Increased reporting of venous and arterial thromboembolic events reported with tixagevimab–cilgavimab for coronavirus disease 2019

Abstract

Objectives

As two phase three clinical trials indicated a disproportion in the number of thromboembolic events in the tixagevimab/cilgavimab group than in the placebo group, there has been a cardiovascular safety concern with the use of anti–SARS-CoV-2 monoclonal antibody (mAb). Whether tixagevimab/cilgavimab use in real life increases the risk of thromboembolic events is unclear.

Methods

We used VigiBase, WHO's individual case safety reports database, to assess the risk of reporting arterial or venous thromboembolic events in patients with COVID-19 (aged ≥12 years) exposed to tixagevimab/cilgavimab compared with patients with COVID-19 exposed to other anti–SARS-CoV-2 mAbs, including casirivimab/imdevimab, bamlanivimab/etesevimab and sotrovimab.

Results

Among the 8952 reports of patients with an anti–SARS-CoV-2 mAb, 31 reports of thromboembolic events were associated with tixagevimab/cilgavimab, mainly deep vein thrombosis (10), pulmonary embolism (8) and myocardial infarction (7). Compared with other anti–SARS-CoV-2 mAbs, the use of tixagevimab/cilgavimab was associated with an increased risk of reporting arterial thromboembolic events (reporting OR 3.25; 95% CI 1.73, 6.10). Concerning venous thromboembolic events, a significant increase in the risk of reporting was observed with the use of tixagevimab/cilgavimab (reporting OR 3.59; 95% CI 2.16, 5.96).

Discussion

This observational study corroborates in a real-world setting in which the cardiovascular safety signal has already been found for tixagevimab/cilgavimab in two clinical trials. Owing to these thromboembolic safety concerns and considering the lack of clinical trials supporting protection against the omicron variant, there is an urgent need to improve knowledge on the effectiveness of tixagevimab/cilgavimab with new COVID-19 variants.

Introduction

Tixagevimab/cilgavimab, casirivimab/imdevimab, bamlanivimab/etesevimab and sotrovimab are monoclonal antibodies (mAbs) with neutralizing activity against the spike protein of SARS-CoV [1]. They have been recommended by the Food and Drug Administration and the European Medicines Agency to prevent COVID-19 (pre or postexposure prophylaxis of COVID-19) or to treat early-stage COVID-19 in patients who are at a high risk of progressing to severe COVID-19. Although data suggest efficacy against alpha or delta variants of SARS-CoV-2, there are concerns about the risk of arterial or venous thromboembolic events with tixagevimab/cilgavimab [2]. In the phase three PROVENT trial, evaluating the effect of tixagevimab/cilgavimab for the prevention of symptomatic and severe COVID-19 in adults, there were a higher number of serious thromboembolic events in the tixagevimab/cilgavimab group than the placebo group (5‰ versus 2‰) [2,3]. Events reported with tixagevimab/cilgavimab were myocardial infarction (n = 9, with one death), pulmonary embolism (n = 2) and deep vein thrombosis. In another phase three clinical trial (TACKLE study), assessing whether tixagevimab/cilgavimab can treat outpatient adults with COVID-19 and prevent severe COVID-19, higher thromboembolic events were reported in tixagevimab/cilgavimab group than in placebo group (1.3% versus 0.4%) [2,4]. Considering this safety concern and the lack of real-world data, there is an urgent need for more information on the risk of thromboembolic events with tixagevimab/cilgavimab. We performed a large pharmacovigilance study to investigate the risk of reporting arterial or venous thromboembolic events in patients with COVID-19 treated with tixagevimab/cilgavimab compared with patients with COVID-19 treated with other anti–SARS-CoV-2 mAbs.

Methods

We used VigiBase, WHO's individual case safety reports database, to assess the risk of reporting arterial or venous thromboembolic events in patients with COVID-19 exposed to tixagevimab/cilgavimab compared with patients with COVID-19 exposed to other anti–SARS-CoV-2 mAbs (including casirivimab/imdevimab, bamlanivimab/etesevimab and sotrovimab). VigiBase contains more than 30 million spontaneously generated adverse drug reactions, from 136 countries, covering >90% of the world's population [5]. We considered only reports of patients (aged ≥12 years) with COVID-19 registered up to 12 July 2022. The risk of arterial or venous thromboembolic events was calculated using the reporting ORs (RORs) with their 95% CI, a ratio similar in concept to OR in case–control studies. The ROR corresponds to the exposure odds among reported cases of thromboembolic events over the exposure odds among reported non-cases [6]. As conducted in previous pharmacovigilance studies and to assess the robustness of the primary analysis, we made sensitivity analyses restricting to serious cases or limiting to one anti–SARS-CoV-2 mAb in the comparator group [7,8]. We also used the PRR method (Proportional reporting ratio method) which compares the rate of reporting of one event (here, arterial or venous thromboembolic events) among all reports for a given drug (tixagevimab/cilgavimab) with the rate of the same event among the other drugs (other anti–SARS-CoV-2 mAbs). A signal of disproportionate reporting was defined as a drug–event pair for which the statistical analyses led to a PRR ≥2 associated with a chi-square ≥4. According to clinical research in French law, a review from an ethics committee is not required for such observational studies. As all data from VigiBase were de-identified, patient-informed consent was not necessary.

Results

Among the 8952 reports of patients with an anti–SARS-CoV-2 mAb registered up to 12 July 2022, we found 164 thromboembolic events (1.8%), with 68 arterial and 100 venous thromboembolic events. These thromboembolic events originated from USA (118), Europe (42), Australia (2) and Singapore (1) involving mostly men (103, 63%), with a mean age of 64.5 years. We found 31 reports of thromboembolic events associated with tixagevimab/cilgavimab, mainly deep vein thrombosis (10), pulmonary embolism (8) and myocardial infarction (7). Most of the reports with tixagevimab/cilgavimab (n = 29, 94%) were serious according to the WHO definition [9].

Compared with other anti–SARS-CoV-2 mAbs, the use of tixagevimab/cilgavimab was associated with an increased risk of reporting arterial thromboembolic events (ROR 3.25; 95% CI 1.73, 6.10) (Table 1 ). Concerning venous thromboembolic events, a significant increase in the risk of reporting was observed with the use of tixagevimab/cilgavimab (ROR 3.59; 95% CI 2.16, 5.96). Results were consistent in sensitivity analyses, in particular, when we restricted to reports with serious effects. Using PRR method, we found disproportionate reporting of arterial thromboembolic events (PRR = 3.20, chi-square = 15.1) and venous thromboembolic events (PRR = 3.5, chi-square = 27.8).

Table 1.

Reporting OR for the association between thromboembolic events and the use of tixagevimab/cilgavimab for COVID-19 in VigiBase^c

Events	Casesb	Non-casesc	ROR (95% CI)a
Arterial thromboembolic events
Primary analysis
Anti-SARS-CoV-2 mAbsd	56	8334	1 (reference)
Tixagevimab/cilgavimab	12	550	3.25 (1.73, 6.10)
Restricting to reports of serious adverse effectse
Anti-SARS-CoV-2 mAbsd	49	5118	1 (reference)
Tixagevimab/cilgavimab	12	344	3.64 (1.92, 6.91)
Restricting to one anti-SARS-CoV-2 mAbs
Bamlanivimab/etesivimab	9	1987	1 (reference)
Tixagevimab/cilgavimab	12	550	4.82 (2.02, 11.50)
Casirivimab/imdevimab	35	4962	1 (reference)
Tixagevimab/cilgavimab	12	550	3.09 (1.59, 5.99)
Sotrovimab	12	1386	1 (reference)
Tixagevimab/cilgavimab	12	550	2.52 (1.13, 5.64)
Venous Thromboembolic events
Primary analysis
Anti-SARS-CoV-2 mAbsd	81	8309	1 (reference)
Tixagevimab/cilgavimab	19	543	3.59 (2.16, 5.96)
Restricting to reports of serious adverse effectse
Anti-SARS-CoV-2 mAbsd	77	5090	1 (reference)
Tixagevimab/cilgavimab	17	339	3.31 (1.94, 5.66)
Restricting to one anti-SARS-CoV-2 mAbs
Bamlanivimab/etesivimab	25	1971	1 (reference)
Tixagevimab/cilgavimab	19	543	2.76 (1.51, 5.05)
Casirivimab/imdevimab	47	4950	1 (reference)
Tixagevimab/cilgavimab	19	543	3.69 (2.15, 6.33)
Sotrovimab	9	1389	1 (reference)
Tixagevimab/cilgavimab	19	543	5.25 (2.43, 12.01)

mAbs, monoclonal antibodies; ROR, reporting OR.

^aROR is a ratio similar in concept to OR in case–control studies and corresponds to the exposure odds among reported cases of bradycardia over the exposure odds among reported non-case.

^bReports containing any terms including in the standard medical dictionary for regulatory activities Queries “Embolic and thrombotic events, arterial” or “Embolic and thrombotic events, venous” found in medical dictionary for regulatory activities, available at https://www.meddra.org/.

^cAll other adverse events.

^dCasirivimab/imdevimab, bamlanivimab/etesevimab and sotrovimab.

^eOccurrence of death, a life-threatening adverse event, inpatient hospitalisation or prolongation of hospitalisation, significant disability or congenital anomaly.

Discussion

Such pharmacovigilance analysis could be subject to limitations such as confounding by indication. To mitigate the confounding, we used as comparator group, anti–SARS-CoV-2 mAbs used in postexposure prophylaxis (casirivimab/imdevimab) or as a curative COVID-19 treatment (sotrovimab) in which the risk of thromboembolic events is higher than pre-exposure prophylaxis (cilgavimab/tixagevimab). Despite these methods, confounders, including risk factors of thromboembolic events could affect our findings. Another limitation is the under-reporting that could be differential between groups of comparison. In addition, owing to the nature of VigiBase (spontaneous reports), it could be that all the events recorded were not completely attributable to the drugs reported. We were unable to clinically validate the reports, in particular data concerning thromboembolic events. Given that arterial and venous thromboembolic events are previously identified safety concerns, it could be that these findings are due to surveillance bias, with more proactive screening findings of thromboembolic events. However, we can also assume that this monitoring applies to the whole class of anti–SARS-CoV-2 mAbs and, therefore, does not explain the disproportionality found.

The study corroborates in a real-world setting with the cardiovascular safety signal already determined with tixagevimab/cilgavimab in two clinical trials [[2], [3], [4]]. Owing to these thromboembolic safety concerns and considering the lack of clinical trials supporting protection against the omicron variant, there is an urgent need to improve knowledge on the effectiveness of tixagevimab/cilgavimab with new COVID-19 variants [10].

Author contributions

F.M. conceived and designed the study. F.M. acquired the data and did the statistical analyses. All authors analysed and interpreted the data. F.M. wrote the manuscript, and all authors critically revised the manuscript. F.M. supervised the study and is the guarantor. All authors approved the final version of the manuscript and are accountable for its accuracy.

Transparency declaration

F.M. has received funding under the Vigi-Drugs COVID-19 project from the French National Research Agency (Agence Nationale de la Recherche) for the evaluation of pharmacovigilance data of drugs and vaccines used in the management or prevention of COVID-19 (ANR-21-CO17-0001-01). The other authors certify that they have not received any funding from any institution, including personal relationships, interests, grants, employment, affiliations, patents, inventions, honoraria, consultancies, royalties, stock options/ownership or expert testimony related to this topic.

Editor: L. Scudeller