The role of anticoagulation in preventing myocardial infarction and improving outcomes in COVID-19 patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with cardiovascular (CV) complications including myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The infection is more severe in patients with pre-existing cardiovascular disease (CVD), where systemic inflammation due to cytokine storm, hypercoagulation, as well as high hematocrit and platelet (PLT) count may contribute to an increased CV risk. The authors hypothesize that anticoagulants and antiplatelets prevent miocardial infarction (MI) in patients with pre-existing CVD.
METHODS: A cohort study enrolled patients with a confirmed diagnosis of COVID-19. Clinical and laboratory data, total and CV mortality, as well as MI incidence and treatment regimens were compared according to the time of hospitalization: 40-day period in April-May (Group 1) and in October-November (Group 2).
RESULTS: A total of 195 patients were enrolled: 93 in Group 1, with 36.5%, and 102 in Group 2 with 38.2% pre-existing CVD. Group 1 was managed with infusion therapy; only 10.7% received anticoagulation. Group 2 received preventive anticoagulants, antiplatelets, and infusion therapy. In Group 1, seven cases of MI were recorded compared to only three in Group 2. No significant difference in overall mortality (4.3% vs 6.86%, p = 0.441) and MI incidence (7.5% vs 2.9%, p = 0.149) was found, but significant differences were seen in the incidence of severe and critically ill cases between the groups (69.9% and 7.5% vs 75.5% and 20.6%, p < 0.001).
CONCLUSIONS: Poorer outcomes in the early COVID-19 wave were associated with inadequate anticoagulation due to lack of knowledge about the new virus. Despite significantly more severe cases, there was no significant difference in overall mortality and MI incidence in patients with anticoagulation.

Introduction

People of all ages can be infected by COVID-19. People aged 60 years and older, as well as those with underlying medical problems such as high blood pressure, heart and lung diseases, diabetes, obesity, and cancer, are at higher risk of developing serious illness [10]. Involvement of the cardiovascular system is common in COVID-19 [1-6]. Myocardial injury is a common condition among patients hospitalized with COVID-19 and is associated with a higher risk of in-hospital mortality [1, 2]. COVID-19 has been associated with various cardiovascular complications including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism [9]. Infection is severe in patients with pre-existing cardiovascular disease, and in these cases the systemic inflammatory response due to cytokine storm can lead to acute MI [7]. MI caused by the rupture of atherosclerotic plaque resulting in intraluminal thrombus is defined as type 1 MI [8]. Several potential mechanisms can contribute to the high risk of plaque destabilization and consequently to acute coronary ischemic syndromes in patients with systemic viral infection [11]. Viral products known as pathogen-associated molecular patterns entering the systemic circulation activate immune receptors on cells in existing atherosclerotic plaques and predispose to plaque rupture [12]. It is also believed that such pathogen-associated molecular structures activate inflammasomes and lead to the conversion of emerging pro-cytokines into biologically active cytokines [13]. Infection and inflammation can also lead to coronary vascular endothelial dysfunction and cause vasoconstriction and thrombosis [14]. In these cases, patients usually present with dyspnea that is attributed to pneumonia—therefore MI can be easily overlooked.

With COVID-19 infection, the majority of MIs are type 2 and are related to the primary infection, as well as hemodynamic and respiratory impairment. However, hypercoagulation in COVID-19 can also predispose patients to fatal vascular events [15].

Furthermore, these patients also have high hematocrit and PLT values, which, in turn, contribute to the high risk of vascular events.

The authors hypothesize that the use of antiocoagulants and antiplatelets is vital for the prevention of acute coronary syndromes, especially in patients with pre-existing cardiovascular diseases.

Methods

A prospective cohort study was conducted in patients with a confirmed diagnosis of COVID-19 admitted to Nork National Center of Infectious Diseases, Armenia. In all, 193 patients were divided into two groups according to the time of hospitalization: 40-day period in April–May (Group 1) and in October–November (Group 2). Severity of COVID-19 was defined according to the WHO scale criteria. Clinical and laboratory data, total and CV mortality, the incidence of MI, as well as treatment regimens were compared in the two groups.

Results

In Group 1, 21 (22.6%) moderately, 65 (69.9%) severely, and seven (7.5%) critically ill patients were enrolled with a mean age of 49 (28–79), of which 45.2% were male. A total of 90 patients had pneumonia; in 11 cases lesions involved more than 50% of the lung parenchyma, and SpO2 fluctuated between 64–97%. Acute respiratory distress syndrome (ARDS) was reported in eight cases. The mortality rate in Group 1 was 4.3%. In all, 36.5% of patients had pre-existing cardiovascular diseases (arterial hypertension: 28, arrhythmia: nine, chronic heart failure: six, coronary artery disease: 10, previous MI: five). A total of 19 patients were regularly receiving aspirin, 16 patients were receiving angiotensin-converting enzyme (ACE) inhibitors, and 12 patients statins. During hospitalization, Group 1 received minimal infusion therapy, 23 of the patients received aspirin, 10 (10.7%) of the patients received anticoagulants, and nine patients received corticosteroids. Mean hospitalization time was 14.3 days (Table 1).

Table 1

Clinical characteristics for the Group 1

	Group 1 N = 93	Group 2 N = 102
Age n (%)
≤ 49 years	32 (34.4)	25 (24.5)
50–69 years	47 (50.5)	64 (62.75)
≥ 70 years	14 (15.1)	13 (12.75)
Sex, male n (%)	42 (45.2)	48 (47.1)
Arterial n (%)	28 (30.1)	38 (37.2)
SVT n (%) VT/VF n (%)	7 (7.5) 2 (2.15)	10 (9.8) 1 (0.98)
Chronic heart n (%)	6 (6.5)	10 (9.8)
disease n (%)	10 (10.7)	14 (13.7)
Previous MI	5 (5.35)	6 (5.9)
PCI	6 (6.45)	9 (8.8)
Diabetes mellitus n (%)	19 (20.4)	22 (21.6)
Other comorbidities n (%)	14 (13.6)	12 (11.8)
BMI ≥ 30 n (%)	45 (48.4)	53 (51.9)

SVT supraventricular tachycardia, VT/VF ventricular tachycardia/ventricular fibrillation, MI myocardial infarction, PCI percutaneous coronary intervention, BMI body mass index

Group 2 included four (3.9%) moderately, 77 (75.5%) severely, and 21 (20.6%) critically ill patients with a mean age of 53 (27–82) and 47.1% were male. The mortality rate was 6.8%. A total of 38.2% of the patients from Group 2 had pre-existing cardiovascular diseases (arterial hypertension: 21, arrhythmia: four, chronic heart failure: 10, coronary artery disease: 14). All patients in Group 2 had pneumonia confirmed by chest computed tomography (CT), 41 with involvement of more than 50% of lung parenchyma. In 58 cases, this was complicated by ARDS. SpO2 fluctuated between 45 and 93%.

Prior to hospitalization, 27 patients were receiving anticoagulants (Xarelto 10–30 mg: 14, enoxaparin 4000 U: eight, aspirin 75–100 mg: 34). All patients in Group 2 received enoxaparin 4000 U od subcut. After laboratory tests and re-evaluation of the risk of thrombosis, doses of anticoagulants were changed. D‑dimer was 0.4–1.5 FEU/ml in 41 patients, 1.6–3 FEU/ml in 45, 3.1–10 in 11, and ≥ 10 in five. In all, 13 patients experienced adverse events (bleeding) from the anticoagulation; therefore, doses for these patients were adjusted or anticoagulation was ceased. A total of 96 patients received corticosteroids as part of their treatment during hospitalization. Mean hospitalization for this group was 14.1 days.

Study data revealed that Group 1 was managed with minimal infusion therapy and only 10.7% received anticoagulation. In contrast, Group 2 received preventive doses of anticoagulants and antiplatelets, and proper infusion therapy was administered. In Group 1, seven cases of MI were recorded on the 15–18th day of disease (three of these with a history of MI). In six cases, MI developed during hospitalization, and in one case, on the third day following hospital discharge (23rd day of disease). In Group 2, only three cases of MI were recorded (one of these with previous MI) (Table 2).

Table 2

Treatment comparison between Group 1 and Group 2

Treatment	Group 1	Group 2
Aspirin 75–100 mg/day, n (%)	23 (24.7)	31 (30.4)
Anticoagulation, n (%)	10 (10.75)	102 (100)
Nadroparin, n (%)
4000 U/day	8 (8,.6)	22 (21.56)
8000 U/day	0	44 (43.13)
16,000 U/day	0	8 (7.8)
Heparin  U/8 h, n (%)	0	23 (22.5)
Xarelto 10–20 mg/day n (%)	2 (2.15)	5 (4.9)

Elevation of PLT count was recorded in the 3rd week of disease. The mean level of PLT in Group 1 was 813 ± 473 × 109/µL and 722 ± 383 × 109/µL in Group 2. There was also a drastic difference in other laboratory test results between the two groups (Table 3).

Table 3

Laboratory test results for the two groups

Laboratory data	Group 1	Group 2
PLT (N-150–400 × 109/µL) mean; range	839; 366–1312	722; 125–1010
HCT (36–47%) mean; range	38.4; 372–51.1	38.2; 37–49.2
D‑dimer (< 0.55 FEU/ml) mean; range	–	2.3; 0.5–13.8
INR (0.85–1.2) mean; range	0.98; 0.64–2.1	1.02; 0.72–3.1
APTT (25–43 sec) mean; range	34.6; 27–43.8	36.2; 25–44.5
Fibrinogen (200–400 mg/dl) mean; range	449.7; 225–635	497.8; 240–675

PLT platelet, HCT hematocrit, INR international normalized ratio, APTT activated partial thromboplastin time

Statistical revealed no significant difference in overall mortality (4.3% vs 6.86%, p = 0.441) and MI incidence (7.5% vs 2.9%, p = 0.149) between the two groups. In contrast, there was a significant difference in incidence of severely and critically ill cases between the two groups (69.9% and 7.5% vs 75.5% and 20.6%, p < 0.001) (Table 4).

Table 4

Endpoints

Hospitalization, mean ± SD (days)	14.3 ± 5.2	14.1 ± 4,6
MI n (%)	7 (7.5)	3 (2.9)	p = 0.149
Mortality n (%)	4 (4.3)	7 (6.86)	p = 0.441
CV mortality n (%)	3 (3.2)	1 (0.98)

SD standard deviation, MI myocardial infarction, CV cardiovascular

Two cases of ST-segment elevation myocardial infarction (STEMI) in patients with COVID-19 in Group 2 are presented below. In both cases, patients were receiving lower doses of anticoagulants due to bleeding complications.

Case presentations

Case 1

A 51-year-old woman with a history of uncontrolled high blood pressure was admitted to hospital on the 8th day of COVID-19 disease with the following symptoms: fever, weakness, shortness of breath, cough, and bleeding from hemorrhoids. Chest CT was performed on admission, which revealed progressive bilateral nonspecific interstitial pneumonia with ground-glass opacity (GGO) covering 70% of lungs. Clinical findings for this patient on admission included: temperature: 37.2 C, SpO2: 86% in room air, 92% with oxygenation, heart rate (HR): 113 bpm, blood pressure (BP): 140/80 mm Hg, body mass index (BMI): 33. Blood test results are presented in Table 5.

Table 5

Blood test results

	Results	Normal range
WBC	6.17	4–10 × 109/µL
LYM	0.86	1–3.0 × 109/µL
NEU	4.91	1.6–7 × 109/µL
PLT	952	150–400 × 109/µL
RBC	6.26	3.9–5.6 × 1012/µL
HGB	154	110–160 g/l
CRP	68	> 5 mg/l
D‑dimer	0.613	< 0.55 FEU/ml
PCT	0.01	< 0.05 ng/ml
Ferritin	790	13–350 ng/ml
INR	1.12	0.85–1.2
APTT	40.6	25–43 sec
Fibrinogen	548	200–400 mg/dl
Glucose	25	< 6 mmol/l

WBC white blood cell count, LYM lymphocyte count, NEU neutrophil count, PLT platelet count, RBC red blood cell count, HGB hemoglobin CRP C-reactive protein, PCT procalcitonin, INR international normalized ratio, APPT activated partial thromboplastin time, FEU fibrinogen-equivalent units

The patient had previously taken hypotensive drugs once or twice a month only in critical situations. Before hospitalization, the patient was taking only vitamins, aspirin, and azithromycin for 6 days.

A treatment regimen with a combination of steroid therapy (dexamethasone 12 mg/day) and preventive anticoagulation (fraxiparine 4000 U/day s.c.) was initiated. The patient received a low-dose anticoagulant due to bleeding hemorrhoids. Following hospitalization, the patient continued to have fever for 2 days, cough and dyspnea persisted, and on the third day ARDS developed and the patient was transferred to the intensive care unit (ICU).

Blood tests were repeated, the results of which are presented in Table 6.

Table 6

Intensive care unit blood test results

	Results	Normal range
WBC	10.76	4–10 × 109/µL
LYM	0.45	1–3.0 × 109/µL
NEU	10.01	1.6–7 × 109/µL
PLT	1345	150–400 × 109/µL
CRP	19	> 5 mg/l
D‑dimer	1.23	< 0.55 FEU/ml
Ferritin	821	13–350 ng/ml
INR	1.17	0.85–1.2
APTT	41.8	25–43 sec
Fibrinogen	556	200–400 mg/dl

WBC white blood cell count, LYM lymphocyte count, NEU neutrophil count, PLT platelet count, CRP C-reactive protein, INR international normalized ratio, APPT activated partial thromboplastin time, FEU fibrinogen-equivalent units

At 18 h following admission to the ICU, the patient experienced discomfort in the right shoulder. Electrocardiography (ECG) was performed, which revealed ST elevation in leads V1–V3. The troponin T level was also elevated (395 ng/L) and further increased to 948 ng/L. Due to ARDS and low SpO2 (81%) even with oxygenation, percutaneous coronary intervention (PCI) was not possible and the patient passed away soon after the diagnosis of STEMI.

Case 2

A 62-year-old man with cardiovascular risk factors, including coronary artery disease, hypertension, as well as previous MI and PCI, was admitted with COVID-19-induced pneumonia on the 8th day of disease. The patient had fever, weakness, and shortness of breath. COVID-19 was confirmed by real-time reverse transcription-polymerase chain reaction testing from a nasopharyngeal swab. Clinical findings after physical examination included: temperature: 38.1 C, SpO2: 83–84% in room air and 90% with oxygenation, HR: 92 bpm, BP: 140/80 mm Hg. ECG was without abnormalities. The patient had been treated with antibiotics and corticosteroids before hospitalization. ECG was performed on admission, revealing no significant abnormalities. Laboratory results are presented in Table 7.

Table 7

Blood test results

	Results	Normal range
WBC	11.06	4–10 × 109/µL
LYM	1.03	1–3.0 × 109/µL
NEU	8.84	1.6–7 × 109/µL
PLT	1636	150–400 × 109/µL
RBC	5.72	3.9–5.6 × 1012/µL
HGB	165	110–160 g/l
CRP	69	> 5 mg/l
D‑dimer	1.73	< 0.55 FEU/ml
PCT	0.08	< 0.05 ng/ml
INR	2.1	0.85–1.2
APTT	44.6	25–43 sec
Fibrinogen	621	200–400 mg/dl

WBC white blood cell count, LYM lymphocyte count, NEU neutrophil count, PLT platelet count, RBC red blood cell count, HGB hemoglobin CRP C-reactive protein, PCT procalcitonin, INR international normalized ratio, APPT activated partial thromboplastin time, FEU fibrinogen-equivalent units

This patient also received a low-dose anticoagulant (nadroparine 4000 U/day ubcut) due to severe nasal bleeding.

During day 1 of hospitalization, the patient had a drop in SpO2 to 78% with oxygenation during minimal physical activity. There were signs of encephalopathy. On the 2nd day of hospitalization, the patient experienced severe chest pain and discomfort and had a drop in BP to 70/40 mm Hg. The 12-lead ECG before symptoms showed an extreme left axis deviation, T wave inversion in lead III, and ascending (not significant) ST elevation in lead I and aVL (Fig. 1). The 12-lead ECG performed immediately after symptoms showed ST elevation in leads II, III, and aVF, as well as reciprocal ST depression in leads V3–V6, extreme left axis (Fig. 2).

Fig. 1

Electrocardiogram on the 2nd day of hospitalization

Fig. 2

A 12-lead electrocardiogram

The patient’s troponin T levels came back elevated at 193.3 ng/L (normal: 20 ng/L). The patient received heparin 10,000 U i.v. and analgesics. After 1 h, the troponin T level rose to 1807.2 ng/L. Acute myocardial infarction with ST elevation was diagnosed and the patient was transferred to a hospital with a catheterization laboratory. Coronary angiography revealed a proximal lesion in the right coronary artery (RCA) with 85% stenosis, and another lesion in the distal RCA (with 90% stenosis) extending to the posterior descending artery, where thrombi were localized (Fig. 3). Other coronary arteries were affected: 30% stenosis of the distal left anterior descending artery (LAD), 70% stenosis of the proximal left circumflex artery (LCX), and 70% stenosis of the first diagonal artery. Immediate RCA stenting with a drug-eluting stent was performed (Fig. 4). On the following day, selective PCI was performed with stenting of the LCX. Dual antiplatelet therapy consisting of oral clopidogrel (75 mg od) and aspirin (81 mg od) was initiated. After 32 days of prolonged hospitalization, the patient was discharged under long-term monitoring of a cardiologist and a hematologist. After 2 weeks, the patient was followed-up in an outpatient clinic. His physical strength and nutritional status had slightly improved, and there were no complications from the dual antiplatelet therapy.

Fig. 3

Right coronary artery stenosis on coronary angiogram

Fig. 4

Right coronary artery after percutaneous coronary intervention

Conclusion

A broad range of risk factors and potential cardiovascular complications were assessed and considered in the clinical management tactics.

The poorer outcomes in the early stages of the pandemic were associated with inadequate administration of anticoagulation treatment due to a lack of information about the novel virus and clinical management specificities.

Although Group 2 had significantly higher rates of severe cases, there was no significant difference in overall mortality and MI incidence. The authors conclude that anticoagulants and antiplatelets were crucial for preventing cardiovascular complications especially in patients with comorbidities. Patients with high platelet levels were at higher risk of developing MI, and subsequently of having a worse outcome.