PACER Trial

Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia (the PACER trial)

Van Baarle FLF, Van De Weerdt EK, Van Der Velden WJFM, Ruiterkamp RA, Tuinman PR, Ypma PF, et al. Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia. N Engl J Med. 2023 May 25;388(21):1956–65.

Blog written by Dr Jose Chacko 

Background

The risk of major bleeding complications associated with the insertion of central venous catheters (CVC) in thrombocytopenic patients is considered to be low. Variable thresholds are followed for prophylactic platelet transfusion, ranging between 20 –50,000, based on guideline recommendations and clinical experience (1–3). However, no robust evidence supports an optimal threshold for prophylactic platelet transfusion before CVC insertion. The routine use of ultrasound guidance may reduce the incidence of bleeding complications (4); evidence from retrospective studies suggest CVC insertion may be safe even with platelet counts less than 20,000/cu mm (5). There is concern regarding transfusion-related complications, besides shortage of platelets due to their short shelf-life.

In the Prophylactic Platelet Transfusion before Central Venous Catheter Placement in Patients with Thrombocytopenia (PACER) trial, investigators hypothesized that in patients with a platelet count between 10–50,000/cu mm, the risk of catheter-related bleeding complications might not increase without prophylactic platelet transfusion (6).

Population and design

The PACER trial was conducted across the hematology wards and ICUs of 10 hospitals in the Netherlands. Patients with a platelet count between 10–50,000/ cu mm within 24 hours of the procedure were eligible. They were randomized in a 1:1 ratio to receive prophylactic transfusion of one unit of platelet concentrate or no transfusion before CVC insertion. The study was unblinded. Randomization was stratified according to center and by catheter type – whether dialysis catheter or regular CVC.

Excluded

Patients on therapeutic anticoagulation, those with a history of coagulation factor deficiency, or an INR of ≥1.5 were excluded. The upper limit of INR was later raised to 3.0 based on fresh evidence suggesting higher-level safety.

Procedure

CVC insertion was performed under ultrasound guidance by experienced operators who had performed at least 50 procedures. All procedures were performed according to local guidelines within 1 hour of randomization. The catheter could be of any diameter, tunneled or non-tunneled, and could be inserted into the internal jugular, subclavian, or femoral vein. The incidence and severity of bleeding were assessed using the scale proposed by Zeidler et al. (7) (Table 1).

Table 1. Assessment of grade of bleeding (Zeidler et al.⁷)

Sample size

The authors assumed that 1% of patients will have grade 2, and none, grade 3 or 4 bleeding. A non-inferiority margin of 2.5% absolute increase in the risk of grade 2–4 bleeding was assumed in the no-transfusion group. This corresponded to an upper limit of the confidence interval (CI) of 3.5 in the relative risk. A sample size of 196 in each group provided the trial with 80% power to establish the non-inferiority of a strategy of no prophylactic platelet transfusion with a one-side alpha level of 0.05.

Results

Among 411 patients who underwent randomization, 393 were included in the intention-to-treat analysis – 18 patients were excluded for lack of appropriate consent. The per-protocol analysis was carried out on 373 patients after excluding patients who had crossed over, met exclusion criteria, or had other protocol violation. There was no loss to follow up. Patients were well-matched at baseline; the median platelet count was 30,000 in both groups. The most common approach was internal jugular, followed by the subclavian, and femoral veins.

The primary outcome: grade 2–4 bleeding

The incidence of grade 2–4 bleeding within 24 hours of placement was higher in the no-transfusion group [22/ 185 (11.9%) vs. 9/288 (4.8%); relative risk: 2.45, 95% CI: 1.27–4.70]. The upper limit of the CI for relative risk exceeded the pre-set non-inferiority margin of 3.5. Thus, non-inferiority of a no prophylactic platelet transfusion strategy could not be established. A secondary analysis revealed a higher risk of grade 2–4 bleeding with lower platelet counts, with the highest risk between 10,000 to 20,000/cu mm

Other bleeding-related outcomes

Grade 1 bleeding was also more common in the no-transfusion group. Grade 4 bleeding was not reported in either group. The risk of grade 3 or 4 bleeding was also lower in the prophylactic transfusion group (2.1% vs. 4.9%) (Table 2). There was no significant difference in the number of red- cell transfusions within 24 hours of CVC placement; however, the no-transfusion group received more red-cell transfusions for CVC-associated bleeding. The ICU length of stay was shorter in the no-transfusion group; mortality was similar in both groups.

Table 2. Incidence of bleeding

Other outcomes

Patients in the transfusion group had higher platelet counts at 1 and 24 hours after CVC insertion. In the 24-hour period following CVC insertion, the no-transfusion group received more platelet transfusions.  On subgroup analysis, bleeding complications were more among hematology patients compared to ICU patients and with tunnelled compared with non-tunnelled catheters. Three allergic reactions and one case of transfusion-associated lung injury were reported.

Cost analysis

The overall costs were higher in the transfusion group mainly due to the cost of prophylactic platelet transfusion, with a net saving of $410 per catheter placement.  However, in the first 24 hours after CVC insertion, the cost related to transfusion was higher in the no-transfusion group.

Conclusion

Among patients who underwent CVC insertion with a platelet count of 10 –50,000/cu mm, bleeding complications were higher without prophylactic platelet transfusion. The pre-defined margin of non-inferiority of a no-transfusion strategy was not fulfilled.

Strengths 

• Multicenter, RCT with good external validity
• Included hematology and ICU patients
• Insertion using different approaches, tunneled and un-tunneled, dialysis catheters, and conventional central venous catheters – all reflecting real-world practice

Limitations

• The study was confined to the Netherlands
• The overall incidence of bleeding was substantially higher than previously reported (7)
• The results may not apply to the blind approach to CVC insertion
• Unblinded study – may have led to bias in assessment, although the investigators tried to keep the operator blinded to the assigned arm
• Platelet count was not carried out after prophylactic transfusion, prior to the procedure
• All patients received a single unit of platelet concentrate regardless of the count
• The clinical relevance of grade 2 bleeding may be questionable (bleeding stopped with compression for <20 min or a minor procedure)

References

1. Estcourt LJ, Birchall J, Allard S, Bassey SJ, Hersey P, Kerr JP, et al. Guidelines for the use of platelet transfusions. Br J Haematol. 2017 Feb;176(3):365–94.
2. Klein AA, Arnold P, Bingham RM, Brohi K, Clark R, Collis R, et al. AAGBI guidelines: the use of blood components and their alternatives 2016. Anaesthesia. 2016 Jul;71(7):829–42.
3. Vlaar AP, Oczkowski S, de Bruin S, Wijnberge M, Antonelli M, Aubron C, et al. Transfusion strategies in non-bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine. Intensive Care Med. 2020 Apr;46(4):673–96.
4. Cavanna L, Citterio C, Nunzio Camilla D, Orlandi E, Toscani I, Ambroggi M. Central venous catheterization in cancer patients with severe thrombocytopenia: Ultrasound-guide improves safety avoiding prophylactic platelet transfusion. Mol Clin Oncol. 2020 May;12(5):435–9.
5. van de Weerdt EK, Biemond BJ, Baake B, Vermin B, Binnekade JM, van Lienden KP, et al. Central venous catheter placement in coagulopathic patients: risk factors and incidence of bleeding complications. Transfusion (Paris). 2017 Oct;57(10):2512–25.
6. Van Baarle FLF, Van De Weerdt EK, Van Der Velden WJFM, Ruiterkamp RA, Tuinman PR, Ypma PF, et al. Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia. N Engl J Med. 2023 May 25;388(21):1956–65.
7. Zeidler K, Arn K, Senn O, Schanz U, Stussi G. Optimal preprocedural platelet transfusion threshold for central venous catheter insertions in patients with thrombocytopenia. Transfusion (Paris). 2011 Nov;51(11):2269–76.