Prophylactic platelet transfusions versus no prophylaxis in hospitalized patients with thrombocytopenia: A systematic review with meta‐analysis

Thrombocytopenia is a common condition in several populations of hospitalized patients, including those with hematological and solid tumor cancer,1, 2 those with chronic liver disease,3 and critically ill neonates4 and adults,5 and it has been associated with increased rates of bleeding, transfusion requirements, and mortality.6-9 Prophylactic platelet transfusions are often recommended in patients with severe thrombocytopenia, but the supporting evidence is primarily derived from trials in hematological patients10-12 and clinical practice varies considerably.13-15 Prior to prophylactic platelet transfusion, the risk of bleeding and the beneficial effects of transfusion must be viewed in light of the potentially harmful effects, which, although rare, include serious and potentially life-threatening reactions, such as anaphylaxis, transfusion-transmitted infections, and transfusion-related acute lung injury.16 Harm from platelet transfusions has been observed in randomized clinical trials (RCTs) among preterm infants17 and patients with intracerebral hemorrhage.18 Therefore, we aimed to assess the benefits and harms of prophylactic platelet transfusions versus no prophylaxis on patient-important outcomes in hospitalized patients with thrombocytopenia. We hypothesized that the evidence base for non-hematological patients would be sparse and uncertain. This systematic review with meta-analyses and trial sequential analyses (TSA) was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021236014) and conducted in accordance with a published protocol.19 We followed the recommendations by the Cochrane Collaboration,20 the Grading of Recommendations Assessment, Development and Evaluation (GRADE)21 approach and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement (checklist available in Supplement S1).22 All RCTs and cluster RCTs comparing prophylactic platelet transfusion in any dose versus no prophylaxis or placebo in non-bleeding hospitalized patients with thrombocytopenia (as defined in the trials) were eligible for inclusion without restriction regarding age, diagnoses, or settings. Cohort studies, case–control studies, reviews, quasi-randomized trials, and cross-over trials were excluded. We did not allow concomitant use of other interventions unless they were used in both allocation groups. Clinically important bleeding, nosocomial infection, venous or arterial thrombo-embolic, and transfusion-related adverse events were defined in the included trials. The unit of analysis was randomized patients, and all outcomes were assessed at the longest follow-up.19 Additional details are available in the protocol19 and Supplement S3. We collected data on the number of units of platelets, red blood cells (RBC) and fresh frozen plasma (FFP) transfused per participant. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, and Epistemonikos and searched for ongoing trials in the U.S. National Library of Medicine (ClinicalTrials.gov), EU Clinical Trials Register, and the World Health Organization (WHO) International Clinical Trials Registry. The searches were conducted without restrictions on language or publication status on March 29, 2021 and updated in PubMed on February 3, 2022 (Supplement S4). All records were independently screened for eligibility by two authors (CTA, AG, PS, and NZ). Potential eligible articles were assessed in full text by two authors (CTA, AG, PS, and NZ). We resolved disagreements by discussion and consulted a third author (MHM and LR) if needed. We used Covidence (https://www.covidence.org; Veritas Health Innovation, Melbourne, Australia) to facilitate the study selection. Two authors independently (CA and AG) extracted data from the included studies. We extracted data on trial characteristics, population characteristics, interventions, co-interventions, outcomes, and process variables as specified above (Supplement S5). We contacted the corresponding authors at least twice for clarifications and unpublished or missing outcome data, if applicable. We resolved disagreements by discussion and involved a third author (MHM and LR) if needed. Two authors independently (CA and PS) assessed the risk of bias using the Risk of Bias 2.0 tool.23 We assessed the risk of bias on the outcome level within all five domains: “bias arising from the randomization process,” “bias due to deviations from intended interventions,” “bias due to missing outcome data,” “bias in measurement of the outcome,” and “bias in selection of the reported result.” For each outcome in each RCT, the overall risk of bias judgment was judged as low risk of bias if all domains were judged to be low risk of bias, as some concerns if at least one domain was judged to be of some concerns, and as high risk of bias if at least one domain were judged to be high risk of bias.20, 23 Disagreements were resolved by consulting a third author (AG or MHM). We planned to base our primary conclusions on results from RCTs with an overall low risk of bias,19 but this was only feasible for the primary outcome as no trials were judged to be low risk of bias for the secondary outcomes. We calculated relative risks (RRs) with confidence intervals (CIs) for dichotomous outcomes and mean differences (MDs) with CIs for continuous outcomes. We contacted the corresponding authors for additional data if alternative statistical measures for continuous outcomes were reported.19 We did not convert medians and interquartile range (IQR) to means and SDs, as correct conversion requires normally distributed data. Instead, we reported the results descriptively. Results are based on the analysis of intention-to-treat populations, and data was analyzed for superiority regardless of the original trial designs. We adjusted thresholds for statistical significance using a compromise between no adjustment and a complete Bonferroni adjustment.24, 25 We divided the pre-specified p-value (.05) with the value half-way between 1 (no adjustment) and the number of primary or secondary outcomes meta-analyzed (Bonferroni adjustment).24, 25 As we were able to meta-analyze the primary outcome and three secondary outcomes, the thresholds considered statistically significant were a p-value of <.05 and <.025, respectively. For outcomes that were not meta-analyzed, a p-value of <.05 were considered statistically significant. The reported CIs and TSA-adjusted CIs matched these significance thresholds. We assessed statistical heterogeneity by the calculation of inconsistency (I2), diversity (D2) statistics, and the χ2 test for subgroup differences and considered a p-value of <.05 as statistically significant.19 We report results from fixed effect models (FEM) if the I2 = 0%. If I2 > 0% we used both FEM and random effects models (REM) and based conclusions on the most conservative estimate (highest p-value).19 Results from both FEM and REM for the primary analyses are presented in Supplement S9. Additional details and the a priori hypothesized directions of subgroup effects are available in the protocol19 and in Supplement S6. Clinical heterogeneity was assessed using the Clinical Diversity in Meta-analysis tool26 and the credibility of the subgroup analyses were assessed using the Instrument for assessing the Credibility of Effect Modification Analyses (ICEMAN) tool.27 We planned to assess small trial bias but as all analyses included fewer than 10 RCTs, this was not feasible.19 We conducted TSA to assess the risk of random errors due to repetitive testing in cumulative meta-analyses.28 In short, TSA estimates the required information size (RIS) needed for a conclusive meta-analysis to detect or reject a predefined effect size. When data are sparse and/or statistical diversity is present, the TSA will adjust (expand) the CIs to account for the uncertainty around the overall effect estimate.28 We report TSA-adjusted CIs when feasible. We applied trial sequential monitoring boundaries according to 15% RR reduction for dichotomous outcomes and a MD of 1 day for continuous outcomes, an alpha of 5% and 2.5% for the primary and secondary outcomes, respectively, a beta of 10%, and a control event rate or variance suggested by the control groups in trials reporting on the outcome.19 TSA is not feasible if the accrued information size was less than 5% of the RIS and in these circumstances, full TSAs were not presented. Analyses were conducted using R version 4.1.0 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria) with the “meta” package (version 5.1.0), and TSA was performed using the Copenhagen Trial Unit's TSA Software version 0.9.5.10b (available from http://www.ctu.dk/tsa). We conducted a sensitivity analysis on the primary and secondary outcomes.19 We performed analyses that included all bleeding episodes (i.e., not restricted to clinically important bleedings) and analyses restricted to long-term all-cause mortality, defined as mortality beyond 90 days. The impact of missing outcome data was assessed by performing best-worst and worst-best (BW/WB) case analyses,24 and the information from zero-event trials was accounted for by performing empirical continuity corrections.29 The overall certainty of evidence was rated independently by two authors (CA and AG) using the GRADE methodology21 and disagreements were settled by discussion. We rated the certainty for each outcome as high, moderate, low, or very low based on assessments of risk of bias, inconsistency, indirectness, imprecision, and small trial bias. We screened 15,696 records, assessed 66 records in full text and included nine trials in the qualitative synthesis30-38; one trial did not report any relevant outcome data34 and one trial was ongoing.37 Hence, seven RCTs30-33, 35, 36, 38 enrolling a total of 1642 participants were included in the quantitative analysis (Figure 1).39 The trials were published from 1980 until 2017.30-36, 38 Five trials were published as full reports,30, 32, 33, 36, 38 one as a letter to the editor,35 one as an abstract,34 and one remained unpublished.31 The smallest trial randomized 12 patients34 whereas the largest randomized 600 patients.36 Two trials were conducted at multiple centres36, 38 and all trials were conducted in hospitalized patients with hematological malignancies31, 33-36, 38 or dengue fever.30, 32 One trial included pediatric (hematological) patients only,33 and one was a non-inferiority trial.36 Trial characteristics are presented in Table 1 and further detailed in the Supplement S7. Pakistan 1 Dengue HDU Primary: Secondary: Canada 1 Hospital ward Primary: Not specified Secondary: Singapore, Malaysia 5 Hospital wardb Primary: Secondary: USA 1 Hospital wardb Primary: Not specified Secondary: Netherlands 1b Hospital wardb Primary: Not specified Secondary: USA 1b Hospital wardb Primary: Not specified Secondary: United Kingdom, Australia 14 Hospital ward Primary: Secondary: Germany 8 Hospital ward Primary: Secondary: China 1 Unclear Other causes of chronic live disease than chronic hepatitis B infection, previous decompensation, intracranial hemorrhage, use of anti-platelet or anticoagulants therapy within 4 weeks, esophageal variceal bleeding within 1 week, platelet transfusion within 1 week, malignant disease, pregnancy or breastfeeding, severe chronic extra-hepatic disease. Considered not suitable for inclusion by researchers. Primary: Secondary: Netherlands 11 Hospital ward/ICU Primary: Secondary: All trials assessed prophylactic platelet transfusion compared with no prophylaxis; however, in two trials, prophylactic platelet transfusions were also administered in the no prophylaxis group under specific circumstances with a perceived high risk of bleeding.35, 38 Two trials administered prophylactic platelets in both groups prior to invasive procedures or surgery31, 36 and most trials administered platelets in both treatment groups when bleeding occurred.31, 32, 35, 36, 38 One trial used a platelet count ≤30 × 109/L as a threshold for prophylactic transfusion,30 five trials used ≤20 × 109/L31-35 and two trials used ≤10 × 109/L.36, 38 Duration of the intervention, type of platelets, number of units administered per transfusion and platelets per unit varied between trials (Table 2). Clinically important bleeding: “Severe bleeding” defined as WHO grade 3 and 4 Any bleeding: “New onset bleeding” defined as WHO grade 1–4 Assessor: Not reported Assessment: Patients were assessed for WHO bleeding ever 12 h Clinically important bleeding: “Severe bleeding” Any bleeding: “Mild bleeds” defined as bleeds not requiring active intervention Assessor: The clinical team performed the assessment Assessment: Daily clinical assessment for signs of bleeding. Fundoscopic examination twice when the platelet count was ≤20 × 4 units not platelets each day the platelet count was ≤20 × 109/L until day or If bleeding platelet transfusions were at the in both groups Clinically important bleeding: according to the WHO dengue or by or by of any bleeding: Not reported Assessor: Not reported Assessment: Daily clinical assessment from day 1 until day or and at day of clinically important bleeding: bleeding episodes was defined as or bleeding requiring bleeding, bleeding, any bleeding, or bleeding requiring red blood bleeding was not of any bleeding: Not reported Assessor: Not reported Assessment: Not reported Clinically important bleeding: Not reported Any bleeding: Not reported Assessor: Not reported Assessment: Not reported Clinically important bleeding: Any bleeding: Assessor: Assessment: transfusion with 1 unit of primarily × 109/L platelets when platelet count was × 109/L and until the platelet count is than 10 × 109/L for groups were transfused with platelets if bleeding of WHO grade 2 or and prior to invasive procedures or Clinically important bleeding: bleeding” was defined as bleeding of a WHO grade 2 or Any bleeding: Not reported Assessor: for and for patients Assessment: Daily bleeding assessment were each day that the was in bleeding were for patients were transfusion with 1 unit × or × platelets was when platelet count was ≤10 × 109/L If bleeding one platelet transfusion, further transfusions was at the of the in both groups Clinically important bleeding: relevant bleeding” was defined as a WHO grade 2 or Any bleeding: Not reported Assessor: or Two to treatment the bleeding report WHO Assessment: Clinical bleeding assessments was performed twice Clinically important bleeding: Any bleeding: Assessor: Assessment: transfusion with 1 unit of not platelets prior to of The platelets at clinical in both in case of bleeding Clinically important bleeding: WHO grade Any bleeding: Not reported Assessor: Not reported Assessment: Clinical bleeding will be assessed at 1 h and h Clinical at 1 h and h will be used to size of in a Two trials reported bleeding as the primary 36 trials performed the assessment of bleeding 36, 38 and the of bleeding assessment was in five 36, 38 trials used the WHO in the or a 38 to grade bleeding whereas used a study specific bleeding or at We used the of clinically important bleeding, varied (Table 2). of risk of bias for all outcomes are in Table 3, with available in Supplement For the primary one trial was judged as overall low risk of bias. The domains “bias due to deviations from intended and “bias in selection of the reported were of in the trials. For the outcomes, all trials were judged to be of or risk of with the domain “bias in measurement of the concerns for outcomes. One low risk of bias trial reported data on all-cause mortality at the longest = and results to = TSA not be performed as only of the RIS of patients been The certainty of evidence was low (Table The sensitivity analysis was with the primary analysis (Supplement low low low low Five trials reported data on all-cause mortality at longest = 33, 35, 36, 38 meta-analysis results RR of to = (Figure 2). TSA not be performed as only of the RIS of patients been We observed no statistical heterogeneity = = = and low clinical diversity (Supplement The certainty of evidence was very low (Table analyses did not heterogeneity of the treatment effect (Supplement but the credibility was rated as very low as the analysis of effect was based on a and the number of trials was very low (Supplement analyses for long-term all-cause mortality and empirical continuity were with the primary but case results (Supplement Five trials reported data on clinically important bleeding = 36, 38 The meta-analysis that prophylactic platelet transfusion the of patients with at least one of clinically important bleeding RR to (Figure but the TSA that only of the RIS of patients been accrued adjusted to (Figure We significant statistical heterogeneity = = = by the clinical diversity (Supplement all trial estimates the prophylaxis The certainty of evidence was very low (Table from a subgroup of patients with acute = from one of the trials were not as they were reported per treatment but fewer clinically important bleeding episodes in the prophylactic group = as compared to the group = to versus to analyses were with the primary but the results were no statistically significant for all bleeding episodes (i.e., not restricted to clinically important bleedings) and in case (Supplement Two trials reported data on this outcome = but the available data did not allow 36 trial reported the mean number of with clinically important bleeding to be in the prophylactic group versus in the no prophylaxis = and a trial = that prophylactic platelet transfusions the number of with clinically important bleeding to = The TSA was as than of the RIS of been We clinical diversity (Supplement The certainty of evidence was low (Table analysis results (Supplement third = reported on the of with clinically important bleeding of the total number of on a platelet count was available and that the prophylactic the of with bleeding, with a effect on with platelet × As data was not reported with patients as the unit of the trial was not included in the the GRADE evidence for this One trial reported data on = as of serious adverse and we that these were The author did not further details We results of to = and TSA not be performed as only of the RIS of patients been The certainty of evidence was low (Table analysis results (Supplement trials reported data on this outcome = 36, 38 The meta-analysis results RR to = (Supplement TSA not be performed as only of the RIS of patients been were differences in the reported event rates between studies, and we statistical heterogeneity = = = and clinical diversity (Supplement The certainty of evidence was very low (Table The empirical continuity with the primary but the case results (Supplement trials reported data on this outcome = 36, 38 but the statistical measures and only data from two trials were 38 results in the meta-analysis suggested that the effect of the intervention be of to no clinical MD to = (Supplement The third study reported a (IQR) of of 12 in both groups with no impact from prophylactic platelet We did not detect statistical heterogeneity = = = but clinical diversity (Supplement The certainty of evidence was low (Table case results (Supplement trials reported data on venous or arterial without or of Two reported the number of platelet units and red blood units transfused per = 38 meta-analysis that patients in the prophylaxis group platelet units as compared with the no prophylaxis group MD to I2 = and fewer red blood units MD to = I2 = (Supplement This systematic review seven RCTs with relevant outcome data comparing prophylactic platelet transfusion to no prophylaxis in 1642 hospitalized patients with 35, 36, 38 We results for all-cause mortality at longest between patients to prophylactic platelet transfusion versus no prophylaxis when low risk of bias trials only and when data from all trials. The uncertainty the effect is the CIs were and included both clinically relevant and and less than 5% of the RIS been The overall certainty of evidence was low or very low, respectively, that the evidence is to conclusions on the effect of prophylactic platelet transfusions on all-cause The primary for the use of prophylactic platelet transfusions in patients with severe thrombocytopenia is to We that prophylactic platelet transfusion the of patients with at least one of clinically important bleeding. less than 15% of the RIS has been the TSA-adjusted was and included clinically relevant and and the overall certainty of evidence was very We observed statistical due to clinical as the included trials were conducted a of and differences in populations, interventions, of outcome and in and of clinically important bleeding. the and of bleeding in patients with hematological and dengue all estimates the prophylaxis a effect of prophylactic platelet two trials reported on the number of with clinically important bleeding per was to be in the prophylaxis the evidence that prophylactic platelet transfusion the risk of clinically important bleeding, but uncertainty For the secondary outcomes, we uncertainty around effect estimates for the of patients at least one nosocomial or transfusion-related adverse and the evidence was sparse to any For the of we the between the allocation groups to be of or no clinical but the certainty of evidence was trials reported on venous or arterial without or of with a previous systematic review in patients with hematological with or that also high of heterogeneity in the of outcome and in the and assessment of bleeding and uncertainty around the effect on mortality and adverse As our review a but including of the trials, it to the uncertainty around the effect of prophylactic platelet transfusions in patients the hematological This review has several We conducted the review in accordance with the protocol19 and followed the recommendations by the Cochrane including selection of studies, data and assessment of risk bias using the 2.0 tool.23 We used TSA to estimate the RIS and TSA-adjusted CIs We used the approach to grade the overall certainty of evidence and we clinical diversity and subgroup credibility using the tool26 and the respectively. This review also has important due to the of the the included trials were with to the populations, and dose of the intervention, of outcome and and of bleeding outcomes, uncertain. as we only low to clinical diversity for all outcomes and as the evidence base was sparse and event rates rare, meta-analysis to the we no of very serious inconsistency in the the number of patients and event rates were low, to results and increased risk of type two In patients with acute from one of the trials due to the data the effect of prophylactic platelet transfusions on clinically important bleeding as these patients in are at increased risk of bleeding due to a of trials defined clinically important bleeding as WHO grade 36, 38 has been as WHO grade 2 bleeding not be considered clinically most outcomes were at risk of bias, the overall of our was evidence to assess from prophylactic platelet and the included populations were restricted to patients and dengue patients, the to other hospitalized populations with for thrombocytopenia, such as patients, and In prophylactic platelet transfusion clinically important bleeding in hospitalized patients with hematological or dengue but the evidence is very and the to other populations is The effects on mortality and adverse events are and data from non-hematological are RCTs are to test the benefits and harms of platelet transfusion in hospitalized populations with thrombocytopenia. We would to and for additional information The primary and author from the of The primary author also from the The were not involved in the of this The of at AG, PS, and LR) has for other from the and and for has from and an from for other and no of The is not for the or of any supporting information by the Any than missing be to the corresponding author for the

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.