BTS response to the national shortage of alteplase in relation to pleural infection management

The Department of Health and Social Care released a National Patient Safety Alert (NPSA) on 3 August 2022 in response to a national shortage of alteplase (tPA or Actilyse®). A disruption to supply chains has occurred and it is expected there will be some issues for the remainder of 2022.

Read the National Patient Safety Alert here

Alteplase is licenced for use in the treatment of acute myocardial infarction (MI), acute ischaemic stroke and massive pulmonary embolism (PE) with haemodynamic instability. It can also be used in combination with dornase alfa (DNase) for the treatment of pleural infection particularly where surgical options are not suitable for a patient or surgical access is delayed for any reason (MIST-2 study1 ).

Going forward national alteplase supplies will be prioritised towards treatment of acute stroke, MI and PE. It may thus be less available for treatment of pleural infection. BTS has taken advice from the BTS Pleural Specialty Advisory Group (SAG), in consultation with the wider pleural community to propose alternative best options. These are outlined below.

Proposed stepwise approach to intrapleural therapy for pleural infection in the context of limited availability of alteplase:

• Optimise use of existing alteplase supplies by using a lower dose of 5mg combined with DNase (i.e. alteplase 5mg + DNase 5mg twice daily for 3 days) ∑
  
  
• Where alteplase is not available - urokinase 100,000 U + DNase 5mg twice daily for 3 days as an alternative ∆
  
  
• If access to both fibrinolytic agents becomes restricted (or in centres without existing access), intrapleural 0.9% sodium chloride irrigation 250ml three times daily for 3 days can be used (as per the PIT study protocol5) as an alternative

Note: Randomised controlled trial level data for an alternative with equivalent efficacy is absent. Above are best likely alternatives.

∆: Urokinase or DNase used as monotherapy is not effective - combination is advised 2 . Adequate safety data for use of these agents in combination in the human pleural space exists. Urokinase supply chains are likely to be stressed by the alteplase shortage.

∑: Based on the case series data from ADAPT study3 suggest temporarily using half dose (5mg) alteplase in the MIST-2 regimen to optimise the use of existing supplies. Alteplase comes in vials of various doses, including 10mg. We have confirmed from the summary of product characteristics that the reconstituted solution is stable for 24 hours if kept in the fridge (2oC – 8oC)4. Thus, a single 10mg vial can be partially used and then stored to deliver a full day of alteplase treatment for a patient however this is a decision for clinicians to take in consultation with their local pharmacy department.

BTS is grateful for the assistance of the following in the preparation of this information:
EO Bedawi, JM Wrightson, R Bhatnagar, A Bibby, S Walker, A Stanton, D De Fonseka, RJ Hallifax, A Clive, L McNaughton, K Blyth, K Marshall, J Corcoran, E Belcher, M Munavvar, N Maskell, N Rahman, and M Evison.

References:

1. Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CW, Ali N, Kinnear W, Bentley A, Kahan BC, Wrightson JM, Davies HE, Hooper CE, Lee YC, Hedley EL, Crosthwaite N, Choo L, Helm EJ, Gleeson FV, Nunn AJ, Davies RJ. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011 Aug 11;365(6):518-26. doi: 10.1056/NEJMoa1012740. PMID: 21830966.
   
   
2. Luque Paz D, Bayeh B, Chauvin P, Poizeau F, Lederlin M, Kerjouan M, Lefevre C, de Latour B, Letheulle J, Tattevin P, Jouneau S. Intrapleural use of urokinase and DNase in pleural infections managed with repeated thoracentesis: A comparative cohort study. PLoS One. 2021 Sep 21;16(9):e0257339. doi: 10.1371/journal.pone.0257339. PMID: 34547022; PMCID: PMC8454966.
   
   
3. Popowicz N, Bintcliffe O, De Fonseka D, Blyth KG, Smith NA, Piccolo F, Martin G, Wong D, Edey A, Maskell N, Lee YCG. Dose De-escalation of Intrapleural Tissue Plasminogen Activator Therapy for Pleural Infection. The Alteplase Dose Assessment for Pleural Infection Therapy Project. Ann Am Thorac Soc. 2017 Jun;14(6):929-936. doi: 10.1513/AnnalsATS.201609-673OC. PMID: 28324671.
   
   
4. Actilyse – summary of product characteristics (smpc) – EMC https://www.medicines.org.uk/emc/medicine/308#gref
   
   
5. Hooper CE, Edey AJ, Wallis A, Clive AO, Morley A, White P, Medford AR, Harvey JE, Darby M, Zahan-Evans N, Maskell NA. Pleural irrigation trial (PIT): a randomised controlled trial of pleural irrigation with normal saline versus standard care in patients with pleural infection. Eur Respir J. 2015 Aug;46(2):456-63. doi: 10.1183/09031936.00147214. Epub 2015 May 28. PMID: 26022948.