Abstract
Objective
This study focused on Bulgarian patient cohorts harbouring a single documented chronic comorbidity–cardiovascular pathology, an oncological disease or a chronic pulmonary diseases (CPD) comparing the outcomes in fully vaccinated and non-vaccinated populations classified by sex and age groups in ambulatory, hospital and intensive care unit (ICU) settings at the national level.
Design
Retrospective analysis
Settings, participants and outcome measures
In total, 1 126 946 patients with confirmed COVID-19, on a national level, were retrospectively analysed between March 2020 and April 2022, using data from the Ministry of Health’s United Information Portal, launched in March 2020.
Results
Of all the confirmed 247 441 hospitalised cases of COVID-19, 67 723 (27.3%) had documented cardiovascular disease (CVD), 2140 (0.9%) had confirmed solid malignancy (regardless of stage) and 3243 (1.3%) had established CPD as their only chronic pathology. The number of cumulative deaths in each subgroup was 10 165 (in-hospital=5812 and ICU=4353); 4.0% vaccinated (410/10 165, p<0.001), 344 (in-hospital=196 and ICU=148), 4.9% vaccinated (17/344, p<0.001), 494 (in-hospital=287 and ICU=207) and 5.2% vaccinated (26/494, p<0.001), respectively. Statistical significance (p<0.001) was obtained in favour of reduced ambulatory, hospitalisation and both in-hospital and ICU-related mortality in the vaccinated cohorts, and BNT162b2 was the most effective at preventing mortality in all age groups.
Conclusions
This retrospective analysis shows that patients vaccinated against COVID-19 demonstrated trends of reduced hospitalisations and premature mortality in patients with CVD, solid malignancy or CPD as a single comorbidity.
Keywords: COVID-19, Public health, PREVENTIVE MEDICINE
STRENGTHS AND LIMITATIONS OF THIS STUDY.
To the best of our knowledge, this was the first study to directly compare the outcomes of vaccinated and non-vaccinated patients with COVID-19.
This study reported the observational associations in the outcomes of patients harbouring a single comorbidity at the national level during a set period of 2 years.
The study did not evaluate vaccine efficacy.
This study pooled different viral variants that dominated throughout a set time period.
The study pooled the effects of all the available vaccines in Bulgaria together.
Introduction
The pandemic caused by SARS-CoV-2 took everyone by surprise, despite warnings highlighting the importance of developing programmes involved in pathogen discovery in emerging disease hotspots, in addition to increasing health promotion for key modifiable risk factors as a strategy for pandemic preparedness.1 Unfortunately, because almost no such measures were taken globally, the pandemic led to countless unnecessary and premature deaths.2 3
Unfortunately, Bulgaria was among the leading countries with regard to the prevalence and mortality from chronic diseases (such as cardiovascular (CVD), oncological and chronic pulmonary diseases (CPD)), even before the COVID-19 pandemic.4 Therefore, higher vaccination rates are paramount for reducing additional premature deaths due to COVID-19 in the previously mentioned high-risk populations. Bulgaria currently occupies the lower end of the spectrum regarding vaccination status.5 During the first wave in March 2020, the country reacted swiftly by declaring a state of emergency and establishing various governance mechanisms and strict non-pharmacological measures. This initial response benefited from both a centralised approach and high level of public trust; however, it only proved to be a short-term solution.
Over time, political and economic considerations began to dominate decision-making, and public communication became contradictory, leading to a dramatic decline in public trust.6 This has resulted in vaccination rates dropping to a few hundred doses per day, while hospitalisation and mortality rates remain high. Unsurprisingly, according to surveys conducted by some independent sociological agencies, approximately 45% (of the 1008 participants) people were firmly against COVID-19 vaccines; in addition, approximately 30% were hesitant and unsure due to safety concerns in January 2021).7 According to the Eurobarometer, in the winter of 2021,8 while most European Union (EU) citizens wanted to be vaccinated as soon as possible, only 19% people supported that opinion in Bulgaria. Only 21% people wished to be vaccinated ‘sometime in 2021’. Another 32% people wanted to receive a shot ‘later’, while 22% answered that they ‘never want to get inoculated’. As of March 2022, >75% participants (out of 812) were unwilling to be vaccinated, and <40% obtained vaccine-related information from authorised sources.9 Vaccine efficacy and safety have been reported by many international and local outlets, with the latest data showing the full benefits of vaccination, particularly in populations with a high burden of comorbidities.10 11 As the Bulgarian population has a very high prevalence of chronic diseases and at the same time has demonstrated very low vaccination rates due to hesitancy, we aimed to identify whether an association exists between vaccination status, hospitalisation, intensive care unit (ICU) admissions and deaths, on a nationwide level, in various high-risk patient cohorts harbouring a single socially significant disease: either CVD, solid malignancy (regardless of disease stage) or CPD.
Materials and methods
Patient cohort criteria
This study retrospectively examined 1 126 946 individuals with SARS-CoV-2 infection confirmed using real-time PCR (612 378) or antigen testing (436 196). In total, 47% (486 182) of the patients were men, and 53% (562 393) were women. Raw patient data were obtained from the Bulgarian Ministry of Health and ‘United Information Portal’. Here, we focused on data regarding COVID-19 severity and outcomes in fully vaccinated and non-vaccinated Bulgarian patients harbouring a single, chronic, socially significant disease, including CVD (coronary artery disease or stroke), oncological disease (only solid malignancies, regardless of disease stage) and CPD (chronic bronchitis and/or emphysema). A flow chart of the selection process is shown in figure 1. These patient cohorts were further categorised into the following age groups: 0–19, 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, 80–89 and >90 years. Additional data were derived by subgrouping the vaccinated cohort by sex and vaccine type. The following vaccines are currently available in Bulgaria: BNT162b2 (Comirnaty), CX-024414 (Spikevax), ChAdOx1-SARS-COV-2 (Vaxzevria) and Ad26.COV2-S (Janssen COVID-19 vaccine). Practically, ChAdOx1-SARS-COV-2 has not been used since May 2021, owing to a lack of demand based on recommendations from the regulatory decisions of European Medical Association (EMA).12 The first batch of BNT162b2 was received on 27 December 2020 while CX-024414 and Ad26.COV2-S followed thereafter. As of March–April 2021, because of sufficient quantities of all four types of vaccines, the vaccination of high-risk priority groups began.
Figure 1.
The patient cohort selection process. The patient selection process was identical between the groups. The isolated patient groups had to harbour cardiovascular disease, an oncological disease or a chronic pulmonary disease as their only documented pathology. Duplicates, if present, or intensive care unit transfers were excluded from the study.
Statistical analysis
The statistical analyses were performed using the Statistical Package for the Social Sciences (V.26.0; SPSS) and GraphPad Prism V.6 (GraphPad, LA Jolla, California, USA) softwares. Associations between different variables were examined using the Pearson’s χ2 test. The Pearson’s correlation coefficient was calculated to evaluate the correlation between different variables. A p≤0.05 was considered statistically significant, p≤0.01 was considered high statistical significance, and p≤0.001 was considered very high statistical significance, respectively.
Patient and public involvement
No patients were engaged in setting the research question or outcome measures, nor were they involved in the study design or implementation. There are no plans to directly disseminate the results of the research to the study participants or relevant patient cohorts.
Results
The most recent public data September 2021 estimate that Bulgaria’s population is 6 520 314.13 As of 2 April 2022, the overall number of confirmed cases of COVID-19 [using reverse transcription (RT)-PCR and antigen testing] in Bulgaria was 1 126 946 (online supplemental figure 1). The total number of COVID-19-related hospitalisations was 247 441. The number of non-ICU hospitalisations was 222 338, whereas the number of ICU admissions was 25 103. Our analysis showed that for the period March 2020–April 2022, the actual COVID-19-related deaths in the hospital setting, with real time-PCR-confirmed infections, totalled 30 755, of which 24 124 resulted from the disease (figure 2). The remaining patients died of other causes accompanied by SARS-CoV-2 infection. With regard to the patient subgroups, of all the hospitalised cases of RT-PCR-confirmed COVID-19, 67 723 (27.4%) had documented CVD, 2140 (0.9%) had documented oncological disease and 3243 (1.3%) patients had CPD. The cumulative deaths in each subgroup were 10 105 (in-hospital=5812 and ICU=4353; 4.0% vaccinated (410/10 165, p<0.001), 344 in-hospital=196 and ICU=148; 4.9% vaccinated (17/344, p<0.001) and 494 in-hospital=287 and ICU=207; 5.2% vaccinated (26/494, p<0.001), respectively).
Figure 2.
An overview of the COVID-19 pandemic in Bulgaria by age as of April 2022
bmjopen-2022-068431supp001.pdf (745.3KB, pdf)
In the CVD cohort, the highest number of hospitalisations was observed in non-vaccinated women aged between 70–79 years (approximately 45% (9100/19 963 (♂8952+♀11011))); however, the highest mortality was documented in non-vaccinated men in the same age group (approximately 51% (2072/4076 (♂2187+♀1889))) (figure 3). The average patient age in this cohort was 68 years, and the univariate analysis demonstrated a statistically significant difference (p<0.001) regarding the number of ambulatory cases (1.6%), hospitalisations (0.1%), ICU admissions (0.3%) and deaths (0.6%), in contrast to the much lower values observed in the vaccinated patient group (table 1).
Figure 3.
Hospitalisations and mortality by age, sex and vaccination status in patients with cardiovascular disease as of April 2022. Vaccinated men=♂+V; Unvaccinated men=♂-V; Vaccinated women=♀+V; Unvaccinated women=♀-V. CVD, cardiovascular disease.
Table 1.
Patients with a CVD (only) by vaccination status, hospitalisation and mortality: average age ~68 years, varying from <1 year to 100 years
| Condition | Unvaccinated | Vaccinated | Total | P value |
| Ambulatory | 34 513 (75.63%) | 11 123 (24.37%) | 45 636 | <0.001 (df=2) |
| Hospitalised | 7437 (98.91%) | 82 (1.09%) | 7519 | <0.001 (df=2) |
| ICU admission | 4210 (95.62%) | 193 (4.38%) | 4403 | <0.001 (df=2) |
| In-hospital (non-ICU) deaths | 5586 (96.12%) | 226 (3.88%) | 5812 | <0.001 (df=2) |
| In-hospital (ICU) deaths | 4169 (95.78%) | 184 (4.22%) | 4353 | <0.001 (df=2) |
| Total (CVD) | 55 915 (82.57%) | 11 808 (17.43%) | 67 723 | <0.001 (df=2) |
CVD, cardiovascular disease; ICU, intensive care unit.
In the cohort of patients harbouring a solid malignancy, the highest number of hospitalisations was seen in non-vaccinated women aged between 60 and 69 years ~47% (269/573 (♂245+♀328)); however, the highest mortality was recorded in non-vaccinated men aged between 70 and 79 years ~57% (71/124 (♂75+♀49)) (figure 4). The average patient age in this cohort was 63 years, and univariate analysis demonstrated similar results to those of the previous disease category. A statistically significant difference (p<0.001) was observed in the number of ambulatory cases (308/2140=14.4%), hospitalisations (15/2140=0.7%), ICU admissions (8/2140=0.4%) and deaths (17/2140=0.8%) in the vaccinated patient group demonstrating much lower values (table 2).
Figure 4.
Hospitalisations and mortality by age, sex and vaccination status in patients with a solid malignancy as of April 2022. Vaccinated men=♂+V; unvaccinated men=♂-V; vaccinated women=♀+V; unvaccinated women = ♀-V.
Table 2.
Patients with a solid malignancy (only) by vaccination status, hospitalisation and mortality
| Condition | Unvaccinated | Vaccinated | Total | P value |
| Ambulatory | 1119 (78.42%) | 308 (21.58%) | 1427 | <0.001 (df=2) |
| Hospitalised | 200 (93.03%) | 15 (6.97%) | 215 | <0.001 (df=2) |
| ICU admission | 146 (94.81%) | 8 (5.19%) | 154 | <0.001 (df=2) |
| In-hospital (non-ICU) deaths | 185 (94.39%) | 11 (5.61%) | 196 | <0.001 (df=2) |
| In-hospital (ICU) deaths | 142 (95.95%) | 6 (4.05%) | 148 | <0.001 (df=2) |
| Total (solid malignancy) | 1792 (83.74%) | 348 (16.26%) | 2140 | <0.001 (df=2) |
Average age ~63 years, varying from 1 year old to 94 years of age.
ICU, intensive care unit.
In the group of patients with a CPD, the highest number of hospitalisations was seen in non-vaccinated men aged between 60 and 69 years (~43% (331/769 (♂421+♀348))). In contrast, the highest mortality was recorded in non-vaccinated men aged between 70 and 79 years (~54% (99/184 (♂109+♀75))) (figure 5). The average patient age in this cohort was 63 years, and the univariate analysis demonstrated a statistically significant difference (p<0.001) regarding the previously mentioned criteria in vaccinated versus non-vaccinated patients with CPD, contrasting with the much lower values observed in the vaccinated cohort (table 3).
Figure 5.
Hospitalisations and mortality by age, gender and vaccination status in patients with a CPD as of April 2022. Vaccinated men=♂+V; unvaccinated men=♂-V; vaccinated women=♀+V; unvaccinated women=♀-V. CPD, chronic pulmonary disease.
Table 3.
Patients with a CPD (only) by vaccination status, hospitalisation and mortality
| Condition | Unvaccinated | Vaccinated | Total | P value |
| Ambulatory | 1663 (76.71%) | 505 (23.29%) | 2168 | <0.001 (df=2) |
| Hospitalised | 324 (91.02%) | 32 (8.98%) | 356 | <0.001 (df=2) |
| ICU admission | 214 (95.12%) | 11 (4.88%) | 225 | <0.001 (df=2) |
| In-hospital (non-ICU) deaths | 270 (94.08%) | 17 (5.92%) | 287 | <0.001 (df=2) |
| In-hospital (ICU) deaths | 198 (95.66%) | 9 (4.34%) | 207 | <0.001 (df=2) |
| Total (CPD) | 2669 (82.31%) | 574 (17.69%) | 3243 | <0.001 (df=2) |
Average age ~63 years, varying from <1 year old to 97 years of age.
CPD, chronic pulmonary disease; ICU, intensive care unit.
To obtain a more in-depth analysis, we compared mortality rates in the vaccinated cohorts according to the vaccine type administered to the patients. In the CVD cohort, the most frequently used vaccine type was BNT162b2, followed by Ad26.COV2-S, CX-024414 and ChAdOx1-SARS-COV-2 administered to 7507, 1706, 823 and 586 patients, respectively. The relative mortalities in this cohort were: 2.88% (216/7507), 4.74% (81/1706), 3.16% (26/823) and 12.96% (76/586), respectively. In patients with a solid malignancy, the most commonly administered vaccine type was BNT162b2, followed by Ad26.COV2-S, CX-024414, and ChAdOx1-SARS-COV-2 administered to 210, 55, 38 and 17 patients, respectively. The mortality rates were 4.28% (9), 3.63% (2), 7.89% (3) and 17.64% (3), respectively. Finally, in the cohort of patients suffering from a CPD, the most commonly administered vaccine was also BNT162b2, followed by Ad26.COV2-S, CX-024414 and ChAdOx1-SARS-COV-2. The number of completed courses of vaccination in this cohort was 316, 121, 53 and 27, respectively. Mortality rates were 4.11% (13/316), 4.95% (6/121), 1.88% (1/53) and 11.11% (3/27), respectively (table 4).
Table 4.
A comparison of the type of vaccine administered and recorded mortality in patients with a CVD, solid malignancy or CPD
| Vaccine type | Fully vaccinated with CVD | Mortality (CVD) | Fully vaccinated with a solid malignancy | Mortality (malignancy) | Fully vaccinated with a CPD | Mortality (CPD) |
| BNT162b2 | 7507 (63.58%) | 216 (2.88%) | 210 (60.34%) | 9 (4.28%) | 316 (85.50%) | 13 (4.95%) |
| CX-024414 | 823 (6.97%) | 26 (3.16%) | 38 (10.92%) | 3 (7.89%) | 53 (9.23%) | 1 (1.88%) |
| ChAdOx1-SARS-COV-2 | 586 (4.97%) | 76 (12.96%) | 17 (4.88%) | 3 (17.64%) | 27 (4.70%) | 3 (11.11%) |
| Ad26.COV2-S | 1706 (14.45%) | 81 (4.74%) | 55 (15.80%) | 2 (3.63%) | 121 (21.08%) | 6 (4.95%) |
| CX-024414+BNT162b2 | 251 (2.12%) | 2 (0.80%) | 7 (2.01%) | 0 | 13 (2.26%) | 0 |
| ChAdOx1-SARS-COV-2+BNT162b2 | 619 (5.25%) | 7 (1.13%) | 12 (3.45%) | 0 | 29 (5.05%) | 3 (10.34%) |
| ChAdOx1-SARS-COV-2+CX-024414 | 42 (0.35%) | 0 | 0 | 0 | 2 (0.35%) | 0 |
| ChAdOx1-SARS-COV-2+Ad26.COV2-S | 1 (0.008%) | 0 | 0 | 0 | 0 | 0 |
| Ad26.COV2-S+BNT162b2 | 222 (1.88%) | 2 (0.90%) | 8 (2.30%) | 0 | 10 (1.74%) | 0 |
| Ad26.COV2-S+CX-024414 | 48 (0.40%) | 0 | 1 (0.30%) | 0 | 3 (0.52%) | 0 |
| ChAdOx1-SARS-COV-2+BNT162b2+CX-024414 | 2 (0.016%) | 0 | 0 | 0 | 0 | 0 |
| ChAdOx1-SARS-COV-2+Ad26.COV2-S+CX-024414 | 1 (0.008%) | 0 | 0 | 0 | 0 | 0 |
| Total (vaccinated) | 11 808 | 410 (0.73%) | 348 | 17 (0.94%) | 574 | 26 (0.96%) |
| Total (non-vaccinated) | NA | 55 915 (99.27%) | NA | 1792 (99.06%) | NA | 2669 (99.04%) |
The total mortality rates of the unvaccinated cohorts were added for reference.
CPD, chronic pulmonary disease; CVD, cardiovascular disease; NA, not applicable.
Discussion
Vaccinations are the most powerful and affordable means in the history of public health, and the most specific and effective methods of preventing infectious diseases and saving millions of lives from suffering, disabilities and premature death.14 Although many individuals had asymptomatic COVID-19, and other groups had few symptoms or mild-to-moderate illness, there is a substantial minority at a higher risk of severe disease requiring hospital admission and adverse outcomes, including death.15 This is particularly true for older individuals and those with comorbidities; in such cases, COVID-19 became a threat to the health and life expectancy for all societies. Various vaccines against severe COVID-19 became available 1 year after the pandemic began, significantly curbing the severity of the pandemic by preventing severe illnesses in most cases.16 Despite the continuous viral circulation due to rapid spreading, antigenic evolution and waning immunity, data have unequivocally demonstrated that highly vaccinated nations have significantly fewer cases of severe disease, hospitalisations and mortality resulting from SARS-CoV-2 infections, especially in patients harbouring comorbidities.15 17 This not only minimised premature death rates, but also provided a means to return to the routine of normal daily life.
The in-hospital COVID-19-related mortality in Bulgaria between March 2020 and April 2022 was 24 124. This means that approximately 1 in 270 Bulgarians died due to COVID-19 (Bulgarian population 24 124/~6.52 million). The global average during this period was 1/1 285 (6.15 million deaths/~7.9 billion population). As demonstrated by the results of this study, Bulgaria has unequivocally failed the vaccination campaign against COVID-19, especially with regard to high-risk patients harbouring socially significant comorbidities, such as CVD, solid malignancies and CPD, for which several studies, including the present one, have demonstrated clear benefits.17 18
The results of this study showed that in all three patient subgroups of interest, the vaccinated cohorts were associated with reduced numbers of ambulatory cases, hospitalisations, ICU admissions, in-hospital (non-ICU) mortality and in-hospital (ICU) deaths. This study had several limitations. First, the study did not evaluate vaccine efficacy directly but merely reported on tendencies observed between the vaccinated and non-vaccinated patient cohorts. Second, the study pooled the different viral variants dominating through different time points during the period of interest and did not include a post hoc analysis of the different variants of concern. Finally, the study mainly pooled and focused on all available Bulgarian vaccines. Nonetheless, table 4 shows a greater reduction in mortality rates in all patient subgroups vaccinated with mRNA-based vaccine types, in contrast to the reduction seen in the cohorts vaccinated with vector-based vaccines.
Although the risks of SARS-CoV-2 infection, potentially severe disease and premature death have decreased in vaccinated populations,19 breakthrough infections do still occur. There is convincing evidence that individuals aged over 65 years and those with comorbidities have the greatest risk, possibly because postvaccination immunity wanes more quickly in these groups.12 20 In addition, the burden of COVID-19 was found to be much higher in low/middle-income countries than in high-income countries, and with Bulgaria ranking among the poorest EU states, coincidence is unlikely.21
A report published by the European Commission in 2018 concluded that among all EU countries, Bulgaria was the ‘least likely to agree that vaccines are safe’.22 This was well before SARS-CoV-2 emerged with countless conspiracy theories of spawning.
In Bulgaria, such theories began when the EMA and European Commission recommended avoiding ChAdOx1-SARS-COV-2 in individuals aged between 55 and 70 years, only a few months after the vaccine was released to the public.23 This, in turn, led Bulgarian national health authorities to pin withdrawal due to the lack of vaccine efficacy and safety data.6 This resulted in further augmentation of existing vaccine hesitancy in Bulgaria. Unfortunately, this was also one of the crucial factors that halted Bulgaria’s vaccination rates, as an earlier governmental decision to rely solely on ChAdOx1-SARS-COV-2 owing to it being a more affordable and easier to store product, resulting in the Ministry of Health declining the full share of BNT162b2 jabs it had access to under the EU’s joint procurement scheme.
This negative trend of distrust in vaccines against COVID-19 could be directly linked to vaccine hesitancy, which several nationwide surveys have partially attributed to ill-informed general practitioners (GPs) responsible for accomplishing this task regarding evidence-based vaccine indications and contraindications.9 The correlation between GP confidence and confidence among the public is well established.24
Taken together, initial vaccine scepticism, poor management, delivery delays and ill-informed healthcare professionals have left the country with the lowest vaccination rate in Europe, ranking among the highest in terms of mortality rates. A chaotic, confusing and often contradictory information campaign was established, which worsened the situation. In addition, the fact that some healthcare professionals refused to be vaccinated added further to the public distrust.
To overcome this, we developed a free-to-use, physician-oriented, evidence-based decision support tool to facilitate higher vaccination rates against COVID-19. The ‘algorithmic calculator’ takes into account the anthropological status and current epidemiological risk and comorbidity-related parameters (if applicable) in assessing the individually oriented recommendation whether it be for children above the age of 5 years, adults and pregnant or lactating women. This tool provides evidence-based support and streamlines the entire decision-making process, providing the vaccinator with the most relevant and objective recommendation for the patient in less than a minute. The project received full support from the Bulgarian Medical Association, which can be accessed via its website free of charge.25 Unlike other similar and successful digital solutions,26 our platform targets healthcare professionals. Preliminary survey data showed that approximately 77% of the physicians (out of 127 participants) reported increased confidence when using this tool (unpublished data). Hopefully, when implemented at the national level, this tool will facilitate higher vaccination rates in Bulgaria, resulting in better preparedness for future waves.
Conclusion
At the beginning of the pandemic, there were major differences among EU countries regarding epidemiological measures, disease staging, treatment and prioritisation of the population for vaccination. Therefore, we would like to emphasise that future health policies and individual behaviour will determine the form, propagation and public impact of endemic COVID-19. In Bulgaria, the pandemic is not over and with approximately 33% vaccination coverage, the majority of the population remains vulnerable to infection. Therefore, further efforts are warranted to improve the vaccination status of the Bulgarian population. Such efforts would also be beneficial for other vaccination programmes (eg, the lifelong vaccination programme) and developing free-to-use evidence-based decision support tools is a step in the right direction.
Supplementary Material
Footnotes
Contributors: GD conceptualised the study, wrote the body of the manuscript, assisted with data analysis and generated the figures. TV coauthored the main text and assisted with data analysis. HB proofread the article and contributed to the discussion. OK conducted all the statistical analyses. GM proof read the article and assisted with the discussion. RA supervised the analysis and the writing process and is responsible for the overall content as the guarantor.
Funding: This study was conducted without any external funding. The tasks performed by Kounchev were supported by the following projects: KP-06-N42-2 and KP-06-N52-1 at the Bulgarian NSF.
Competing interests: None declared.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
Data availability statement
Data are available on reasonable request.
Ethics statements
Patient consent for publication
Not applicable.
Ethics approval
Approval for this retrospective analysis was granted by the Bulgarian Ministry of Health (document number 94-4750 on 9 November 2022).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
bmjopen-2022-068431supp001.pdf (745.3KB, pdf)
Data Availability Statement
Data are available on reasonable request.