Ed – this post supports a webinar Dan gave with Thrombosis UK. We hope to link to that content when it’s ready.
First of all, thanks to Thrombosis UK for inviting me to speak at this webinar and to all of you who dialled in. We had over 800 participants from 6 continents registered. Events like this are a wonderful opportunity for us to share international understanding and experience of this complex disease.
This is a very interesting time to be an intensivist with a research interest in blood clots. As such I wanted to use this time to talk about how COVID 19 has changed our approach to diagnostics, therapeutics and even to evidence-based medicine. This blog post accompanies the talk, highlighted on the thrombosis UK website, and contains hyperlinked references to the literature discussed. Like always at St Emlyns, we would strongly encourage you to review this literature for yourself and draw your own conclusions on the matter.
How do we usually diagnose VTE?
We have a long standing approach to acute VTE diagnosis across the world; brains and blood tests. We use our clinical experience to consider VTE within the differential of any presentation, and we then use our gestalt and objective clinical risk scores to try and estimate pretest probability. Until March, the evidence base had been firmly supportive of this and had even been pushing us away from invasive testing, with new NICE guidance endorsing the PERC rule and supporting higher cut points for d-dimer rule out testing. However, COVID-19 now makes this tricky. Can we be sure that the PERC/Wells/Geneva score perform equally well in patients with COVID-19 who are acutely unwell? And how do we decide which patients to investigate for concurrent VTE? Everyone is hypoxic and tachycardic. We perhaps need to reset our thresholds for testing in COVID-19 patients and consider a lower threshold for investigation as suggested by the British Thoracic Society, particularly for those patients who are very unwell,
The D-dimer would usually be our friend in this situation. However, even old friends can’t be trusted in these perilous times. The D-dimer has previously been helpful given the excellent negative likelihood ratio with most modern assays, at a standard cut point of 500ng/mL FEU1. There are 2 problems with this now. First, it is difficult to identify which COVID-19 patients are clearly at low pretest probability. Second, the inflammatory nature of COVID-19 and the in-situ release of fibrin degredation products within local lung tissue, mean that the d-dimer level is usually above the standard cut point in >84% of hospitalised patients2. A test that will be positive in >80% patients having it, is often a test not worth doing….
Several authors have tried to reset the bar for exclusion of VTE, using retrospective cohort data. Leonard-Lorent et al3 suggest that a new cut point of >2660ng/mL may be sufficient to exclude VTE. This data is not generalisable and needs further prospective validation work. Cui et al4 examine the diagnostic test characteristics associated with a cut point of >1500ng/mL and report a sensitivity of only 85%. Any test that misses 15% of PEs is not one I will be rushing to adopt…
So, we are onto Imaging then?
Yes. Absolutely. Everyone’s getting a CXR of course, with hypoxia out of keeping with radiological changes potentially spurring us on to further tests for VTE. POCUS for the win is then a likely war cry from the ultrasound enthusiasts, but outside of lower limb screening I am genuinely not sure how helpful this is in our current situation. All the usual markers of RV strain, pulmonary hypertension and RV dysfunction can unfortunately be mimicked by severe COVID-19 in isolation. I have had multiple calls from colleagues over the last few weeks asking about empirical thrombolysis for deteriorating patients with US evidence of RV dysfunction – we have gone on to image all after careful discussion and none (as yet) have had central PE. Just goes to show….
V/Q has little place in imaging of the unwell, given the ventilation abnormalities seen with COVID-19. As such when we need a definitive answer, it appears we are looking at CTPA imaging. The British Society of Thoracic imaging has produced a good guideline on the role of CT imaging that promotes early use when the clinical picture does not quite fit the chest XR. They have also expanded on this in a later review article5, where they highlight the challenges of VTE diagnosis and support CTPA imaging where the diagnosis will affect patient management. There is also discussion of hybrid techniques such as ‘dual energy’ scans. Where we should place the bar for this imaging however, is a matter for real discussion. And it behoves us all to consider every imaging request carefully. If we are writing ‘worsening hypoxaemia’ or ‘failure to wean’ on our request cards, then we are essentially screening, rather than diagnosing symptomatic events. We need to bear this in mind as we consider incidence.
What are we finding, when we do investigate these patients?
A lot of our reports have been coming back as ‘suspicious’ for small subsegmental emboli. Interesting stuff. Is this genuine thromboembolic disease? Or is this more of an in situ immunothrombosis secondary to local inflammation, exaggerated by challenges with inter-rater reliability and assessor bias? We have, after all, seen this latter phenomenon before with ARDS6. However, lots of recent publications suggest high composite incidence rates of VTE outside the lung in COVID-19 patients. Could COVID-19 carry an additional risk of both immunothrombosis AND proximal disease? To answer that, I suppose we need to examine what the baseline incidence is of VTE in critical care, whether that incidence is altered in COVID-19 patients, and what the histopathological findings are in these patients.
Baseline incidence rates are always hotly debated topics on critical care, as units and regions are heterogenous and practice widely variable. However, ‘the harder you look for it, the more you will find’ rings true for VTE throughout the literature, as it does for many other conditions. In randomised controlled studies of vascular access catheter placement for example, screening during follow up will pick up VTE in >1/5th of patients7. If you add on a CTPA every time you want to image someone’s lungs, as previous researchers have done,8 you will find PE in about the same proportion. And if you systematically screen for the incidence of DVT in all patients admitted to critical care9, you will find disease in at least 10% of patients. That is 4 times more DVT than you would see without surveillance, even in the most recent studies. Add all these issues together as a composite outcome, and it becomes clear that there is a lot of VTE in critical care. How much of it is symptomatic, and how much needs treatment, are long standing questions.
Comparing these findings to recent observational cohort data on critically ill patients with COVID19, we see equally high, if not higher rates of disease. Helms et al10 report a 25% PE rate in those imaged, while Middledorp2 and Klok11 report composite VTE incidence rates of 47 and 49%, respectively. We are all clearly looking hard for VTE.
What about the anatomy of disease?
This is where it gets particularly interesting. The anatomical location of VTE in these cohort studies is different, and asks real questions about the genuine thromboembolic nature of disease. When compiling the Helms, Middledorp and Klok data, we see the vast majority of disease reported as segmental and subsegmental PE. Other studies, such as that by Ren et al12, further highlight low rates of proximal disease and report high event rates for distal DVT, on screening. Such anatomy lends itself well to the theory of local immunothrombosis in situ, rather than thromboembolic VTE from bedrest/inflammatory illness.
Histological findings from autopsy studies also suggest high rates of microvascular thrombi. Lax et al13 note thrombosis of small and mid-sized arteries in 100% of 11 autopsy patients with COVID-19, and report that segmental and subsegmental vessel thrombosis may contribute to mortality. Certainly, this concept has face validity – if a patient has multiple diseased lung units with shunt from alveolar inflammation and oedema, coupled to dead space from microvascular emboli in good lung units, it is easy to see a hypoxic spiral. Wichmann et al14 report more proximal thrombi in addition to diffuse alveolar damage. Patients can clearly have proximal VTE when critically unwell, as they always could, but they also seem prone to higher rates of microvascular complication with COVID.
So, what shall we do about treatment for all this?
Firstly, I think it is worth highlighting that we don’t know the exact answer to this question at present. The literature continues to emerge and requires careful critical appraisal. As such, every decision on investigation and treatment of VTE in these patients should be made by a senior MDT where possible, and be based on the balance of risks and benefits for the intervention proposed. We have always tried to do this for our critically ill patients and have a lot experience on balanced decision making from neuroscience, trauma and other specialties – we should continue to weigh up every case to determine individual benefit and risk profiles for any treatment.
If we have a confirmed diagnosis of VTE, a desire to treat and an absence of major bleeding risk, the key treatment appears to be heparin at therapeutic dose. Jecko Thachil has written a great summary on the versatility of heparin15 and the multiple potential effects of this drug, in addition to anticoagulation. Potential efficacy from anti-inflammatory action, endothelial protection and anti-viral properties are all highlighted. Certainly, experience with heparin compounds and their ability to side step issues with absorption, hepatic excretion, therapeutic range16 and complex drug interactions make them an ideal choice for use in the most severely ill patients. Only when the dust has settled and patients are making a good recovery, does enteral therapy seem sensible. There are caveats though – heparin monitoring in COVID-19 may be challenging using routine APTR guidance, given the high levels of factor 8 and vWF17 leading to shortened APTR values and a risk of overanticoagulation. Many centres are opting directly for factor Xa monitoring at usually established time intervals, in attempt to assure themselves of adequate anticoagulation.
What about empirical treatment for those at highest risk?
If we have not diagnosed VTE, but are worried about risk in general, then should we just treat everyone with therapeutic dose heparin? Some articles propose this, citing a decreased hazard ratio for anticoagulated patients admitted to critical care, and raising the issue of CT imaging being impractical in severely ill patients. I am not sure I agree with the latter, as this is simply another question of risk, and I am certainly not sure the evidence base we have justifies empirical treatment dose anticoagulation. This research letter has led to several convincing media headlines, but is at real risk of multiple sources of bias as an uncontrolled study, and through multiple known and unknown confounders.
Are there any other options?
Many clinicians have sought to use tissue plasminogen activator for this disease, when severe. The rationale for this can be clearly understood, but the risks of therapy are unclear. A case series in JTH suggests that of 3 patients receiving a half dose regimen of thrombolysis, only 1 had a potentially sustained benefit in oxygenation. Other case series abound, but we should be cautious about using this low level of evidence to promote broad use of a therapy we know to be harmful, in all but the most severe cases of proximal PE. We have also previously experimented with various nebulised anticoagulant options in ARDS. Clinical data is limited and the issues with aerosol generation in COVID-19 add further challenges to this avenue of intervention.
Interventional radiology is another option for those with bleeding risks, but huge logistical challenges surround the transfer of COVID patients to a theatre environment. And if these clots are small, then this is a therapy unlikely to be of widescale benefit.
Many clots described in the literature are occurring in situ with iatrogenic devices, or within extracorporeal circuits. There are always alternative pharmacological and mechanical options for this type of disease. Re-site the line, heparinise the circuit, lock the line with medication; we use regional citrate for our renal replacement therapy for example, and chose to increase the dose based on early experience of reduced filter life.
Last but not least, we perhaps need to think outside the box. If COVID-19 is indeed a disease of in situ immunothrombosis, with local inflammation predisposing to microvascular changes, then perhaps anticoagulation just won’t cut it. Many argue we should be looking upstream at immunomodulatory agents in order to treat this disease and starting them early in attempt to avoid the downstream complications of multi-organ inflammation and failure. We are lucky to have several randomised controlled trials in the UK already leading on this, with the RECOVERY trial and REMAP-CAP recruiting to a wide platform of novel agents, in attempt to provide high level evidence that can inform patient care.
What are the risks of treatment, and do we understand them?
Lastly, when talking about the benefits of treatment for VTE, we have to talk about the risks. As previously mentioned on the webinar, these treatments are not benign. Although we are far better at recording VTE outcomes than we are bleeding, early data paints a bleak picture. The powerful RIETE registry is already rising to this challenge, with unpublished data suggesting a 5.5% major bleeding risk with intermediate dosing in a real world cohort. The publication from Mount Sinai reports a 7.5% major bleeding rate with anticoagulation in critically ill patients – 3 times what we would expect. And of course there are consequences to all other potential therapies – immunomodulation, steroids, device exchange and removal. Every patient will be different. Hence the importance of balancing risk.
What is happening to help solve these issues?
Thankfully, lots of research is in motion to help us. Therapeutic anticoagulation in COVID-19 is being assessed within the context of multiple randomised controlled trials; ATTAC for hospitalised patients, RAPID COVID COAG for hospitalised patients at high risk by d-dimer and REMAP-CAP for patients admitted to critical care. Even dipyridamole is being dusted off the shelf and repurposed. All these prospective high quality trials will help shine a light on the risks and benefits of empirical therapy prior to diagnosis of VTE and help us share decision making with our patients and families. VTE screening studies are in progress as well, with clinically relevant outcomes in the design. Lastly, t-PA has not been left behind. Several projects such as this one have been set up to evaluate the use of this drug in COVID-19 and capture a real picture of the associated harms.
What do we do until then?
What to believe and when to change is always hard. My personal take on this is that severely ill patients on ICU are highly complex, and do not lend themselves well to broad algorithmic based care. They get the best deal from senior MDT discussion, informed by accurate and up to date history, imaging and coagulation studies, such that individual decisions on risk/benefit can be made. Perhaps think about how you foster such care on your units and in your hospitals.
This article by Chris Nickson et al highlights some of the key issues involved with changing practice when the data is not robust. First, it is essential to consider other evidence in your decision making; we cannot forget all we know about thrombosis and bleeding in these difficult times. Second, the burden of proof required for practice change is by definition affected by the nature of the therapy. I would argue that both empirical therapeutic dose anticoagulation and t-PA require a high burden of proof given their established bleeding rates. Comparative cost effectiveness, labour intensiveness and critical appraisal will of course all figure in the decision making.
There is lots to think about. But then there always is, with big decisions, that have serious consequences for our patients.
I hope that was a helpful summary.
Best wishes all, and here’s hoping your lockdown ends any day now…..
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