Anticoagulation and antiplatelet therapy can reduce risk for venous thromboembolism in COVID-19; however, research suggests these treatments may not influence risk for mortality, speakers reported.

Moreover, researchers concluded that colchicine should not be used in patients with COVID-19, regardless of illness severity.

Three trials presented at the European Society of Cardiology Congress evaluated the utility of anticoagulant and antiplatelet therapies in the setting of SARS-CoV-2 infection, at the outpatient, inpatient and ICU settings: ACT Outpatient, ACT Inpatient and COVID-PACT.

John W. Eikelboom

“Clearly, the world has been overwhelmed with SARS-CoV-2, with an estimated 3.8 billion people infected by the end of 2021,” John W. Eikelboom, MBBS, MSc, professor in the division of hematology and thromboembolism, Jack Hirsh/PHRI chair in thrombosis and atherosclerosis research at McMaster University and Canada research chair in cardiovascular medicine at the Canadian Institutes for Health Research, said during a press conference. “We understood that the two major features of disease progression are a florid immune response and hypercoagulability. Importantly, at postmortem, more than 80% of patients have small vessel thrombosis that we believe is a reason for organ failure and death.”

Colchicine and aspirin in outpatient setting

The ACT Outpatient trial was a multinational, open-label, factorial, randomized trial that evaluated the utility of anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin for outpatients with SARS-CoV-2.

Researchers enrolled 3,917 outpatients in 11 countries and independently compared colchicine with controls and aspirin with controls for a total treatment duration of 28 days.

The primary outcome in the colchicine cohort was a composite of hospitalization or death.

The occurrence of the primary outcome (colchicine, 3.4%; controls, 3.3%; P = .93), or either of the individual components, was no different in the colchicine group compared with controls (hospitalization: colchicine, 3.2%; controls, 3.1%; P = .92; death: 0.6% in both groups; P = .84).

The primary outcome in the aspirin cohort was a composite of major thrombosis, hospitalization or death. It was not significantly different between the aspirin group compared with controls (aspirin, 3%; controls, 3.8%; P = .21).

“We found no evidence for benefit of either colchicine or aspirin in outpatients with COVID-19,” Eikelboom said during the press conference. “We saw much lower than expected rates of thromboembolism, only about one to two per 1,000, and much lower rates of hospitalization, only about one in 30, than we had originally planned for. The mortality rate, however, was as expected, about one in 200.”

Over the duration of the trial, which was conducted between August 2020 and February 2022, the researchers observed waning event rates in both arms of the study, which Eikelboom attributed to the emergence of less virulent strains of SARS-CoV-2, the rise of herd immunity and changing medical practice.

“The results of the ACT Outpatient trial provide no reason to use either colchicine or aspirin in outpatients with COVID-19,” Eikelboom said. “We recognize that neutral trials are never as exciting as positive trials, but they are critically important because hereby we identify treatment that should not be used, and we can redirect our attention to other areas.”

Colchicine and rivaroxaban/aspirin in inpatient setting

The ACT Inpatient trial was an open-label, factorial, randomized trial that evaluated the utility of colchicine and rivaroxaban (Xarelto, Janssen/Bayer) for inpatients with COVID-19.

The researchers enrolled 2,500 patients and randomly assigned them 1:1:1:1 to receive colchicine and rivaroxaban plus aspirin, colchicine alone, rivaroxaban plus aspirin or neither for 28 days.

The primary outcome for patients who received colchicine was a composite of death, mechanical ventilation or need for high flow oxygen.

Researchers observed no difference in the primary outcome between patients who received colchicine and those who did not (colchicine, 28.2%; controls, 27.2%; P = .58). There was also no difference between the groups in mechanical ventilation or need for high flow oxygen (colchicine, 18.9%; controls, 19.3%; P = .84) or in death (colchicine, 20.2%; controls, 19.1%; P = .38).

The primary outcome for patients who received rivaroxaban plus aspirin was a composite of major thrombosis, death, mechanical ventilation or need for high flow oxygen.

Researchers observed no difference in the composite primary outcome between patients who received rivaroxaban plus aspirin and those who did not (rivaroxaban/aspirin, 26.4%; controls, 28.4%; P = .32). There was also no difference between the groups in any thrombosis (P = .63), high flow oxygen or ventilation (P = .27) and death (P = .66).

Sanjit Jolly

“Colchicine should not be used in the treatment for patients hospitalized with COVID-19,” Sanjit Jolly, MD, MSc, clinical trialist and interventional cardiologist at McMaster University, said during the press conference. “Low-dose rivaroxaban and aspirin should not be used for patients hospitalized for COVID-19. Intensified anticoagulation does appear in the totality of data to reduce venous thromboembolism but does not reduce mortality.”

Jolly and colleagues also completed two meta-analyses to better evaluate the relationship between use of colchicine and anticoagulation in the setting of SARS-CoV-2 infection. The researchers determined there was no association between colchicine use and lower mortality in patients with COVID-19 (RR = 1; 95% CI, 0.94-1.07; P for heterogeneity test = .54) and although intensified anticoagulation reduced risk for venous thromboembolism (RR = 0.57; 95% CI, 0.44-0.73; P for heterogeneity test = .25), mortality was unaffected (RR = 0.94; 95% CI, 0.8-1.1; P for heterogeneity test = .03).

“When we put all of the data together in a meta-analysis, we in fact see no benefit in outpatients; no benefit in inpatients for mortality; and, together, colchicine does not have a role to play in the treatment of COVID-19, irrespective of the severity,” Jolly said during the press conference. “The story in anticoagulation is a little bit different and a little bit nuanced. On balance, if you intensify anticoagulation, you reduce venous thromboembolism by about 40%. But this 40% reduction in VTE does not appear to reduce mortality.”

Antithrombotics in COVID-19 requiring ICU admission

Patients admitted to the ICU with severe COVID-19 are at an approximately 10% to 20% increased risk for developing potentially life-threatening blood clots, David D. Berg, MD, MPH, cardiologist at Brigham and Women’s Hospital and member of the TIMI Study Group, said during the press conference.

Therefore, researchers conducted the multicenter, randomized controlled COVID-PACT trial to assess the efficacy and safety of clopidogrel plus anticoagulation therapy in this high-risk population.

Berg and colleagues enrolled 390 patients at 34 U.S. sites and, for 28 days or until hospital discharge, patients received either full-dose anticoagulation or standard-dose prophylactic anticoagulation, with or without clopidogrel.

The primary endpoint was a composite of death from venous/arterial thromboembolism, pulmonary embolism, clinically evident deep vein thrombosis, type 1 MI, ischemic stroke, systemic embolic event or acute limb ischemia and clinically silent deep vein thrombosis.

The secondary endpoint was a similar composite but excluded clinically silent deep vein thrombosis.

The COVID-PACT trial was halted early due to declining ICU admission for severe COVID-19.

In patients with severe COVID-19 requiring ICU admission, full-dose anticoagulation was associated with an approximately 44% reduction in risk for the primary endpoint compared with standard-dose prophylactic anticoagulation (HR = 0.56; 95% CI, 0.32-0.99; P = .046). The key secondary endpoint trended in favor of full-dose anticoagulation but was not significant (HR = 0.55; 95% CI, 0.28-1.08). The risk for all-cause mortality was not significantly different between the two regimes (HR = 0.91; 95% CI, 0.56-1.48).

The addition of clopidogrel to either anticoagulation regime did not significantly affect the primary or secondary outcomes (HR for primary endpoint = 0.9; 95% CI, 0.48-1.69; P = .75).

The primary safety outcome in the COVID-PACT trial was a composite of fatal bleeding and life-threatening bleeding and the secondary safety outcome was a composite of Global Strategies for Opening Occluded Coronary Arteries (GUSTO) moderate and severe bleeding.

Moderate bleeding was defined as requiring transfusion without hemodynamic compromise and severe bleeding was defined as fatal, intracranial or causing hemodynamic compromise.

Researchers observed no difference in the primary safety outcome between patients assigned to either anticoagulation strategy, with and without antiplatelet therapy. However, they did observe increased risk for GUSTO moderate and severe bleeding associated with full-dose anticoagulation compared with standard dose (P < .05).

“In critically ill patients with COVID-19, a strategy of full dose anticoagulation, as compared with standard-dose prophylactic anticoagulation, reduced clotting complications and increased non-life-threatening bleeding,” Berg said during the press conference. “Weighing clotting and bleeding risk, full dose anticoagulation should be considered to prevent blood clots in selected critically ill patients with COVID-19. These findings may be relevant when revisiting current consensus treatment guidelines for critically ill patients with COVID-19, including those managed with advanced noninvasive respiratory support, which were well represented in our trial cohort.”

References:

• Berg D, et al. Hot Line 10. Presented at: European Society of Cardiology Congress; Aug. 26-29, 2022; Barcelona, Spain (hybrid meeting).
• Jolly S, et al. Hot Line 10. Presented at: European Society of Cardiology Congress; Aug. 26-29, 2022; Barcelona, Spain (hybrid meeting).

Perspective

The first take-home message is that COVID-19 as a disease is clearly evolving. Whether that is because the virus itself is evolving, our therapies are evolving or, most likely, a combination of the two, it does mean that we have to remember that findings from a prior iteration of COVID-19 may not apply to what we are seeing in our patients today. That was nicely highlighted in Dr. Eikelboom’s presentation. He showed how the hospitalization and death rates have changed over time, and importantly, how the impact of an anti-inflammatory drug like colchicine, which maybe would have had more benefit earlier on, is not much from February 2021 onwards. That is a striking finding that I take away from the trials as a whole.

Another point that stands out is that many of our original theories about how thrombosis occurs for patients with COVID-19 have not necessarily led to therapies that we can easily implement. We think there is likely an inflammatory component leading to thrombosis, so you would think that drugs that attack the inflammatory system like colchicine would be beneficial. But now we see two studies, one in hospitalized patients and one in ambulatory patients, showing colchicine did not seem to have any real impact.

When we look at the role of antiplatelet agents, there were underwhelming results across the board. That leaves us with our traditional approach of anticoagulation, for which we need to figure out who is the right patient, what is the right drug, what is the right dose and what is the right timing. Those are the four questions we have to ask when trying to figure out when to give anticoagulation to prevent thrombosis.

What was intriguing was that the researchers found such a striking benefit in the reduction of thrombotic events with full-dose anticoagulation in the sickest of the sick patients in the ICU. At first glance, that goes against the prior literature where we found no benefit with therapeutic-dose anticoagulation. However, COVID-PACT was looking at thrombotic endpoints and not at mortality endpoints. There is likely some disconnect between those two. We are seeing some consistency that anticoagulation can reduce thrombotic events. Whether that translates to actual mortality outcomes, we have not yet seen, at least in the most critically ill patients.

Geoffrey Barnes, MD, MSc

Associate Professor of Internal Medicine

University of Michigan