To the Editor,
Previous studies have shown that common comorbidities were significantly associated
with the increased risk of adverse outcomes in patients with coronavirus disease 2019
(COVID-19)
1
. As we know, hypertension was the most common comorbidities among COVID-19 patients
2
. Recently, a paper in the Journal of Infection by Zheng et al
3
has reported that the proportion of hypertension was significantly higher in critical/mortal
patients compared to the non-critical patients (hypertension: odds ratio (OR) = 2.72,
95%: confidence interval (CI) 1.60-4.64, P = 0.0002). However, the findings were based
on unadjusted effect estimates. It was worth mentioning that the data based on unadjusted
effect estimates indicated hypertension was an important risk factor for the adverse
outcomes of COVID-19 patients, but the pooled effects based on adjusted effect estimates
were significantly reduced or even disappeared in several studies4, 5, 6, 7, 8. For
instance, in the study of Wang et al., univariate analysis showed that hypertension
was a risk factor for death in patients with COVID-19 (OR = 5.000, 95% CI: 1.748-14.301),
while multivariate analysis showed that hypertension was not significantly associated
with the risk of mortality (OR= 1.099, 95% CI: 0.264-4.580)
7
. Similarly, univariate analysis in Cummings et al. indicated that hypertension was
significantly associated with patient death (hazard ratio (HR) = 2.24, 95% CI: 1.40-3.59),
but this association disappeared in the multivariate analysis (HR = 1.58, 95% CI:
0.89-2.81)
5
. The same findings were also observed in Wang et al.’s study
8
. This meant that the association of hypertension with the adverse outcomes of COVID-19
patients might be affected by various factors such as age, gender and other comorbidities.
Therefore, it is urgently required to clarify the association between hypertension
and the adverse outcomes of COVID-19 patients by a systematically quantitative meta-analysis
on the basis of the published studies reporting the adjusted effect estimates.
Therefore, we systematically searched the electronic databases, including Web of Science,
Chinese National Knowledge Infrastructure (CNKI) and PubMed to identify all observational
studies published between Jan 1, 2020 and June 15, 2020 that compared outcomes in
hospitalized COVID-19 patients with and without hypertension. These search engines
used the following two sets of keywords to capture available literature: "Coronavirus
2019, 2019-nCoV, SARS-CoV-2, COVID-19" and "Hypertension”. Only articles that reported
adjusted effect estimates of hypertension and adverse outcomes (severity including
severe and critical, and mortality) in patients with COVID-19 were qualified. All
calculations were implemented with Stata 11. 2 software. The pooled OR and pooled
HR with their corresponding 95% CI were used to evaluate the risk of adverse outcomes
in patients with COVID-19 and hypertension. The degree of heterogeneity between studies
was tested using I2 statistics. The I2 values were 25%, 50%, and 75%, indicating low,
medium, and high heterogeneity, respectively
9
. If there was no evidence of between-studies heterogeneity (I2 ≤ 50%), a fixed-effects
model was used to calculate the combined effects. Otherwise, a random-effects model
was selected
10
. The sensitivity analysis was used to evaluate the robustness of the results. Both
Begg's test and Egger's test were used to evaluate publication bias.
Overall, 521 documents were initially identified according to our search criteria,
and the final analysis included 19 studies of 15,302 patients4, 5, 6, 7, 8
,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24. As shown in Table 1
, the median age of COVID-19 patients ranged from 43.9 to 71 years, of which 38.2%
had hypertension. The sample size ranged from 63 to 2,877. Seventeen studies were
retrospective and two prospective.
Table 1
: Characteristics of the included studies.
Table 1
Author
Location
Case
Age (years)
Male (%)
Study design
HTN
Adjusted effect estimate(95%CI)
Confounders
Chen C [12]
China
150
59(16)
84(56)
R
49(32.6)
OR 2.586(0.609-10.980)
Age, gender, NT-proBNP, cTnI, hs-CRP, creatinine, CHD
Wang D [7]
China
107
51(31-65)
57(53.3)
R
26(24.3)
OR 1.099(0.264-4.580)
Age, gender, CVD, creatinine concentration
Sun H [21]
China
244
NR
137(54.5)
R
138(56.6)
OR 0.82(0.24-2.75)
Age, gender, vital signs, previous respiratory diseases, laboratory values
Shi S [20]
China
671
63(50-72)
322(48)
R
199(29.7)
HR 1.07(0.46-2.53)
Age, gender, diabetes, CHD, chronic renal disease, chronic heart failure, atrial fibrillation,
CVD, COPD, procalcitonin, CRP
Yan X [23]
China
1004
NR
493(49.1)
R
235(23.4)
OR 2.606(0.988-6.870)
NLR, hs-CRP, NT-proBNP, BUN, respiratory failure, digestive system disease, CVD
Wang G [8]
China
209
NR
105(50.2)
R
27(12.9)
OR 0.357(0.078-1.639)
Age, gender, creatine kinase, lymphocyte, AST, CRP
Cummings MJ [5]
American
257
62(51-72)
171(67)
P
162(63)
HR 1.58(0.89-2.81)
Age, gender, symptom duration before hospital presentation, chronic cardiac disease,
COPD or interstitial lung disease, diabetes, interleukin-6, D-dimer
Phipps MM [6]
American
2273
65(52-76)
1297(57)
R
1375(60)
OR 1.15(0.85-1.56)
age, peak ALT, BMI >35, diabetes, intubation, renal replacement therapy
Galloway JB [14]
UK
1157
71(57-82)
666(57.6)
R
611(52.9)
HR 1.53(1.24-1.90)
Age, gender
Huang S [16]
China
310
62(40-70)
174(56.1)
R
113(36.5)
OR 1.562(0.929-2.625)
Age, gender
Escalera-Antezana JP [13]
Bolivia
107
43.9(17.6)
55(51.4)
R
10(9.35)
OR 3.284(1.276-6.291)
Age
Gao C [15]
China
2877
NR
1479(51.1)
R
850(29.5)
HR 2.06(1.10-3.83)
Age, gender, medical history of diabetes, insulin-treated diabetes, myocardial infarction,
underwent PCI/CABG, renal failure, stroke, heart failure, COPD
Zhao M [24]
China
1000
61(46-70)
466(46.6)
R
282(28.2)
HR 1.974(1.297-3.003)
Age
Sabri A [19]
Iran
63
54.1(15.5)
NR
R
15(23.8)
OR 1.42(1.13-1.71)
History of heart disease, pericardial effusion, blood oxygen saturation
Lim JH [18]
Korea
160
NR
86(53.8)
R
77(48.1)
HR 1.34(0.71-2.52)
Acute kidney injury network, age, gender, diabetes
Chen F [4]
China
660
55(34-68)
295(44.7)
R
230(34.8)
OR 0.920(0.420-2.016)
Age, cerebral infarction, SOFA, CRP, LDH
Targher G [22]
China
310
47
149(48.1)
R
NR
OR 2.68(1.20-5.98)
Age, gender
Lala A [17]
American
2736
66.40(15.8)
1630(59.6)
R
1065(38.9)
OR 0.99(0.79-1.23)
Age, gender, troponin strata, race, ethnicity, coronary artery disease, diabetes,
heart failure, atrial fibrillation, chronic kidney disease
Cen Y [11]
China
1007
61 (49-68)
493(49.0)
P
270(26.8)
HR 1.442(1.109-1.876)
Age, gender, smoking, diabetes, chronic obstructive lung disease, coronary artery
disease, duration of anti-viral therapy
All values are n (%), mean (SD) or median (IQR); NR, not reported; HTN, hypertension;
P, prospective; R, retrospective; HR, hazard ratio; OR, odds ratio; NT-proBNP, amino-terminal
pro-brain natriuretic peptide; cTnI, cardiac troponin I; hs-CRP, high-sensitivity
C-reactive protein; CHD, Coronary heart disease; CVD, cardiovascular or cerebrovascular
disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; NLR,
neutrophil-to-lymphocyte ratio; BUN, blood urea nitrogen; ALT, alanine aminotransferase;
AST, aspartate aminotransferase; BMI, body mass index; SOFA, Sequential Organ Failure
Assessment; PCI/CABG, percutaneous coronary intervention (PCI) or coronary artery
bypass grafting (CABG); LDH, lactate dehydrogenase.
Totally, our meta-analysis showed that hypertension was significantly associated with
the increased risk of adverse outcomes in COVID-19 patients on the basis of 19 studies
with 15,302 cases (OR= 1.44, 95% CI [1.24-1.66]; I2 = 41.4%, random-effects model)
(Fig. 1
A). Of the 19 studies, 12 reported adjusted OR and 7 reported adjusted HR. Therefore,
we conducted a subgroup analysis based on the adjusted OR and adjusted HR. We also
found a significant correlation between hypertension and adverse outcomes on the basis
of both 12 OR-adjusted studies with 8,173 cases (OR= 1.37, 95% CI [1.08-1.72]; I2 = 51.9%)
and 7 HR-adjusted studies with 7,129 cases (HR= 1.55, 95% CI [1.35-1.78]; I2 = 0.0%)
(Fig. 1A). As shown by the sensitivity analysis, none of the studies had a significant
impact on the overall results, which proves the robustness of our results (Fig. 1B).
No publication bias was detected in Begg's test (P=0.889) or Egger's test (P=0.432).
Fig. 1
The pooled effects and their 95% confidence interval (CI) of the relationship between
hypertension and adverse outcomes in patients with COVID-19 (A). Sensitivity analysis
of the relationship between hypertension and adverse outcomes in patients with COVID-19
(B).
Fig 1
Previous studies have suggested that hypertension was a risk factor for adverse outcomes
of COVID-19 patients, but the studies did not consider the effects of confounding
factors on the findings
2
,
25, 26, 27, 28. Presently, our results showed that hypertension was significantly
associated with the increased risk of adverse outcomes in COVID- 19 patients on the
basis of the adjusted effect estimates, which suggests that hypertension is an independent
risk factor for predicting the severity and mortality of COVID-19 patients. Thus COVID-19
patients with hypertension deserve more clinical attention. It should be acknowledged
that some limitations existed in our study. Firstly, the judgment criteria of adverse
results in the included studies were not uniform. Secondly, all the included studies
reported the adjusted effect estimates, but the confounding factors adjusted in each
study were not entirely consistent. Thirdly, the stage of hypertension and whether
it is controlled or poorly controlled are also unknown. The included studies did not
adequately report data on chronic hypertension medications and therefore these could
not be analyzed.
In summary, our meta-analysis demonstrated for the first time that hypertension was
an independent risk factor for predicting the adverse outcomes of patients with COVID-19.
Further well-designed studies with larger sample sizes are required to verify the
findings of our present study.
Declaration of Competing Interest
All authors report that they have no potential conflicts of interest.