Support Care Cancer DOI 10.1007/s00520-014-2160-0
ORIGINAL ARTICLE
Characteristics of unplanned hospital admissions due to drug-related problems in cancer patients Alexandre Chan & Deren Soh & Yu Ko & Yu-Chu Huang & Joen Chiang
Received: 11 September 2013 / Accepted: 3 February 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background Studies have examined drug-related problems (DRPs) that have led to hospital admissions in the general population. However, there is a lack of information on the characteristics of DRPs in the cancer population. Objective The objective of this study was to investigate the type, causality, severity, and preventability of DRPs that result in unplanned hospitalizations among cancer patients. Methods This was a prospective, cohort study conducted in two oncology wards between July and December 2012. All patients who were diagnosed with solid tumor or lymphoma and required unplanned hospitalization were included. The incidence of DRPs among hospital admissions was captured, and the nature of the DRPs (causality, severity, and preventability) was characterized. Results There were 1,299 admissions and 1,275 were eligible for analysis. Among the 1,275 eligible admissions, 158 (12.4 %) were considered to be associated with a DRP. In the 158 admissions associated with DRPs, 164 DRPs were found. The majority of the DRP-related admissions were adverse drug reactions (ADRs) (n=155/164, 94.5 %), probable (n=98, 59.8 %), moderately severe (n=155, 94.5 %), and probably or definitely preventable (n=86, 52.4 %). Most patients with DRPs recovered and were discharged. Febrile neutropenia was the most common adverse drug reaction, and drug combinations involving antihypertensives and long-term
A. Chan (*) : D. Soh : Y. Ko : Y.
corticosteroids raised the risks for potential drug-drug interactions among patients with cancer. Conclusion The incidence of DRP-induced unplanned hospital admissions was 12.4 % among cancer patients. Approximately half of these were preventable events. Keywords Drug-related problems . Hospital . Drug-drug interactions . Oncology
Introduction According to the Pharmaceutical Care Network Europe (PCNE), a drug-related problem (DRP) is defined as an event or a circumstance involving drug therapy that actually or potentially interferes with desired health outcomes [1]. Patients with cancer are vulnerable to DRPs because chemotherapeutic drugs possess narrow therapeutic indices and are often cytotoxic to healthy cells at therapeutic doses [2]. In addition to chemotherapy and supportive care medications to prevent side effects or manage symptoms, many patients manifest comorbidities that may require additional medications, which may further increase the risk of manifesting adverse effects. Previous studies have shown that patients with cancer often experience hospitalizations due to the manifestations of DRPs during their cancer treatment [3, 4]. In one study, the number of adverse drug reactions (ADRs) experienced by patients admitted into a cancer center was high, with an average of 2.7 ADRs per admission [5]. In another study, an evaluation of unplanned hospital admissions discovered that 13 % of such admissions were associated with an ADR, the most common of which was febrile neutropenia [3]. ADRs can be potentially fatal and are a leading cause of death [6]. Another commonly observed DRP among cancer patients is drug-drug interactions (DDIs). Cancer patients are at particular risk for DDIs as they receive numerous medications for their cancer and other
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comorbidities, together with supportive care medications such as antiemetics, analgesics, anti-infective agents, and growth factors [7]. One study revealed that 27 % of ambulatory cancer patients had potential DDIs, with most involving anticoagulants and antihypertensives [8]. Furthermore, we have previously identified potential DDI coprescriptions in 5.4 % of patients receiving oral anticancer agents [9]. There is a scarcity of published information on the prevalence of ADR-related hospitalizations among cancer patients. The majority of previously published studies have focused on patients who were not diagnosed with cancer. In the literature, there is also a lack of epidemiological data investigating the DRP-associated hospitalizations among Asian patients with cancer. Hence, the primary objective of this study was to investigate the type, causality, severity, and preventability of the DRPs that led to hospitalizations among cancer patients. This study aimed to evaluate the patterns of DRPs in cancer patients to prevent DRP-related hospitalizations. Knowing the type and characteristics of the DRPs patients commonly face would allow health policy makers to design appropriate management pathways for this group of patients.
cancer diagnoses, and comorbid illness data were collected (Fig. 1). Using this set of collated data, the DRPs that contributed to hospitalizations were classified by their type, causality, severity, and preventability. Description of DRPs Several descriptions were used to characterize the DRPs in this study, including their identification, causality, severity, and preventability. Identification of DRPs All DRP admissions were classified into six different types in accordance with the PCNE DRP classification V5.01 [1]. Micromedex® 2.0 DRUG-REAX® was used as a reference to identify all of the DRPs [10]. Causality of DRPs The Naranjo algorithm was used to estimate the causality of DRP types I, II, and III (i.e., adverse reactions, interactions, and drug choice problems) [11]. Another causality classification by Hallas et al. was used to estimate the causality of DRP types IV, V, and VI (i.e., dosing problems, drug use problems, and other problems) [12]. DRP causality
Methods Study design This was a prospective, observational study of cancer patients admitted to two oncology wards at Singapore General Hospital between July and December 2012. The hospital is Singapore’s largest tertiary acute hospital and serves over a million people annually. This study was reviewed and approved by the local institutional review board. The patients’ informed consent was not required in this study. Patients All patients who were diagnosed with solid tumor or lymphoma and required unplanned hospitalization were included in this study. Patients under the age of 21 and those receiving treatment within a clinical trial were excluded. Data collection All patient information was recorded using a data collection form designed for this study. Data were collected from patients’ medical and pharmacy records. During the initial screening process, the medical records of all of the patients were examined to determine whether their admission was associated with a DRP. Data such as medications used before admission, current chemotherapy regimen, and pertinent lab results were collected. Among the admissions that were classified as non-DRP related, only the patients’ demographics,
Fig. 1 Study procedure
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was ranked as definite, probable, possible, or doubtful. Only DRPs that fell under the definite, probable, or possible categories were considered to be DRPs and included in the analysis. Doubtful drug-related admissions were excluded. Severity of DRPs A classification scheme developed by McDonnell and Jacobs to assess the level of severity was used for all of the DRPs [13]. DRP severity was ranked from minor or moderate to severe.
Among all 1,275 admissions, 158 (12.4 %) were considered to be associated with a DRP. For admissions that were not associated with a DRP, the most common cause of admission was disease progression (n=431, 33.8 %) where the patient experienced symptoms that were due to tumor growth or metastasis. Other causes of hospitalizations included elective admissions for chemotherapy (n=171, 13.4 %) and treatment of infections (n=145, 11.4 %) (Table 2). Identification and causality of DRPs
Preventability of DRPs Preventability was determined using a series of modified questions from the criteria of Schumock and Thornton [5]. DRP preventability was ranked as definitely preventable, probably preventable, or not preventable. Statistical considerations Descriptive statistics were used to summarize the patient demographic data. The number and percentages of different DRP characteristics were tabled for analyses. Independent sample t test was used to determine whether there were any differences between the ages of patients with and without DRPs. Chi-square test was used to determine whether there were any differences in the genders of patients with and without DRPs. Statistically significant results are those with p values <0.05. All of the statistical analyses were performed using SPSS version 19 (SPSS Inc., Chicago, IL).
Results Demographics A total of 1,299 admissions (1,275 deemed eligible for analysis) were processed between July and December 2012. Twenty-five admissions were excluded. Specifically, 11 patients were below 21 years old, 13 patients were participating in clinical trials, and the cause of admission was unclear for 1 patient. Nine hundred and fifty-nine patients were admitted, 217 of whom had repeated admissions that were included in the total admissions (Table 1). The mean age was 61.3 years (standard deviation=12.8), and 527 of the patients (55.0 %) were male. The most common cancer type was gastrointestinal cancer (25.5 %). Sixty percent of all of the patients (n= 573) manifested at least one comorbidity, and the most common comorbidity was hypertension (n=379, 39.5 %). Patients with DRPs were significantly younger (58.1 vs. 61.7 years, p=0.03) than those without DRPs. A significantly higher proportion of patients with DRPs were female (54.3 %, p=0.015) compared to patients without DRPs. This correlates with the higher proportion (28.3 %) of breast cancer incidence in patients with DRPs, as compared to a 10.9 % breast cancer incidence in patients without DRPs.
Among the 158 admissions associated with DRPs, 164 DRPs were identified. The analysis results on the causality of all 164 DRPs suggested that the majority of the DRPs were probable in nature (n=98, 59.8 %) (Table 3). There were six patients who had more than one DRP during an admission: two admissions were associated with two different ADRs, three admissions were associated with both ADR and DDI, and one admission was associated with an ADR and a drug overdose. The different DRP types are summarized in Table 4. DDI incidence was found to be low (n=3, 1.8 %). The majority of the DRP-related admissions were due to ADRs (n=155, 94.5 %), while the other types of DRPs were uncommon. Overall, 12.2 % (155/1,275) of the admissions were associated with ADRs. Among all 164 DRPs, some patients experienced multiple symptoms that led to hospitalization. The most common causes of admission were infections (n = 42), gastrointestinal-related ADRs (nausea, vomiting, and diarrhea) (n=38), and neutropenic fever (n=32). Two hundred and sixty-two drugs were associated with the 164 DRPs found. The cytotoxic agents most commonly associated with DRPs included cyclophosphamide (n=35), doxorubicin (n=25), cisplatin (n=25), docetaxel (n=18), and paclitaxel (n=16). Severity of DRPs In terms of the severity, the majority of the DRPs were classified as moderately severe (n=155, 94.5 %). Of the seven severe DRPs, four were found in five patients who died as a result. The remaining patient experienced a moderately severe DRP. The reasons for mortality in those five patients are summarized in Table 5. All of them were male and were taking different drugs. All of the suspected offending drugs involved antineoplastic agents. Patient 5’s DRP was classified as moderately severe. The other four patients’ DRPs were classified as severe. Preventability of DRPs Regarding the preventability, 86 DRPs (52.4 %) were categorized as probably preventable or definitely preventable in nature (Table 3), with majority of them being classified as
Support Care Cancer Table 1 Patient characteristics (N=959)
a
Patients may have more than one comorbid illness
N (%) Characteristics All admissions Mean age, standard deviation Gender Male
Patients with DRPs 127 (100) 58.1, 12.7
Patients without DRPs 832 (100) 61.7, 12.8
All patients 959 (100) 61.3, 12.8
58 (45.7)
469 (56.4)
527 (55.0)
Female Cancer type Gastrointestinal Lung Breast Lymphoma Genitourinary Gynecologic Other Metastatic disease Comorbid illnessa
69 (54.3)
363 (43.6)
432 (45.0)
19 (15.1) 19 (15.1) 36 (28.3) 15 (11.9) 9 (7.1) 7 (5.5) 22 (17.3) 50 (39.4)
226 (27.2) 154 (18.5) 91 (10.9) 90 (10.8) 57 (6.9) 38 (4.6) 176 (21.2) 410 (49.3)
245 (25.5) 173 (18.0) 127 (13.2) 105 (10.9) 66 (6.9) 45 (4.7) 198 (20.6) 460 (48.0)
79 (62.2) 43 (33.9) 38 (29.9) 24 (18.9) 8 (6.3) 4 (3.1)
494 (59.4) 336 (40.4) 227 (27.3) 153 (18.4) 29 (3.5) 29 (3.5)
573 (59.7) 379 (39.5) 263 (27.4) 177 (18.5) 37 (3.9) 33 (3.4)
Yes Hypertension Dyslipidemia Diabetes mellitus Liver disease Renal disease
probably preventable. Seventy-five admissions (45.7 %) were not preventable. There were three patients who had received their chemotherapy in other institutions before being referred to our institution for admission. This resulted in a lack of patient information to assess DRP preventability levels, and therefore, these three admissions were not categorized.
associated hospitalizations in patients with general conditions have been examined in several reports. Several studies conducted in developed countries such as the UK, Spain, and Australia have reported that the incidence of ADR-associated hospitalizations ranges from 1.7 to 6.9 % [14–17], which is lower than the incidence of 12.2 % identified in this study. The
Discussion
Table 3 Characteristics of DRP (N=164)
Information regarding the frequency of ADRs as causes of hospitalizations in oncology is scarce. However, ADRTable 2 Causes of admissions (N=1,275)
Causes
n (%)
All admissions DRP Unclear Non-DRP Disease progression Others Chemotherapy Infection Examination Other treatment Accident
1,275 (100) 158 (12.4) 1 (0.1) 431 (33.8) 239 (18.7) 171 (13.4) 145 (11.4) 94 (7.4) 31 (2.4) 5 (0.4)
DRP characteristics Causality Probable Possible Definite Doubtful Severity Moderate Severe Minor Preventability Not preventable Probably preventable Definitely preventable Not applicablea a
Frequency % (n)
59.8 (98) 39.0 (64) 1.2 (2) 0 (0) 94.5 (155) 4.3 (7) 1.2 (2) 45.7 (75) 37.2 (61) 15.2 (25) 1.8 (3)
Unable to assess preventability due to lack of patient information
Support Care Cancer Table 4 Types of DRP (N=164)
lower incidence of ADRs in patients with general conditions compared to cancer patients can be explained in the following ways. Cancer patients are more susceptible to ADRs because chemotherapeutic drugs have a narrow therapeutic index and are cytotoxic to healthy cells at therapeutic doses [2]. As such, these patients are at much higher risk of experiencing toxic events and, subsequently, unwanted admission. Furthermore, cancer patients may suffer from malnutrition, organ dysfunctions, and edema, all of which can lead to modified drug pharmacokinetics and may raise the risk of ADRs. This study also successfully investigated the type, causality, severity, and preventability of DRPs that led to hospitalizations among local cancer patients. A large proportion of these DRPs belong to ADRs, with 12.2 % of the subsequent hospital admissions associated with an ADR. However, DDIs and other types of DRPs were not commonly observed in this study. Consistent with a Brazilian study, it was found that one of the most common reasons for unwanted hospitalization was the occurrence of febrile neutropenia [4]. It was also identified in this study that cyclophosphamide and doxorubicin in combination were most frequently associated with DRPs. The myelosuppressive nature of these two cancer drugs explains why febrile neutropenia and infections were among the most common causes of unwanted hospital admissions in this study. A local study has reported a high incidence (13.8 %) of febrile neutropenia occurrence in breast cancer patients receiving concomitant doxorubicin and cyclophosphamide [18].
Judicious use of granulocyte colony-stimulating factor prophylaxis has been shown to reduce the occurrence of febrile neutropenia and infection-related mortality in solid tumor and lymphoma patients [19]. Several studies have evaluated the predictors for febrile neutropenia in solid tumor and lymphoma patients, and results of these studies can guide the appropriate usage of prophylactic antibiotic and growth factor support [18, 20, 21]. In contrast, the incidence of DDIs as a cause of hospitalization was low at 1.8 %, which is similar to a study conducted in Brazil that reported an incidence of 2.0 % [3]. The low occurrence of DDIs in our cancer population may be due to the vigilant screening performed by healthcare professionals to prevent DDIs. Furthermore, the incorporation of DDI alerts in electronic prescribing systems may have alerted prescribers with potentially interacting combinations; hence, these agents were not prescribed and this lowered the number of prescriptions manifesting DDIs. Out of the three patients with potential DDIs, two suffered from pharmacodynamic DDIs between two classes of antihypertensive agents. The DDIs involved enalapril with losartan and nifedipine with hydrochlorothiazide, which resulted in weakness and dizziness in the patients and led to their hospital admissions. Hypertension was the most common comorbidity in this study; thus, it is not surprising that antihypertensive drugs were involved in these DDIs. The last DDI admission was due to a drug interaction between ketoconazole and hydrocortisone. It is postulated that the patient’s hydrocortisone levels were increased with the concomitant use of ketoconazole. This patient experienced severe hyperglycemia, with a peak blood glucose reading of 39.6 mmol/L (660 mg/dL). Two of the three DDI cases were classified as probably preventable, while one was classified as definitely preventable. Our findings are congruent with another study that evaluated the potential drug-interacting combinations in cancer patients admitted to the hospital. In that study, the five DDI combinations involved warfarin and phenytoin, captopril and hydrochlorothiazide, captopril and dexamethasone, warfarin and omeprazole, and aspirin and enoxaparin. Clinicians should be aware that cancer
Table 5 Admissions resulting in death
Types
n (%)
All DRPs Adverse reaction Drug interactions Dosing problem Drug use problem
164 (100) 155 (94.5) 3 (1.8) 3 (1.8) 3 (1.8)
Drug choice problem Other
0 (0) 0 (0)
Patient number
Age
Gender
Offending drugs (suspected)
Cause of death
1
70
Male
Gefitinib
Transaminitis and pulmonary embolism
2 3 4
60 54 66
Male Male Male
Cisplatin Doxorubicin Docetaxel
5
56
Male
Capecitabine
Sepsis Neutropenic sepsis Type 1 respiratory failure due to docetaxel-induced pneumonitis Head trauma and dehydration due to diarrhea
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patients who are long-term users of corticosteroids and antihypertensives are at higher risk for potential DDIs that may lead to unwanted admissions. It is essential to note that over half of the DRPs were considered to be preventable, and more steps could be taken to avoid such potentially fatal consequences and ensure drug safety in cancer patients. There are several ways to prevent DRPs from occurring that minimize the risk of hospitalization among cancer patients. Physicians play a pivotal role by reducing unnecessary prescriptions and understanding the issues associated with DRPs and polypharmacy. Medication review and reconciliation conducted by pharmacists and the prevention of polypharmacy can lower the risks of a DRP. A challenge to preventing DRPs from occurring is patient compliance. More can be done to enhance compliance by changing drug administration frequency for patients’ convenience without compromising clinical outcomes. Another way to improve compliance is by emphasizing the importance of compliance via drug counseling implemented by pharmacists during dispensing. Patients who are at a high risk of DRPs such as those receiving multiple drugs or drugs that are more likely to cause DRPs, females, and geriatric patients should be identified. Healthcare professionals should be aware of these high-risk patients and spend more time monitoring them. This study has its limitations. Although the study population is representative of general cancer patients in the public setting, information from a single institution may not be generalizable to other settings. This study includes a mix pool of solid tumor and lymphoma patients, which may not be representative in other healthcare settings. Moreover, although this was a prospective study, information collected on drug use at admission may be incomplete as it may have missed over-the-counter drug use, which would not be found in study databases. It could be argued that our assessment of DRP severity was limited by subjectivity and misclassification; however, the evaluation of DRP characteristics was performed by applying systemic assessment algorithms such as the Naranjo algorithm.
Conclusion This prospective study identified that 12.4 % of hospitalizations among cancer patients were associated with DRPs. Among these DRPs, approximately half were preventable. This study provides a better understanding of the characteristics of DRPs that lead to hospitalizations, which may assist healthcare professionals to be more vigilant in drug prescribing, dispensing, and monitoring to prevent future DRPs from occurring. DRPs in cancer patients can be severe and even fatal, and more care must be taken to avoid DRPs for this group of patients. Future studies should evaluate the feasibility to incorporate routine medication reviews conducted by
pharmacists in patients with cancer, in order to reduce the occurrence of polypharmacy and associated DRPs. Conflict of interest None.
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