Search
Close
Search
Advanced Search
Search Menu
AI Discovery Assistant

To the  Editor—We thank Chia et al. for their comments supporting the importance of vaccination in mitigating long coronavirus disease 2019 (COVID-19).

We would also like to thank Anil Makam for highlighting his concern on test-negative dates and time-zero (T0) in our article on long-term cardiovascular, cerebrovascular, and thrombotic sequelae following COVID-19 infection [1]. The assignment of T0 to test-negative individuals was to ensure that the follow-up distributions between test-positives and test-negatives were similar. Two potential biases were described, which may be introduced by the assignment of T0; however, these biases would only surface if we were comparing short-term risks of cardiovascular, cerebrovascular, and thrombotic sequelae following COVID-19 versus non–COVID-19 acute respiratory infection (ARI), and if the test-negative population exclusively comprised individuals with ARI attributable to a respiratory virus other than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Here, our article is instead focused on long-term risks of cardiovascular, cerebrovascular, and thrombotic sequelae following SARS-CoV-2 infection, versus test-negatives, whereas the studies cited demonstrate increased risk of heart attacks, strokes, and thromboembolic events following influenza infection, risks of these outcomes were increased in the immediate week (short term) following acute infection [2–4], rather than in the long term. Ascertainment issues in the period after non–COVID-19 ARI due to delayed T0 would therefore be negligible. Because evidence also suggests that short-term, rather than long-term complications are present for non–COVID-19 ARI [2–4], immortal time biases would rather lead to an underestimate of cardiovascular, cerebrovascular, and thrombotic sequelae following COVID-19 infection because this would lead to a capture of a greater proportion of non–COVID-19 cardiovascular sequelae attributable to the short rather than long term. Furthermore, although individuals tested for COVID-19 generally had symptoms compatible with ARI (eg, fever, cough, rhinorrhea, sore throat), this does not imply that all symptomatic individuals who tested negative for SARS-CoV-2 had an acute respiratory tract infection attributable to a respiratory virus other than SARS-CoV-2 (eg, influenza). In fact, rates of infection with non–COVID-19 respiratory viruses dropped drastically during the pandemic because of public health measures in Singapore [5, 6]; in a cohort of patients hospitalized during the pandemic who presented with symptoms compatible with ARI and who were tested extensively for respiratory pathogens, microbiological diagnosis was obtained in less than one quarter, with none testing positive for influenza [7].

Nevertheless, to allay the concerns raised, we have verified that there are no major changes in our results by running our main estimates on an exactly contemporaneous cohort, with T0 set as test-negative date, rather than a randomly assigned date that matched the follow-up distribution of the test-positive group. The test-negative group was taken from individuals who tested negative for SARS-CoV-2 between 1 September and 30 November 2021 and survived the first 30 days, which matched to the exact enrollment dates of the test-positive group. No overestimation of hazard ratios were noticeable using either the test-negative date as T0 versus that of a randomly assigned T0, over either the composite or individual outcomes that were studied (Table 1).

Table 1.
Open in new tab

Hazard Ratios of Prespecified Cardiovascular, Cerebrovascular, and Other Thrombotic Complications in the Coronavirus Disease 2019–exposed Group and Control Groups

OutcomeTest Negative Date As T0aRandomly Assigned T0a
HR (95% CI)HR (95% CI)
Composite outcomes
Any cardiovascular, cerebrovascular, and other thrombotic complications1.09 (1.01–1.18)b1.16 (1.07,1.25)b
MACE1.13 (1.02–1.24)b1.14 (1.02,1.26)b
Cerebrovascular disorders1.09 (.95–1.24)1.12 (.973,1.29)
Dysrhythmias1.21 (1.06–1.38)b1.32 (1.15,1.52)b
Inflammatory heart diseases…c1.76 (.47,6.64)
Ischemic heart diseases0.96 (.86–1.08)1.04 (.92,1.17)
Other cardiac disorders1.29 (1.10–1.50)b1.33 (1.14,1.55)b
Thrombotic complications1.32 (1.02–1.72)b1.22 (.94,1.58)
Individual outcomes
Stroke1.05 (.91–1.22)1.06 (.91,1.23)
TIA1.11 (.83–1.50)1.21 (.90,1.64)
Atrial fibrillation1.09 (.89–1.32)1.15 (.94,1.40)
Sinus tachycardia1.00 (.74–1.36)1.03 (.76,1.40)
Sinus bradycardia1.71 (1.15–2.52)b1.64 (1.12,2.41)b
Other arrhythmia1.38 (1.11–1.73)b1.68 (1.34,2.12)b
Pericarditis…c…c
Myocarditis…c…c
Myocardial infarction1.03 (.88–1.20)1.08 (.92,1.27)
Acute coronary disease0.90 (.78–1.05)0.96 (.83,1.11)
Ischemic cardiomyopathy0.87 (.52–1.44)1.11 (.67,1.85)
Angina1.18 (.92–1.52)1.24 (.96,1.61)
Heart failure1.27 (1.07–1.51)b1.28 (1.08,1.52)b
Nonischemic cardiomyopathy1.53 (1.07–2.18)b1.63 (1.14,2.32)b
Cardiac arrest1.02 (.60–1.73)1.17 (.68,2.02)
Cardiogenic shock0.98 (.44–2.17)0.76 (.36,1.60)
Pulmonary embolism1.05 (.65–1.71)1.13 (.68,1.85)
Deep venous thrombosis1.22 (.88–1.69)1.12 (.82,1.54)
Superficial venous thrombosis2.55 (1.16–5.63)b1.78 (.83,3.84)
Arterial thromboses0.75 (.21–2.71)0.82 (.23,2.90)
OutcomeTest Negative Date As T0aRandomly Assigned T0a
HR (95% CI)HR (95% CI)
Composite outcomes
Any cardiovascular, cerebrovascular, and other thrombotic complications1.09 (1.01–1.18)b1.16 (1.07,1.25)b
MACE1.13 (1.02–1.24)b1.14 (1.02,1.26)b
Cerebrovascular disorders1.09 (.95–1.24)1.12 (.973,1.29)
Dysrhythmias1.21 (1.06–1.38)b1.32 (1.15,1.52)b
Inflammatory heart diseases…c1.76 (.47,6.64)
Ischemic heart diseases0.96 (.86–1.08)1.04 (.92,1.17)
Other cardiac disorders1.29 (1.10–1.50)b1.33 (1.14,1.55)b
Thrombotic complications1.32 (1.02–1.72)b1.22 (.94,1.58)
Individual outcomes
Stroke1.05 (.91–1.22)1.06 (.91,1.23)
TIA1.11 (.83–1.50)1.21 (.90,1.64)
Atrial fibrillation1.09 (.89–1.32)1.15 (.94,1.40)
Sinus tachycardia1.00 (.74–1.36)1.03 (.76,1.40)
Sinus bradycardia1.71 (1.15–2.52)b1.64 (1.12,2.41)b
Other arrhythmia1.38 (1.11–1.73)b1.68 (1.34,2.12)b
Pericarditis…c…c
Myocarditis…c…c
Myocardial infarction1.03 (.88–1.20)1.08 (.92,1.27)
Acute coronary disease0.90 (.78–1.05)0.96 (.83,1.11)
Ischemic cardiomyopathy0.87 (.52–1.44)1.11 (.67,1.85)
Angina1.18 (.92–1.52)1.24 (.96,1.61)
Heart failure1.27 (1.07–1.51)b1.28 (1.08,1.52)b
Nonischemic cardiomyopathy1.53 (1.07–2.18)b1.63 (1.14,2.32)b
Cardiac arrest1.02 (.60–1.73)1.17 (.68,2.02)
Cardiogenic shock0.98 (.44–2.17)0.76 (.36,1.60)
Pulmonary embolism1.05 (.65–1.71)1.13 (.68,1.85)
Deep venous thrombosis1.22 (.88–1.69)1.12 (.82,1.54)
Superficial venous thrombosis2.55 (1.16–5.63)b1.78 (.83,3.84)
Arterial thromboses0.75 (.21–2.71)0.82 (.23,2.90)

Control groups were defined with enrollment dates as the test-negative date, or randomly assigned enrollment dates to match that of the intervention arm follow-up distribution. HR >1 denotes higher risk of a respective composite/individual new cardiovascular, cerebrovascular, and other thrombotic complications in the coronavirus disease 2019–exposed group versus control group.

Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; HR, hazard ratio; MACE, major adverse cardiovascular event; T0, time zero; TIA, transient ischemic attack.

aEach model is inverse probability weighted and regression adjusted based on demographic characteristics (age, sex, ethnicity), socioeconomic status (housing type), vaccination status (not vaccinated, vaccinated, vaccinated and boosted), and comorbidity burden at baseline (constituent conditions in Charlson comorbidity index).

bDenotes 95% CIs that are bounded away from 0.

cNot estimable because of 0 cases in either the COVID-19 test-positive or test-negative group.

Table 1.
Open in new tab

Hazard Ratios of Prespecified Cardiovascular, Cerebrovascular, and Other Thrombotic Complications in the Coronavirus Disease 2019–exposed Group and Control Groups

OutcomeTest Negative Date As T0aRandomly Assigned T0a
HR (95% CI)HR (95% CI)
Composite outcomes
Any cardiovascular, cerebrovascular, and other thrombotic complications1.09 (1.01–1.18)b1.16 (1.07,1.25)b
MACE1.13 (1.02–1.24)b1.14 (1.02,1.26)b
Cerebrovascular disorders1.09 (.95–1.24)1.12 (.973,1.29)
Dysrhythmias1.21 (1.06–1.38)b1.32 (1.15,1.52)b
Inflammatory heart diseases…c1.76 (.47,6.64)
Ischemic heart diseases0.96 (.86–1.08)1.04 (.92,1.17)
Other cardiac disorders1.29 (1.10–1.50)b1.33 (1.14,1.55)b
Thrombotic complications1.32 (1.02–1.72)b1.22 (.94,1.58)
Individual outcomes
Stroke1.05 (.91–1.22)1.06 (.91,1.23)
TIA1.11 (.83–1.50)1.21 (.90,1.64)
Atrial fibrillation1.09 (.89–1.32)1.15 (.94,1.40)
Sinus tachycardia1.00 (.74–1.36)1.03 (.76,1.40)
Sinus bradycardia1.71 (1.15–2.52)b1.64 (1.12,2.41)b
Other arrhythmia1.38 (1.11–1.73)b1.68 (1.34,2.12)b
Pericarditis…c…c
Myocarditis…c…c
Myocardial infarction1.03 (.88–1.20)1.08 (.92,1.27)
Acute coronary disease0.90 (.78–1.05)0.96 (.83,1.11)
Ischemic cardiomyopathy0.87 (.52–1.44)1.11 (.67,1.85)
Angina1.18 (.92–1.52)1.24 (.96,1.61)
Heart failure1.27 (1.07–1.51)b1.28 (1.08,1.52)b
Nonischemic cardiomyopathy1.53 (1.07–2.18)b1.63 (1.14,2.32)b
Cardiac arrest1.02 (.60–1.73)1.17 (.68,2.02)
Cardiogenic shock0.98 (.44–2.17)0.76 (.36,1.60)
Pulmonary embolism1.05 (.65–1.71)1.13 (.68,1.85)
Deep venous thrombosis1.22 (.88–1.69)1.12 (.82,1.54)
Superficial venous thrombosis2.55 (1.16–5.63)b1.78 (.83,3.84)
Arterial thromboses0.75 (.21–2.71)0.82 (.23,2.90)
OutcomeTest Negative Date As T0aRandomly Assigned T0a
HR (95% CI)HR (95% CI)
Composite outcomes
Any cardiovascular, cerebrovascular, and other thrombotic complications1.09 (1.01–1.18)b1.16 (1.07,1.25)b
MACE1.13 (1.02–1.24)b1.14 (1.02,1.26)b
Cerebrovascular disorders1.09 (.95–1.24)1.12 (.973,1.29)
Dysrhythmias1.21 (1.06–1.38)b1.32 (1.15,1.52)b
Inflammatory heart diseases…c1.76 (.47,6.64)
Ischemic heart diseases0.96 (.86–1.08)1.04 (.92,1.17)
Other cardiac disorders1.29 (1.10–1.50)b1.33 (1.14,1.55)b
Thrombotic complications1.32 (1.02–1.72)b1.22 (.94,1.58)
Individual outcomes
Stroke1.05 (.91–1.22)1.06 (.91,1.23)
TIA1.11 (.83–1.50)1.21 (.90,1.64)
Atrial fibrillation1.09 (.89–1.32)1.15 (.94,1.40)
Sinus tachycardia1.00 (.74–1.36)1.03 (.76,1.40)
Sinus bradycardia1.71 (1.15–2.52)b1.64 (1.12,2.41)b
Other arrhythmia1.38 (1.11–1.73)b1.68 (1.34,2.12)b
Pericarditis…c…c
Myocarditis…c…c
Myocardial infarction1.03 (.88–1.20)1.08 (.92,1.27)
Acute coronary disease0.90 (.78–1.05)0.96 (.83,1.11)
Ischemic cardiomyopathy0.87 (.52–1.44)1.11 (.67,1.85)
Angina1.18 (.92–1.52)1.24 (.96,1.61)
Heart failure1.27 (1.07–1.51)b1.28 (1.08,1.52)b
Nonischemic cardiomyopathy1.53 (1.07–2.18)b1.63 (1.14,2.32)b
Cardiac arrest1.02 (.60–1.73)1.17 (.68,2.02)
Cardiogenic shock0.98 (.44–2.17)0.76 (.36,1.60)
Pulmonary embolism1.05 (.65–1.71)1.13 (.68,1.85)
Deep venous thrombosis1.22 (.88–1.69)1.12 (.82,1.54)
Superficial venous thrombosis2.55 (1.16–5.63)b1.78 (.83,3.84)
Arterial thromboses0.75 (.21–2.71)0.82 (.23,2.90)

Control groups were defined with enrollment dates as the test-negative date, or randomly assigned enrollment dates to match that of the intervention arm follow-up distribution. HR >1 denotes higher risk of a respective composite/individual new cardiovascular, cerebrovascular, and other thrombotic complications in the coronavirus disease 2019–exposed group versus control group.

Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; HR, hazard ratio; MACE, major adverse cardiovascular event; T0, time zero; TIA, transient ischemic attack.

aEach model is inverse probability weighted and regression adjusted based on demographic characteristics (age, sex, ethnicity), socioeconomic status (housing type), vaccination status (not vaccinated, vaccinated, vaccinated and boosted), and comorbidity burden at baseline (constituent conditions in Charlson comorbidity index).

bDenotes 95% CIs that are bounded away from 0.

cNot estimable because of 0 cases in either the COVID-19 test-positive or test-negative group.

References

1

Lim
 
JT
,
En
 
WL
,
Tay
 
AT
, et al.  
Long-term cardiovascular, cerebrovascular, and other thrombotic complications in COVID-19 survivors: a retrospective cohort study
.
Clin Infect Dis
 
2024
;
78
:
70
–
9
.

Google Scholar

Crossref
Search ADS
PubMed

 
2

Kwong
 
JC
,
Schwartz
 
KL
,
Campitelli
 
MA
, et al.  
Acute myocardial infarction after laboratory-confirmed influenza infection
.
N Engl J Med
 
2018
;
378
:
345
–
53
.

Google Scholar

Crossref
Search ADS
PubMed

 
3

Smeeth
 
L
,
Thomas
 
SL
,
Hall
 
AJ
,
Hubbard
 
R
,
Farrington
 
P
,
Vallance
 
P
.
Risk of myocardial infarction and stroke after acute infection or vaccination
.
N Engl J Med
 
2004
;
351
:
2611
–
8
.

Google Scholar

Crossref
Search ADS
PubMed

 
4

Warren-Gash
 
C
,
Hayward
 
AC
,
Hemingway
 
H
, et al.  
Influenza infection and risk of acute myocardial infarction in England and Wales: a CALIBER self-controlled case series study
.
J Infect Dis
 
2012
;
206
:
1652
–
9
.

Google Scholar

Crossref
Search ADS
PubMed

 
5

Tan
 
JY
,
Conceicao
 
EP
,
Sim
 
XYJ
,
Wee
 
LEI
,
Aung
 
MK
,
Venkatachalam
 
I
.
Public health measures during COVID-19 pandemic reduced hospital admissions for community respiratory viral infections
.
J Hosp Infect
 
2020
;
106
:
387
–
9
.

Google Scholar

Crossref
Search ADS
PubMed

 
6

Chow
 
A
,
Hein
 
AA
,
Kyaw
 
WM
.
Unintended consequence: influenza plunges with public health response to COVID-19 in Singapore
.
J Infect
 
2020
;
81
:
e68
–
9
.

Google Scholar

Crossref
Search ADS
PubMed

 
7

Wee
 
LE
,
Hsieh
 
JYC
,
Phua
 
GC
, et al.  
Respiratory surveillance wards as a strategy to reduce nosocomial transmission of COVID-19 through early detection: the experience of a tertiary-care hospital in Singapore
.
Infect Control Hosp Epidemiol
 
2020
;
41
:
820
–
5
.

Google Scholar

Crossref
Search ADS
PubMed

 

Author notes

Jue Tao Lim, Liang En Wee and An Ting Tay contributed equally.

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: [email protected]
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://dbpia.nl.go.kr/pages/standard-publication-reuse-rights)
Issue Section:
Letter Reply
Download all slides