How do you define a last-ditch effort to save someone’s life from COVID-19? Perhaps giving tPA to a severe COVID patient? At this point, I am certain many of us have attempted, with informed consent of course, therapies for our patients that may make theoretical sense but have no evidence to support its use. At the beginning of the pandemic, we understood the hypercoagulability that we were seeing in our patients. The pulmonary emboli, the DVT’s, the d-dimers that were through the roof. For those of us who checked a plethora of labs daily attempting to understand what we were dealing with at the beginning, we noted that there was a correlation between an increasing d-dimer and severity of illness in many patients. As data came out, we realized we were correct in autopsies showing disseminated pulmonary microvascular thrombosis.
When we did not have data to support using dexamethasone or methylprednisolone, many of us were already using it. Many of us used tocilizumab or other such medications before the data supported it, as well. This was simply because it made physiologic sense. From the get-go, many of us recognized that COVID was an inflammatory problem. The data was also coming down the pipeline, but we had patients and families begging us to try something to help them out.
Obviously, we want to do no harm. But only after a few short weeks of dealing with the pandemic, we understood that mechanical ventilation was not compatible with recovery for most. Some of us tried tPA in our COVID patients, much to the chagrin of the academic medical community. Seems like these trial authors may have felt the same way. The positive thing for all of us is that they had the research know-how to create a study out of their hypothesis.
How they performed the study of tPA in COVID
I have to tip my hat to the authors of this trial. They actually started randomizing COVID patients to provide them with tPA in May of 2020. For historical context, the RECOVERY trial showing benefit of dexamethasone had not yet been published. They were able to enroll patients out of eight academic hospitals in the US. They described their paper as a “vanguard, phase 2a, multicenter, open-label, rapidly adaptive, pragmatic, randomized controlled clinical trial”. To me, this means that they were figuring out how to do this on the fly. And appropriately so. Someone with more clinical trial knowhow can educate me should I be wrong. They enrolled 50 patients in total. All on the vent. All sick as stink, as one could imagine.
In the first phase, 36 COVID patients were randomized to receive a 50mg bolus of tPA, 10mg first, then 40mg over the next two hours. A heparin drip was used thereafter for several days. The second phase enrolled patients 37-50 where they received the same 50mg (10mg then 40 over 2 hours) as the first phase, but here they received a tPA drip at 2mg/hr for a total of 24 hours of tPA. Heparin was also used after that for this second phase.
What are the outcomes of giving tPA to COVID Patients?
The ambitions of the authors were reasonable. Their primary outcome was an improvement in oxygenation at 48 hours. The COVID patients had an improvement in their P/F ratio that was statistically significant at 48 hours. Per these data, it seems as if the tPA helped the oxygenation of these patients. The authors also set up a composite outcome that was also positive. One might ask if giving tPA to COVID patients helps with mortality, days on mechanical ventilation, length of stay in the ICU, etc. Here, there are no differences. Although we need to be academically honest with ourselves as this study is not powered for these outcomes. As I write/say that, there was a trend towards benefit in these departments. But trends really don’t mean anything.
When we’ve provided tPA to our COVID patients, we also have informed consent and thorough discussions with family members about what we are trying. The main concern is bleeding. After all, we are providing tPA which could potentially cause more trouble than we bargained for. Thankfully, there was no statistically increased adverse event incidence nor bleeding event incidence. Table 5, which shows the adverse events, is quite impressive in the level of detail provided by the authors.
Should we actually start providing tPA to COVID patients?
The way I choose to interpret these data are that providing tPA to COVID patients can potentially help, will no signals of harm. Between you and I, one could definitely see where harm could happen. That’s a reason why I would strongly recommend significant documented informed consent prior to utilizing this therapy on your patients. After all, this is not medical advice. In my practice, I have done this before. That should make it clear where I stand. The authors are wise in recommending a phase 3 study. I wonder what they’re doing in their practice today, though. As always, read these data for yourself and do not trust me! For more blog posts I’ve written on COVID, CLICK HERE.
Citations for tPA in COVID
Barrett CD, Moore HB, Moore EE, Wang J, Hajizadeh N, Biffl WL, Lottenberg L, Patel PR, Truitt MS, McIntyre RC Jr, Bull TM, Ammons LA, Ghasabyan A, Chandler J, Douglas IS, Schmidt EP, Moore PK, Wright FL, Ramdeo R, Borrego R, Rueda M, Dhupa A, McCaul DS, Dandan T, Sarkar PK, Khan B, Sreevidya C, McDaniel C, Grossman Verner HM, Pearcy C, Anez-Bustillos L, Baedorf-Kassis EN, Jhunjhunwala R, Shaefi S, Capers K, Banner-Goodspeed V, Talmor DS, Sauaia A, Yaffe MB. Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial. Chest. 2022 Mar;161(3):710-727. doi: 10.1016/j.chest.2021.09.024. Epub 2021 Sep 27. PMID: 34592318; PMCID: PMC8474873.
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