Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity

Vered Daitch, Mical Paul, George L Daikos, Emanuele Durante-Mangoni, Dafna Yahav, Yehuda Carmeli, Yael Dishon Benattar, Anna Skiada, Roberto Andini, Noa Eliakim-Raz, Amir Nutman, Oren Zusman, Anastasia Antoniadou, Giusi Cavezza, Amos Adler, Yaakov Dickstein, Ioannis Pavleas, Rosa Zampino, Roni Bitterman, Hiba Zayyad, Fidi Koppel, Yael Zak-Doron, Inbar Levi, Tanya Babich, Adi Turjeman, Haim Ben-Zvi, Lena E Friberg, Johan W Mouton, Ursula Theuretzbacher, Leonard Leibovici, Vered Daitch, Mical Paul, George L Daikos, Emanuele Durante-Mangoni, Dafna Yahav, Yehuda Carmeli, Yael Dishon Benattar, Anna Skiada, Roberto Andini, Noa Eliakim-Raz, Amir Nutman, Oren Zusman, Anastasia Antoniadou, Giusi Cavezza, Amos Adler, Yaakov Dickstein, Ioannis Pavleas, Rosa Zampino, Roni Bitterman, Hiba Zayyad, Fidi Koppel, Yael Zak-Doron, Inbar Levi, Tanya Babich, Adi Turjeman, Haim Ben-Zvi, Lena E Friberg, Johan W Mouton, Ursula Theuretzbacher, Leonard Leibovici

Abstract

Background: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study's population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial.

Methods: The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset.

Results: Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10-16) vs. 8.5 days (IQR 0-15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14.

Conclusion: The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice.

Trial registration: The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012.

Keywords: Antibiotic treatment; Antimicrobial resistance; Population external validity.

Conflict of interest statement

The authors declare that they have no competing interests.

References

    1. Akobeng AK. Assessing the validity of clinical trials. J Pediatr Gastroenterol Nutr. 2008;47(3):277–282. doi: 10.1097/MPG.0b013e31816c749f.
    1. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8(1):18. doi: 10.1186/1741-7015-8-18.
    1. Bracht GH, Glass GV. The external validity of experiments. Am Educ Res J. 1968;5(4):437–474. doi: 10.3102/00028312005004437.
    1. Rothwell PM. Factors that can affect the external validity of randomised controlled trials. PLoS Clin Trials. 2006;1(1):e9. doi: 10.1371/journal.pctr.0010009.
    1. Paul M, Bronstein E, Yahav D, Goldberg E, Bishara J, Leibovici L. External validity of a randomised controlled trial on the treatment of severe infections caused by MRSA. BMJ Open. 2015;5(9):e008838. doi: 10.1136/bmjopen-2015-008838.
    1. Claessens YE, Aegerter P, Boubaker H, Guidet B, Cariou A. Are clinical trials dealing with severe infection fitting routine practices? Insights from a large registry. Crit Care. 2013;17(3):R89. doi: 10.1186/cc12734.
    1. Travers J, Marsh S, Williams M, Weatherall M, Caldwell B, Shirtcliffe P, Aldington S, Beasley R. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax. 2007;62(3):219–223. doi: 10.1136/thx.2006.066837.
    1. Saunders C, Byrne CD, Guthrie B, Lindsay RS, McKnight JA, Philip S, et al. External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants? Diabet Med. 2013;30(3):300–308. doi: 10.1111/dme.12047.
    1. Steg PG, López-Sendón J, de Sa EL, Goodman SG, Gore JM, Anderson FA, et al. External validity of clinical trials in acute myocardial infarction. Arch Intern Med. 2007;167(1):68–73. doi: 10.1001/archinte.167.1.68.
    1. Fortin M, Dionne J, Pinho G, Gignac J, Almirall J, Lapointe L. Randomized controlled trials: do they have external validity for patients with multiple comorbidities? Ann Fam Med. 2006;4(2):104–108. doi: 10.1370/afm.516.
    1. Yessaian A, Mendivil AA, Brewster WR. Population characteristics in cervical cancer trials: search for external validity. Am J Obstet Gynecol. 2005;192(2):407–413. doi: 10.1016/j.ajog.2004.08.027.
    1. Milojevic K, Beltramini A, Nagash M, Muret A, Richard O, Lambert Y. Esmolol compared with Amiodarone in the treatment of recent-onset atrial fibrillation (RAF): an emergency medicine external validity study. J Emerg Med. 2019;56(3):308–318. doi: 10.1016/j.jemermed.2018.12.010.
    1. Dickstein Y, Leibovici L, Yahav D, Eliakim-Raz N, Daikos GL, Skiada A, Antoniadou A, Carmeli Y, Nutman A, Levi I, Adler A, Durante-Mangoni E, Andini R, Cavezza G, Mouton JW, Wijma RA, Theuretzbacher U, Friberg LE, Kristoffersson AN, Zusman O, Koppel F, Dishon Benattar Y, Altunin S, Paul M, AIDA consortium Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol. BMJ Open. 2016;6(4):e009956. doi: 10.1136/bmjopen-2015-009956.
    1. Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, Skiada A, Andini R, Eliakim-Raz N, Nutman A, Zusman O, Antoniadou A, Pafundi PC, Adler A, Dickstein Y, Pavleas I, Zampino R, Daitch V, Bitterman R, Zayyad H, Koppel F, Levi I, Babich T, Friberg LE, Mouton JW, Theuretzbacher U, Leibovici L. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 2018;18(4):391–400. doi: 10.1016/S1473-3099(18)30099-9.
    1. EUCAST. Breakpoint tables for interpretation of MICs and zone diameters version 2.0, valid from 2012-01-01. . Accessed 7 Feb 2018.
    1. Ha C, Ullman TA, Siegel CA, Kornbluth A. Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population. Clin Gastroenterol Hepatol. 2012;10(9):1002–1007. doi: 10.1016/j.cgh.2012.02.004.
    1. Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials. 2015;16(1):495. doi: 10.1186/s13063-015-1023-4.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel