Prophylactic platelet transfusion plus supportive care versus supportive care alone in adults with dengue and thrombocytopenia: a multicentre, open-label, randomised, superiority trial

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David C Lye, Sophia Archuleta, Sharifah F Syed-Omar, Jenny G Low, Helen M Oh, Yuan Wei, Dale Fisher, Sasheela S L Ponnampalavanar, Limin Wijaya, Linda K Lee, Eng-Eong Ooi, Adeeba Kamarulzaman, Lucy C Lum, Paul A Tambyah, Yee-Sin Leo

Presented by:

Dr Mohd Redzuan Bin Abdullah

Mmed Transfusion Medicine (2^nd year)

The Lancet, March 7, 2017

About this study :

• Conducted by a group of researchers from Singapore and Malaysia.

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• Tan Tock Seng Hospital, Singapore
• National University Hospital, Singapore
• Singapore General Hospital, Singapore
• Changi General Hospital, Singapore
• University Malaya Medical Centre, Malaysia

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• Ethical approval were granted by the National Healthcare Group Domain Specific Review Board (E/2009/00235) and SingHealth Centralised Institutional Review Board (F/2009/565) in Singapore and by the University of Malaya Medical Centre Medical Ethics Committee in Malaysia.

Why I choose this article :�

• Field of interest
• Common belief vs evidence-based medicine
• High impact
• Local research

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Outline

Introduction

• Dengue is a vector-borne viral infection estimated to affect 390 million people worldwide, with 96 million clinically apparent infections in 2010. (1)

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• The global spread can be attributed to (2):

(a) international trade and travel

(b) urban crowding

(c) failure in vector control

(d) Climate change

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• Substantial cost to the health-care sector and national economy in endemic countries. (3)

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1. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature 2013; 496: 504–07.
2. Simmons CP, Farrar JJ, Nguyen vVC, Wills B. Dengue. N Engl J Med 2012; 366: 1423–32.

(3) Suaya JA, Shepard DS, Siqueira JB, et al. Cost of dengue cases in eight countries in the Americas and Asia: a prospective study. Am J Trop Med Hyg 2009; 80: 846–55.

Introduction

• Thrombocytopenia is reported in 79–100% of inpatients with dengue.(1)

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• Platelet transfusion was administered to 22–50% of adult patients in various settings and could be inappropriate in 22–23% of patients. (2)

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• Results from a survey of 306 doctors in 20 countries showed that 116 (38%) would give prophylactic platelet transfusion with varying platelet count thresholds. (3)

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• In a retrospective study of 106 children in Malaysia, prophylactic platelet transfusion was a/w fluid overload and prolonged hospital stay without reduced bleeding or improved platelet recovery. (4)

(1) Chaudhary R, Khetan D, Sinha S, et al. Transfusion support to dengue patients in a hospital based blood transfusion service in north India. Transfus Apher Sci 2006; 35: 239–44.

(2) Chaurasia R, Zaman S, Chatterjee K, Das B. Retrospective review of platelet transfusion practices during 2013 dengue epidemic of Delhi, India. Transfus Med Hemother 2015; 42: 227–31.

(3) Whitehorn J, Rodriguez Roche R, Guzman MG, et al. Prophylactic platelets in dengue: survey responses highlight lack of an evidence base. PLoS Negl Trop Dis 2012; 6: e1716.

(4) Lum LC, Abdel-Latif Mel A, Goh AY, Chan PW, Lam SK. Preventive transfusion in dengue shock syndrome—is it necessary? J Pediatr 2003; 143: 682–84.

Introduction

• No effect on bleeding or platelet recovery was found in 256 adults with dengue and thrombocytopenia (<20 000 platelets per μL) in another retrospective study in Singapore. (1)

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• In small randomised trial in Pakistan (n=87), 18 prophylactic platelet transfusion led to severe transfusion reactions and deaths, but without any benefit in bleeding reduction. (2)

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• Results from a large retrospective study (2005-2008,Singapore) of 788 adult patients with dengue confirmed that transfusion did not reduce bleeding but led to slower platelet recovery and longer hospital stay compared with those who did not receive transfusion. (3)

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• Little evidence exists to guide decision on prophylactic platelet transfusion.

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(1) Lye DC, Lee VJ, Sun Y, Leo YS. Lack of efficacy of prophylactic platelet transfusion for severe thrombocytopenia in adults with acute uncomplicated dengue infection. Clin Infect Dis 2009; 48: 1262–65.

(2) Khan Assir MZ, Kamran U, Ahmad HI, et al. Effectiveness of platelet transfusion in dengue fever: a randomized controlled trial. Transfus Med Hemother 2013; 40: 362–68.

(3)Lee TH, Wong JG, Leo YS, et al. Potential harm of prophylactic platelet transfusion in adult dengue patients. PLoS Negl Trop Dis 2016; 10: e0004576.

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Hypothesis

Prophylactic platelet transfusion in patients with dengue and thrombocytopenia (≤20 000 per μL) could reduce clinical bleeding by 50%.

Methodology- study design

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• Open-label, randomised, superiority trial was done at four hospitals in Singapore and one hospital in Malaysia.
• First rigorous, large, randomised trial of prophylactic platelet transfusion in adult dengue.
• Involved 372 patients, which was divided into 2 cohorts :

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1. 188 patients assigned to prophylactic platelet transfusion and supportive care.
2. 184 patients assigned to supportive care only.

Methodology- Subject selection

• Inclusion criteria :

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• ≥ 21 years old.
• platelet count of ≤ 20 000 per μL.
• positive for dengue PCR or NS1 in blood (ie, confirmed dengue), or positive for acute dengue serology with probable dengue criteria defined in WHO 1997 or 2009 guidelines.

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• Exclusion criteria :

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• persistent or recurrent epistaxis, haematemesis, melaena, menorrhagia, inter-menstrual bleeding, haematochezia, or rectal bleeding.
• pregnant or breastfeeding.
• likely to die within 48 h.
• active peptic ulcer disease within 3 months.
• anticoagulant use within 4 weeks.
• chronic liver or kidney diseases or haemodialysis.
• active haematological or autoimmune disorders.
• had platelet transfusion within the same illness episode.

Trial Profile

• April 29,2010 to Dec 9, 2014
• 3738 patients were assessed for eligibility.
• Randomly assigned to receive prophylactic transfusion + supportive care (n :188) or supportive care alone (n:184)

Methodology- Procedures

• Patients in the transfusion group were given 4 unit of pooled platelets each day if their platelet count ≤ 20 000 per μL.
• Supportive care : bed rest, fluid therapy and fever/ pain medication.

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• Full blood count was assessed at 1 h, 12 h, and 24 h after transfusion .
• Patients were discharged from hospital if they showed defervescence, stable vital signs, rising platelet trend, and good oral intake.

Methodology- Outcomes

• Primary endpoint
• clinical bleeding (excluding petechiae) up to hospital discharge or 7 days after randomisation.

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• Secondary efficacy endpoints
• rate of change of platelet count at 1 h, 12 h, and 24 h post-transfusion.
• median time to sustained platelet count greater than 50 000/μL.
• clinical bleeding (excluding petechiae) within 21 days of randomisation.

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• Secondary safety endpoints
• plasma leakage (at least 20% change in HCT, development of pleural effusion, or ascites)
• dengue haemorrhagic fever or dengue shock syndrome (as defined in WHO 1997 dengue guidelines)
• admission to intensive care unit, death, or secondary bacterial infection
• median length of hospital stay
• adverse events from platelet transfusion
• severe bleeding, defined as gastrointestinal bleeding, any internal bleeding (eg, retroperitoneal or intracranial), menorrhagia, or inter-menstrual bleeding not controlled by progesterone, or any clinical bleeding requiring endoscopy or surgery.

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Statistical Analysis

• P value < 0.05 consider significant.
• All statistical analyses were done with SAS version 9.3 (SAS Institute, Cary, NC, USA) .

Results

Characteristics of patients at study enrolment

Laboratory test at enrolment

• All patients in the transfusion group received 4 units of pooled- platelet transfusion, except for 8 patients who received 1 unit of single donor-derived platelet transfusion because of a shortage of platelet at the time of randomisation.

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• 46 (25%) required a second platelet transfusion to maintain a platelet count ≥ 20 000/μL.

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• The mean number of units of platelets given in the transfusion group was 4·71 (SD 2·17).

• Clinical bleeding by day 7 or hospital discharge occurred in 40 (21%) patients in the transfusion group and 48 (26%) in the control group. (RD–4·98% [95% CI –15·08 to 5·34]; RR 0·81 [95% CI 0·56 to 1·17]; p=0·16;.

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• In both groups, the commonest type of bleeding was gingival bleeding, followed by epistaxis.

Table 2 : Clinical bleeding by day 7 (or hospital discharge)

Table 2 : Clinical bleeding by Day 21

• clinically important bleeding was reported in 42 (22%) patients in the transfusion group and 49 (27%) patients in the control group (–4·46% [–14·59 to 5·86]; 0·83 [0·58 to 1·19]; p=0·34)

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• By day 21, severe bleeding occurred in three (2%) patients in the transfusion group and seven (4%) patients in the control group (RD –2·24% [95% CI –12·4 to 8·06]; RR 0·42 [95% CI 0·11 to 1·59]; p=0·21.

Result

• Plasma leakage occurred in ten (11%) patients in the transfusion group and eight (10%) patients in the control group (RD 1·11% [95% CI –13·97 to 16·17]; RR 1·11 [95% CI 0·46 to 2·67]; p=1·00).

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• Dengue haemorrhagic fever or shock syndrome was reported in two (1%) patients in the transfusion group and two (1%) patients in the control group (–0·08% [–11·03 to 10·86]; 0·94 [0·13 to 6·59]; p=1·00).

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• One (1%) patient in the transfusion group and one (1%) in the control group were admitted to intensive care unit (–0·02% [–10·25 to 10·22]; 0·96 [0·06 to 15·28]; p=1·00)

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• The median length of hospital stay was 4 days (IQR 4–5) in the transfusion group and 5 days (4–6) in the control group (p=0·47).

Result – comparison pattern of increment of platelet

- median time to sustained platelet count above 50 000 per μL was similar between the two groups - 4 days [IQR 3–5] in the transfusion group vs 4 days [3–4] in the control group

Result – Platelet Count

- No difference in mean daily plt count was seen between the two groups from day 1 to day 21, except on day 2 (30·49 × 10³ per μL [SD 18·78 × 10³] vs 20·89 × 10³ per μL [13·18 × 10³]; p<0·0001

Result

• Mean increase from baseline platelet count in transfused patients was 17·56 × 10³ per μL (SD 13·76 × 10³) at 1 h, 16·68 × 10³ per μL (17·37 × 10³) at 12 h, and 29·23 × 10³ per μL (23·59 × 10³) at 24 h.

Result – Transfusion adverse event�

• 13 adverse events occurred in the transfusion group and two occurred in the control group (RD 5·81% [95% CI –4·42 to 16·01]; RR 6·26 [95% CI 1·43 to 27·34]; p=0·0064.

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• Nine adverse events (transfusion group) included 3 urticaria, 1 maculopapular rash, one pruritus, and 1 chest pain; the remaining three resulted in serious adverse events: one each of anaphylaxis, transfusion-related acute lung injury, and fluid overload.

Discussion

• This study show that prophylactic platelet transfusion was not superior to supportive care in the prevention of bleeding in adult patients with dengue.

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• The effect of prophylactic platelet transfusion on platelet recovery was transient, with similar platelet counts beyond day 2 post-transfusion.

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• The duration of thrombocytopenia and time to platelet recovery were similar between the two treatment groups

Discussion

• With similar bleeding risk and platelet recovery, as well as potential harm, prophylactic platelet transfusion should not be recommended.

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• Ease demand on blood products in dengue-endemic and resource-limited countries.

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• Careful observation is the preferred approach for these patients since most clinical bleeding was mild and self-resolving.

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Discussion

• In a paediatric study of DSS in Malaysia (n=114), shock and low HCT, but not plt count, were identified as independent predictors of severe haemorrhage. (1)

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• Results from two retrospective studies in adults showed that female sex, elevated lymphocyte count (>500 per μL), thrombocytopenia, use of antiplatelet drugs, APTT time of more than 60 s, and INR greater than 2 were independent predictors of bleeding risk. (2)

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• Results from this study provide evidence to support present WHO guidelines on dengue in recommending against prophylactic platelet transfusion in patients with low plt count. (3)

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(1) Lum LC, Goh AY, Chan PW, El-Amin AL, Lam SK. Risk factors for hemorrhage in severe dengue infections. J Pediatr 2002; 140: 629–31.

(2) Bhaskar E, Sowmya G, Moorthy S, Sundar V. Prevalence, patterns, and factors associated with bleeding tendencies in dengue. J Infect Dev Ctries 2015; 9: 105–10.

(3) Chamnanchanunt S, Kanagaraj D, Thanachartwet V, Desakorn V, Rojnuckarin P. Early predictors of clinically significant bleeding in adults with dengue infection. Southeast Asian J Trop Med Public Health 2012; 43: 890–99.

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Conclusion

• Prophylactic platelet transfusion was not superior to supportive care in the prevention of bleeding or improvement in platelet recovery in adult patients with dengue and thrombocytopenia (≤20 000 platelets per μL)

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• It might be associated with adverse events.

Clinical Practice Guidelines

Thank You