The Effect of Prophylactic Platelet Transfusion Dose on The Hypoliferative

Thrombocytopenia Outcomes Areej Al mugairi Hematological Pathology (PGY4)University of AlbertaJan 25,2011

Background

• It has been standard of practice in most hematology/ oncology units to use prophylactic platelet transfusion for severely thrombocytopenic patients.

• The circulating platelets has a basic role in endothelial support and to maintain hemostasis in the healthy individuals.

• The platelet loss from the circulation for endothelial support has been calculated to be 7.1 x 109/L.

Background

• Several studies and the currently used guideline provide the evidence that the threshold for prophylactic platelet transfusion can be safely reduced to 10 x 109/L.

• The optimal number of platelets in a prophylactic platelet transfusion is controversial.

BJH 2003:122;10-23N Engl J Med.1997;337:1870-1875Blood 1998 ;91:3601-3606

Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage

(PLADO)

N.Engl.J.Med. 2010; 362:600-13

The Question (PICO)

• Population: Hospitalized patients of any age with hypoproliferative thrombocytopenia (Chemo or Hematopoietic Transplant) 10 x 109/L.

• Intervention: Low dose (110 x 109/m2) prophylactic platelet transfusion.

• Comparison: Standard (220 x 109/m2) or high dose (440 x 109/m2) prophylactic platelet transfusion.

• Outcome: Incidence of WHO grade 2 or higher bleeding.

Study Design

•Multicenter (26) NHLBI Sponsored RCT, with patients enrolled between 2004-2007.

•Exclusion Criteria:▫ Severe thrombocytopenia duration <5 days.▫ Extremes of Weight (<10 kg, >135 kg).▫ PT or PTT >1.3X Normal.▫ Fib <1 g/L.▫ Pre-existing bleeding (≥WHO Grade 2)▫ Platelet refractoriness within the last 30 days.▫ Acute promyelocytic leukemia .▫ ITP, TTP/HUS.▫ Drugs affecting Platelet number or function.▫ Major surgery within previous 2 week.▫ Pregnancy.▫ Planed prophylactic transfusion.

N=1351 Patients enrolled

N=1272 Randomized

High dose(440 x 109/m2)

N=432

Medium dose(220 x 109/m2)

N=423

Low dose(110 x 109/m2 )

N=417

Dose adherence* 86% Dose adherence** 93% Dose changed in 7% Trigger changed in 25%

Dose adherence* 92% Dose adherence** 98% Dose changed in 9% Trigger changed in 26%

Dose adherence* 79% Dose adherence** 86% Dose changed in 17% Trigger changed in 32%

79 did not receive platelet

7 died(1 from Hge)4 died9 died

417 Analyzed

423Analyzed

432 Analyzed

F/U

30

Day

s*The attempted dose adherence among 1162 patients.

**The attempted dose adherence for 5384 transfusions.

4% withdraw from the study

Validity?

1. Did the experimental and the control groups begin the study with a similar prognosis?

• The patients were randomized.• The randomization was concealed by means of

computer-generated permuted blocks.• The patients was analyzed in the groups to which they

were randomized regardless of whether they actually received the intervention (Intention-To-Treat Analysis).

Validity?

• The patients in the 3 treatment arms were equally distributed in regard of demographics,primary diagnosis and laboratory test results.

Baseline Characteristics

Primary Diagnosis and Stratification Low Dose Medium Dose High Dose

( N=417) P value ( N=423) P value ( N=432) P value

Primary diagnosis-no.(%) 0.35 0.40 0.45• Acute Leukemia 202(48) 186(44) 185(43)• Lymphoma 91(22) 89(21) 84(19)• Myeloma 39(9) 59(14) 56(13)• Chronic Leukemia 24(6) 24(6) 33(8)• Myelodyspalsia 16(4) 26(6) 14(3)• Solid tumors 5(1) 6(1) 7(2)• Others 40(10) 33(8) 53(12)

Stratification categories-no.(%) 1.00 0.96 0.97• Allogenic HST 173(41) 173(41) 177(41) • Autologous HST 138(33) 142(34) 149(34) • Chemo or Radiation 104(25) 105(25) 104(24)

for hematologic cancer• Chemo or radiation 2(<1) 3(1) 2(<1) for solid tumors

Baseline Lab Characteristics

Validity?

2. Did experimental and the control groups retain a similar prognosis after the study started?

• The clinician may be aware of the group allocation :▫ The different size of the platelet bags( as the low dose is half of

the medium dose).▫ Some of the clinicians changed the platelet dose when the

patient bleeds.

• The outcome assessor were not aware of the group allocation ▫ Bleeding grade was calculated by computer based system.

Clinical Assessment

•Research staff Performed :▫Daily assessment of the bleeding (physical

examination).▫Patient interview .▫Chart reviews .▫Daily platelet count.▫Daily hemoglobin and hematocrit.

•3 non study physician adjudicated whether bleeding is the cause of death.

Validity?

• Patient follow up in the 3 arm considered complete when one these conditions occurred( which ever occurred first):▫ At hospital discharge(71%). ▫ After 10 day period without PLT transfusion(14%).▫ 30 days after the first PLT transfusion(10% ).▫ At withdrawal from the study(4%).▫ At death(2%).

The Precision of The Results Low Dose Medium Dose High Dose ( N=417) P value ( N=423) P value ( N=432) P value

>1Episode of 71% 0.60 69% 0.71 70% 0.94

grad 2 bleeding(% of patient)

Highest 0.30 0.65 0.54 Grade of bleed • Grade1 30% 32% 30%• Grade2 58% 59% 60%• Grade3 9% 7% 8%• Grade4 3% 2% 2%

>1 RBC transfusion 95% 0.12 92% 1.00 92% 0.09 (% of patients)

Total RBC units /patient 4 0.62 4 0.70 4 0.90

(2-8) (2-8) (2-8)

Low Dose Medium Dose High Dose ( N=417) P value ( N=423) P value ( N= 432) P value

No. of Platelet 5 <0.001 3 0.09 3 <0.001Transfusions/patient (3-9) (2-6) (2-6)

Total No. of platelet 925 0.002 1125 <0.001 1963 <0.001Transfused( x10-9 ) (491-1791) (699-2276) (1061-3744)

Death from 0 0 1.00 1 1.00hemorrhage

Response to Platelet Transfusion

Low Dose Medium Dose High Dose ( N=417) P value ( N=423) P value ( N=432) P value

No. of transfusions 2193 1646 1386( all data available)

Pre transfusion PLTcount (x10-3 /mm-3 ) 9(7-16) 0.48 9(7-19) 0.08 9(7-12) 0.21

Post transfusion PLTcount (x10-3 /mm-3 ) 22(16-30) <0.001 34(24-48) <0.001 50(33-68) <0.001

PLT increment(x10-3 /mm-3 ) 10(5-17) <0.001 19(11-30) <0.001 38(22-54) <0.001

Post transfusion CCI * 10(5-15) 0.08 10(6-16) 0.03 11(6-15) 0.98

(x10-3 /mm-3 )

Applicability of The Results

1. Were the study patients similar to the patient in my practice?

• Yes.• The medium platelet dose(220 x 109/m2 ) in the trial is

equivalent to the standard adult dose considering 70kg adult has body surface area(BSA)of1.8 m2.

Applicability of The Results

2. Where all clinically important outcome considered?• Primary end point: Bleeding of grade 2 or higher .

• Secondary end point:The highest grade of bleeding.Total number of platelets transfused.Number of platelet transfusion.• • Surrogate end points: Total number of RBC transfusion.

A randomized controlled trail comparing standard and low dose strategies for transfusion of platelets (SToP) to patientswith thrombocytopenia.

Blood 2009 113: 1564-1573

Study Design

• Multicenter international study(6 sites) conducted by BEST collaborative .

• 129 Patients recruited ( Oct. 2003 and Jun 2007).• A double blind randomized controlled trail (RCT).• Non-inferiority study.• Eligibility criteria similar to PLADO trial .• 2 arm study:

• Low dose arm , platelet count (150-300x109/product).• Standard dose arm ,platelet count ( 300-600 x109/product).

Study Design

• Primary outcome:▫Bleeding Grade 2 or higher.

• The study was terminated by March 2008 by the Data Safety Monitoring Board( DSMB) because the difference in grade 4 bleed reached the prespecified threshold of 5% in the low dose arm.

Validity?

1.Did the experimental and control groups begin the study with a similar prognosis?

• The patients were allocated through a secure central web-based randomization system.

• The randomization was concealed with block randomization .• The patients analyzed in the groups to which they were

randomized.• The 2 arms were similar with respect to the prognostic variable

except for the baseline platelet count (31x109 /l in low dose arm vs 46x109 /l in standard dose arm).

Baseline Criteria

The Primary Diagnosis

Validity?

2.Did experimental and control groups retain a similar prognosis after the study started?

• It is double blinded study as the clinician and outcome assessor were not aware of the treatment allocation but 7 patients were prematurely removed from the study at the request of the treating physician (6 in the low arm).

• The follow up was complete till the DSMB stopped the trail .

The Precision of the Results

Standard Dose Low Dose

Type of the bleeding n=61 n=58

No. of patients with bleeding(%)

Grade1 48(78.7) 53(91.4)

Grade2 28(45.9) 28(48.9)

Grade3 6(9.8) 5(8.6)

Grade4 0 3(5.2)

Grade 2 or higher 30(49.2) 30(51.7)

Percentage of days with bleeding (proportion)

Grade2 or higher 8.5(73/854) 12.1(111/918)

Grade 4 0 0.5(5/918)

The Precision of the Results

• The proportion of patient with grade 2 bleeding was 52%(30/58)in the low dose arm and 49% ( 30/61) in the standard dose arm ( RR=1.05;CI 0.73-1.50).

Conclusion

• After a trigger threshold of 10x109/l platelet is reached , the platelet dose has no significant effect on the incidence of bleeding in patients of hypoprliferative thrombocytopenia .

• The rate of bleeding seen in PLADO trial was higher compared to other previous studies.

• The strategy of low dose platelet transfusion is effective and can preserve the blood supply.