Although no signal was found in clinical trials, a case series of stage III hypertension with mRNA CoV-2 vaccines (8 with tozinameran Pfizer, 1 with mRNA-1273 Moderna) was recently reported [1], suggesting that hypertension could be an adverse drug reaction (ADR) of Covid-19 vaccines. In order to validate this signal, we investigated the data registered in VigiBase®, the WHO pharmacovigilance database [2].
Reports with known age and gender in patients ≥ 18 years, reported with tozinameran, Vaxzevria® Astra Zeneca, mRNA-1273 and NRVV-Ad26 Janssen by physicians and registered between 1 January 2021 and 10 May 2021, were extracted. The study was, first, a description of hypertension and investigation of a potential signal using disproportionality analyses [3, 4]: cases were reports containing the MedDRA term “hypertension” and defined as “suspected or interacting” and non-cases all other reports. Second, we assessed the specific risk of each vaccine. Sensitivity analyses were performed, first, including only hypertension occurring after 24 h, 48 h or 72 h in order to investigate occurrence delays and, second, according to age groups (18–44, 45–64, 65–74, ≥ 75 years). Risk was calculated using the reporting odds ratio (ROR), a ratio similar to the odds ratio in case–control studies with 95% confidence intervals. RORs were adjusted on age, gender and exposure to antihypertensive and antidiabetic drugs.
Among the 175,916 reports, 91,761 involved Covid-19 vaccines with 1776 hypertension: 1325 with tozinameran (mean age 62 (18) years, 76% females, 5% in association with antihypertensives, 1% with antidiabetics), 392 with Vaxzevria® (59.1 (13.9) years, 64%, 7%, 1%), 58 with mRNA-1273 (71.9 (15.9) years, 88%, 10%, 3%) and 1 with NRVV-Ad26. The main coreported term was headache (22% for tozinameran and Vaxzevria®, 20% for mRNA-1273). Tozinameran was associated with a higher risk of hypertension compared to non-users (ROR = 2.25 (2.08–2.43)). No association was found for Vaxzevria® (ROR = 1.02 (0.92–1.14)) or mRNA-1273 (ROR = 0.88 (0.68–1.14)). A higher reporting risk was also found for tozinameran versus Vaxzevria® or mRNA-1273 in the whole population (Table 1) as well as in the different age groups (not shown). We also found increased RORs including only hypertension occurring 24, 48 or 72 h after vaccination (Table 1).
Table 1.
Adjusted reporting odds ratios for the association between hypertension and exposure to the different Covid-19 vaccines in VigiBase®
| Cases | Non-cases | Adjusted RORa | 95% CI | |
|---|---|---|---|---|
| Hypertension | ||||
| Tozinameran versus Vaxzevria® | 1325/392 | 56,534/26,842 | 1.40 | 1.25–1.58 |
| Tozinameran versus mRNA-1273 | 1325/58 | 56,534/3518 | 1.76 | 1.36–2.32 |
| Hypertension after 24 hb | ||||
| Tozinameran versus Vaxzevria® | 515/139 | 57,250/27,040 | 1.42 | 1.18–1.72 |
| Tozinameran versus mRNA-1273 | 515/31 | 57,250/3540 | 1.40 | 0.99–2.07 |
| Hypertension after 48 hb | ||||
| Tozinameran versus Vaxzevria® | 339/92 | 57,426/27,087 | 1.39 | 1.10–1.77 |
| Tozinameran versus mRNA-1273 | 339/23 | 57,426/3548 | 1.26 | 0.84–1.98 |
| Hypertension after 72 hb | ||||
| Tozinameran versus Vaxzevria® | 261/69 | 57,504/27,110 | 1.44 | 1.10–1.89 |
| Tozinameran versus mRNA-1273 | 261/16 | 57,504/3555 | 1.39 | 0.87–2.41 |
ROR reporting odds ratio, CI confidence interval, 95% CI 95% confidence interval, Cases reports of hypertension in VigiBase®, Non-cases all other reports in VigiBase®
aRORs were adjusted on age, gender and exposure to antihypertensive and antidiabetic drugs
bHypertension ≥ 24 h (48 h, 72 h) means that analysis were performed with only cases of hypertension occurring 24, 48 or 72 h after vaccination
The study shows that hypertension was reported as ADRs with Covid-19 vaccines. We found a signal for tozinameran but not for Vaxzevria®. The results with mRNA-1273 should be interpreted cautiously due to the small number of reports. Mechanisms of hypertension remain unknown. One could suggest an increase in sympathetic tone for immediate hypertension and/or an interaction with the renin-angiotensin system for tardive hypertension. Involvement of vaccine excipients could be also discussed. Finally, we found that most of hypertension with tozinameran is delayed: 39% occurred after 24 h, 26% after 48 h and 20% after 72 h.
The study has some limitations. The main one is underreporting, as in any pharmacovigilance study based on spontaneous reporting. However, it was shown that underreporting does not differ within the same therapeutic group [5]. Another concern is the possibility of confounding, such as comorbidity factors or unknown data. We circumvented the difficulty associated with the absence of blood pressure values by including only reports reported by physicians, thus improving clinical validity. The main strengths are inclusion of reports collected throughout the whole world, which allows generalization of results and use of a method validated to detect rare events [3, 4] and previously found to be in accordance with meta-analyses [6].
Despite these compulsory limits, an increased risk of hypertension was found with tozinameran compared to other vaccines, requiring further studies to confirm and fully interpret this signal. These results suggest the value of measuring arterial blood pressure in vaccinated patients. Further studies are warranted to determine the incidence of new-onset hypertension following administration of different Covid-19 vaccines and its clinical implications.
Acknowledgements
The authors acknowledge the Uppsala Monitoring Centre (UMC) that provided and gave permission to use the data analysed in the present study. The authors are indebted to the National Pharmacovigilance Centres that contributed data. The opinions and conclusions in this study are not necessarily those of the various centres or of the WHO or ANSM (Agence Nationale de Sécurité du Médicament et des produits de santé, France).
Author contribution
BB, JLM, FM and FH designed the study. ST extracted the data from the database and performed the statistical analysis. All the authors analysed and discussed the data. All the authors reviewed the successive versions of the manuscript and approved the final version.
Funding
The work was performed during the university research time of the authors using the database, which is available without fees in the department of the authors. According to French law, review from the ethics committee is not required for such observational studies. Doctor François Montastruc has received funding under the Vigi-Drugs COVID-19 project from the French National Research Agency (ANR, Agence Nationale de la Recherche) for the evaluation of pharmacovigilance data of drugs and vaccines used in the management or prevention of Covid-19. 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.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
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References
- 1.Meylan S, Livio F, Foerster M, Genoud PJ, Marguet M, Wuerzner G, on behalf of the CHUV COVID Vaccination Center Stage III hypertension in patients after mRNA-based SARS-CoV-2 vaccination. Hypertension. 2021;77:e56–e57. doi: 10.1161/HYPERTENSIONAHA.121.17316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Moore N, Berdaï D, Blin P, Droz C. Pharmacovigilance - the next chapter. Therapie. 2019;74:557–567. doi: 10.1016/j.therap.2019.09.004. [DOI] [PubMed] [Google Scholar]
- 3.Montastruc JL, Sommet A, Bagheri H, Lapeyre-Mestre M. Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database. Br J Clin Pharmacol. 2011;72:905–908. doi: 10.1111/j.1365-2125.2011.04037.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Faillie JL. Case-non-case studies: principle, methods, bias and interpretation. Therapie. 2019;74:225–232. doi: 10.1016/j.therap.2019.01.006. [DOI] [PubMed] [Google Scholar]
- 5.Pierfitte C, Bégaud B, Lagnaoui R, Moore ND. Is reporting rate a good predictor of risks associated with drugs? Br J Clin Pharmacol. 1999;47:329–331. doi: 10.1046/j.1365-2125.1999.00881.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Khouri C, Petit C, Tod M, et al. Adverse drug reaction risks obtained from meta-analyses and pharmacovigilance disproportionality analyses are correlated in most cases. J Clin Epidemiol. 2021;134:14–21. doi: 10.1016/j.jclinepi.2021.01.015. [DOI] [PubMed] [Google Scholar]