Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Westendorp WF, Vermeij J-D, Zock E, et al, for the PASS investigators. The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial. Lancet 2015; published online Jan org/ /s (14)

2 Supplementary Appendix Preventive Antibiotics in Stroke Study The following centres and investigators participated in the Preventive Antibiotics in Stroke Study: Academisch Medisch Centrum, Amsterdam: D. van de Beek, P.J. Nederkoorn, W.F. Westendorp, J-D. Vermeij; Albert Schweitzer Ziekenhuis, Dordrecht: H. Kerkhoff, Elles Zock, Ruud P. Kleyweg; Onze Lieve Vrouwe Gasthuis, Amsterdam: J.L.W. Bosboom, V.I.H. Kwa; Kennemer Gasthuis, Haarlem: M. Weisfelt; Slotervaartziekenhuis, Amsterdam: N.D. Kruyt; Amphia Ziekenhuis, Breda: M.J.M. Remmers; Radboud Universitair Medisch Centrum, Nijmegen: E.J. van Dijk; Sint Franciscus Gasthuis, Rotterdam: F. Vermeij; Atrium Medisch Centrum, Heerlen: A. Schreuder; Ziekenhuis Rijnstate, Arnhem: S.E. Vermeer; Medisch Centrum Alkmaar, Alkmaar: R. ten Houten; Erasmus MC, Rotterdam: D.W.J. Dippel; Universitair Medisch Centrum Utrecht, Utrecht: L.J. Kappelle, H.B. van der Worp; Spaarne Ziekenhuis, Hoofddorp: I.S.J. Merkies; HagaZiekenhuis, Den Haag: S.F.T.M. de Bruijn, K.F. de Laat; Medisch Centrum Haaglanden, Den Haag: K. Jellema; Catharina Ziekenhuis, Eindhoven: K. Keizer, M.C. de Rijk, A.J. Vermeij; VU Medisch Centrum, Amsterdam: M.C. Visser; Reinier de Graaf Groep, Delft: L.A.M. Aerden; Martini Ziekenhuis, Groningen: E.S. Schut; Ziekenhuisgroep Twente, Almelo: L.J.A. Reichman; Groene Hart Ziekenhuis, Gouda: K. de Gans; Zaans Medisch Centrum, Zaandam: R.M. van den Berg-Vos; Laurentius Ziekenhuis, Roermond: M.P.J. van Goor; IJselland Ziekenhuis, Capelle aan den IJssel: A.D. Wijnhoud; Westfriesgasthuis, Hoorn: T.C. van der Ree; BovenIJ Ziekenhuis, Amsterdam: M. Janmaat; Orbis Medisch Centrum, Sittard: N. van Orshoven; Bronovo Ziekenhuis, Den Haag: S.M. Manschot. Study group: D. van de Beek, P.J. Nederkoorn, D.W.J. Dippel, M.G.W. Dijkgraaf, T. van der Poll, J.M. Prins, L. Spanjaard, F.H. Vermeij. 1

3 Supplementary table 1. Patients loss-to-follow-up PASS no. Reason Follow-up based on Patient and representative could not be reached Report of visit outclinic Neurology Patient refused participation in follow-up Report of visit outclinic Neurology interview Patient refused participation in follow-up Report of visit outclinic Neurology interview Patient withdrew from study Report of visit outclinic Neurology Patient and representative could not be reached Report of visit outclinic Neurology Representative could not be reached Report of visit outclinic Neurology Patient and representative could not be reached Report of visit outclinic Neurology Patient and representative could not be reached Report of visit outclinic Neurology Patient withdrew from study Report of visit outclinic Neurology Patient and representative could not be reached Report of visit outclinic Neurology Patient withdrew from study Report of visit outclinic Neurology Patient withdrew from study Discharge letter nursing home Patient and representative could not be reached Discharge letter hospital Patient withdrew from study Discharge letter hospital Patient withdrew from study Chart review and discharge letter Patient withdrew from study Report of visit community health service Patient withdrew from study Chart review and discharge letter Patient withdrew from study Discharge letter hospital Patient refused participation in follow-up Case Record Forms PASS interview Patient refused participation in follow-up Report of visit outclinic Neurology interview Patient and representative could not be reached Report of visit outclinic Neurology Patient refused participation in follow-up interview Report of revalidation clinic, discharge letter Patient and representative could not be reached Discharge letter hospital Patient withdrew from study Discharge letter of readmission 2

4 Supplementary table 2. Other diagnosis according to treatment allocation. Diagnosis Ceftriaxone group (n=20) Control group (n=29) Functional neurologic symptoms 8 13 Delirium 1 0 Epilepsy 2 2 Encephalopathy 0 1 Hypoperfusion due to carotid artery stenosis 0 1 Hypoglycaemia 1 0 Migraine 3 0 Multiple sclerosis 0 1 Myelopathy 1 0 Peripheral neuropathy 1 1 Peripheral vascular disease 1 0 Posterior reversible encephalopathy syndrome 1 0 Retinal infarction 0 1 Rhombencephalitis 0 2 Subdural haemorrhage 0 1 Uncertain 1 3 Vestibular neuritis 0 1 Vestibulopathy 0 2 3

5 Supplementary table 3. Sensitivity analysis including follow-up of 24 patients lost-to-follow-up according to last-observation carried-forward (LOCF) outcome assessment Primary analysis of primary outcome Result of the primary analysis of primary outcome: adjusted common odds ratio, 0 95; 95%CI, ; P= Secondary analysis of primary outcome Ceftriaxone group Control group Odds Ratio 95 percent confidence interval P value (n=1268) (n=1270) Unfavourable outcome* All patients 489 (39) 508 (40) Ischemic stroke 395 (38) 419 (40) Transient ischemic 5 (11) 10 (20) attack Haemorrhagic stroke 81 (57) 68 (54) Other Mortality Discharge 57 (5) 61 (5) months 131 (10) 136 (11) *Unfavourable outcome at 3 months was evaluated in 1257 patients in the ceftriaxone group and 1257 patients in the control group; 24 outcomes were imputed according to protocol. No. of patients with characteristic (percentage). Mortality was evaluated at discharge in 1267 patients in the ceftriaxone group and 1269 patients in the control group; mortality at 3 months was evaluated in 1268 patients in the ceftriaxone group and 1270 patients in the control group. 4

6 Supplementary Table 4. Baseline characteristics of thrombolysed patients. Characteristic* Ceftriaxone group (n=437) Control group (n=399) Age year (interquartile range) 72 (62-80) 73 (61-80) Male sex no. (%) 252/437 (58) 234/399 (59) History no. (%) Atrial fibrillation/flutter 37/436 (9) 51/399 (13) Stroke 150/437 (34) 140/399 (35) Hypercholesterolemia 117/435 (27) 105/394 (27) Hypertension 218/436 (50) 209 (52) Myocardial infarction 62/437 (14) 64/399 (16) Cardiac valve disease 16/436 (4) 22/399 (6) Peripheral vascular disease 27/437 (6) 30/398 (8) Obstructive pulmonary disease 28/437 (6) 21/398 (5) Immunocompromise 23/437 (5) 12/399 (3) Current smoker no. (%) 96/433 (22) 104/395 (26) Prior medication no. (%) Anticoagulants 12/437 (3) 12/399 (3) Antiplatelet 209/437 (48) 186/399 (47) Statin 165/437 (38) 145/399 (36) ACE-inhibitor 118/437 (27) 79/399 (20) Beta-blocker 148/437 (34) 136/399 (34) Protonpompinhibitor 110/437 (25) 99/399 (25) Modified Rankin Scale score Median 0 0 Range National Institutes of Health Stroke Scale score** Median 6 6 Range Dysphagia no. (%) 103/403 (26) 107/376 (29) Discharge diagnosis no. (%) Cerebral infarction 426 (98) 380 (95) Transient ischemic attack 3 (1) 7 (2) Cerebral haemorrhage 0 0 Other 8 (1) 12 (3) *Plus-minus values are means ± SD. IQR denotes interquartile range, ACE denotes Angiotensin-converting enzyme. 5

7 Supplementary table 5. Patients with allergic reaction as noted by physician that caused cessation of ceftriaxone PASS no. Allergic reaction 1091 Skin rash during 2 nd dose ceftriaxone Skin rash after 2 nd dose ceftriaxone Dizziness, chest pain, sweating, nausea and vomiting, no cardiac cause was found Skin rash during 1 st dose ceftriaxone Itching without skin rash during 2 nd dose ceftriaxone Swelling of tongue after ceftriaxone, possibly also due to thrombolysis Cessation after 1 st dose ceftriaxone because of allergic reaction to penicillin in medical history which was not noted at time of inclusion Skin rash after 2 nd dose ceftriaxone Supplementary table 6. Infections with ceftriaxone resistant organisms PASS no. Infection 2001 Urinary tract infection (by physician and panel) by Escherichia coli and Proteus mirabilis after 2 days of treatment with ceftriaxone therapy changed to sulfamethoxazole/trimethoprim 2dd 960 mg 5 days Physician: pneumonia. Panel: urinary tract infection. Urinary culture positive for Staphylococcus epidermidis, resistant to oxacilline, sensitive to vancomycin and rifampicin. Tracheal cultures showed Pseudomonas aeruginosa sensitive to penicillin Diagnosis urinary tract infection and pneumonia by physician and panel. ESBL producing E. coli cultured from urine, no symptoms, no treatment initiated Other infection by physician, no other infection by panel Other infection by physician and panel: sepsis by candida. No antibiotic resistance reported Urinary tract infection by physician, not by panel Urinary tract infection and pneumonia by physician and panel. As treatment for pneumonia ceftriaxone continued (no resistant micro-organisms reported in discharge letter) and urinary tract infection treated with nitrofurantoin (no resistant MO reported) Pneumonia by physician, not by panel. In discharge letter no resistant micro-organism reported and treatment with amoxicillin/clavulanate potassium was started Pneumonia by physician and panel. No resistant microorganism reported Urinary tract infection by physician during treatment with ceftriaxone, treatment with gentamycin and tobramycin was started (not scored as infection by panel) Pneumonia by physician, urinary tract infection by panel. No data on resistant micro-organisms reported 6

8 Supplementary table 7. Protocol violations in eligibility Diagnosis Ceftriaxone group Control group Score of 0 on NIHSS 2 1 Infection at admission 2 0 Randomization in another intervention trial 2 0 Use of antibiotics < 24 hours of admission 1 0 Onset of stroke > 24 hours ago 2 0 Supplementary table 8. Explanation of protocol violations in eligibility PASS no. Explanation of protocol violation in eligibility Score of 0 on NIHSS and diagnosis subdural hematoma Score of 0 on NIHSS Infection and use of antibiotic at admission Score of 0 on NIHSS Patient was already randomized in another intervention trial Use of antibiotics < 24 hours of admission Onset of stroke > 24 hours ago Onset of stroke > 24 hours ago Infection at admission Patient was already randomized in another intervention trial 7

9 Supplementary table 9. Subanalysis on infections in patients with severe stroke (NIHSS>9) Ceftriaxone group Control group OR (95%CI) n=310 n=317 As defined by physician All infections 72 (23) 122 (38) 0 48 ( ) Pneumonia 46 (15) 56 (18) 0 81 ( ) Urinary tract infection 21 (7) 67 (21) 0 27 ( ) As defined by expert panel Infection 27 (10) 45 (14) 0 58 ( ) Pneumonia 15 (6) 20 (6) 0.76 ( ) Urinary tract infection 11 (4) 27 (9) 0 40 ( ) Supplementary table 10. Subanalysis on infections in patients with mild stroke (NIHSS<=9) Ceftriaxone group n=958 Control group n=953 OR (95%CI) As defined by physician All infections 58 (6) 96 (10) 0.58 ( ) Pneumonia 25 (3) 32 (3) 0.77 ( ) Urinary tract infection 25 (3) 60 (6) 0.40 ( ) As defined by expert panel Infection 13 (1) 44 (5) 0.28 ( ) Pneumonia 8 (1) 14 (1) 0.56 ( ) Urinary tract infection 5 (1) 33 (3) 0.15 ( ) 8

10 Supplementary Figure 1. Kaplan-Meijer curves for occurrence of infection: infections defined by physician in ceftriaxone (blue line) and control group (green line). Panel A shows curves for all patients, Panel B shows curves for patients with severe stroke, as defined as of NIHSS score of 10 or more on admission. Panel A: all patients 1,0 0,8 ceftriaxon Ceftriaxone Standaard zorg zonder ceftriaxon Standard care ceftriaxon-censored Standaard zorg zonder ceftriaxon-censored Development of infection 0,6 0,4 0,2 0, Days after randomisation Panel B: patients with severe stroke (NIHSS>9) 1,0 0,8 Randomisatie code ceftriaxon Ceftriaxone Standaard zorg zonder ceftriaxon Standard care ceftriaxon-censored Standaard zorg zonder ceftriaxon-censored Development of infection 0,6 0,4 0,2 Page 1 0, Days after randomization 9