Key Points
Question
Are cryopreserved platelets cost-effective compared with liquid-stored platelets for managing active bleeding in patients undergoing cardiac surgery at high risk of platelet transfusion at Australian tertiary hospitals?
Findings
In this economic evaluation including 202 adults enrolled in a randomized clinical trial, the mean difference in per-patient cost was A$15 035 (95% CI, −A$1878 to A$31 949) with cryopreserved platelets compared with liquid-stored platelets, although the difference was not significant. Mean blood loss within 24 hours after intensive care unit admission was 121 (95% CI, 5 to 237) mL higher with cryopreserved platelets, a significant difference.
Meaning
These findings suggest that treatment with cryopreserved platelets was more costly and less effective than liquid-stored platelets; therefore, liquid-stored platelets were preferred in cardiac surgery.
This economic evaluation examines the cost-effectiveness of cryopreserved platelets vs liquid-stored platelets for managing surgical bleeding in patients undergoing cardiac surgery.
Abstract
Importance
Platelet transfusion is critical in managing major bleeding, but access to liquid-stored platelets is limited by their 5- to 7-day shelf life. Cryopreserved platelets last up to 2 years and may improve availability, although their cost-effectiveness remains uncertain.
Objective
To evaluate the cost-effectiveness of cryopreserved platelets vs liquid-stored platelets for managing surgical bleeding.
Design, Setting, and Participants
An economic evaluation was conducted from the Australian government funder perspective alongside the CLIP-II randomized clinical trial, following intention-to-treat principles. Adult patients (age ≥18 years) undergoing cardiac surgery at 11 Australian tertiary hospitals between August 2021 and April 2024 were screened for eligibility. Eligible patients were those at high risk for platelet transfusion, identified by risk prediction score or clinician judgment, excluding female patients aged 18 to 55 years who were rhesus D (RhD) negative or with unknown RhD status and patients with coagulopathy or prior thromboembolism. Data were analyzed between January and April 2025.
Interventions
Participants received at least 3 units of either cryopreserved or liquid-stored platelets intraoperatively or within 24 hours postsurgery.
Main Outcomes and Measures
Costs were estimated in 2023 Australian dollars (A$) by assigning unit costs to patient-level resource use in each trial group, including intensive care unit (ICU) admissions, hospitalizations, and blood products. Effectiveness measures included postoperative bleeding volume (first 24 hours post-ICU admission and total), 90-day mortality, type 4 bleeding (based on the Bleeding Academic Research Consortium criteria), and serious adverse events. Given the 90-day follow-up period, discounting was not applied.
Results
Among 202 participants (median [IQR] age, 66 [57-74] years, 153 [75.7%] male), 104 received cryopreserved platelets and 98 received liquid-stored platelets. The mean difference in per-patient cost was A$15 035 (95% CI, −A$1878 to A$31 949) with cryopreserved platelets vs liquid-stored platelets. Mean blood loss within 24 hours following ICU admission was 121 (95% CI, 5 to 237) mL higher, total postoperative blood loss was 504 (95% CI, 145 to 862) mL higher, and type 4 bleeding was 12.3% (95% CI, 1% to 23.6%) higher with cryopreserved platelets compared with liquid-stored platelets. The difference in 90-day mortality between cryopreserved platelet and liquid-stored platelet groups was not statistically significant (7.4% [95% CI, −0.3% to 15.1%]). Only 1 serious adverse event was observed in each group.
Conclusions and Relevance
In this economic evaluation, cryopreserved platelets were dominated by liquid-stored platelets for managing bleeding in cardiac surgery. Further research is needed to assess the potential economic benefits of cryopreserved platelets in broader populations, particularly in regional and remote hospitals where platelet availability is limited.
Introduction
Platelet transfusion is a crucial, lifesaving treatment for managing major bleeding. However, commonly used liquid-stored platelets stored under standard blood banking conditions (20 °C to 24 °C), have a short shelf life of 5 to 7 days, due to bacterial proliferation.1 Consequently, patients in rural, smaller hospitals or military field hospitals often have limited or no access to urgent platelet transfusions.2 Freezing platelets at −80 °C with a cryoprotectant (dimethyl sulfoxide) extends their shelf life to at least 2 years,3 reduces the risk of infectious disease transmission, and may enhance the hemostatic activity of platelets.4,5 This cryopreservation approach presents a promising solution for hospitals facing restricted access to platelets while alleviating the burden on blood banks.
Cryopreserved platelets were recently compared with liquid-stored platelets in adult patients undergoing cardiac surgery at high risk of platelet transfusion in the CLIP-II trial.6 However, the cost-effectiveness of cryopreserved platelets remains unknown. In this study, we assessed the cost-effectiveness of cryopreserved platelets compared with liquid-stored platelets alongside the CLIP-II trial for the management of cardiac surgical bleeding.
Methods
This economic evaluation was conducted as part of the CLIP-II trial, which was approved by the Human Research and Ethics Committees of Austin Hospital, Melbourne, and the Australian Red Cross Lifeblood. Written informed consent was obtained from all participants prior to their enrollment in the study. Reporting of this study followed the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guideline.7
This was a trial-based cost-effectiveness analysis comparing transfusion with cryopreserved platelets and liquid-stored platelets, as prespecified in the CLIP-II trial protocol8 and health economic analysis plan.9 A full economic evaluation was conducted, adhering to intention-to-treat principles and adopting a health care system perspective focused on inpatient services from the Australian government funder. As the follow-up was limited to 90 days, discounting of costs and benefits was not applied.
Study Design and Participants
CLIP-II was a multicenter, blinded, randomized clinical trial (RCT) conducted in Australian metropolitan hospitals to evaluate the efficacy and safety of cryopreserved platelets compared with liquid-stored platelets in patients undergoing cardiac surgery.8 Adults aged at least 18 years who were identified preoperatively as being at high risk of requiring platelet transfusion were eligible for inclusion. High-risk status was defined as a score of 1 or greater on the Adult Cardiac Surgery Platelet Transfusion risk prediction tool10 or determined by clinical judgment. The primary outcome was the volume of bleeding within the first 24 hours following admission to the intensive care unit (ICU) after surgery. Further details regarding trial methods are available in the CLIP-II trial protocol8 and in the CLIP-II primary report.6
Cost Estimation
Costs were estimated in 2023 Australian dollars (A$), equivalent to US $0.73 per A$1, based on the 2023 purchasing power parity conversion factor.11 Unit costs were then applied to quantities of resource use identified and measured in each trial group using patient-level data collected on case report forms (CRFs).8 Health care resources were measured from ICU admission after surgery up to 90 days or death, whichever occurred sooner, based on the length of the index ICU stay, index hospitalization (measured excluding all index ICU stays), ICU readmissions during the index hospitalization, hospital readmissions, inpatient rehabilitation, and blood products received.
The index ICU stay was categorized by the number of organs supported each day, based on the CRF data, including invasive mechanical ventilation, kidney replacement therapy, and extracorporeal membrane oxygenation. Since stratified ICU costs by the number of organs supported were unavailable in Australia, data from the UK National Cost Collection were used to estimate ICU admission costs.12 Weighted factors were calculated by dividing the mean daily ICU cost across all 5 organ support categories by the cost for each category. These weighted factors were then applied to the mean cost per ICU bed-day in Australia (A$6125 in 2022-2023, adjusted from A$4375 in 201313 using the Consumer Price Index [CPI] in Health from the Australian Bureau of Statistics).14 This approach was used to estimate the cost of the index ICU stay based on the number of organs supported each day (eTable 1 in Supplement 1). The costs of subsequent ICU readmissions were calculated using the same mean daily rate, adjusted from 2013 values.13
The costs of index hospitalizations and hospital readmissions were estimated using an inflation-adjusted 2022 to 2023 national mean cost of A$2499 per bed-day. Because admission-level diagnostic codes were not collected in the CLIP-II trial, diagnosis-specific hospital costing was not possible. Instead, we applied the 2021 to 2022 national mean cost per acute admission (A$5808.5), inflated it to 2022 to 2023 values using the ratio of health CPIs (December 2022 to December 2023), and divided this by the national mean length of stay (LOS) of 2.44 days in public acute hospitals to derive a cost per bed-day.15 This approach is consistent with standard methods when only length of stay data are available. Additionally, the cost of rehabilitation was calculated based on the 2021 to 2022 mean cost per subacute cardiac separation, adjusted to 2022 to 2023, and estimated at A$19 675.15
Although drugs and fluids account for only 5% of ICU costs and are typically included in overall ICU expenses,13 the use of platelets, red blood cells (RBC), fresh frozen plasma, and cryoprecipitate in this study was measured separately using CRFs. Costs of these blood components were estimated using unit costs published in the 2022 to 2023 Annual Report of the Australian National Blood Authority.16 The costs associated with cryopreserved platelet manufacturing, logistics, and reconstitution were calculated with assistance from the Australian Red Cross Lifeblood (eTable 2 in Supplement 1).
Health Outcome Measures
The following secondary health outcomes of the CLIP-II trial were included as effectiveness measures: the volume of postoperative bleeding (in milliliters) in the first 24 hours after ICU admission, the total volume of postoperative bleeding (in milliliters), 90-day mortality, a composite bleeding outcome based on the Bleeding Academic Research Consortium (BARC) criteria, and serious adverse events (SAEs). BARC type 4 bleeding is defined as the presence of any of the following: intracranial bleeding within 48 hours, reoperation after closure of sternotomy, transfusion of 5 or more units of whole blood or RBC within the 48 hours (intraoperative or postoperative), or chest tube output 2 or more L within a 24-hour period.17 Only SAEs reasonably suspected by the site principal investigator to be possibly, probably, or definitely related to the study treatment were included.
Cost-Effectiveness Outcomes
The cost-effectiveness of cryopreserved platelets vs liquid-stored platelets was assessed by comparing the mean costs and health outcomes between treatment groups. Incremental cost-effectiveness ratios (ICERs) were calculated by dividing the difference in mean total per-patient costs between the cryopreserved platelets and liquid-stored platelets groups by the corresponding difference in health outcomes. The cost-effectiveness outcomes included the cost per 1 mL of postoperative bleeding avoided within the first 24 hours post-ICU admission, cost per 1 mL of total postoperative bleeding avoided, cost per 1% reduction in 90-day mortality, cost per 1% reduction in BARC4 bleeding, and cost per 1% reduction in SAEs.
Statistical Analysis
All analyses were conducted using Stata statistical software version 18 (StataCorp). Statistical significance was 2-sided and set at 5%. Baseline characteristics, intraoperative bleeding, and fluid resuscitation were summarized as proportions for categorical variables and medians with IQRs for continuous variables, given their nonnormal distribution. Differences between study groups were reported with 95% CIs using a generalized linear model with an identity link and binomial family for categorical variables and median regression for continuous variables. However, comparisons of resource use, costs, and health outcomes were presented as means with SDs or as counts with percentages to ensure alignment with ICER calculations.
To assess uncertainty, probabilistic sensitivity analysis was performed using bootstrapping with 1000 iterations for both incremental costs (between-group differences in mean total per-patient costs) and incremental effectiveness (between-group differences in mean health outcomes). Both unadjusted and adjusted bootstrapping were conducted, with adjustments made for hospital site, EuroSCORE II risk score, and baseline imbalance (extracardiac arteriopathy), consistent with the primary outcome of the RCT. In adjusted models, mean differences with 95% CIs were estimated using generalized linear model, using a binomial family distribution for binary outcomes and a γ family distribution for continuous outcomes. Cost-effectiveness planes were used to visualize bootstrapping results where appropriate.
Additionally, subgroup analyses were performed to explore heterogeneity in cost-effectiveness based on surgery complexity, as the primary outcome did not differ across 3 prespecified subgroups: blood group compatibility, preoperative aspirin usage, and first transfusion location (operating room vs ICU). Surgeries were classified as complex if they met any of the following criteria: involvement of multiple cardiac valves; at least 1 valve procedure in addition to the coronary arteries, aortic root, or ventricular wall; procedures involving the aortic arch or descending aorta; procedures for infective endocarditis; or procedures affecting the pulmonary circulation.
Results
Baseline Characteristics
Among 202 trial participants (153 [75.7%] male, median [IQR] age 66 [57-74] years), 104 were randomized to the cryopreserved platelets group and 98 were randomized to liquid-stored platelets. Compared to the liquid-stored platelets group, the cryopreserved platelets group had a higher proportion of males (81 [78%] vs 72 [73%]) and were older (median [IQR] age, 66 [57-74] vs 64 [55-74] years). Overall, baseline characteristics were well balanced between the groups (Table 1).
Table 1. Baseline Characteristics of Study Participants.
| Characteristic | Participants, No.(%) | |
|---|---|---|
| Cryopreserved platelets (n = 104) | Liquid-stored platelets (n = 98) | |
| Age, median (IQR), y | 66 (57-74) | 64 (55-74) |
| Sex | ||
| Male | 81/104 (78) | 72/98 (73) |
| Female | 23/104 (22) | 26/98 (27) |
| Blood group | ||
| A | 45/104 (43) | 40/98 (41) |
| B | 13/104 (13) | 10/98 (10) |
| AB | 1/104 (1) | 3/98 (3) |
| O | 45/104 (43) | 45/98 (46) |
| Rh+ | 90/104 (86) | 84/98 (86) |
| Platelets, median (IQR), ×103/µL | 199 (157-245) | 204 (171-259) |
| aPTT, median (IQR), s | 31 (29-34) | 31 (29-34) |
| Fibrinogen, median (IQR), mgd/L | 370 (300-460) | 370 (300-450) |
| International normalized ratio, median (IQR) | 1.1 (1-1.1) | 1.1 (1-1.1) |
| Hemoglobin, median (IQR), g/dL | 13.1 (11.7-14.5) | 13.7 (12.2-14.7) |
| Elective surgery | 73/104 (70) | 68/98 (69) |
| Creatinine clearance >85 mL/min | 40 (38) | 41 (42) |
| Previous cardiac surgery | 28/104 (27) | 31/98 (32) |
| Chronic lung disease | 15/104 (14) | 11/98 (11) |
| Endocarditis | 13/104 (12) | 8/98 (8) |
| Cardiogenic shock | 4/104 (4) | 0/98 (0) |
| Extracardiac arteriopathy | 9/104 (8.6) | 1/98 (1) |
| NYHA classification of HF severity | ||
| I | 28/104 (27) | 38/98 (39) |
| II | 45/104 (43) | 37/98 (38) |
| III | 28/104 (27) | 22/98 (22) |
| IV | 3/104 (3) | 1/98 (1) |
| Left ventricular function ≥51% | 78/104 (76) | 64/98 (66) |
| MI in the past 90 d | 7/104 (7) | 12/98 (12) |
| Pulmonary hypertension | 28/104 (27) | 26/98 (26) |
| EuroSCORE II risk score, median (IQR) | 3 (2-8) | 3/98 (2-6) |
| Anticoagulant therapy in the past 7 d | 62/104 (60) | 58/98 (59) |
| Tranexamic acid in the past 24 h | 8/104 (8) | 7/98 (7) |
Abbreviations: aPTT, activated partial thromboplastin time; EuroSCORE II, European System for Cardiac Operative Risk Evaluation II; HF, heart failure; MI, myocardial infarction; NYHA, New York Heart Association.
SI conversion factors: To convert fibrinogen to grams per liter, multiply by 0.01; hemoglobin as grams per liter, multiply by 10; platelets to ×109/L, multiply by 1.
Resource Use and Costs
Participants in the cryopreserved platelets group remained in the ICU a mean of 1.6 (95% CI, 0.1 to 3.2) days longer and required 0.9 (95% CI, 0.5 to 1.2) additional unit of platelets during the index ICU stay compared with those in the liquid-stored platelets group. While participants in the cryopreserved platelets group used more resources, including ICU readmissions and readmission LOS, RBC, fresh frozen plasma, and cryoprecipitate, these differences were not statistically significant. Conversely, a higher proportion of participants in the liquid-stored platelets group were rehospitalized and had a mean hospital LOS 3 (95% CI, −1 to 8) days longer than those in the cryopreserved platelets group, although these differences were also not statistically significant. Detailed resource use is provided in Table 2.
Table 2. Resource Utilization Up to 90 Days Postdischarge by Study Groups.
| Resource | Mean (SD) | Difference (95% CI) | |
|---|---|---|---|
| Cryopreserved platelets (n = 104) | Liquid-stored platelets (n = 98) | ||
| Index hospital LOS, d | 18.9 (16.3) | 17.1 (13.3) | 1.8 (−2.3 to 5.9) |
| During index ICU stay | |||
| Index ICU LOS, d | 5.9 (6.9) | 4.3 (4.1) | 1.6 (0.1 to 3.2) |
| Participants readmitted to ICU, No. (%) | 7/104 (7) | 3/98 (3) | 4 (−2 to 10) |
| ICU readmission LOS, d | 5.6 (3.6) | 7.3 (1.5) | −1.7 (−6.1 to 2.6) |
| First platelet order-to-receipt time, min | 81 (67) | 81 (73) | 0 (19 to 20) |
| Participants receiving, No. (%) | |||
| 3 study platelet units | 21/104 (20) | 18/98 (18) | 2 (−9 to 13) |
| 2 study platelet units | 41/104 (40) | 26/98 (27) | 13 (0 to 26) |
| 1 study platelet unit | 42/104 (40) | 54/98 (55) | −15 (−28 to −1) |
| Study platelets, units | 1.8 (0.7) | 1.6 (0.8) | 0.2 (−0.1 to 0.4) |
| Nonstudy platelets, units | 1.1 (1.9) | 0.2 (0.7) | 0.9 (0.5 to 1.2) |
| RBC, units | 6.7 (6.4) | 5.1 (5.7) | 1.6 (−0.4 to 3.7) |
| FFP, units | 4.7 (3.7) | 4.2 (2.8) | 0.5 (−0.6 to 1.6) |
| Cryoprecipitate, units | 11.0 (7.3) | 8.8 (7.2) | 2.2 (−0.4 to 4.7) |
| Post-ICU to hospital discharge LOS, d | 12.7 (12.1) | 12.6 (11.8) | 0.1 (−3.3 to 3.4) |
| Postdischarge to 90 d | |||
| Rehospitalized participants, No. (%) | 15/104 (14) | 19/98 (19) | −5 (−15 to 5) |
| Rehospitalization LOS, d | 4.2 (2.7) | 7.2 (8.4) | −3 (−8 to 1) |
| Discharged to rehabilitation, No. (%) | 10/93 (10.7) | 11/94 (11.7) | −1 (−10 to 8) |
Abbreviations: FFP, fresh frozen plasma; ICU, intensive care unit; LOS, length of stay; RBC, red blood cells.
The differences in resource use were reflected in mean per-patient costs. The total mean per-patient cost in the cryopreserved platelets group was A$81 029 (A$72 395), with a mean difference of A$15 035 (95% CI, −A$1878 to A$31 949) in the cryopreserved platelets group vs liquid-stored platelets group (Table 3). Mean per-patient costs were nearly 50% higher for index ICU stay and 8 times higher for cryopreserved platelets transfusion compared with those in the liquid-stored platelets group. With the exception of index hospitalization and ICU readmissions, the cryopreserved platelets group incurred significantly higher mean per-patient costs compared with the liquid-stored platelets group.
Table 3. Per-Patient Costs in and Health Outcomes by Study Group.
| Measure | Mean (SD) | Difference (95% CI) | |
|---|---|---|---|
| Cryopreserved platelets (n = 104) | Liquid-stored platelets (n = 98) | ||
| Costs, A$ | |||
| Index ICU stay | 36 615 (51 211) | 24 803 (27 030) | 11 812 (636 to 22 998) |
| Index hospitalization | 31 646 (30 383) | 31 493 (29 509) | 153 (−8086 to 8393) |
| ICU readmissions | 2297 (10 105) | 1375 (7893) | 922 (−1565 to 3408) |
| Rehospitalizations | 1514 (4479) | 3494 (11 565) | −1980 (−4419 to 460) |
| Rehabilitation | 1892 (5828) | 2208 (6243) | −316 (−1980 to 1347) |
| Study platelets | 3211 (1349) | 400 (191) | 2811 (2550 to 3073) |
| Nonstudy platelets | 266 (463) | 53 (162) | 213 (119 to 308) |
| Red blood cells | 1775 (2220) | 1071 (1809) | 704 (148 to 1259) |
| Fresh frozen plasma | 539 (575) | 323 (443) | 216 (76 to 357) |
| Cryoprecipitate | 1274 (1294) | 775 (1123) | 499 (166 to 832) |
| Total | 81 029 (72 395) | 65 993 (48 940) | 15 035 (−1878 to 31 949) |
| Health outcomes | |||
| Blood loss, mLa | |||
| Within 24 h post-ICU admission | 736 (491) | 615 (341) | 121 (5 to 237) |
| Total postoperative | 1724 (1614) | 1220 (905) | 504 (145 to 862) |
| BARC4 bleeding, No. (%) | 33/104 (31.7) | 19/98 (19.4) | 12.3 (1 to 23.6) |
| Serious adverse events, No. (%) | 1/104 (1) | 1/98 (1) | 0 (−2.7 to 2.7) |
| Mortality at 90 d, No. (%) | 13/104 (12.5) | 5/98 (5.1) | 7.4 (−0.3 to 15.1) |
Abbreviations: BARC4, type 4 bleeding according to the Bleeding Academic Research Consortium; ICU, intensive care unit.
Conversion factor: To convert Australian dollars (A$) to US dollars, multiply by 0.73.
Excludes one participant from the cryopreserved group due to a missing value.
Health Outcome Summaries
Participants in the cryopreserved platelets group had a mean (SD) blood loss of 736 (491) mL within 24 hours post-ICU admission, which was 121 (95% CI, 5 to 237) mL higher than the liquid-stored platelets group. Similarly, the mean (SD) total postoperative blood loss was 1724 (1614) mL in the cryopreserved platelets group, 504 (95% CI, 145 to 862) mL higher than in the liquid-stored platelets group. Additionally, 33 patients (31.7%) in the cryopreserved platelets group experienced BARC4 bleeding, compared with 19 patients (19.4%) in the liquid-stored platelets group. Only 1 SAE was observed in each group. The mortality rate during the study follow-up was 12.5% in the cryopreserved platelets group, with a difference of 7.4% (95% CI, −0.3% to 15.1%) compared with the liquid-stored platelets group. Further details are presented in Table 3.
Cost-Effectiveness Summaries
In both unadjusted and adjusted bootstrapping analyses, cryopreserved platelets were dominated by liquid-stored platelets across all cost-effectiveness outcomes, indicating that the cryopreserved platelets group had higher costs and worse health outcomes relative to the liquid-stored platelets group (Table 4). This dominance is evident on cost-effectiveness planes for all cost-effectiveness outcomes (Figure; eFigures 1-5 in Supplement 1).
Table 4. Summary of Cost-Effectiveness Outcomes.
| Outcome | Incremental cost (95% CI), A$ | Incremental effectiveness (95% CI) | ICER (95% CI) |
|---|---|---|---|
| Unadjusted | |||
| Cost per 1 mL of bleeding avoided within 24 h ICU admissiona | 15 193 (−1647 to 33 546) | −119 (−238 to −2)b | Dominatedc |
| Cost per 1 mL of total postoperative bleeding avoided | 15 193 (−1647 to 33 546) | −494 (−860 to −159 )b | Dominatedc |
| Cost per 1% reduction in BARC4 bleeding | 14 567 (−2355 to 32 417) | −11.8 (−24.2 to −0.2)d | Dominatedc |
| Cost per 1% reduction in 90-d mortality | 14 567 (−2355 to 32 417) | −7.4 (−15.1 to −0.2)d | Dominatedc |
| Adjusted for EuroSCORE II risk score, site, and baseline imbalance (extracardiac arteriopathy) | |||
| Cost per 1 mL of bleeding avoided within 24 h ICU admissiona | 12 791 (−758 to 25 935) | −91 (−219 to 24)b | Dominatedc |
| Cost per 1 mL of total postoperative bleeding avoided | 12 791 (−758 to 25 935) | −324 (−605 to −55)b | Dominatedc |
| Cost per 1% reduction in BARC4 bleeding | 12 738 (−772 to 27 124) | −12.2 (23.5 to −0.9)d | Dominatedc |
| Cost per 1% reduction in 90-d mortality | 12 738 (−772 to 27 124) | −6.6 (−15.1 to 1.8)d | Dominatedc |
Abbreviations: BARC4, type 4 bleeding according to the Bleeding Academic Research Consortium; EuroSCORE II, European System for Cardiac Operative Risk Evaluation II; ICER, incremental cost-effectiveness ratio; ICU, intensive care unit.
Conversion factor: To convert Australian dollars (A$) to US dollars, multiply by 0.73.
Excludes 1 participant from the cryopreserved group due to a missing value.
Expressed as milliliters.
Dominated indicates that the mean cost was higher and the health outcome was worse in the cryopreserved platelet group compared with the liquid-stored platelet group.
Expressed as percentage.
Figure. Cost-Effectiveness Plane of Incremental Costs and Incremental Effectiveness for Cryopreserved Platelets vs Liquid-Stored Platelets.
Incremental effectiveness was measured as bleeding avoided within 24 hours of intensive care unit (ICU) admission. To convert Australian dollars (A$) to US dollars, multiply by 0.73.
Subgroup Analyses
Across all cost-effectiveness outcomes, cryopreserved platelets were dominated by liquid-stored platelets, regardless of cardiac surgery complexity (eTable 3 in Supplement 1). As the subgroup analysis findings were consistent with the main analysis, cost-effectiveness planes were not generated.
Discussion
This cost-effectiveness study found that treatment with cryopreserved platelets was more costly and less effective than standard therapy with liquid-stored platelets for managing active bleeding in patients undergoing cardiac surgery at metropolitan Australian hospitals. The higher mean per-patient costs of cryopreserved platelets were primarily driven by longer ICU stays and a 7-fold increase in the costs of cryopreserved platelets utilization, including manufacturing and transportation of frozen platelets. Additionally, cryopreserved platelets were associated with greater bleeding volumes and higher mortality rates. In this economic evaluation, we provide novel evidence supporting the dominance of liquid-stored platelets over cryopreserved platelets in postoperative bleeding management following cardiac surgery.
To our knowledge, no previous cost-effectiveness analyses have compared cryopreserved platelets with liquid-stored platelets, and this study provides novel evidence on differences in health outcomes and costs between these products. The observed mean difference in 24-hour blood loss did not reach the clinically meaningful threshold defined in the CLIP-II trial (20% of the anticipated primary outcome blood loss, or approximately 1 unit of RBC transfused, equivalent to 258 mL in Australia). However, the greater total postoperative blood loss and higher rates of BARC4 bleeding in the cryopreserved platelets group were consistent with the longer ICU and hospital stays observed. It is well established that bleeding and blood transfusion in patients undergoing cardiac surgery lead to increased health care resource use and hospital costs. In 2 large US studies including a total of 182 800 patients undergoing cardiac surgery, those who experienced bleeding or received a blood transfusion had longer hospital and ICU stays and higher hospitalization costs compared with those without bleeding or transfusion.18,19 Similar findings were reported in studies conducted in Australia,20 Germany,21 and England,22 where patients with higher bleeding volumes had greater hospitalization costs. Our study confirms the association of increased hospital expenditure with bleeding volume and blood transfusion use and contributes new evidence to the limited economic literature on cryopreserved platelets by presenting their associated costs.
Platelet storage methods and duration may affect transfusion safety and effectiveness. A systematic review of 23 studies found that older platelets, compared with fresh platelets, were associated with a higher risk of transfusion reactions (relative risk [RR], 1.53 [95% CI, 1.04-2.25]), shorter transfusion intervals (RR, 0.25 [95% CI, 0.13-0.38] days), and increased platelet use.23 There was no significant difference in bleeding risk (RR, 1.13 [95% CI, 0.97-1.32]), and no significant difference in mortality was observed (RR, 1.03 [95% CI, 0.86-1.24]). In our study, cryopreserved platelets were frozen on day 2 after collection,5 stored for 12 months,24 and transfused within 4 hours of thawing.25 This process may have limited their effectiveness. Given these potential limitations and the minimal platelet wastage in metropolitan areas,26 routine use of cryopreservation in these settings may not be warranted.
Cryopreservation offers a viable solution for regional and remote areas where access to platelets is limited by low demand, transport constraints, and high waste associated with the 5- to 7-day shelf life of liquid-stored platelets. Platelet use in Australia has nearly doubled over 2 decades,16,27 and 80% of requests require supply within 24 hours,26 highlighting the urgency of timely availability. Although our study found that cryopreserved platelets were dominated by liquid-stored platelets in metropolitan cardiac surgery settings, this does not preclude their potential value in nonmetropolitan hospitals. In many regional and remote locations, liquid-stored platelets are often unavailable, making the relevant comparator no platelets at all rather than liquid-stored platelets. In such settings, cryopreserved platelets may improve equity by providing access to transfusion support that would otherwise be inaccessible. Further evaluation is warranted to assess the potential costs and health benefits of cryopreserved platelet implementation for emergency bleeding management in nonmetropolitan service environments.
Strengths and Limitations
There are several notable strengths and limitations of this cost-effectiveness analysis. Key strengths include the rigorous trial design, which ensured that differences in costs and outcomes were directly attributable to the intervention, and the use of prespecified patient-level health care resource utilization data, enabling accurate cost assessment.
Nonetheless, several limitations should be considered when interpreting the findings. The strict inclusion and exclusion criteria of the RCT produced a relatively homogeneous study population, which may not fully represent patients undergoing cardiac surgery in clinical practice. Additionally, because resource use was collected from 11 high-resource metropolitan hospitals, external validity may be limited, as cost structures and clinical practices in regional and remote settings may differ. ICU cost weights by organ support were derived from UK National Cost Collection data due to the lack of Australian equivalents; differences in case-mix, practice patterns, and resource use between these countries may limit the precision of these estimates.
Readmission outcomes may also have been affected by informative censoring, as higher mortality and longer index admissions in the cryopreserved platelets group reduced the time at risk for subsequent rehospitalization. Therefore, rehospitalization rates and readmission LOS should be interpreted with caution. Furthermore, the economic evaluation did not account for societal costs, such as productivity loss, which could influence the overall cost-effectiveness of cryopreserved platelets. While the RCT was sufficiently powered to detect clinical differences in postoperative bleeding within 24 hours post-ICU admission among 202 participants, it was not powered to detect cost differences, as cost data tend to be highly variable and often require larger sample sizes than clinical outcomes. Furthermore, the cost of cryopreserved platelets used in the trial may be overestimated, as production costs would likely decrease if cryopreserved platelets were manufactured routinely, rather than as a clinical trial product.
Conclusions
This economic evaluation found that among patients undergoing cardiac surgery in metropolitan hospitals in Australia, standard therapy with liquid-stored platelets was more effective and cost-efficient than cryopreserved platelets for managing active bleeding. However, further evaluation of the potential costs and benefits of cryopreserved platelets implementation in regional and remote settings may be warranted to ensure equitable access to emergency bleeding management across the country.
eTable 1. Unit costs of resource utilisation for the CLIP-II trial
eTable 2. Components of cryopreserved platelet costs per unit obtained from the Australian Red Cross Lifeblood
eTable 3. Subgroup analyses by complexity of cardiac surgeries
eFigure 1. Cost-effectiveness plane of incremental costs and total postoperative bleeding for CPP vs LSP (adjusted)
eFigure 2. Cost-effectiveness plane incremental costs and incremental effectiveness (24-hour bleeding for CPP vs LSP (unadjusted)
eFigure 3. Cost-effectiveness plane incremental costs and total postoperative bleeding for CPP vs LSP (unadjusted)
eFigure 4. Cost-effectiveness plane of incremental costs and incremental effectiveness (BARC4 bleeding) for CPP vs LSP
eFigure 5. Cost-effectiveness plane of incremental costs and incremental effectiveness (90-day mortality) for CPP vs LSP
eReferences.
Data Sharing Statement
References
- 1.Prax M, Bekeredjian-Ding I, Krut O. Microbiological screening of platelet concentrates in Europe. Transfus Med Hemother. 2019;46(2):76-86. doi: 10.1159/000499349 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Flint AW, McQuilten ZK, Irwin G, Rushford K, Haysom HE, Wood EM. Is platelet expiring out of date: a systematic review. Transfus Med Rev. 2020;34(1):42-50. doi: 10.1016/j.tmrv.2019.08.006 [DOI] [PubMed] [Google Scholar]
- 3.Valeri CR. Hemostatic effectiveness of liquid-preserved and previously frozen human platelets. N Engl J Med. 1974;290(7):353-358. doi: 10.1056/NEJM197402142900702 [DOI] [PubMed] [Google Scholar]
- 4.Jimenez-Marco T, Castrillo A, Hierro-Riu F, Vicente V, Rivera J. Frozen and cold-stored platelets: reconsidered platelet products. Platelets. 2022;33(1):27-34. doi: 10.1080/09537104.2021.1967917 [DOI] [PubMed] [Google Scholar]
- 5.Johnson L, Reade MC, Hyland RA, Tan S, Marks DC. In vitro comparison of cryopreserved and liquid platelets: potential clinical implications. Transfusion. 2015;55(4):838-847. doi: 10.1111/trf.12915 [DOI] [PubMed] [Google Scholar]
- 6.Reade MC, Marks DC, Howe BD, et al. Cryopreserved vs Liquid Platelets II (CLIP-II) Investigators; the Australian and New Zealand Intensive Care Society Clinical Trials Group; the Australian and New Zealand College of Anaesthetists Clinical Trials Network; Australasian Society of Cardiac and Thoracic Surgeons . Cryopreserved vs liquid-stored platelets for the treatment of surgical bleeding: the CLIP-II randomized clinical trial. JAMA. Published online December 8, 2025. doi: 10.1001/jama.2025.23355 [DOI] [Google Scholar]
- 7.Husereau D, Drummond M, Augustovski F, et al. ; CHEERS 2022 ISPOR Good Research Practices Task Force . Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) statement: updated reporting guidance for health economic evaluations. Value Health. 2022;25(1):3-9. doi: 10.1016/j.jval.2021.11.1351 [DOI] [PubMed] [Google Scholar]
- 8.Reade MC, Marks DC, Howe B, et al. ; CLIP-II and CLIPNZ-II Investigators.; CLIP-II and CLIPNZ-II Investigators . Cryopreserved platelets compared with liquid-stored platelets for the treatment of surgical bleeding: protocol for two multicentre randomised controlled blinded non-inferiority trials (the CLIP-II and CLIPNZ-II trials). BMJ Open. 2022;12(12):e068933. doi: 10.1136/bmjopen-2022-068933 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Orman Z, Reade MC, Marks DC, et al. Health economic analysis plan for the CLIP-II trial: Comparing cryopreserved platelets with conventional liquid-stored platelets in the management of surgical bleeding. Accessed December 17, 2024. https://www.monash.edu/__data/assets/file/0011/3808550/HEAP-CLIP-FINAL-1.1.pdf
- 10.Flint AWJ, Bailey M, Reid CM, et al. Preoperative identification of cardiac surgery patients at risk of receiving a platelet transfusion: the Australian Cardiac Surgery Platelet Transfusion (ACSEPT) risk prediction tool. Transfusion. 2020;60(10):2272-2283. doi: 10.1111/trf.15990 [DOI] [PubMed] [Google Scholar]
- 11.World Bank . Purchasing power parity conversion factor (GDP) (LCU per international $)—Australia. Accessed November 18, 2025. https://data.worldbank.org/indicator/PA.NUS.PPP?year=2023
- 12.National Health Service in England . National cost collection for the NHS. Accessed April 15, 2025. https://www.england.nhs.uk/costing-in-the-nhs/national-cost-collection/
- 13.Hicks P, Huckson S, Fenney E, Leggett I, Pilcher D, Litton E. The financial cost of intensive care in Australia: a multicentre registry study. Med J Aust. 2019;211(7):324-325. doi: 10.5694/mja2.50309 [DOI] [PubMed] [Google Scholar]
- 14.Australian Bureau of Statistics . Consumer Price Index, Australia. Accessed October 8, 2024. https://www.abs.gov.au/statistics/economy/price-indexes-and-inflation/consumer-price-index-australia/jun-quarter-2024
- 15.Independent Health and Aged Care Pricing Authority . National hospital cost data collection: public sector report, 2021-22. Accessed November 21, 2025. https://www.ihacpa.gov.au/resources/national-hospital-cost-data-collection-nhcdc-public-sector-2021-22
- 16.National Blood Authority . Annual report 2022-23. Accessed November 21, 2025. https://www.blood.gov.au/sites/default/files/documents/nba-annual-report-2022-23.pdf
- 17.Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736-2747. doi: 10.1161/CIRCULATIONAHA.110.009449 [DOI] [PubMed] [Google Scholar]
- 18.Stokes ME, Ye X, Shah M, et al. Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients. BMC Health Serv Res. 2011;11(1):135. doi: 10.1186/1472-6963-11-135 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Zbrozek A, Magee G. Cost of bleeding in trauma and complex cardiac surgery. Clin Ther. 2015;37(9):1966-1974. doi: 10.1016/j.clinthera.2015.06.007 [DOI] [PubMed] [Google Scholar]
- 20.Newcomb AE, Dignan R, McElduff P, Pearse EJ, Bannon P. Bleeding after cardiac surgery is associated with an increase in the total cost of the hospital stay. Ann Thorac Surg. 2020;109(4):1069-1078. doi: 10.1016/j.athoracsur.2019.11.019 [DOI] [PubMed] [Google Scholar]
- 21.Christensen MC, Krapf S, Kempel A, von Heymann C. Costs of excessive postoperative hemorrhage in cardiac surgery. J Thorac Cardiovasc Surg. 2009;138(3):687-693. doi: 10.1016/j.jtcvs.2009.02.021 [DOI] [PubMed] [Google Scholar]
- 22.Al-Attar N, Johnston S, Jamous N, et al. Impact of bleeding complications on length of stay and critical care utilization in cardiac surgery patients in England. J Cardiothorac Surg. 2019;14(1):64. doi: 10.1186/s13019-019-0881-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kreuger AL, Caram-Deelder C, Jacobse J, Kerkhoffs JL, van der Bom JG, Middelburg RA. Effect of storage time of platelet products on clinical outcomes after transfusion: a systematic review and meta-analyses. Vox Sang. 2017;112(4):291-300. doi: 10.1111/vox.12494 [DOI] [PubMed] [Google Scholar]
- 24.Reade MC, Marks DC, Bellomo R, et al. ; Cryopreserved vs Liquid Platelet (CLIP) Investigators, the Australian and New Zealand College of Anaesthetists Clinical Trials Network, and the Australian and New Zealand Intensive Care Society Clinical Trials Group . A randomized, controlled pilot clinical trial of cryopreserved platelets for perioperative surgical bleeding: the CLIP-I trial (Editorial, p. 2759). Transfusion. 2019;59(9):2794-2804. doi: 10.1111/trf.15423 [DOI] [PubMed] [Google Scholar]
- 25.Cohn CS, Dumont LJ, Lozano M, et al. Vox Sanguinis International Forum on platelet cryopreservation. Vox Sang. 2017;112(7):e69-e85. doi: 10.1111/vox.12532 [DOI] [PubMed] [Google Scholar]
- 26.Fedele PL, Polizzotto MN, Grigoriadis G, et al. Profiling clinical platelet and plasma use to inform blood supply and contingency planning: PUPPY, the prospective utilization of platelets and plasma study. Transfusion. 2016;56(10):2455-2465. doi: 10.1111/trf.13778 [DOI] [PubMed] [Google Scholar]
- 27.Cobain TJ, Vamvakas EC, Wells A, Titlestad K. A survey of the demographics of blood use. Transfus Med. 2007;17(1):1-15. doi: 10.1111/j.1365-3148.2006.00709.x [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Unit costs of resource utilisation for the CLIP-II trial
eTable 2. Components of cryopreserved platelet costs per unit obtained from the Australian Red Cross Lifeblood
eTable 3. Subgroup analyses by complexity of cardiac surgeries
eFigure 1. Cost-effectiveness plane of incremental costs and total postoperative bleeding for CPP vs LSP (adjusted)
eFigure 2. Cost-effectiveness plane incremental costs and incremental effectiveness (24-hour bleeding for CPP vs LSP (unadjusted)
eFigure 3. Cost-effectiveness plane incremental costs and total postoperative bleeding for CPP vs LSP (unadjusted)
eFigure 4. Cost-effectiveness plane of incremental costs and incremental effectiveness (BARC4 bleeding) for CPP vs LSP
eFigure 5. Cost-effectiveness plane of incremental costs and incremental effectiveness (90-day mortality) for CPP vs LSP
eReferences.
Data Sharing Statement
