Characteristics and outcomes of patients with COVID-19 with and without prevalent hypertension: a multinational cohort study

Objective To characterise patients with and without prevalent hypertension and COVID-19 and to assess adverse outcomes in both inpatients and outpatients. Design and setting This is a retrospective cohort study using 15 healthcare databases (primary and secondary electronic healthcare records, insurance and national claims data) from the USA, Europe and South Korea, standardised to the Observational Medical Outcomes Partnership common data model. Data were gathered from 1 March to 31 October 2020. Participants Two non-mutually exclusive cohorts were defined: (1) individuals diagnosed with COVID-19 (diagnosed cohort) and (2) individuals hospitalised with COVID-19 (hospitalised cohort), and stratified by hypertension status. Follow-up was from COVID-19 diagnosis/hospitalisation to death, end of the study period or 30 days. Outcomes Demographics, comorbidities and 30-day outcomes (hospitalisation and death for the ‘diagnosed’ cohort and adverse events and death for the ‘hospitalised’ cohort) were reported. Results We identified 2 851 035 diagnosed and 563 708 hospitalised patients with COVID-19. Hypertension was more prevalent in the latter (ranging across databases from 17.4% (95% CI 17.2 to 17.6) to 61.4% (95% CI 61.0 to 61.8) and from 25.6% (95% CI 24.6 to 26.6) to 85.9% (95% CI 85.2 to 86.6)). Patients in both cohorts with hypertension were predominantly >50 years old and female. Patients with hypertension were frequently diagnosed with obesity, heart disease, dyslipidaemia and diabetes. Compared with patients without hypertension, patients with hypertension in the COVID-19 diagnosed cohort had more hospitalisations (ranging from 1.3% (95% CI 0.4 to 2.2) to 41.1% (95% CI 39.5 to 42.7) vs from 1.4% (95% CI 0.9 to 1.9) to 15.9% (95% CI 14.9 to 16.9)) and increased mortality (ranging from 0.3% (95% CI 0.1 to 0.5) to 18.5% (95% CI 15.7 to 21.3) vs from 0.2% (95% CI 0.2 to 0.2) to 11.8% (95% CI 10.8 to 12.8)). Patients in the COVID-19 hospitalised cohort with hypertension were more likely to have acute respiratory distress syndrome (ranging from 0.1% (95% CI 0.0 to 0.2) to 65.6% (95% CI 62.5 to 68.7) vs from 0.1% (95% CI 0.0 to 0.2) to 54.7% (95% CI 50.5 to 58.9)), arrhythmia (ranging from 0.5% (95% CI 0.3 to 0.7) to 45.8% (95% CI 42.6 to 49.0) vs from 0.4% (95% CI 0.3 to 0.5) to 36.8% (95% CI 32.7 to 40.9)) and increased mortality (ranging from 1.8% (95% CI 0.4 to 3.2) to 25.1% (95% CI 23.0 to 27.2) vs from 0.7% (95% CI 0.5 to 0.9) to 10.9% (95% CI 10.4 to 11.4)) than patients without hypertension. Conclusions COVID-19 patients with hypertension were more likely to suffer severe outcomes, hospitalisations and deaths compared with those without hypertension.


GENERAL COMMENTS
This is the largest multinational COVID-19 cohort study that describes some associations of arterial hypertension with COVID-19 outcomes, particularly hospitalizations and death. First of all, the authors should clarify whether ethics full review waiver was obtained from each participating centre. Additionally, approval of local health administrators/managers is required to allow processing and publicizing the obtained data. Protocol numbers and dates of approval/waiver by each participating centre are requested. Methods. How arterial hypertension was defined and diagnosed at each participating centre?
The abstract needs to be revised to clearly reflect data in connection with the analyzed groups. Statistical analyses. Please clarify whether percentages (prevalence) of arterial hypertension in COVID-19 and COVID-19 plus hypertension groups were statistically compared. It would be appropriate to provide details about the outcomes related to thrombotic events leading to death (myocardial infarction and ischaemic stroke). Presumably, arterial hypertension confounded thrombotic events rather than other causes of death in COVID-19 patients. Having cardiac arrhythmias and cardiovascular events in Table 2 without myocardial infarction and Ischaemic stroke columns looks odd.

GENERAL COMMENTS
The present manuscript describes the results from a multinational network designed to characterize patient with and without hypertension and to assess the adverse outcomes. This is a retrospective study from 15 healthcare databases from the US, Europe and Asia. All patients diagnosed/hospitalized with COVID-19 were included and stratified by hypertension status. Follow-up was from COVID-19 diagnosis/hospitalization to death, end of the study period, or 30-days outcomes (hospitalization, adverse events or death). They included 2,851,035 diagnosed and 563,708 hospitalized patients with COVID-19. Hypertensive patients diagnosed with COVID-19 were predominantly >50-year-old and female and were frequently diagnosed with obesity, heart disease, dyslipidaemia, and diabetes. Patients with hypertension had more hospitalizations and mortality. Hospitalized patients with hypertension were more likely to have acute respiratory distress syndrome, arrhythmia, and increased mortality.
Strengths and limitations were properly identified in the manuscript. In particularly, the main strength is that it encompasses the whole spectrum of COVID-19 patients and not just hospitalized patients, being less biased compared to previous studies and meta-analysis. Table 1 should include aggregated information. Although it is described in the main text, visually it could have more impact.
Of particular relevance is the great variability in outcomes according to the cohort, and this deserves a more detailed comment by the authors. For instance, hospitalization in hypertensive patients is described to be in the range of 1.3 to 41.1% and death of 0.3 to 18.5%. This range is very large. The study in interesting, with a large sample size and results are solid.

GENERAL COMMENTS
The article is relevant and has a robust sample that tries to elucidate hypertension as a predictor of severity in Covid-19. The article has limitations because it deals with different studies, from countries with different health systems, but the authors are aware of these limitations and assume them as a possibility. The same happens when they assume that patients treated on an outpatient basis may have been hospitalized. Despite the limitations assumed, the grandeur of the study and the way the method was conducted in order to reduce such limitations, mean that the article does have innovative content and is endowed with scientific and social relevance. For these reasons, I recommend PUBLISHING the article after improving the visibility of your figures.

Reviewer: 1 Dr. Armen Yuri Gasparyan, Dudley Group NHS Foundation Trust (Teaching Trust of the University of Birmingham)
Comments to the Author: This is the largest multinational COVID-19 cohort study that describes some associations of arterial hypertension with COVID-19 outcomes, particularly hospitalizations and death.

1-First of all, the authors should clarify whether ethics full review waiver was obtained from each participating centre.
Authors response: We agree and understand the concerns of the reviewer regarding the ethics approvals and the sharing of data, given the multinational-multidata base nature of this study. Please see answer to the Editor (point 1 above) This study is encompassed in the "Characterizing Health Associated Risks, and Your Baseline Disease In SARS-COV-2 (CHARYBDIS): protocol for an OHDSI network study" which protocol can be accessed through this link: https://github.com/ohdsistudies/Covid19CharacterizationCharybdis/blob/master/documents/Protocol_COVID-19%20Charybdis%20Characterisation_V5.docx Authors' Action: No further action taken (please see the included changes in the response to editors above) 2-Additionally, approval of local health administrators/managers is required to allow processing and publicizing the obtained data. Protocol numbers and dates of approval/waiver by each participating centre are requested.

Authors response:
Approval from all participating databases (or exemption of this in some cases as mentioned above) has been included in the manuscript together with the code of approval from each committee. Additionally, at least one researcher from each database participated in this manuscript as a coauthor, including the review of the presented results and the acceptance of the current version of the manuscript. Finally, it is important to mention that the diagnosis of hypertension is registered by a medical doctor in each patient's electronic health records.

Authors' Action:
Changes can be seen in page 10 lines 252-253 as follows:

4-The abstract needs to be revised to clearly reflect data in connection with the analyzed groups.
Authors' Response: We agree with the reviewer that the abstract needs more details on the data gathered for each cohort so that it clearly reflects our methods and results.
For this reason, changes have been made accordingly in the abstract.

5-Statistical analyses. Please clarify whether percentages (prevalence) of arterial hypertension in COVID-19 and COVID-19 plus hypertension groups were statistically compared.
Authors' Response: The prevalence of hypertension was presented with their 95% CI (please see supporting table 1 in the supplementary file). Although we agree with the reviewer that it would be interesting to analyse the association between hypertension and diagnosis or hospitalization of COVID this was out of the scope of this study as it was intended to be descriptive in nature.
This was stated in page 12, lines 285-287: "This is a descriptive study and no causal inference is intended. Multivariable regression or adjustment for confounding was therefore considered out of remit, and not included in our study." Authors' Action: No further action taken 6-It would be appropriate to provide details about the outcomes related to thrombotic events leading to death (myocardial infarction and ischaemic stroke). Presumably, arterial hypertension confounded thrombotic events rather than other causes of death in COVID-19 patients.
Authors' Response: Yes, indeed thrombotic events might be a confounder when analyzing the association between hypertension and death. However, as answered in point nº5, this study is descriptive and no casual inference were analysed. Unfortunately, not all the databases register the cause of death and therefore this information cannot be retrieved even at a descriptive level.
Authors Action: No further action taken Table 2 without myocardial infarction and Ischaemic stroke columns looks odd.

7-Having cardiac arrhythmias and cardiovascular events in
Authors Response: Yes, we agree with the reviewer that this needs to be clarified. We gathered a longer list of outcomes but not all of them were available for all the databases so after several revisions we decided to include only those that were available for most databases. The complete list of outcomes is publicly available at https://data.ohdsi.org/Covid19CharacterizationCharybdis/ The total cardiovascular event is a compound outcome which included: ischemic stroke, haemorrhagic stroke, heart failure (heart failure during hospitalization for the hospitalized cohort), acute myocardial infarction or sudden cardiac death. This is detailed in the methods section (page 11, lines 268-270), however we agree that this needs to be clarified in the notes of table 2 too.
No further action taken.

2-Of particular relevance is the great variability in outcomes according to the cohort, and this deserves a more detailed comment by the authors.
For instance, hospitalization in hypertensive patients is described to be in the range of 1.3 to 41.1% and death of 0.3 to 18.5%. This range is very large. The study in interesting, with a large sample size and results are solid.
Reviewer: 3 Dr. Thereza Moreira, State University of Ceara Comments to the Author: The article is relevant and has a robust sample that tries to elucidate hypertension as a predictor of severity in Covid-19. The article has limitations because it deals with different studies, from countries with different health systems, but the authors are aware of these limitations and assume them as a possibility. The same happens when they assume that patients treated on an outpatient basis may have been hospitalized. Despite the limitations assumed, the grandeur of the study and the way the method was conducted in order to reduce such limitations, mean that the article does have innovative content and is endowed with scientific and social relevance.
1-For these reasons, I recommend PUBLISHING the article after improving the visibility of your figures.

Authors' Response:
We appreciate the reviewers' comments and the interest for this study. We have improved the visibility of the figures as suggested by the reviewer.

GENERAL COMMENTS
My concerns were properly adressed by the authors and in my opinion, the suggestions from other reviewers were also managed properly