Arterial hypertension and the risk of severity and mortality of COVID-19

To the Editor,

We have read with great interest the recently published study from Guan et al. [1] entitled Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis. To the best of our knowledge this is the first large scale study that focuses on independent clinical risk factors associated with a composite outcome (death, use of ventilator or ICU requirement), using a Cox regression model.

This study found that arterial hypertension was the most prevalent comorbidity (16.9%), followed by diabetes (8.2%), cardiovascular disease (3.7%), cerebrovascular disease (1.9%), COPD (1.5%) and malignancy (1.1%). In the Cox regression model, after age and smoking status adjustment the independent risk factors associated with the composite outcome were malignancy (HR 3.5, 95%CI 1.60–7.64), COPD (HR 2.68, 95%CI 1.42–5.05), diabetes (HR 1.59, 95%CI 1.03–2.45) and hypertension (HR 1.58, 95%CI 1.07–2.32).

We have some concerns about the results showed in that analysis, especially those related to arterial hypertension. Initial Chinese epidemiological studies suggested that cardiovascular diseases (including arterial hypertension) and diabetes were associated with mortality or severity in patients affected by coronavirus disease-19 (COVID-19). Wu et al. [2] published that in 44 672 patients with confirmed COVID-19 the overall case-fatality rate was 2.3% and that it was elevated in comorbid conditions: 10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease and 6% for hypertension. Guan et al. [3] found that in 1099 patients with confirmed COVID-19, hypertension was a more prevalent condition in those who lead the primary composite end point (admission to an intensive care unit, the use of mechanical ventilation or death; 35.8% versus 13.7%) and in those with severe disease (23.7% versus 13.4%). Ruan et al. [4] also described that in 150 patients with confirmed COVID-19, cardiovascular disease and hypertension were more frequent in those cases who died compared with those who were discharged (19% versus 0%, p<0.001 and 43% versus 28%, p=0.07, respectively). Moreover, a systematic review and meta-analysis [5] which included 46 248 infected patients found that the most prevalent comorbidity was hypertension (17±7%; 95%CI 14–22%) and that, compared with non-severe patient, the pooled odds ratio of hypertension and cardiovascular disease were OR 2.36 (95%CI 1.46–3.83), and OR 3.42 (95%CI 1.88–6.22), respectively. All the evidence seems to be concordant. Remarkably, none of these studies had performed a multivariable adjustment. The effect of arterial hypertension on the severity or mortality outcome could be explained by potential confounders.

To adress this unsolved issue, we conducted a medical literature search in PubMed on April 8th, 2020, using the following strategy:

(COVID-19[tiab]OR SARS-CoV-2[tiab]) AND (mortality[tiab] OR severity[tiab])

We included in the analysis the papers that were designed to find clinical predictors of mortality or severity for SARS-CoV-2 infection. The data of these articles is shown in table 1.

Both studies shown in table 1 found that, like hypertension, age and history of coronary artery disease were predictors of COVID-19 severity or mortality in the univariate analysis. But in both studies, hypertension was not included in the final multivariate logistic regression model. The first study [6] included in the final multivariate model to predict critical COVID-19 the elevated troponin I (TnI) (OR 26.91, 95%CI 4.09–177.23; p 0.001) and history of coronary artery disease (OR=16.61, 95%CI 2.29–120.58; p 0.005). The multivariable regression performed to predict COVID-19 death in the second study [7] included age (OR 1.10, 95%CI 1.03–1·17; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (OR 5.65, 95%CI 2.61–12.23, p<0·001), and D-dimer greater than 1 µg·mL⁻¹ on admission (OR 18.42, 95%CI 2.64–128.55, p=0·003).

As we previously mentioned, preceded cardiovascular disease is associated with higher mortality and severity of COVID-19 in the univariate analysis [2, 4, 5]. Thus, this association is also maintained in at least one of the multivariate models showed, but not between hypertension and hard COVID-19 outcomes. In this sense, it is well known that: 1- the prevalence of essential hypertension and coronary artery disease increases with age, and 2- coronary disease and hypertension frequently coexist in the same patient. In this way, the association between hypertension and COVID-19 mortality or severity could be explained in part by the increased age and higher prevalence of cardiovascular disease. Both are well known risk factors for mortality in critical patients. Furthermore, it has been communicated [8] that those patients with cardiac injury (elevated TnI) had worse prognosis, suggesting that it could be a specific target organ damage by SARS-CoV-2. This finding could explain why patients with prevalent cardiovascular disease are associated with worse hard COVID-19 outcomes.

For these reasons, we consider that in order to conclude that hypertension could be an independent predictor of COVID-19 mortality or severity, the model should be adjusted by cardiovascular disease, to exclude its potential confounding effect.