of pain, need for dialysis, CKD as a post-dialysis sequela (considered as patients with ICD-9 code: 585 who did not have CKD before admission), creatinine (baseline, peak on admission, on discharge and at six months following admission), albuminemia on admission, K on admission, hospital stay (days), death (date). Renal function was measured with creatinine analyzed by Jaffe's method, alkaline picrate and kinetic reading; traceability was guaranteed with the isotopic dilution mass spectrometry (IDMS). Glomerular filtration (GF) was calculated with MDRD4 IDMS.

Exacerbated CKD was considered as a patient previously diagnosed with CKD who had a creatinine level of more than 0.3 mg/dL over their baseline creatinine value, which had been measured at least one month before admission.

The pharmacy data of the population were obtained from the computerized prescription files of the primary health care services. Drugs of interest were classified by groups based on ATC codes (World Health Organization Anatomical, Therapeutic, Chemical classification system): ACEI, ARB-II, diuretics and NSAIDs (not including acetylsalicylic acid 100-300 mg, paracetamol or metamizole). The ACEI and ARB-II groups were considered a single drug type because of their similar mechanism of action. The use of one, two or three diuretics and NSAIDs were considered separately. Drugs prescribed during hospitalization were not considered.

Data for hospitalization costs, which are calculated yearly with the full-costing system, were obtained from the Serveis de Salut Integrats (SSIBE) costs file. This system follows the methodology and recommendations from the analytical accounting workgroup of the Servei Català de la Salut [Catalan Health Service] Central Financial Office11,12 and the Red Española de Costes Hospitalarios (RECH) [Spanish Hospital Costs Network]13,14. The cost associated with each hospitalization episode was calculated individually using the clinical and activity information recorded from admission to discharge. Thus, the cost of each hospitalization episode was obtained based on the number of hospitalization days, minutes in the operating room, dialysis sessions, single medication doses, laboratory tests, imaging tests and other tests performed from admission to discharge. In the 2011 fiscal year, the mean hospital stay cost at Palamós Hospital was €279.63, one minute in the operating room was €10.39 and each dialysis session was €146.45. The cost of single medication doses was assigned directly to the episode at the weighted mean price. Finally, the costs for laboratory tests, diagnostic imaging tests and the remaining tests was input according to the mean cost of each technique performed based on each department's catalogue of services.

In order to identify the hospitalizations due to AKITW in association with these drugs, we conducted a univariate statistical analysis with frequency, mean and standard deviation, according to the characteristics of each variable.

Drug combinations were analyzed as exclusive categories. To measure the impact of drug use, the population incidence was measured for each category with its 95% confidence interval.

To compare groups in the case-control analysis, a bivariate statistical analysis was conducted with Student's t-test or chisquare test, depending on the variable's characteristics. Fisher's exact test was used when applicable. P < 0.05 was considered statistically significant. The IBM SPSS Statistics 20.0 program was used.

Out of the 8,029 hospital admissions during the study period, 415 cases of AKI were identified, of which 368 were drug-related AKI and 85 were attributed directly to the use of ACEI/ ARB-II, diuretics and/or NSAIDs (AKITW) (Figure 1).

These 85 cases had a similar distribution between both sexes and mean age was 78.72 years (SD 11.69). When analyzed by age groups, the case distribution clearly shifted to the older age ranges (Table 1).

Practically half of the cases had a history of CKD or CHF prior to admission. In two-thirds of cases, there was a prerenal cause associated with ACEI/ARB-II, diuretics and/or NSAIDs (history of fever, vomiting or diarrhea in the days before admission). In four out of five cases, the medical records did not specify a cause of pain justifying the chronic use of NSAIDs; in 59% of cases where the cause was specified, it was chronic joint pain.

The mean baseline creatinine value prior to admission was 1.32 mg/dL (SD 0.50) and the mean creatinine increase from baseline to admission was 1.77 mg/dL (SD 1.51). In 34% of patients, peak creatinine doubled baseline creatinine levels. Six months after discharge, mean creatinine had an increase of 13.89% from the pre-admission baseline creatinine. The mean baseline GFR was 57.3 mL/min/1.73m2, and at six months it was 52.77 mL/min/1.73 m2, which was a decrease of 4.6%.

More than half the patients had hypoalbuminemia, which was serious (< 2.5 g/dL) in 19% of cases. One-third were admitted with hyperkalemia, and three cases were serious enough to cause death after admission. One patient required dialysis and more than 10% of patients had CKD as a sequela for six months after admission.

With respect to the drugs the patients were taking before admission, ACEI prescriptions were identified in half of cases; three-quarters of these patients had been taking them for more than four weeks. The most widely used ACEI was enalapril, which was consumed by three out of four ACEI users. One-third of patients were ARB-II users, most of whom had been on treatment for more than four weeks. The most widely used form was losartan, which was being taken by a third of ARB-II users. Diuretics were prescribed in almost nine out of ten cases to treat the following: HTN in 55.4% of cases, CHF in 33.8%, and edema in 6%. Almost three-quarters of patients had been on treatment for more than four weeks and almost one-quarter had been prescribed more than one type of diuretic. The most widely used diuretic was furosemide, followed by hydrochlorothiazide. NSAIDs were prescribed in just over one-fifth of cases; two-thirds of them had been on treatment for more than four weeks. The most widely used NSAID was ibuprofen (Table 2).

Out of patients the admitted, 88.2% were on dual or triple therapy: 54% dual therapy, 39% combined ACEI/ARB-II + diuretics, and 34% Triple Whammy.

From a population of 87,160 people, a total of 15,307 were on the target drugs, which represented 175.62 users/1,000 inhabitants (Figure 1).

The population prevalence of use for each type of drug (alone and in various possible combinations among them) is shown in Figure 2. The most common type of use in the study population was monotherapy, which accounted for more than half of these users. The most common monotherapy was ACEI/ARB-II, and the least used were diuretics. More than one-third of these users were on dual therapy, the most frequent being ACEI/ARB-II + diuretics. Just over 1 person per 100 inhabitants had been prescribed the Triple Whammy.

Figure 2.

– Prevalence of use of ACEI/ARB-II, diuretics and NSAIDs in Baix Empordà, February 2011. ACEI: Angiotensin converting enzyme inhibitor; ARB-II: Angiotensin-II receptor blocker; NSAID: Non-steroidal anti-inflammatory drug.

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Table 3 shows the incidence of AKI associated with ACEI/ ARB-II, diuretics and NSAIDs in the population consuming these drugs. Overall incidence was 3.40 cases/year/1,000 users, which generally increased with the number of drugs combined. In monotherapy, the diuretics group had a relevant incidence, which increased when they were combined with ACEI/ARB-II or NSAIDs in a dual therapy. In contrast, the incidence of AKI associated with ACEI/ARB-II and NSAIDs, alone or combined among them, was lower. The incidence of associated AKI in Triple Whammy users was similar to that of users of dual therapies that included diuretics.

In the comparison of the AKITW cases with paired non-AKI controls, no statistically significant differences were found for mean hospital stay between the two groups: 7.6 days (SD 6.4) for cases and 5.8 (SD 4.5) for controls (p = 0.07). The total number of hospital stays generated in one year due to AKI secondary to the target drugs was 473 days for 87,160 inhabitants. This represents an estimated 543 days of avoidable hospital stay/100,000 inhabitants/year.

Regarding costs, the mean cost was €3,016 (SD 2,468) for cases and €2,663 (SD 2,876) for controls, with no significant differences between them (p = 0.43). When we consider that the total one-year cost was €187,049 for 87,160 inhabitants, we can estimate an annual avoidable cost of €214,604/100,000 inhabitants/year.

Mortality was 11.3% for cases and 6.5% for controls during hospitalization and 40.3% and 38.7%, respectively, during the 12-month follow-up. No statistically significant differences were found between the groups at those time points or during the follow-up at three, six and nine months (Figure 3).

Figure 3.

– Mortality for AKI secondary to ACEI/ARB-II, diuretics and NSAIDs compared to admission of patients with no AKI (Palamós Hospital, 2011). (a) Control group: Hospitalizations of patients with no acute kidney injury paired by sex, age and comorbidity according to Clinical Risk Group (CRG) categories. All comparisons were non-significant (p > 0.05 based on Fischer's exact test). TW: Triple Whammy.

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