Thrombolytics have proven efficacy and an acceptable safety profile in the management of central venous access devices in cancer care. The choice of agent used is governed by many factors, including availability, convenience, comparative efficacy and cost
Helen Roe MSc
Chemotherapy Forum Lead, UKONS;
Consultant Cancer Nurse/
Acute Oncology Service Lead,
North Cumbria University Hospitals NHS Trust, UK
Venous access is a necessity for many patients with cancer due to treatment regimes being complex, and in some instances requiring repeated or continual venous access.(1) Access is achieved through the use of central venous access devices (CVADs), which include implanted ports, skin-tunnelled or non-skin-tunnelled catheters and peripherally inserted central catheters. Because these are centrally placed, they allow large volumes of fluid to be infused directly into the venous circulation, including intravenous drugs, fluids, blood products and parental nutrition(2) and cytotoxic drugs (especially vesicant drugs).(3)
This form of administration allows for rapid dilution of the fluids in a safe and comfortable manner, as well as minimising the risk of chemical phlebitis and possible extravasation.(1) In 2013, the American Society of Clinical Oncology (ASCO) produced a set of clinical guidelines regarding the management of CVADs, which recommended routine flushing with saline and the use of a tissue plasminogen activator for restoring patency of occluded CVADs. They no longer recommended the prophylactic use of warfarin or low-molecular weight heparin.(4)
Common causes of device occlusion
The insertion of a CVAD is not without complications, although these are often underestimated.(4) A common complication is catheter occlusion,(1) of which there are two main classifications.
Intraluminal occlusion is associated with reflux of blood into the lumen of the device, which in turn causes thrombus formation that ultimately occludes the catheter. Another cause may be connected to the mixing of drugs and/or infusate in the lumen, which can cause precipitation and ultimately occlusion3 or when there is inadequate flushing between drugs.(1)
Extraluminal occlusion occurs most frequently when a fibrin sheath has formed around the catheter, usually encompassing the tip. This results in withdrawal occlusion, which is an inability to aspirate because the fibrin sheath acts as a ‘one-way valve’, that is, when applying negative pressure while attempting to aspirate through the catheter, the fibrin sheath prevents aspirations. However, the fibrin sheath is pushed away from the tip of the catheter when applying positive pressure, allowing drugs to be infused through the catheter.(3) This type of occlusion may initially present as a partial occlusion when the infusion of drugs and/or infusate and the aspiration of blood is sluggish.(1)
Other external causes are pressure on the device caused by tumour mass or enlarged lymph glands pressing on the catheter, kinking or twisting of the catheter, external clamps, or sutures that have been secured too tightly and cause constriction of the catheter. Compression of the catheter between the clavicle and first rib as a result of the patient raising or lowering the arm is often referred to as ‘pinch off syndrome’ and can result in catheter breakage. The CVAD may also become damaged or fractured due to a traumatic insertion, or if the original CVAD was defective.(2)
The incidence of CVAD-associated thrombus in patients with cancer is reported to be between 27% and 66% when routine screening has been performed, although it must be remembered that many patients remain asymptomatic(4) and therefore might not be screened.
Use and importance of thrombolytics
Patients with cancer may be at a higher risk of developing thrombosis because of tumour cell activation causing hypercoagulability of clotting, vessel wall injury and stasis.(1) However, it is thought that most CVAD occlusions are due to poor infusion technique, that is, flushing CVADs and disconnecting other devices.(1) There is also evidence supporting the fact that the chemotherapy may cause chemical phlebitis, which then leads to thrombosis.(5)
The need to remove a CVAD prematurely can be distressing for patients, especially if the device was inserted because of poor venous access,(6) and can have consequences in terms of a negative effect on quality of life,(1) as well as the possible need for hospitalisation.(4) This process can lead to a delay in delivering treatment,(1) which can translate to a further risk of morbidity and mortality.(2)
It is therefore imperative that assessment of possible causes is undertaken and patency restored depending on the cause of the occlusion(6) before considering removal. If the cause is found to be a fibrin sheath creating a partial occlusion, a lineogram/cathetergram can demonstrate the extent of the occlusion.(3) A Cochrane review was undertaken in 2012 into the interventions for restoring patency of occluded central venous catheter lumens.(2) It concluded that there was only low-quality evidence regarding the effectiveness of using thrombolytic agents to unblock thrombus-occluded lumens. However, they did acknowledge that the numbers in the studies were low and there could have been a degree of bias introduced because of the study designs.(2)
Managing an occluded CVAD
If the device is occluded because of a thrombus or fibrin sheath, consideration should be given to instilling an anti-thrombolytic agent into the CVAD. This is usually carried out with a 10ml syringe containing the anti-thrombolytic agent and employing a gentle push-pull technique. This method and the size of the syringe ensures that too much pressure is not applied, which could lead to the catheter rupturing.(3)
If this method is not successful, the three-way tap technique can be used, that is, attaching an empty 10ml syringe and another 10ml syringe containing the anti-thrombolytic agent to a three-way tap. The tap to the CVAD is closed and aspiration into the empty syringe is carried out, thereby creating a vacuum. The tap to the empty syringe is then closed and the anti-thrombolytic agent is aspirated into the CVAD to dissolve the fibrin/thrombus.(3) This technique might need to be carried out a number of times and is not always successful.
The final option before removal is to set up an infusion of an anti-thrombolytic agent.3 Removal and replacement of a CVAD is an invasive procedure, with associated risks for the patient; it is also costly.(1) ASCO guidance recommends that this be done when a radiologically confirmed thrombus does not respond to treatment.(4)
Urokinase-type plasminogen activator was the standard anti-thrombolytic agent used for the management of occluded CVADs until around 1999, when it was removed from the market because of concerns around possible contaminating pathogens in the product. A number of other products have been used in an attempt to resolve occluded CVADs, with some success;2 in many cases the use has been ‘off license’. Alteplase, a tissue-type plasminogen activator, is one such product.(2) It is produced from the Chinese hamster ovary cell line, using a recombinant DNA technique, and is licensed as a thrombolytic treatment for both acute myocardial infarctions and pulmonary embolism and, as a fibrinolytic treatment, for acute ischaemic stroke.(7)
Another key drug that has been used is streptokinase,(1) which originates from β-haemolytic streptococci8 and is licensed for thrombolytic treatment of acute myocardial infarction, deep vein thrombosis, pulmonary embolism and retinal venous and arterial thrombosis.(8) Because of the risk of developing antibodies to streptokinase, which can ultimately reduce the effectiveness of future treatments, streptokinase should not be repeated beyond four days of the prior treatment.(9)
Many drugs have been used in an attempt to restore the patency of occluded CVADs, including heparin. However, the Cochrane Review undertaken in 2012 felt that there was only low-quality evidence that appeared to suggest that urokinase may be effective in treating thrombus occlusions (withdrawal or total), of CVADs in both children and adults.(2) Although there are currently a number of drugs listed in the British National Formulary that have ‘thrombolytic treatment of occluded CVADs’ listed under indications, only urokinase and Actilyse Cathflow® specify dosages.(9)
Actilyse Cathflow® is only licensed as a thrombolytic treatment for occluded CVADs and can be instilled into the lumen of the CVAD and left for 30 minutes before aspirating. If this is unsuccessful, a repeat dose can be delivered two hours after the first.(10)
Syner-Kinase® is a highly purified form of urokinase derived from human urine. Because it is of human origin, it is not antigenic, although some allergic reactions have been reported following its use. It is offered in the form of a freeze-dried powder that can be stored at room temperature and is reconstituted with sterile saline. It has the additional benefit of not containing human albumin.
The licensing indications for Syner-Kinase® have changed recently, and it is the only licensed thrombolytic agent in the UK for the ‘lysis of blood clots in thrombosed intravascular catheters’ as an infusion or instillation and may be used in the management for adults and children of all ages.(8) Additional uses include the management of extensive acute proximal deep vein thrombosis, acute massive pulmonary embolism and acute occlusive peripheral arterial disease with limb-threatening ischaemia.(11) When managing an occluded CVAD, the same administration procedures can be used for managing both children and adults, that is, Syner-Kinase® 5000-25,000 IU instilled in the lumen and left for between 20 and 60 minutes before removal. This procedure may require repetitions, alternatively as an infusion over 90-180 minutes.(11)
When considering using Syner‑Kinase®, patients must be assessed for contraindications, precautions and interactions with other medications they might be receiving.(11) This anti-thrombotic agent is eliminated rapidly from circulation by the liver and has a half-life of 20 minutes. Caution must be used when treating the elderly and those with hepatic impairment. The fibrinolytic affect of Syner-Kinase® may increase the thrombin time. Decreased plasma levels of fibrinogen and plasminogen and increased levels of degradation products of fibrinogen and fibrin are observed up to 24 hours following discontinuation of an infusion.(8)
There are limited data relating to its use in pregnant women and so is not advised to be used during pregnancy or in the immediate post-partum period unless no alternative option is available. One point to consider is that Syner-Kinase® contains highly purified urokinase, obtained from human urine, hence there is a possible risk of the transmission of infectious agents, but there are strict controls in place to reduce this risk. (Evidence is required that all batches of product are free from HIV, hepatitis B and hepatitis C and that there is no risk of the product transmitting animal spongiform encephalopathy agents.)
Although there are few data from clinical trials relating to possible side effects to Syner-Kinase®, these may include a local sensation of warmth, dull ache in the vessel being treated, pyrexia, increased risk of bleeding and embolic events following the release of the ‘clot fragment’.(8,11)
Consideration needs to be given to maintaining venous access of patients receiving treatment for cancer in terms of an ongoing process, including the importance of managing occlusions with anti-thrombolytic agents when appropriate. UK practice guidelines need to reflect best practice and newer products that are available or changes in their licensed indications concerning managing this frequent complication in both children and adults. Practice needs to be based on evidence that relates to availability of drugs in the UK, because different drugs are available and have different licensed indications in other countries. As always, there is a need for further research into the management and outcomes of occluded CVADs in light of the increased number of these devices being used in everyday practice in the UK.
- Consider the individual patient requirements regarding the need for a central venous access device (CVAD) and potential risk of complications.
- If the CVAD becomes occluded, ensure the patient is fully assessed and the cause established.
- Attempt to salvage the CVAD by using antithrombolytic agents when appropriate.
- Removal of a CVAD should be a last resort, and ensure that the implications of this are discussed with the patient.
- Ensure local guidelines are based on the latest evidence available and reflect products accessible in the UK.
- Cummings-Winfield C, Mushani-Kanji T. Restoring patency to central venous access devices. Clin J Oncol Nurs 2008;12(6):925-34.
- Van Miert C, Hill R,Jones L. Interventions for restoring patency of occluded central venous catheter lumens (review). Cochrane Database Syst Rev 2012;4:CD007119.
- Gabriel J. Vascular device occlusion: causes, prevention and management. Nurs Stand 2011;25:49-55.
- Schiffer C et al. Central venous catheter care for the patients with cancer: American Society of Clinical Oncology Clinical Guidelines. J Clin Oncol 2013;31(10):1357-70.
- Kahan J et al. Venous thrombosis rates in early breast cancer patients receiving standard chemotherapy, a retrospective analysis. Investigations and treatment of upper limb symptoms. Eur J Cancer 2011;47(S238):0959.
- Gabriel J. Vascular access devices: securement and dressing. Nurs Stand 2010;24(52):41-6.
- Boehringer Ingelheim Ltd. Actilyse. Summary of Product Characteristics;2011. www.medicines.org.uk/emc/document.aspx?documentId=308 (accessed 1 July 2013).
- Goldberg LA. Urokinase for managing central venous catheters. Hosp Pharm Eur 2007;32:47-8.
- Joint Formulary Committee. British National Formulary 2013. Fibrinolytic drugs;2.10.2:163-5.
- Boehringer Ingelheim Ltd. Actilyse Cathflo. Summary of Product Characteristics. www.medicines.org.uk/emc/medicine/24604 (accessed 1 July 2013).
- Syner-Med. Syner-Kinase. Summary of Product Characteristics. www.medicines.org.uk/emc/medicine/19031/spc (accessed 1 July 2013).