cbs journal club

57
1 CBS Journal CBS Journal Club Club Christopher Sharpe MD, Christopher Sharpe MD, FRCPC FRCPC R7 Transfusion Medicine R7 Transfusion Medicine October 4, 2011 October 4, 2011

Upload: constance-nicholson

Post on 31-Dec-2015

38 views

Category:

Documents


0 download

DESCRIPTION

CBS Journal Club. Christopher Sharpe MD, FRCPC R7 Transfusion Medicine October 4, 2011. 1. Objectives. to highlight the clinical implications of neutropenia - PowerPoint PPT Presentation

TRANSCRIPT

11

CBS Journal ClubCBS Journal Club

Christopher Sharpe MD, FRCPCChristopher Sharpe MD, FRCPCR7 Transfusion MedicineR7 Transfusion Medicine

October 4, 2011October 4, 2011

22

ObjectivesObjectives• to highlight the clinical implications of

neutropenia

• to systematically review the literature to assess the potential benefit of granulocyte transfusions given as prophylaxis against infection in the setting of neutropenia

• critical appraisal of a systematic review

Focus of Journal ClubFocus of Journal Club

““Granulocyte transfusions for Granulocyte transfusions for preventing infections in patients with preventing infections in patients with neutropenia or neutrophil dysfunction neutropenia or neutrophil dysfunction (Review)(Review)” ”

Massey E, Paulus U, Doree C, Stanworth SMassey E, Paulus U, Doree C, Stanworth S

The Cochrane CollaborationThe Cochrane Collaboration

20092009

44

IntroductionIntroduction• infections in the setting of neutropenia are often

severe and life-threatening despite appropriate antimicrobial therapy

• neutropenia is usually encountered post-chemotherapy or post-hematopoietic stem cell transplantation

• G-CSF does not lead to appreciable granulocyte production in the setting of neutropenia

55

IntroductionIntroduction• granulocyte transfusions may be potentially

beneficial to neutropenic patients (prophylactic vs. therapeutic)

• however...granulocytes for transfusion purposes are difficult to procure/process/store: - apheresis procedure is required (takes several hours) - separation of the granulocyte component is difficult - donor exposure to G-CSF (? safety concerns) - difficulty in securing donors (random vs. directed) - granulocytes have a finite storage period at room temperature (several hours) - product irradiation required (risk of TA-GVHD) - cross-match compatible product required

66

IntroductionIntroduction• dose of transfused granulocytes is important

• studies performed prior to the availability of G-CSF involved granulocyte dosages that were lower than the minimally acceptable dose of 1 x 1010 cells per transfusion and showed no benefit (Cochrane Reviews: Vamvakas 1997 Stanworth 2005)

• the use of granulocyte transfusion disappeared from clinical use from ~1985-1995 due to improvements in antimicrobials and supportive care

77

IntroductionIntroduction• However...

• a single donor stimulated with G-CSF and steroids

can procure a granulocyte dose of 5-10 x 1010 (renewed clinical interest in this area)

• Adkins (1997) reported a mean ANC increment of 1000/microL that was maintained for 1 to 1.5 days with a mean granulocyte dose of 5.1 x 1010

• limited evidence exists to demonstrate that transfused granulocytes maintain their function

88

Determinants of the efficacy of prophylactic granulocyte transfusions: a meta-analysis Vamvakas EC, Pineda AA. Journal of Clinical Apheresis 1997; 12:74-81

• Objective: meta-analysis of studies of prophylactic granulocyte transfusions to identify the determinants of efficacy of this intervention

• Selection Criteria: RCTs from 1970-1995 involving the efficacy of prophylactic granulocyte transfusions

• Results: 8 RCTs eligible. Transfusion of adequate doses of granulocytes reduced the RR of infection, death, and death from infection in transfused patients vs. controls (RR=0.075, 0.224, 0.168, respectively; P<0.05)

99

Granulocye transfusions for treating infectons in patients with neutropenia or neutrophil dysfunction Stanworth S, Massey E, Hyde C, et al. Cochrane Database Syst Rev 2005

• Objective: To determine the effectiveness of granulocyte transfusions compared to no transfusion for treating patients with neutropenia

• Selection Criteria: RCTs involving THERAPEUTIC granulocyte transfusions to patients with neutropenia

• Results: 8 RCTs involving 310 patients

1100

Granulocye transfusions for treating infectons in patients with neutropenia or neutrophil dysfunction Stanworth S, Massey E, Hyde C, et al. Cochrane Database Syst Rev 2005

• Results: RR for mortality for 6 trials was 0.64 in favour of transfusion (95% CI 0.33-1.26); chi-square 11.3; I2=56% (significant clinical heterogeneity between studies) - RR for mortality for 4 studies that transfused granulocyte doses greater than 1.0 x 1010 was 0.37 (95% CI 0.17-0.82); chi-square 3.9; I2=23%

• Conclusion: Inconclusive evidence exists from RCTs to support or refute the use of granulocyte transfusions in neutropenic patients

1111

Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropenia Mohan P, Broklehurst P, Cochrane Database Syst Rev 2003 Mar 16; 3

• Objective: To determine the efficacy and safety of granulocyte transfusions as adjuncts to antibiotics for the TREATMENT of confirmed or suspected sepsis in neonates with neutropenia in reducing all-cause mortality (and several secondary outcomes)

• Selection Criteria: RCTs and quasi-randomized studies involving neonates with suspected or confirmed sepsis and neutropenia who received granulocyte transfusions at any dose or duration compared with placebo or no granulocyte transfusion

1122

Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropenia Mohan P, Broklehurst P, Cochrane Database Syst Rev 2003 Mar 16; 3

• Results: - 4 RCTs involving 79 neonates - RR for all-cause mortality was 0.89 (95% CI 0.43-1.86) with no statistical heterogeneity in the results

• Conclusion: Inconclusive evidence exists from RCTs to support or refute the use of granulocyte transfusions in neonates with sepsis and neutropenia to reduce mortality (and morbidity)

1133

IntroductionIntroduction• no systematic reviews examining the efficacy of

PROPHYLACTIC granulocyte transfusions in the setting of neutropenia have been performed in over ten years (Vamvakas 1997)

• no prior Cochrane review exists which examines no prior Cochrane review exists which examines the use of the use of PROPHYLACTIC granulocyte granulocyte transfusion in neutropenic patients using a transfusion in neutropenic patients using a significant number of trials that would have used significant number of trials that would have used G-CSFG-CSF

Focus of Journal ClubFocus of Journal Club

““Granulocyte transfusions for Granulocyte transfusions for preventing infections in patients with preventing infections in patients with neutropenia or neutrophil dysfunction neutropenia or neutrophil dysfunction (Review)(Review)” ”

Massey E, Paulus U, Doree C, Stanworth SMassey E, Paulus U, Doree C, Stanworth S

The Cochrane CollaborationThe Cochrane Collaboration

20092009

1155

Study ObjectivesStudy Objectives

• systematic review to assess the effectiveness and safety of prophylactic granulocyte transfusions in patients with neutropenia or disorders of neutrophil function compared with a control population not receiving this intervention for preventing:

- mortality - mortality due to infection - evidence of infection - adverse events

1166

Cochrane Review: Outcomes

• Primary Outcome: - overall mortality

• Secondary Outcomes: - mortality due to infection - number of infections - number of days with fever - number of days on treatment with antimicrobials - neutrophil count increment post-transfusion (x109/L) - duration of neutropenia reversal after transfusion

1177

Cochrane Review: Outcomes

• adverse events for patients or granulocyte donors

- death

- hospitalization

- significant disability

- requiring discontinuation of intervention

1188

Cochrane Review• Search strategy Search strategy (up to October 2008)(up to October 2008)::

- - the Cochrane Central the Cochrane Central Register of Controlled Trials (CENTRAL) 2008Register of Controlled Trials (CENTRAL) 2008

- MEDLINE - MEDLINE

- EMBASE - EMBASE

- other specialized databases (including ongoing trial - other specialized databases (including ongoing trial databases) databases)

- contact with experts in the field - contact with experts in the field

- article reference list searches - article reference list searches

1199

Cochrane Review

• Study Selection Criteria: - studies involving patients with neutropenia or inherited

disorders of neutrophil function (excluding neonates) in which granulocyte transfusions were given as prophylaxis prior to the development of documented infection compared to a control group not receiving granulocyte transfusions

• RCTs and quasi-randomised, controlled studies (allocation to receive granulocyte transfusion was dependent upon the availability of suitably-matched donors)

2200

Cochrane Review

• Control group: - prophylactic granulocyte transfusions were not administered

• subgroup analysis: subgroup analysis: - performed on the study outcomes based on the - performed on the study outcomes based on the dose of granulocytes transfuseddose of granulocytes transfused

2211

Cochrane Review• two review authors independently assessed studies two review authors independently assessed studies

for eligibility and extracted data onto study specific for eligibility and extracted data onto study specific data extraction formsdata extraction forms

• criteria for evaluation of study methodological quality: criteria for evaluation of study methodological quality: - - generation of allocation sequencegeneration of allocation sequence

- concealment of treatment allocation schedule - concealment of treatment allocation schedule

- blinding of outcome assessment - blinding of outcome assessment (for clinician, participant, and outcome assessor) (for clinician, participant, and outcome assessor)

- the proportion of randomized participants included in the - the proportion of randomized participants included in the main analysismain analysis

2222

Cochrane Review

• studies were assigned a label of adequate, studies were assigned a label of adequate, unclear, or inadequate for each of the criteriaunclear, or inadequate for each of the criteria

2233

Cochrane Review• Study details collectedStudy details collected: :

- - place and date of publication place and date of publication

- population characteristics - population characteristics

- study setting - study setting

- detailed nature of study intervention - detailed nature of study intervention

- detailed nature of study comparator - detailed nature of study comparator

- detailed nature of study outcome - detailed nature of study outcome

- use of therapeutic granulocyte transfusions during the study - use of therapeutic granulocyte transfusions during the study

- use of colony-stimulating factors in recipients - use of colony-stimulating factors in recipients

- use of prophylactic and therapeutic antimicrobials - use of prophylactic and therapeutic antimicrobials

- method of preparation and source of transfused granulocytes - method of preparation and source of transfused granulocytes

2244

Study Specific Data Extraction Form

2255

Cochrane Review• Review Manager 5 was used for data analysis

- main method of analysis was qualitative (conclusions were based on the patterns of results across studies)

• statistical heterogeneity between studies was tested using the chi-squared and I2 test (a statistical significance level of < 0.10 was interpreted as evidence of heterogeneity)

• the main summary outcome was a summary risk ratio (dichotomous data) and a weighted mean difference (continuous data) - fixed and random effect models were used

2266

Cochrane Review: Included Trials

2277

Cochrane Review: Results

• ten prospective clinical trials met inclusion criteria (8 from US, one from Spain, one from UK)

• control arm received no prophylactic therapy except in one trial in which the control group received specific prophylactic antibiotics

• all trials were conducted prior to 1987 with the exception of one trial from 2006

2288

Cochrane Review: Results

• Granulocyte donor priming:

- four trials did not administer any form of medication to the donors to increase the granulocyte yield

• five trials administered steroids to donors - dexamethasone, hydrocortisone, prednisone

• one trial administered G-CSF to donors (Oza 2006)

2299

Cochrane Review: Results

• Granulocyte procurement method:

- 8 trials used either intermittent or continuous flow centrifugation

- one study used only filtration leukapheresis (FL) (Winston 1980); FL is rarely used currently

- one study used both FL and continuous flow centrifugation (Clift 1978)

3300

Cochrane Review: Results

• Granulocyte transfusion triggers:

- 0.2 x 109 in two studies - 0.5 x 109 in six studies

• Donor selection: - three studies did not assess leukocyte (HLA) compatibility between the granulocyte recipient and donor - seven studies selected donors on the basis of some criteria of HLA compatibility

3311

Cochrane Review: Results

• most of the participants in the studies had acute myeloid leukemia (AML) +/- allogeneic stem cell transplantation

3322

Cochrane Review: Results

• Study Sample Size: - the median number of patients enrolled,

randomized and analyzed in all the studies was 55 (range 18-151)

- only one trial (Oza 2006) made an attempt to justify the statistical analysis or required sample size (limited evidence was available from the remainder of the trials on sample sizes required to power the trial around a main outcome)

3333

Cochrane Review: Results

• eight studies randomly allocated patients to receive prophylactic granulocyte transfusions with no other intervention

• one trial (Oza 2006) was quasi-randomized (allocation to prophylactic granulocyte transfusion was based on ABO-matching and availability of donors)

• one trial (Petersen 1987) randomized between prophylactic granulocyte transfusions and prophylactic systemic antibiotics (Vancomycin, Ticarcillin)

3344

Cochrane Review: Results

• data on neutrophil increment one-hour post-granulocyte transfusion was available from five studies

CCI = count increment (mm3) x body surface area (m2) divided by the number of granulocytes transfused (x 1010)

• total number of granulocyte transfusions given per patient was 2 to 23 (the ten included studies had a variable transfusion schedule)

• granulocyte dose varied between studies: - for nine studies the mean range was 0.9 x 1010 (Sutton 1982) to 5.9 x 1010 (Oza 2006) - one trial did not state dose (Petersen 1987)

3355

Cochrane Review: Results

• differences were found between studies with respect to the cointerventions given to patients (antibiotics)

• specific regimens for anti-fungal therapy (Amphotericin B) were stated explicitly in only two trials (Oza 2006, Winston 1980)

3366

Cochrane Review: Results

• definition of infection used to recruit uninfected patients into the study or to identify those who became infected during study: - temperature - clinical signs of infection - isolation of organisms

• different criteria for the definition of infection were used by the studies (such as fever definition)

3377

Comparison 1: Overall Mortality

3388

Comparison 2: Mortality due to Infection

3399

Comparison 3: Patients with infection episodes

4400

Comparison 4: Patients with fever

4411

Comparison 5: Patients starting antibiotics

4422

Cochrane Review: Results

• Subgroup analysis - excluding trials which transfused granulocyte doses of < 1.0 x 1010 (Strauss 1981, Sutton 1982)

4433

Comparison 1: Overall Mortality,

excluding low dose studies

4444

Comparison 2: Mortality due to

infection, excluding low dose studies

4455

Comparison 3: Patients with infection episodes, excluding low

dose studies

333

Cochrane Review: ResultsResults

• blinding was not achieved in the trials since it is diificult to apply in this setting

• no data was available on whether or not outcome assessors were blinded in any of the trials

• adverse event data was reported for all trials except one (Oza 2006)

4

333

Cochrane Review: ResultsResults• a high rate of adverse reactions were seen in recipients of granulocyte transfusions:

- fever - TA-GVHD (one death) - HLA-alloimmunization - pulmonary reactions

• the predominant reactions for granulocyte donors were febrile/shivering episodes (reported in two trials)

4

333

Cochrane Review: ConclusionsConclusions• prophylactic granulocyte transfusions given to neutropenic patients at a

dose of at least 1 x 1010 do not decrease the risk of overall mortality but may possibly reduce the risk of mortality from infection and reduce the number of infective episodes

• the majority of studies included in this systematic review are dated and involved the transfusion of lower numbers of granulocytes than what is currently recommended; standards of supportive care have also improved

4

333

Cochrane Review: ConclusionsConclusions• granulocyte transfusions cannot be recommended outside the

setting of a clinical trial due to the resource and cost implications: - small sample sizes in studies - heterogeneous study definitions of infection

• larger clinical trials that are adequately powered are required before the potential benefits of granulocyte transfusions can be validated

• an NHLBI sponsored RCT studying THERAPEUTIC granulocyte transfusion using currently available doses in neutropenic patients is currently underway in the USA

4

333

Critical Appraisal: Systematic Critical Appraisal: Systematic ReviewsReviews

• Systematic review: using methods designed to reduce the likelihood of bias

• Meta-analysis: a systematic review that uses quantitative methods to summarize the results

4

333

Critical Appraisal: Systematic Critical Appraisal: Systematic ReviewsReviews

• Are the results valid? - yes (with respect to

the time period and context in which the majority of the studies were performed) - however… the study results were influenced in a systematic fashion in that the majority of the trials involved granulocyte transfusions of < 1.0 x 1010

• Did this review address a focused clinical question?

- yes (do

prophylactic granulocyte transfusions improve patient outcomes in the setting of neutropenia?)

4

333

Critical Appraisal: Systematic Critical Appraisal: Systematic ReviewsReviews

• Were the criteria for article inclusion appropriate? - yes (RCTs which allocated uninfected neutropenic patients to receive prophylactic granulocyte transfusions or not)

• Is it unlikely that relevant studies were missed? - yes

(the number of studies published on this subject are few and generally dated)

• Was the validity of the included studies appraised? - yes (the criteria for the evaluation of study methodological quality was systematically assessed and explicitly stated)

4

333

Critical Appraisal: Systematic Critical Appraisal: Systematic ReviewsReviews

• Was the assessment of studies reproducible? - yes (standardized data extraction forms were used which recorded key features of each of the studies that were included in the systematic review)

• Were the results similar from study to study? - no - variation existed in the results between studies - amount of weight carried by each study with respect to outcome varied significantly - end points for the outcome analysis varied - differences existed in the definition of some study outcomes (eg. infection)

4

333

Critical Appraisal: Systematic Critical Appraisal: Systematic

ReviewsReviews • What are the overall results of the review?

- prophylactic granulocyte transfusions given to patients with neutropenia at a dose of at

least 1.0 x 1010 do not decrease overall mortality but may reduce mortality due to infection

• How precise are the results? - the confidence intervals of the relative risk (RR) statistic for the study outcomes were

wide - there was no evidence of significant heterogeneity in the main outcomes when all 10

studies were included which suggests that variation in results may have occurred by chance alone

4

333

Critical Appraisal:Critical Appraisal:Systematic ReviewsSystematic Reviews

• Will the results help me in my patient care? - not currently and possibly not in the future either since the use of prophylactic granulocyte transfusions is not

being actively investigated (therapeutic granulocyte transfusions may become indicated once definitive evidence of benefit exists)

• Can the results be applied to my patients? - not currently outside of the investigational setting

4

333

Critical Appraisal:Critical Appraisal:Systematic ReviewsSystematic Reviews

• Were all clinically important outcomes considered? - yes

(overall mortality, mortality due to infection, number of episodes of infection)

• Are the benefits worth the harms and costs? - no (harms to the granulocyte recipient and donor and resource utilization are significant factors to consider)

4

16161616

Questions or Questions or comments?comments?