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CME / ABIM MOC / CE

Is COVID-19 an Independent Risk Factor for Heart Attack and Stroke?

  • Authors: News Author: Megan Brooks; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 9/2/2021
  • THIS ACTIVITY HAS EXPIRED FOR CREDIT
  • Valid for credit through: 9/2/2022, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for primary care providers, cardiologists, infectious disease specialists, pharmacists, nurses and other members of the healthcare team who treat and manage adults at risk for infection with COVID-19.

The goal of this activity is to assess the risk for acute myocardial infarction (AMI) and stroke associated with infection with COVID-19.

Upon completion of this activity, participants will:

  • Analyze the association of influenza and AMI
  • Evaluate the impact of COVID-19 on the risks for AMI and stroke
  • Outline implications for the healthcare team


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News Author

  • Megan Brooks

    Freelance writer, Medscape

    Disclosures

    Disclosure: Megan Brooks has disclosed no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine
    Irvine, California

    Disclosures

    Disclosure: Charles P. Vega, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: GlaxoSmithKline; Johnson & Johnson

Editor/CE Reviewer

  • Esther Nyarko, PharmD

    Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships.

CME Reviewer/Nurse Planner

  • Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP, has disclosed no relevant financial relationships.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.


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CME / ABIM MOC / CE

Is COVID-19 an Independent Risk Factor for Heart Attack and Stroke?

Authors: News Author: Megan Brooks; CME Author: Charles P. Vega, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED FOR CREDIT

CME / ABIM MOC / CE Released: 9/2/2021

Valid for credit through: 9/2/2022, 11:59 PM EST

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Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to COVID-19 vaccines may be provided in this activity to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.

Clinical Context

Acute respiratory infections promote systemic inflammation, the type of inflammation that promotes a higher risk for acute myocardial infarction (AMI) and stroke. Barnes and colleagues assessed this issue in a systematic review and meta-analysis of case-control studies of influenza and myocardial infarction (MI). The results of their study were published in the November 2015 issue of Heart.[1]

The review involved 16 studies, including 8 studies that evaluated the role of influenza vaccination in protecting against MI. Recent influenza infection or influenza-like illness was associated with a 2-fold increase in the risk for AMI. Meanwhile, influenza vaccination was associated with a pooled odds ratio (OR) of 0.71 (95% CI: 0.56, 0.91) for AMI.

COVID-19 is associated with an even more robust inflammatory response compared with influenza. Is the SARS-CoV-2 virus associated with a higher risk for AMI and stroke? The current study by Katsoularis and colleagues assesses this issue.

Study Synopsis and Perspective

New data from Sweden provide the strongest evidence to date that COVID-19 is an independent risk factor for AMI and ischemic stroke, the researchers said.

The risk for acute MI and ischemic stroke increased by roughly 8-fold and 6-fold, respectively, in the first week after onset of COVID-19 when day 0 (exposure day) was included in the analysis. Even when day 0 was excluded (reducing the risk for bias), the risk for AMI and stroke was increased by roughly 3-fold.

"The fact that the risk is still increased even when day 0 is excluded indicates that COVID-19 is indeed an independent risk factor for [AMI] and ischemic stroke," senior author Anne-Marie Fors Connolly, MD, PhD, with Umeå University, Umeå, Sweden, told theheart.org | Medscape Cardiology.

"Our results indicate that acute cardiovascular [(CV)] complications might represent an essential clinical manifestation of COVID-19 and the long-term effects might be a challenge for the future," she and her colleagues said.

Their study was published online July 29 in The Lancet.[2]

Digging Deeper

Previous studies that have suggested that COVID-19 is a "probable" risk factor for acute CV complications involved relatively few hospitalized patients.

In what is believed to be the largest study to date to investigate this association, Swedish researchers linked data from national registers for outpatient and inpatient clinics and the cause of death register for all 86,742 patients (median age, 48 years; 43% male) with COVID-19 between February 1 and September 14, 2020, and 348,841 matched control patients.

They used 2 methods to assess the association of COVID-19 with risk for AMI and stroke.

One was a self-controlled case series (SCCS) method, which was used to compare incidence rate ratios (IRRs) for first AMI and stroke before and after patients were determined to have COVID-19.

The other was a matched cohort study, which determined the odds of AMI or stroke in the 14 days after COVID-19 onset in comparison with control individuals who had not been diagnosed with COVID-19.

Because the date of infection was unknown, the researchers identified the closest date possible and denoted it as day 0 (exposure date).

There was a large peak in cases of both AMI and ischemic stroke recorded on day 0, they reported.

In the SCCS, when day 0 was included in the risk period, the IRR for AMI was 8.44 (95% CI: 5.45, 13.08) in the first week; 2.56 (95% CI: 1.31, 5.01) in the second week; and 1.62 (95% CI: 0.85, 3.09) in weeks 3 and 4 after COVID-19.

When day 0 was excluded from the risk period, the IRR for AMI remained significantly elevated in the first week (IRR = 2.89 [95% CI: 1.51, 5.55) and second week (IRR = 2.53 [95% CI: 1.29, 4.94) after COVID-19. The IRR was 1.6 (95% CI: 0.84, 3.04) in weeks 3 and 4 after COVID-19.

The corresponding IRRs for ischemic stroke when day 0 was included in the risk period were 6.18 (95% CI: 4.06, 9.42) in the first week; 2.85 (95% CI: 1.64, 4.97) in the second week; and 2.14 (95% CI: 1.36, 3.38) in weeks 3 and 4 after COVID-19.

When day 0 was excluded from the risk period, the corresponding IRRs for stroke were 2.97 (95% CI: 1.71, 5.15) in the first week; 2.8 (95% CI: 1.6, 4.88) in the second week; and 2.1 (95% CI: 1.33, 3.32) in weeks 3 and 4 after COVID-19.

The matched cohort analysis provided similar results: this time expressed as odds ratios (ORs).

The Day Zero Debate

"The day [zero] has been a cause of discussion between clinicians and statisticians during this study," Connolly told theheart.org | Medscape Cardiology.

"The clinicians (myself included) argued that all events should be included, since we believe it is part of the clinical disease presentation," she explained.

Still, Paddy Farrington, PhD, professor emeritus and statistician of The Open University, Milton Keynes, in Milton Keynes, United Kingdom, and "an important collaboration partner on our study," argued that day 0 should be excluded because it represents a bias. Seeking health care likely precipitates testing for SARS-CoV-2 infection and therefore introduces a test bias that potentially inflates the observed risk, Connolly explained.

The observation that the risk for AMI and stroke remains elevated when day 0 is excluded shows that COVID-19 is an independent risk factor for AMI and ischemic stroke, she emphasized.

Findings Reinforce Importance of Vaccination, but Absolute Risks Are Small

In the matched cohort study, for each weighted Charlson comorbidity index point, the odds for AMI and ischemic stroke increased approximately 40%.

Hence, the findings reinforce the importance of getting vaccinated against COVID-19, particularly for elderly people with comorbid conditions, "to avoid potential acute [CV] events," Connolly told theheart.org | Medscape Cardiology.

Acute myocardial infarction and stroke "could be an extrapulmonary manifestation of COVID-19; therefore, this is good to keep in mind for clinicians who see these types of patients," she added.

The authors of an accompanying comment[2] noted that the transient increase in the risk for MI and stroke in association with influenza, pneumonia, acute bronchitis, and other chest infections has been known for decades.

"It seems reasonable to infer that the persistence of risk for several weeks after SARS-CoV-2 infection is consistent with COVID-19 causing an increased risk of thrombo-occlusive disease, as has been reported for other respiratory infections," wrote Marion Mafham, MD, and Colin Baigent, FMedSci, of the University of Oxford, Oxford, United Kingdom.

They noted, however, that the absolute risks are "small." They also wrote that further studies are needed to evaluate the time course of increased CV risk for patients with COVID-19 and to investigate possible mechanisms.

"However, it is important to keep in mind that the excess risks of [MI] and stroke in a person with COVID-19 are substantially smaller than those resulting from respiratory failure," Mafham and Baigent said.

Funding for the study was provided by Central ALF-Funding and Base Unit ALF-Funding, Region Västerbotten, Sweden; strategic funding during 2020 from the department of clinical microbiology, Umeå University, Sweden; stroke research in Northern Sweden; and the Laboratory for Molecular Infection Medicine Sweden. The authors and editorialists have disclosed no relevant financial relationships.

Study Highlights

  • Researchers drew study data from multiple databases containing health and social information on residents of Sweden. The study period ran from February 1 to September 14, 2020.
  • Investigators performed 2 analyses to assess the risk for first-time AMI and stroke associated with COVID-19. First, they completed a self-controlled case series comparing the risk for AMI and stroke during the peri-infection and postinfection periods with the larger noninfection period among individuals diagnosed with COVID-19. Second, they performed a case-control analysis comparing individuals with and without a diagnosis of COVID-19 who were matched for age, sex, and county of residence.
  • They identified AMI and stroke from diagnosis codes in the databases.
  • The date of COVID-19 onset was represented by the onset of symptoms, healthcare contact, or positive test result.
  • 86,742 individuals were diagnosed with COVID-19 during the study period. The median age of these individuals was 48 years, and 57% were female.
  • In self-controlled case series analysis, there were 186 cases of AMI during the study period, and 36 patients died. The median age of patients with AMI was 73 years, and most were men.
  • Compared with the control period apart for the time of infection, the IRRs for AMI for the following infection periods were:
    • 2.06 (95% CI: 1.31, 3.24) = days −28 to −4 before infection
    • 2.52 (95% CI: 0.78, 8.09) = days −3 to −1 before infection
    • 8.44 (95% CI: 5.45, 13.08) = days 0 to 7 of infection
    • 2.53 (95% CI: 1.29, 4.94) = days 8 to 14 of infection
    • 1.6 (95% CI: 0.84, 3.04) = days 15 to 28 of infection
  • 83,937 individuals with COVID-19 were matched with 340,432 control participants in the case-control analysis.
  • On multivariate analysis in the case-control study, the OR for AMI in comparing individuals with and without a diagnosis of COVID-19 was 3.41 (95% CI: 1.58, 7.36)
  • Compared with the control period apart for the time of infection, the IRRs for stroke for the following infection periods were:
    • 1.89 (95% CI: 1.21, 2.96) = days −28 to −4 before infection
    • 3.96 (95% CI: 1.85, 8.45) = days −3 to −1 before infection
    • 6.18 (95% CI: 4.06, 9.42) = days 0 to 7 of infection
    • 2.85 (95% CI: 1.64, 4.97) = days 8 to 14 of infection
    • 2.14 (95% CI: 1.36, 3.38) = days 15 to 28 of infection
  • On multivariate analysis in the case-control study, the OR for stroke in comparing individuals with and without a diagnosis of COVID-19 was 3.63 (95% CI: 1.69, 7.8).
  • The risk for AMI and stroke on day 0 of infection appeared particularly high. The higher risk for AMI and stroke in the pre-infection period was thought to be because of reverse causality, as patients admitted for these conditions caught COVID-19 in the hospital or shortly after discharge.
  • Adjustment for socioeconomic status did not significantly alter the study's main conclusions.

Clinical Implications

  • In a previous meta-analysis by Barnes and colleagues, recent influenza infection or influenza-like illness was associated with a 2-fold increase in the risk for AMI. Meanwhile, influenza vaccination was associated with pooled odds ratio of 0.71 (95% CI: 0.56, 0.91) for AMI.
  • The current study by Katsoularis and colleagues suggests that COVID-19 is an independent risk factor for AMI and stroke, with the highest risk closest to the onset of the infection.
  • Implications for the healthcare team: The healthcare team can use the results of the current study to promote COVID-19 vaccination and self-protection measures, such as wearing a mask.

 

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