The impact of lockdown enforcement during the SARSCoV-2 pandemic on the timing of presentation and early outcomes of patients with ST-elevation myocardial infarction.

INTRODUCTION: Early reports described decreased admissions for acute cardiovascular events during the SarsCoV-2 pandemic. We aimed to explore whether the lockdown enforced during the SARSCoV-2 pandemic in Israel impacted the characteristics of presentation, reperfusion times, and early outcomes of ST-elevation myocardial infarction (STEMI) patients.
METHODS: A multicenter prospective cohort comprising all STEMI patients treated by primary percutaneous coronary intervention admitted to four high-volume cardiac centers in Israel during lockdown (20/3/2020-30/4/2020). STEMI patients treated during the same period in 2019 served as controls.
RESULTS: The study comprised 243 patients, 107 during the lockdown period of 2020 and 136 during the same period in 2019, with no difference in demographics and clinical characteristics. Patients admitted in 2020 had higher admission and peak troponin levels, had a 2.4 fold greater likelihood of Door-to-balloon times> 90 min (95%CI: 1.2-4.9, p = 0.01) and 3.3 fold greater likelihood of pain-to-balloon times> 12 hours (OR 3.3, 95%CI: 1.3-8.1, p<0.01). They experienced higher rates hemodynamic instability (25.2% vs 14.7%, p = 0.04), longer hospital stay (median, IQR [4, 3-6 Vs 5, 4-6, p = 0.03]), and fewer early (<72 hours) discharge (12.4% Vs 32.4%, p<0.001).
CONCLUSIONS: The lockdown imposed during the SARSCoV-2 pandemic was associated with a significant lag in the time to reperfusion of STEMI patients. Measures to improves this metric should be implemented during future lockdowns.

Introduction

Although the pathophysiological mechanism is not fully known, the incidence of acute myocardial infarctions is expected to increase during times of stress [1-4]. In addition to the economic crisis precipitated by the SARS-CoV-2 pandemic, it impacted on the wellbeing of the global population by imposing social restrictions associated with anxiety and stress. However, one of the lockdown consequences was the withdrawal of patients and a tendency to avoid referral to hospitals. Early reports suggested fewer Acute Coronary Syndrome (ACS)-related admissions [5-9] with longer times from symptom onset to medical contact [7, 10]. On March 20th, due to the rising SARS-CoV-2 morbidity (S1 Table), a lockdown was enforced in Israel. We aimed to examine the impact of the government-imposed lockdown in Israel on the characteristics of presentation, reperfusion times and early outcomes of ST-elevation myocardial infarction (STEMI) patients.

Methods

The current analysis is based on a multicenter prospective cohort from four high-volume cardiac centers in Israel- Hillel Yaffe Medical Center, Rambam Healthcare Campus, Shamir Medical Center and Soroka Medical Center. All participating centers are university-affiliated hospitals with coronary catheterization-laboratories that provide a 24/7 on-call primary PCI(PPCI) service. The study was conducted according to the Declaration of Helsinki, with informed consent being waived due to the observational nature of the study.

Data of all consecutive patients presenting with STEMI, during the lockdown period in Israel, March 20th–end of April 2020 were entered into a dedicated database and compared with retrospective data from the same period in 2019. The Inclusion criterion was a diagnosis of STEMI on admission. The main exclusion criterion was age<18.

The primary endpoints were door-to-balloon(D2B) and pain-to-balloon time intervals(P2B). Secondary endpoints included in-hospital mortality, failure to achieve post-PCI TIMI3 flow, moderately- or severely-reduced left ventricular ejection fraction(<40%) at discharge, need for mechanical ventilation, hemodynamic instability during hospitalization, length of hospital stay, and baseline and peak high sensitivity-troponin level.

Reperfusion times, as well as post PCI TIMI flow were drawn from the PCI report. Hemodynamic instability was defined as a need for vasopressors, cardiogenic shock, or use of mechanical circulatory support.

Multivariable logistic regression models were used to examine the association between 2020 admission and delayed reperfusion intervals. Models were adjusted to baseline demographics and risk factors with 2019 admissions serving as a reference group.

Categorical variables were presented as frequencies and percentages and compared using Pearson’s chi-square test or the Fisher-exact test. Continuous variables were presented as median and interquartile range or mean and standard deviation compared using the T-test or the Mann-Whitney U test, as appropriate. A p-value<0.05 was considered statistically significant. Data analysis was performed using IBM SPSS Statistics for Windows (Version 25.0, Armonk, NY).

Results

Two-hundred and forty- three patients were included in the study including 136 during March 20-April 30 2019 and 107 during March20 -April 30 2020 (22% decrease). Overall, 7 patients did not undergo PCI (three in 2019, four in 2020, p = 0.37). Only one SARS-CoV-2 positive patient was included in the study. Data on reperfusion time was available for all patients. There were no significant differences in patient demographics and clinical characteristics between the groups. P2B time was significantly longer in 2020, with a higher rate of patients presenting with very-long (>12 hours) P2B intervals and a higher rate of patients failing to meet the D2B<90 minutes guideline constraint. More patients in 2020 developed hemodynamic instability, and their admission and peak troponin levels were higher (p = 0.03, 0.01, respectively). More patients were discharged early (<72 hours) in 2019 as reflected in a significant difference in hospital length of stay (Table 1). No significant difference in other in-hospital outcomes was noted.

Table 1

Patients’ clinical characteristics and in hospital outcomes.

	2019 (n = 136)	2020 (n = 107)	P value
Age, year Median (IQR)	61 (51,68)	63 (52,70	0.33
Women, %	18.4	15.9	0.61
Ischemic Heart Disease, %	33.8	27.1	0.26
Diabetes Mellitus, %	29.4	34.6	0.48
Hypertension, %	47.8	52.3	0.48
Dyslipidemia, %	53.7	58.9	0.42
Smoker, %	61	63.6	0.88
Atrial Fibrillation, %	6.6	7.5	0.79
Family History of Ischemic Heart Disease, %	17.8	24	0.24
Infarct Related Artery (IRA)			0.53
LMCA	2.2	2.8
LAD	47.4	36.8
LCX/Ramus intermedius	11.1	12.1
RCA	37.8	45.3
SVG grafts	1.5	1.9
Multivessel Disease	56.6	55.1	0.82
Pre PCI TIMI flow in IRA, %			0.26
TIMI 0	54.1	50
TIMI 1	8.9	5.7
TIMI 2	12.6	21.7
TIMI 3	24.4	22.6
P2B, hours median (IQR)	3 (2,5.75)	4 (3,8.5)	0.01
D2B, Min median (IQR)	49 (31,75)	56 (30, 89)	0.22
D2B >90 min	11.9	24	0.01
P2B >12 hours	7.6	19	0.01
Inability to achieve TIMI 3 flow post PCI, %	5.9	8.5	0.44
Admission Troponin, ng/L median (IQR)	54 (20,623)	150 (43, 608)	0.03
Peak Troponin, ng/L median (IQR)	2,648 (1,033, 6,300)	4,365 (2,000, 10,000)	0.01
CCU length of stay, Days median (IQR)	3 (3,4)	4 (3,5)	0.24
Hospital length of stay, Days median (IQR)	4 (3,6)	5 (4,6)	0.03
Early Discharge, %	32.4	12.4	<0.001
Mechanical Ventilation, %	13.2	12.1	0.81
Hemodynamic instability, %	14.7	25.2	0.04
VF/ Cardiac arrest, %	12.5	14	0.73
LVEF (, % median (IQR)	42 (35, 55)	43 (35,50)	0.66
Reduced LVEF,%	46.6%	46.6%	0.99
Mortality, %	5.2	8.4	0.32

In the 2020 group, the adjusted odds for delayed reperfusion times were significantly higher both for D2B>90 min (OR-2.4, 95%CI:1.2–4.9, p = 0.01) and P2B>12 hours (OR3.3, 95%CI:1.3–8.1, p<0.01, Table 2, Fig 1).

Table 2

Adjusted* odds ratio for delayed reperfusion times.

	Lockdown period 2020
	OR (95% CI)	P value
D2B>90 min	2.4 (1.2–4.9)	0.01
P2B>12 hours	3.3 (1.3–8.1)	<0.01

D2B: Door-to-Balloon, P2B: Pain-to-Balloon

Reference group: 2019 admissions; Adjusted to age, gender, ischemic heart disease, hypertension, Smoker, diabetes mellitus, and dyslipidemia. D2B: Door-to-Balloon, P2B: Pain-to-Balloon

Fig 1

Adjusted* odds ratio for delayed reperfusion times.

* Reference group: 2019 admissions; Adjusted to age, gender, ischemic heart disease, hypertension, Smoker, diabetes mellitus, and dyslipidemia. D2B: Door-to-Balloon, P2B: Pain-to-Balloon.

Discussion

The present multicenter study aimed to evaluate the influence of SARS-CoV-2 pandemic and its attendant government restrictions on the timeliness of STEMI presentation and early outcomes. In contrary to the anticipated rise in cardiovascular events [1-4], early reports revealed a decrease in ACS admissions during the SARS-CoV-2 pandemic [5-9]. Correspondingly, we found a significant 22% decrease in the incidence of STEMI presentations during the lockdown period, compared with the same period in 2019. Possible explanations for this decrease were previously suggested [7] and include a change in lifestyle during the lockdown, fear from contacting SARS-CoV-2 patients in the hospitals, dismissing ACS symptoms as viral related, and avoiding any unnecessary burden on the strained medical staff.

Reperfusion times directly affect the clinical outcomes of STEMI patients [11-13]. We observed a 2.4-fold greater likelihood of prolonged D2B (>90 min) and a 3.3-fold greater likelihood of prolonged P2B (> 12 hours) during lockdown as compared to 2019.

The delayed P2B time may share similar causes as the decrease in the incidence of STEMI. There was no change in the PPCI pathway or STEMI admission policy during the lockdown period. Admitted patients were tested for SARSCoV-2 according to the Ministry of Health guidelines but their admission and treatment were not delayed. However, the increased D2B time may be partly explained by the need of the medical staff to put on personal protective equipment, as well as emergency department (ED) increased workload (for those who arrived through ED). While these differences did not translate to a significant difference in in-hospital mortality (though a nominal increase was observed), both admission and peak troponin levels were higher, and more patients developed hemodynamic instability throughout their hospitalization in the 2020 patient group. The length of hospital stay was longer, and fewer patients were discharged early following PPCI despite a general tendency to shorten the length of hospital stay during the pandemic. These may serve as surrogate markers of severity, with an expected worse long-term prognosis.

Several limitations of this study should be acknowledged. First, we compared the contemporary cohort data to a retrospective one, with its inherent limitation. Second, our short follow-up and the relatively small sample size do not allow us to conclude on hard endpoints such as mortality. However, it should be noted that the association between prolonged reperfusion times and outcomes is well established [11-13].

Conclusion

The lockdown imposed in March -April 2020 during the SARSCoV-2 pandemic was associated with a fewer STEMI admission and a significant lag in the time intervals to reperfusion, higher troponin levels and longer hospital stays of STEMI patients. As reperfusion times directly affect the clinical outcomes of STEMI patients, measures to improve these metrics should be implemented prior to and during any future lockdown.

Weekly confirmed new SARS-CoV-2 cases in Israel during lockdown.

(DOCX)

Click here for additional data file.

18 Sep 2020

PONE-D-20-24693

The impact of lockdown enforcement during the SARSCoV-2 pandemic on the number and timing of presentation of patients with ST-elevation myocardial infarction

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Reviewer #1: The authors present an observational paper exploring the impact in Israel of the enforced lockdown during the SARSCoV-2 pandemic on the characteristics of presentation of STEMI patients. STEMI patients admitted during the same time period in 2019 served as the control group. A total of 342 patients were included from 4 cardiac centres. The major findings reported were i) a 22% decrease in the number of STEMI admissions, ii) 2.4-fold greater likelihood of prolonged door-to-balloon time (> 90 min), and iii) 3.3-fold greater likelihood of prolonged pain-to-balloon time (> 12 hours) post lockdown as compared to 2019. Consistent with delayed time to reperfusion; peak troponin and the incidence of hemodynamic instability were higher in the 2020 cohort. There was no difference in the baseline characteristics of the patients.

While the paper was of interest, there are a number of issues that should be addressed.

A] The title of the paper is “The impact of lockdown enforcement during the SARSCoV-2 pandemic on the number and timing of presentation of patients with ST-elevation myocardial infarction”. However, for some of the analyses the authors include in the 2020 cohort patients admitted prior to when lockdown measures were introduced in Israel (20th March). What is the purpose of this? Subsequently they then compare a pre-lockdown 2020 as well as post-lockdown cohort to the 2019 control group for outcomes such as reperfusion times. This is confusing and does not appear to add to the paper. Was there a particular reason for this approach? If so, please make this clearer in the manuscript.

B] To better interpret the data and impact of lockdown on study measures, it would be helpful to include information on the weekly incidence rate of COVID-19 cases in Israel during the 2020 study period.

C] The authors stated the incident rate for STEMI admissions post-lockdown fell by 22% (RIR 0.78 with a p value of 0.05) compared to 2019. What statistical method was used for comparison?

D] What defined a STEMI admission? Was is someone who underwent PPCI? If so, how do the authors know a fall in STEMI admissions was not driven by a change in threshold to refer / admit to the cath-lab? During the post-lockdown period was there a change to STEMI / PPCI pathways?

E] The authors state that only one SARS-CoV-2 positive patient was included in the study. How many of the 2020 cohort were tested for SARS-CoV-2?

F] With respect to pain to balloon time, door to balloon time and peak troponin, what percentage of patients was data available?

G] Was there a change in the PPCI pathway (e.g. admission / screening through the Emergency Department prior to the cath lab rather than direct to the cath lab) that may account for the increase in door to balloon times observed?

H] Please define the criteria for “haemodynamic instability”.

I] It should be made clearer on the Figure that the odds ratio is

F] In the Introduction the authors state “While early reports described decreased admissions for acute cardiovascular event during the SarsCoV-2 pandemic, the impact of governmental restriction measures on patient outcomes has not been evaluated.” This is not the case. Multiple papers from Europe (including Italy, Spain and the UK) have already looked at the impact of governmental restrictions on patient outcomes. Many of these papers are already referenced in the manuscript. This sentence should be amended (along with a similar sentence in the Abstract).

G] Please replace all NS for p-values with the actual number.

H] The first paragraph of the Discussion is poorly written with too much conjecture. Many of these arguments have already been made in similar published manuscripts and the whole paragraph spends too much copy not adding any original perspective (and indeed references) to the debate as to why STEMI admissions fell during the early phase of COVID-19.

I] The conclusion states: “this study reveals the direct influence of the lockdown restrictions on public health issues and brings to attention the hazard of delayed reperfusion of STEMI patients.” There was no difference in LVEF or mortality. Accordingly, I don’t think the conclusion this study brings to attention the hazard of delayed reperfusion in STEMI is justified nor would it seem to summarise the most important findings of the paper.

J] The paper is reasonably well written but suffers from a number of important grammatical errors that should be amended. For example, the final sentence of the Conclusion “As this it well associated with poor outcome, and some countries and region experience second Covid 19 wave, measures to improve this metric should be implemented prior to any future lockdown” is not well written and could be improved.

In addition to above, the major shortcoming of this paper is that many of the findings have already been published. This is especially the case with respect to the change in incidence of STEMI and baseline characteristics. Published data is already available from much larger datasets and the present manuscript would not seem to add much in this regard. However, there is substantially less data about the impact of COVID-19 (or lockdown) on reperfusion times (currently published studies: Secco GG et al. Decrease and Delay in Hospitalization for Acute Coronary Syndromes during the 2020 SARS-CoV-2 Pandemic. Can J Cardiol. 2020. Tam C-CF et al. Impact of Coronavirus Disease 2019 (COVID-19) Outbreak on ST-Segment-Elevation Myocardial Infarction Care in Hong Kong, China. Vol. 13, Circulation. Cardiovascular quality and outcomes. 2020. Wilson, S. J. et al. Effect of the COVID-19 Pandemic on ST-Segment–Elevation Myocardial Infarction Presentations and In-Hospital Outcomes. Circulation: Cardiovascular Interventions, 13(7). 2020). This would seem to be the major value of this study in terms of adding to the literature. A short report centred on the effect of lockdown measures in Israel on reperfusion times, troponin and other in-hospital outcomes (with 2 clearly defined cohorts: post-lockdown versus calendar-matched 2019 cohort) would seem far more attractive.

Reviewer #2: The study describes the impact of the lockdown on the admission of STEMI stating that it is the first time such data are reported. In fact, many reports have already reported similar results worldwide. Even concerning the impact of the lockdown, it has been already demonstrated for french patients (Lantelme et al ; Arch Cardiovasc Dis Jun-Jul 2020;113(6-7):443-447. This paper does not bring new findings.

The authors stated that the study was performed in 4 high volume University hospitals with PCI facilities. Often such high volume centres were overflowed with severe COVID-19 patients who require most of intensive care facilities. Could it be that some patients with an acute coronary syndrome were directed to other hospitals during this period ? How can the authors rule out this hypothesis ?

Overall, the number of STEMI was rather stable with a sort of redistribution of patients: more STEMI were referred before the lockdown as compared to 2019 and less after. How do the authors explained this increase pre-lockdown referral ?

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7 Oct 2020

Reviewer 1:

A] The title of the paper is “The impact of lockdown enforcement during the SARSCoV-2 pandemic on the number and timing of presentation of patients with ST-elevation myocardial infarction”. However, for some of the analyses the authors include in the 2020 cohort patients admitted prior to when lockdown measures were introduced in Israel (20th March). What is the purpose of this? Subsequently they then compare a pre-lockdown 2020 as well as post-lockdown cohort to the 2019 control group for outcomes such as reperfusion times. This is confusing and does not appear to add to the paper. Was there a particular reason for this approach? If so, please make this clearer in the manuscript.

Response:

According to this and other comments we revised the manuscript to include the lockdown period only (compared to same period in 2019).

B] To better interpret the data and impact of lockdown on study measures, it would be helpful to include information on the weekly incidence rate of COVID-19 cases in Israel during the 2020 study period.

Response:

Thank you for your suggestion. Table S1 now include the weekly confirmed new SARS-CoV-2 cases in Israel during Lockdown

C] The authors stated the incident rate for STEMI admissions post-lockdown fell by 22% (RIR 0.78 with a p value of 0.05) compared to 2019. What statistical method was used for comparison?

Response:

Thank you, as we omitted the pre-lockdown period, RIR calculations were also omitted from the revised manuscript.

D] What defined a STEMI admission? Was is someone who underwent PPCI? If so, how do the authors know a fall in STEMI admissions was not driven by a change in threshold to refer / admit to the cath-lab? During the post-lockdown period was there a change to STEMI / PPCI pathways?

Response:

In the revised methods section, we defined STEMI admission as requested. In the discussion methods we specified that there was no chance in the PPCI pathway and STEMI admission policy during lockdown.

E] The authors state that only one SARS-CoV-2 positive patient was included in the study. How many of the 2020 cohort were tested for SARS-CoV-2?

Response:

Unfortunately we do not have this data, we did not collect this data as this was not a pre-defined outcome.

F] With respect to pain to balloon time, door to balloon time and peak troponin, what percentage of patients was data available?

Response:

This data was available to 100% of the patients.

G] Was there a change in the PPCI pathway (e.g. admission / screening through the Emergency Department prior to the cath lab rather than direct to the cath lab) that may account for the increase in door to balloon times observed?

Response:

Please see respond to “D” – there was no change in the pathway or admission policies.

H] Please define the criteria for “haemodynamic instability”.

Response:

Thank you, haemodynamic instability is now clearly defined in the revised methods section.

I] It should be made clearer on the Figure that the odds ratio is

Response:

OR labels were added to the figure as suggested, thank you

F] In the Introduction the authors state “While early reports described decreased admissions for acute cardiovascular event during the SarsCoV-2 pandemic, the impact of governmental restriction measures on patient outcomes has not been evaluated.” This is not the case. Multiple papers from Europe (including Italy, Spain and the UK) have already looked at the impact of governmental restrictions on patient outcomes. Many of these papers are already referenced in the manuscript. This sentence should be amended (along with a similar sentence in the Abstract).

Response:

Thank you for your justified comment, the sentence was amended.

G] Please replace all NS for p-values with the actual number.

Response:

Revised as requested, see table 1.

H] The first paragraph of the Discussion is poorly written with too much conjecture. Many of these arguments have already been made in similar published manuscripts and the whole paragraph spends too much copy not adding any original perspective (and indeed references) to the debate as to why STEMI admissions fell during the early phase of COVID-19.

Response:

Thank you for your comment, we shortened and edited the paragraph as suggested.

I] The conclusion states: “this study reveals the direct influence of the lockdown restrictions on public health issues and brings to attention the hazard of delayed reperfusion of STEMI patients.” There was no difference in LVEF or mortality. Accordingly, I don’t think the conclusion this study brings to attention the hazard of delayed reperfusion in STEMI is justified nor would it seem to summarise the most important findings of the paper.

Response:

Conclusion section was revised to better reflect the main findings of the study.

J] The paper is reasonably well written but suffers from a number of important grammatical errors that should be amended. For example, the final sentence of the Conclusion “As this it well associated with poor outcome, and some countries and region experience second Covid 19 wave, measures to improve this metric should be implemented prior to any future lockdown” is not well written and could be improved.

Response:

Thank you for your comment. The revised manuscript underwent language editing.

In addition to above, the major shortcoming of this paper is that many of the findings have already been published. This is especially the case with respect to the change in incidence of STEMI and baseline characteristics. Published data is already available from much larger datasets and the present manuscript would not seem to add much in this regard. However, there is substantially less data about the impact of COVID-19 (or lockdown) on reperfusion times (currently published studies: Secco GG et al. Decrease and Delay in Hospitalization for Acute Coronary Syndromes during the 2020 SARS-CoV-2 Pandemic. Can J Cardiol. 2020. Tam C-CF et al. Impact of Coronavirus Disease 2019 (COVID-19) Outbreak on ST-Segment-Elevation Myocardial Infarction Care in Hong Kong, China. Vol. 13, Circulation. Cardiovascular quality and outcomes. 2020. Wilson, S. J. et al. Effect of the COVID-19 Pandemic on ST-Segment–Elevation Myocardial Infarction Presentations and In-Hospital Outcomes. Circulation: Cardiovascular Interventions, 13(7). 2020). This would seem to be the major value of this study in terms of adding to the literature. A short report centred on the effect of lockdown measures in Israel on reperfusion times, troponin and other in-hospital outcomes (with 2 clearly defined cohorts: post-lockdown versus calendar-matched 2019 cohort) would seem far more attractive.

Response:

Thank you for this thoughtful comment. After discussion we felt that we should revised the manuscript as suggested to focus on the reperfusion times and early clinical outcome during lockdown period, as suggested.

Reviewer #2: The study describes the impact of the lockdown on the admission of STEMI stating that it is the first time such data are reported. In fact, many reports have already reported similar results worldwide. Even concerning the impact of the lockdown, it has been already demonstrated for french patients (Lantelme et al ; Arch Cardiovasc Dis Jun-Jul 2020;113(6-7):443-447. This paper does not bring new findings.

The authors stated that the study was performed in 4 high volume University hospitals with PCI facilities. Often such high volume centres were overflowed with severe COVID-19 patients who require most of intensive care facilities. Could it be that some patients with an acute coronary syndrome were directed to other hospitals during this period ? How can the authors rule out this hypothesis ?

Response:

Thank you for your comment. During March-April lockdown intensive care units in our centers were not overflowed and ACS patients were not diverted or directed to other hospitals.

Overall, the number of STEMI was rather stable with a sort of redistribution of patients: more STEMI were referred before the lockdown as compared to 2019 and less after. How do the authors explained this increase pre-lockdown referral ?

Response:

As we revised the manuscript according to Reviewer #1 suggestions , the pre-lockdown period is not included in the revised manuscript

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

9 Oct 2020

The impact of lockdown enforcement during the SARSCoV -2 pandemic on the timing of presentation and early outcomes of patients with ST-elevation myocardial infarction

PONE-D-20-24693R1

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Reviewers' comments:

16 Oct 2020

PONE-D-20-24693R1

The impact of lockdown enforcement during the SARSCoV-2 pandemic on the timing of presentation and early outcomes of patients with ST-elevation myocardial infarction

Dear Dr. Kobo:

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