Abstract
Background
Since the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, administration of the currently available vaccines has mostly been recommended for subjects at high risk, including elderly populations on long-term oral anticoagulation therapy (OAT) with warfarin. However, there is no clear evidence of the stability of the International Normalised Ratio (INR) after vaccine administration in those subjects on long-term OAT. The present study aimed to investigate the effects of COVID-19 vaccination on anticoagulation levels in patients on long-term OAT.
Materials and methods
INR values of patients on long-term OAT who had undergone anti-SARS-CoV-2 vaccination from January to June 2021 were monitored for a total of 90 days follow-up after the first vaccination dose. These were then compared with INR values before vaccination. The second dose, when required, was administered during follow-up. Inclusion criterion was stable long-term INR for at least 6 months before vaccination. Exclusion criteria were recent surgery, intercurrent diseases, or treatment with medication that could compromise findings in the 3 months before vaccination and during follow-up.
Results
No differences were observed in the anticoagulation levels before and after COVID-19 vaccination in any of the patients studied: mean INR values were 2.39 (range 2.20–2.63) before vaccination and 2.40 (range 2.16–2.76) after vaccination (p=0.5). There was no difference in anticoagulation levels in relation to age, sex, indication for OAT, or type of vaccine (p>0.5). No bleeding or thrombotic complications were documented during follow-up.
Discussion
These are the first data to be reported on anticoagulation levels in patients on stable OAT after COVID-19 vaccination. No influence on the quality of OAT was detected after the vaccination; no bleeding or thrombotic complications were recorded in the follow-up. No difference between the four available COVID vaccines was found. Dose adjustment was only required in a few cases, thus confirming the stability of anticoagulation levels.
Keywords: warfarin, TTR, INR, COVID vaccination
INTRODUCTION
Herd immunity seems to be the most efficient strategy to prevent contagion and reduce hospitalisations after the outbreak of the SARS-CoV-2 pandemic, the public health emergency of international concern declared in January 20201,2.
In Europe, four vaccines are currently available: BNT162b2 (Pfizer-BioNTech [Pfizer New York, NY, USA]); mRNA-1273 (Moderna [ModernaTX, Cambridge, MA, USA]); ChAdOx1 nCov-19 (AstraZeneca [Cambridge, UK]); and Ad26.COV2.S (Johnson & Johnson/Janssen [Janssen Pharmaceuticals Beerse, Belgium]). Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is strongly recommended for the entire population, with priority to subjects at high risk, such as elderly populations affected by chronic diseases requiring long-term oral anticoagulation therapy (OAT) with warfarin3,4. Warfarin has a narrow therapeutic window, requiring regular testing of prothrombin time (PT) through the International Normalised Ratio (INR)5.
The SARS-CoV-2 vaccination campaign is still in progress in many countries and there is no clear evidence of INR stability after vaccine administration in long-term OAT. The present study aimed to investigate the effects of COVID vaccination on anticoagulation levels and the occurrence of bleeding and thrombotic events after vaccination in patients on long-term OAT.
MATERIALS AND METHODS
We analysed 320 patients on long-term OAT followed at the Thrombosis Centre of the Careggi University Hospital, Florence, who underwent anti-SARS-CoV-2 vaccination from January to June 2021. Inclusion criterion was stable long-term INR for at least 6 months before vaccination; exclusion criteria were recent surgery or invasive procedure, intercurrent diseases, or treatment with medication that could compromise findings in the 3 months before vaccination and during follow-up. The follow-up was conducted in the 90 days after the first vaccination dose (Figure 1).
Figure 1.
Flow-chart of the study
INR: International Normalised Ratio.
All vaccinations were administered according to the protocols established by the World Health Organization (WHO) strategic advisory group of experts (SAGE): Pfizer-BioNTech - two doses 21–28 days apart; Moderna - two doses 28 days apart; Astrazeneca - two doses with an interval of 8–12 weeks; Johnson & Johnson - one dose. All patients were invited to schedule the first INR check-up 1–2 weeks after vaccination and to report bleeding or thrombotic complications.
In our Center, the usual time interval between two INR measurements for patients on stable OAT is 18–21 days. Therefore, for each patient we considered the five INR values recorded before the date of the first dose of vaccination, corresponding to an observational period of approximately three months, and we calculated the median INR value before vaccination. Similarly, for each patient we considered the five INR results in the period following the first vaccination dose, and we calculated the median INR after vaccination. The second dose, when recommended, was administered as scheduled.
Therefore, the second vaccination dose was administered during follow-up (Figure 1).
We calculated warfarin dose variation between the two observational periods before and after vaccination, considering relevant dose adjustments when a variation ≥10% of the standard dose was required. We also calculated dose variations that occurred in the same population in the interval between 1st February and 1st July 2020.
Bleeding and thrombotic events occurring during follow-up were recorded.
Statistical analysis
A descriptive analysis was performed. Continuous variables are expressed as median with interquartile range (IQR) or as mean±standard deviation (SD). Categorical variables are expressed as frequencies and percentages. Preliminary statistical analysis was performed using Wilcoxon’s signed-rank test (continuous variables) or Fisher’s exact test (categorical data). p<0.05 was considered statistically significant.
SPSS v.26 software (SPSS Inc., Chicago, IL, USA) for Windows was used for data processing.
RESULTS
A total of 320 patients were included in the study: 156 females (48.6%), mean age 77 years (SD±7). All patients were on OAT with warfarin. Indications for OAT are reported in Table I. The Pfizer-BioNTech vaccine was administered in 218 (68.1%), Moderna in 67 (21.2%), Astrazeneca in 31 (9.8%), and Johnson & Johnson in 4 (1.3%) patients.
Table I.
Clinical and demographic characteristics of patients enrolled in the study
| n | 320 |
| Male | 164 |
| Female | 156 |
| Age, years (mean±SD) | 77±7 |
| Mean TTR (%) (range) | 77 (18–100) |
| Indication for OAT | |
| Atrial fibrillation (%) | 158 (49.4) |
| Venous thromboembolism (%) | 72 (22.5) |
| Prosthetic heart valve (%) | 58 (18.1) |
| Other conditions (%) | 32 (10) |
N: number; SD: Standard Deviation; TTR: time in therapeutic range; OAT: oral anticoagulation therapy.
No differences in anticoagulation levels were observed before and after COVID-19 vaccination in any of the patients studied: mean INR values were 2.39 (range 2.20–2.63) before vaccination and 2.40 (range 2.16–2.76) after vaccination (p=0.5).
In addition, no difference was recorded in anticoagulation levels in relation to age, sex, indication for OAT, or type of vaccine (data not shown).
Warfarin dose adjustment was required in 53 patients (16.5%) after vaccination. When we examined the same population in the period from 1st February to 1st July 2020, dose adjustment was required in 50 patients (15.6%) (p=0.7).
No bleeding or thrombotic complications were documented during follow-up.
DISCUSSION
In Italy, COVID vaccination coverage is increasing, particularly among older patients and selected fragile groups at high risk; the aim is to achieve herd immunity as soon as possible2.
To our knowledge, this is the first study to report data on anticoagulation levels in patients on stable OAT after anti-SARS-CoV-2 vaccination.
The main findings of our study were that: 1) no influence on the quality of OAT was detected after vaccination; 2) and no bleeding or thrombotic complications were recorded during follow-up. Moreover, we did not find any difference between the four available COVID vaccines. Similar results have already been observed concerning influenza vaccination6. Dose adjustment was required in only a few cases, thus confirming the stability of anticoagulation levels. Moreover, dose adjustment was similar to that observed before vaccination.
Following the suggestions of The Italian Federation of Anticoagulation Clinics, we have invited all patients to schedule their vaccination as soon as possible. All patients were invited to report adverse events appropriately, and easy access to the Centre has been ensured. Therefore, taking into account the high level of alert due to the fear of vaccination, we are confident that, in our study, under-reporting is negligible.
This study has some limitations. Firstly, INR values were not determined within established time intervals. However, we enrolled only patients on stable OAT, and in the routine management of our centre, the median interval between INR determination was always approximately 3 weeks. Secondly, in the post-vaccination period, the great majority of patients received their second dose, and follow-up after the second dose was shorter. However, over 90% of the patients studied received Pfizer BioNTech or Moderna vaccines, both with the second dose scheduled after 3 or 4 weeks. Therefore, these patients were followed-up for at least 2 months. Since no significant difference in INR values had been recorded within this period, we decided not to continue with our observations, and the study was interrupted.
CONCLUSION
In conclusion, anti-SARS-CoV-2 vaccination with the four vaccines now approved in Europe does not affect anticoagulation levels in patients on stable warfarin treatment.
Footnotes
AUTHORSHIP CONTRIBUTIONS
DP and EL designed the research study. EL, CC and AM collected data. DP and EL analysed the data. DP and EL drafted and revised the manuscript. All Authors approved the final version of the manuscript.
The Authors declare no conflicts of interest.
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