To What Degree Could Clinical Trials in Evidence Based Medicine Reect The Real World in The Treatment of Pneumonia?

Nobuhiro Asai Aichi Medical University Hospital Yuichi Shibata Aichi Medical University Hospital Daisuke Sakanashi Aichi Medical University Hospital Arufumi Shiota Aichi Medical University Hospital Hideo Kato Aichi Medical University Hospital Mao Hagihara Aichi Medical University Hospital Yusuke Koizumi Aichi Medical University Hospital Yuka Yamagishi Aichi Medical University Hospital Hiroyuki Suematsu Aichi Medical University Hospital Hiroshige Mikamo (  mikamo@aichi-med-u.ac.jp ) Aichi Medical University Hospital


Abstract
Background Evidenced based medicine (EBM) is necessary to standardize treatments for infections because EBM has been established based on the results of clinical trials. Since entry criteria for clinical trials are very strict, it may cause skepticism or question whether the results of clinical trials re ect the real world of medical practice.

Methods
To examine how many patients could join any randomized clinical trials for the treatment of community-onset pneumonia, we reviewed all the pneumonia patients in our institute during 2014-2017.
The patients were divided into two groups: patients who were eligible for clinical trials (participation possible group), and those who were not (participation impossible group). Exclusion criteria for clinical trials were set based on previous clinical trials.

Results
A total of 406 patients were enrolled in the present study. Fifty-seven (14%) patients were categorized into the participation possible group, while 86% of patients belonged to the participation impossible group.
Patients in the participation possible group had less comorbidities and more favorable outcomes than those with the participation impossible group. As for the outcomes, there were signi cant differences in the 30-day and in-hospital mortality rates between the two groups. In addition, the participation possible group showed a longer overall survival time than the participation impossible group (p<0.001 by Log-Rank test).

Conclusion
There is a difference in patients' pro le and outcomes between clinical trials and the real world. Though EBM is essential to advance medicine, we should acknowledge the fact s and the limit s of the clinical trial.

Background
Evidence-based medicine (EBM) aims to assist physicians in making rational decisions in general practices. As EBM is established according to the results of clinical trials, clinical trials are considered to be one of the most important undertakings and are put at the top of priority among physicians in constructing therapeutic strategies [1]. There is no room for doubt that current medicine is based on EBM.
However, we skeptically think about that when we consider eligibility of pneumonia patients for EBM guidelines/recommendations in actual practice. Entry criteria for any clinical trial are generally very strict, and most patients might not be suitable for the studies. Thus, it is reasonable to doubt if the results of clinical trials re ect the real world in general practice. We already reported that only 24 % of candidemia patients could be eligible in a clinical trial [2]. Pneumonia remains a leading cause of infection deaths worldwide [3,4]. Especially, elderly patients with pneumonia tend to have more comorbidities than young patients and the mortality rate is higher than other groups [4,5]. We have suspected that there might be a distinct difference of clinical pictures (characteristics) between the patients eligible in the study and those who were excluded from the study and decided to perform this study. This is the rst report demonstrating to what degree clinical data on which EBM is based on, re ects the real world patients.

Study design
Our institute is a 900-bed tertiary care center and is located in the countryside at Aichi prefecture in central Japan. For the purpose of how many community-onset pneumonia patients in our institute could join any randomized clinical trials for the treatment of candidemia, we reviewed all community-onset pneumonia patients who were admitted in our hospital between September 2014 and May 2017. Pneumonia was diagnosed according to the previously published international guidelines [6].
Community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP) were categorized based on the criteria published by the American Thoracic Society/ Infectious Diseases Society of America (ATS/IDSA) in 2006 [7,8]. Severity of pneumonia was evaluated by A-DROP [8], CURB-65 [9], Pneumonia Severity Index (PSI) [10], I-ROAD [11] and SOFA score [12]. Comorbidity was evaluated by the Charlson comorbidity index (CCI) [13]. The patients were divided into two groups: patients who were eligible for clinical trials (participation possible group), and those who were not (participation impossible group).
Then, patients' characteristics (age, sex), pathogens isolated, clinical outcomes such as the treatments, 30-day, or in-hospital mortality and the reasons of exclusion from the clinical trial were evaluated.

Patient selection
Exclusion criteria commonly used in the many past ordinary clinical trials are as follows; [14][15][16] 1. Age 18 years, >80 years 2. Coexisting comorbidities or medical conditions which are di cult to evaluate for the pneumonia such as severe liver dysfunction, severe renal dysfunction or HIV/AIDS (Severe liver dysfunction was de ned as serum total bilirubin, or aspartate aminotransferase/alanine aminotransferase >the upper limit of the normal reference range×3. Severe renal dysfunction was de ned as Creatinine clearance <30ml/min). Unassessable pulmonary diseases include viral pneumonia, pneumocystis pneumonia [17,18], mycobacterium infections, eosinophilic pneumonia and interstitial pneumonitis. Unassessable malignancies were de ned as any malignancy terminated stage or the one with any metastatic lesion to the lung and/or receiving palliative therapy. Unassessable diabetes mellitus was de ned as serum-hemoglobin A1c (NGSP) ≧7.0%. [19,20]

Microbiological evaluation
A sputum sample and two sets of blood were collected from each patient for microbiological examination. Serological tests were performed to detect antibodies against Mycoplasma pneumoniae [21] and Chlamydophila pneumoniae [22]. Additionally, Legionella pneumophila serogroup 1 antigen in the urine was tested by immunochromatography. The antimicrobial susceptibility of isolated bacterial pathogens was assessed on the basis of the minimum inhibitory concentration according to the Clinical and Laboratory Standards Institute guidelines [23]. Methicillin-resistant Staphylococcus aureus, P. aeruginosa, Acinetobacter baumannii, and extended-spectrum β-lactamase-producing organisms were de ned as potentially drug-resistant (PDR) pathogens based on ATS/IDSA guidelines [24].
De nition of appropriate and inappropriate treatment, initial treatment failure Antibiotic treatment was classi ed as appropriate or inappropriate according to whether the identi ed pathogens were sensitive or resistant, respectively, to the initially prescribed antibiotics. Initial treatment failure was de ned as death during the initial treatment or a change in the antibiotic regimen from the initial agents within 72 hours after starting the treatment due to a lack of response or clinical deterioration (e.g. worsening of fever, respiratory condition or radiologic status; requiring mechanical ventilation, aggressive uid resuscitation or vasopressors).

Statistical analyses
The data for categorical variables are expressed as percentages and continuous variables as mean ± standard deviation (SD

Result
A total of 406 patients were enrolled in the present study. Table 1 shows the patients' characteristics and clinical outcomes. Fifty-seven (14%) patients were categorized into the participation possible group, while 86% patients were the participation impossible group. Comparing the two groups, patients with the participation possible group have less comorbidities than those with participation impossible group. The severity of pneumonia was much more severe in patients within the participation impossible group than in those with the participation possible group. As for the outcomes, the patients with the participation possible group had favorable outcomes than those within the participation impossible group. Mechanical ventilations and do not attempt resuscitation (DNAR) orders were frequently seen in participation impossible group than participation possible group. PDR pathogens were seen more frequently in the participation possible group than in those within the participation impossible group (5% v.s. 16%, p = 0.032). There were no signi cant differences in the frequency of anti-pseudomonal agents use as the initial treatment between the two groups. The duration of antibiotics use was longer in patients within the participation impossible group than in those with the participation possible group, while there was no difference of duration of admission between the two groups. As for pathogens isolated, MRSA is more frequently seen in participation impossible group than in participation impossible group (0% v.s. 20%, p = 0.013), while Haemophillus in uenzae was seen more frequently in participation possible group than in participation impossible group (35% v.s. 8%, p = 0.042).  (4) 77 (19) 19 (5) 11 (3) 196 (48) 58 (14) 70 (17) 26 ( 12 (3) 77 (22) 19 (5) 11 (3) 180 (52) 51 (15) 63 (18) 13 ( 19 (5) 23 (6) 37 (9) 42 (22) 59 (14) 0 1 (2) 5 (9) 1 (6) 3 (5) 19 (5) 22 (6) 32 (9) 41 (24) 56 (  Only cases with causative pathogens isolated were analyzed. ***, ****, ***** these denominators whose numbers are positive sputum cultures, are 196, 17 and 179. They were calculated up to the rst digit of the minority. Table 2 shows comparison of patients' characteristics and outcomes between participation possible and impossible group among CAP patients. Fifty-one patients (29%) were participation possible group.
Participation possible groups are older and have more cormobidities than participation impossible group. All severity scores of pneumonia were higher in participation impossible group than in participation possible group. There was no differences of 30-day and in-hospital mortality rates in between the two groups. Mean duration of antibiotic therapy was shorter in participation possible group than in participation impossible group (12.4 ± 10.5 v.s. 17.5 ± 16.0 days, p = 0.025), while duration of hospital stay did not differ between the two groups.  (3) 1 (1) 28 (22) 10 (8) 23 (13) 4 (3) 37 (21) 23 (13) 1.2 ± 1. 1 (1) 28 (23) 10 (8) 22 (17) 2 (2) 33 (26) 23 (18) 1  (13) 7 (4) 4 (3) 70 (40) 30 (17) 26 (15) 22 (   *Patients who obtained a blood culture were evaluated. Then, the denominators are 107, 25, and 82 in all patients, the RCT appropriate group and RCT inappropriate group, respectively. **Patients who had causative pathogens identi ed were evaluated. Then, the denominators are 70, 15, and 55 in all patients, the RCT appropriate group and RCT inappropriate group, respectively. ***, ****, ***** These denominators whose number are positive sputum cultures, are 71, 14, and 57, respectively. They were calculated up to the rst digit of the minority. Table 3 shows comparison of patients' characteristics and outcomes between participation possible and impossible group among HCAP patients. Only 6 patients (3%) were participation possible group among HCAP patients. Although there were no signi cant differences on age and all pneumonia severity scores in between the 2 groups, CCI was higher than in participation impossible group than in participation possible group (0.8 v.s. 2.8, p = 0.022). There was no differences of 30-day and in-hospital mortality rates in between the two groups. There was no differences of duration of hospital stay or antibiotic treatment between the two groups. As for pathogens isolated, isolation of MRSA and Pseudomonas aeruginosa did not differ between the two groups. On the other hand, H. in uenza and Moraxella catarrahis tended to isolate more often in participation possible group than in participation impossible group. ***, ****, ***** These denominators whose number are positive sputum cultures, are 125, 3, and 122, respectively. They were calculated up to the rst digit of the minority.  (7) 11 (5) 40 (17) 72 (31) 65 (28) 51 (22) 10 ( 108 (48) 29 (13) 37 (17) 15 (7) 11 (5) 40 (18) 72 (32) 65 (29) 50 (22) 11 (5) 84 (38) 37 (17) 2 *Patients who obtained a blood culture were evaluated. Then, the denominators are 122, 2, and 120 in all patients, the RCT appropriate group and RCT inappropriate group, respectively. **Patients who had causative pathogens identi ed were evaluated. Then, the denominators are 118, 3, and 115 in all patients, the RCT appropriate group and RCT inappropriate group, respectively. ***, ****, ***** These denominators whose number are positive sputum cultures, are 125, 3, and 122, respectively. They were calculated up to the rst digit of the minority. *Patients who obtained a blood culture were evaluated. Then, the denominators are 122, 2, and 120 in all patients, the RCT appropriate group and RCT inappropriate group, respectively. **Patients who had causative pathogens identi ed were evaluated. Then, the denominators are 118, 3, and 115 in all patients, the RCT appropriate group and RCT inappropriate group, respectively. ***, ****, ***** These denominators whose number are positive sputum cultures, are 125, 3, and 122, respectively. They were calculated up to the rst digit of the minority. *Patients who obtained a blood culture were evaluated. Then, the denominators are 122, 2, and 120 in all patients, the RCT appropriate group and RCT inappropriate group, respectively. **Patients who had causative pathogens identi ed were evaluated. Then, the denominators are 118, 3, and 115 in all patients, the RCT appropriate group and RCT inappropriate group, respectively. ***, ****, ***** These denominators whose number are positive sputum cultures, are 125, 3, and 122, respectively. They were calculated up to the rst digit of the minority.  *Patients who obtained a blood culture were evaluated. Then, the denominators are 122, 2, and 120 in all patients, the RCT appropriate group and RCT inappropriate group, respectively. **Patients who had causative pathogens identi ed were evaluated. Then, the denominators are 118, 3, and 115 in all patients, the RCT appropriate group and RCT inappropriate group, respectively. ***, ****, ***** These denominators whose number are positive sputum cultures, are 125, 3, and 122, respectively. They were calculated up to the rst digit of the minority.
As for overall survival times, the participation possible group displayed a longer overall survival times (OSs) than the participation impossible group (median OS not reached v.s. 43.3 months, p < 0.001 by Log-Rank test) as shown in Fig. 1A. In the sub-analysis of OSs among CAP and HCAP, participation possible group among CAP patients showed a longer OSs than participation impossible group among those (Median OSs not reached v.s. 53.9 months, p < 0.001 by Log-Rank test) (Fig. 1B), while there was no differences in the participation possible and impossible group among HCAP patients (Fig. 1C).
In terms of reasons for not being able to join a clinical trial, underlying diseases or conditions which could not be assessed correctly was the most commonly seen in 254 (73%) patients, followed by age in 180 (52%) patients (Table 4).  (21) 37 (11) 15 (4) 19 (5) 39 (12) 41 (12) 63 (18) 12 (4) 3.  [2]. Like the study, community-onset pneumonia patients with participation possible group showed lesser severity of pneumonia and fewer comorbidities than those with the participation impossible group. We found the participation possible group had higher mortality rates of 30-day and inhospital than the participation impossible group. However, identi cation of PDR pathogens, mechanical ventilation and Do Not Attempt Resuscitation (DNAR) order were more frequently seen in the participation possible group than in the impossible group. In Japan, discussing DNAR order with Japanese family members is still considered to be taboo [25]. Therefore, these results could suggest that patients in the participation impossible group have a worse prognosis than those in the participation possible group do.
It is well known that HCAP patients are more likely to have worse PSs and more comorbidities than those with CAP [4,5,7].
Outstandingly, the OSs in the participation impossible group with CAP were signi cantly shorter OSs than those in the participation the impossible group, while 30-day and in-hospital mortality rate did not differ between the two groups. More comorbidities could affect the prognosis among the participation impossible group. Physicians should pay attention to them after discharge. Besides, 97% of HCAP patients in the studies [4,5,7] was excluded from the clinical trial. In addition, HCAP patients in the participation possible group had much shorted durations of antibiotic treatment and admission than those in the participation impossible group. An appropriate duration of antibiotics is said to be 5-7 days.
The result of our study also suggests that 5-7 days is long enough to treat HCAP. The therapeutic strategy for HCAP patients in the participation impossible group might have to be reconsidered due to the poor general conditions.
There are several limitations in our study. First, this is a retrospective study in a small population. Thus, there might be a bias in data selection and analysis such as the severity of pneumonia. Second, we evaluated only patients who were admitted to our institute. There might be possibility that patients in this study could not re ect the whole of pneumonia patients.

Conclusion
In conclusion, 14% patients could join the clinical trial, while 86% patients could not. There is a difference in patients' pro le and outcomes between the real world and the clinical trial. Though EBM is very important and essential to advanc e medicine, we should acknowledge the fact s and limit s of clinical trials. Every physician should not be overcon dent in EBM based on the results of a clinical trial. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and the local regulations, and was approved by the Institutional Review Board of Aichi Medical University Hospital. Informed consent was waived, since only leftover materials, otherwise discarded, were used, and no additional intervention or change in treatment plan was implemented.

Consent to publish
Not applicable.

Availability of data and materials
All data generated or analyzed during this study are included in this published article.

Competing interests
None declared.

Funding
None declared.
Author contribution statement NA contributed to the study conceptualization, methodology, and writing. HM supervised the study and edited the draft. NA, YS, DS, HK, MH, YK, and YY performed data collection. DS, HK, MH and HS performed microbial testing and analyzing data. AS provided a soft ware to analyze the data. All authors read and approved the nal manuscript.

Figure 1
As for overall survival times, the participation possible group displayed a longer overall survival times (OSs) than the participation impossible group (median OS not reached v.s. 43.3 months, p<0.001 by Log-Rank test) as shown in Figure 1A. In the sub-analysis of OSs among CAP and HCAP, participation possible group among CAP patients showed a longer OSs than participation impossible group among those (Median OSs not reached v.s. 53.9 months, p<0.001 by Log-Rank test) (Fig 1B), while there was no differences in the participation possible and impossible group among HCAP patients ( Fig 1C).