Figure 1
PRISMA flow diagram.
Table 1
Characteristics of the included 63 studies and demographics of COVID-19 patients.
| STUDY CHARACTERISTICS (N = 63) | |
|---|---|
| Systematic reviews only | 14 (22.2%) |
| Systematic review and Meta-Analysis | 49 (77.8%) |
| Peer reviewed | 46 (73.0%) |
| Non-peer reviewed | 17 (27.0%) |
| LOCATION OF PRIMARY STUDIES IN THE REPORTING 56 SYSTEMATIC REVIEWS | |
| Single country studies- from China | 11/56 (19.6%) |
| Multi-country studies | 45/56 (80.4%) |
| DEMOGRAPHICS OF COVID-19 PATIENTS | |
| AGE MEAN/MEDIAN YEARS (RANGE) | NUMBER OF STUDIES (N = 63) |
| ≥50–75 | 10 (16%) |
| ≥40–87 | 15 (24%) |
| ≥30–73 | 5 (8%) |
| ≥20–95 | 6 (10%) |
| ≥8–109 | 1 (2%) |
| Not reported | 26 (41%) |
Figure 2
Origin of primary studies included in the reporting systematic reviews.
Table 2
Summary of cardiac complications in COVID-19 patients.
| CARDIAC COMPLICATIONS IN COVID-19 PATIENTS | ESTIMATES | REFERENCES |
|---|---|---|
| Acute cardiac injury (ACI) (frequency) | ||
| Overall frequency ** | 15% to 33%, and 75% in 1 study | [20, 23, 25, 27, 28, 45, 53, 56, 57, 58, 59, 60, 61] |
| Patients with CVD and/or in severe disease ** | 25%, to 33% | [23, 25] |
| In fatal cases | 61.6% to 72.6% | [53, 59, 60] |
| In patients with Takotsubo syndrome | 75% | [20] |
| Increased risk of ACI in severe disease | (OR) 13.5, 6.6, 6.3 | [23, 30, 31, 47, 60, 62, 63] |
| (RR) 6.0, 13.8, 8.5, 5.7 | ||
| Association of ACI with mortality | (OR) 17.0, 19.6, 20.3, 21.2, 22.5 | [23, 30, 31, 33, 34, 47, 54, 59, 63] |
| (RR) 3.8, 4.9, 8.0, 8.5, 8.9 | ||
| ARRHYTHMIA | ||
| Overall** | 0.3% to 44.0% | [21, 22, 23, 24, 25, 26, 27, 28, 29, 41, 42, 43, 61] |
| Incidence in severe/fatal patients** | 33.0% to 48.0% | [21, 25, 29, 30, 34] |
| Incidence in non-severe patients** | 3.1% to 6.9% | [21, 30, 34] |
| Incidence related to use of HCQ and/or CQ** | 0.3% to 44.0% | [41, 42, 43] |
| QT prolongation (overall frequency) ** | 9% to 44% | [29, 41, 42, 43] |
| Heart failure/shock (frequency)** | 3.4% to 23.7% | [23, 25, 27, 28, 61] |
| Cardiac arrest | 0.3%, 5.7% | [28, 42] |
| Cardiomyopathy | 7% | [25] |
| ACS/CAD | 6.2%, 10%, 33%* | [24, 25, 28] |
[i] OR: odds ratio, RR: Relative risk, HCQ: Hydroxychloroquine, CQ: Chloroquine, ACI: acute cardiac injury, ACS/CAD: Acute coronary syndrome/Coronary artery disease. * Reporting in a case series in a systematic review [24] ** Reporting the lowest and highest proportions.
Table 3
Studies addressing acute cardiac injury and myocardial injury in COVID-19 patients.
| SOURCE | SAMPLE SIZE | PRE-EXISTING CARDIAC DISEASE IN STUDY POPULATION | ACI/MI FREQUENCY | ACI/MI SEVERE VS NON-SEVERE/MILD DS (OR)/(RR) | ACI/MI AND MORTALITY (OR)/(RR) |
|---|---|---|---|---|---|
| Bavishi et al. [45] | 11685 | NA/NR | 20% | – | - |
| De Lorenzo et al. [56] | 1229 | NA/NR | 16% | – | - |
| Zou et al. [53] | 2224 | NA/NR | 24% | – | - |
| Huang et al. [62] | 5328 | NA/NR | – | OR 13.5 [3.6, 50.5] | - |
| Li et al. [30] | 4189 | NA/NR | – | RR 6.0 [3.0, 11.8] | RR 3.8 [2.1, 7.0] |
| Luo et al. [63] | 129380 | NA/NR | – | OR 6.6[3.7, 11.6] | OR 17.0 [7.9, 36.4] |
| Li et al. [64] | 3118 | 45-67% | 15%–44% | – | OR 21.2 [10.2, 43.9] |
| Prastilumkum et al. [57] | 8971 | NA/NR | 20% | – | – |
| Potere et al. [58] | 14866 | 9.4% | 15% | – | – |
| Zeng et al. [54] | 5726 | NA/NR | – | – | RR 4.9 [3.8, 6.2] |
| Zuin et al. [59] | 1686 | NA/NR | 23.90% | – | OR 22.5 [16.1, 31.4] |
| Santosa et al. [47] | 2389 | NA/NR | – | RR 13.8 [5.5, 34.5] | RR 8.0 [5.1, 12.3] |
| Dalia et al. [31] | 5967 | NA/NR | - | RR 8.5 [3.6, 20.0] | RR 8.5 [3.6, 20.0] |
| Gu et al. [60] | 7679 | NA/NR | 21% | RR 5.7 [3.7, 8.8] | |
| Momtazmanesh et al. [23] | 11569 | NA/NR | 25.30% | OR 6.3 [4.2, 9.8] | OR 19.6 [10.3, 37.5] |
| Shoar et al. [32] | 3257 | NA/NR | – | – | OR 20.3 [7.8, 53.3] |
| Martins-Filho et al. [33] | 1141 | NA/NR | – | – | RR 8.9 [4.2, 19.3] |
| Amir et al. [65] | 29056 | NA/NR | 33% | – | – |
| Singh et al. [20] | 12 | NA/NR | 75% | – | – |
| Sardinha et al. [27] | 3316 | 13.08% | 17.09% | – | – |
| Kunutsor et al. [28] | 5815 | 14.6% | 16.30% | – | – |
| Vakili et al. [61] | 6389 | NA/NR | 15.68% | – | – |
[i] NA: Not available, NR: Not reported, ACI: Acute cardiac injury, MI: Myocardial injury, OR: Odds ratio, RR: Relative risk.
Table 4
Arrhythmias and QT prolongation in COVID-19 patients in ascending order of publication.
| SOURCE | STUDIES/(SAMPLE SIZE) | ARRHYTHMIAS (INCIDENCE) | QT PROLONGATION |
|---|---|---|---|
| Li et al. [30] | 22 (4189) | 44.4% (severe), 6.9% (non-severe) | – |
| Jankelson et al. [43] | 10 (NR) | 7.1% on high dose CQ | 10% |
| Kunutsor et al. [28] | 17 (5815) | 9.3% | – |
| Kim et al. [40] | 40 (11437) | – | HCQ + AZ OR 1.8 [1.1, 3.3]. There was no significance with HCQ, high-dose HCQ or AZ monotherapy group. |
| Khadka et al. [39] | 6 (NR) | – | HCQ+AZ OR 0.8 [0.6, 1.2]. Increase in critical QTc threshold OR 1.9 [0.8, 4.6] nor absolute ΔQTc ≥60ms OR 2.0 [0.6, 7.0] among HCQ+AZ versus HCQ alone. |
| Eljaaly et al. [38] | 9 (916) | No HCQ associated cardiac toxicity reported | – |
| Dalia et al. [31] | 20 (5967) | Increased risk in non-survivors/severe disease versus survivors/non-severe disease RR 3.6 [2.0, 6.4] | – |
| Shafi et al. [24] | 61 (NR) | 14% (AF (7%), VT/VF (5.9%) and AFl) | – |
| Momtazmanesh et al. [23] | 35 (11569) | 26.1% | No cardiotoxicity reported |
| Li et al. [34] | 23 (4631) | 43.8% (severe), 3.1% (non-severe). Newly occurring arrhythmias were at a higher risk of developing severe disease/ICU admission RR 13.1 [7.0, 24.5] | – |
| Das et al. [44] | 17 (8071) | No significant risk in HCQ group. significantly increased in the HCQ + AZ group | No significant risk of DILQTS in HCQ group vs control. Significantly increased in the HCQ + AZ group |
| Pranata et al. [21] | 4 (784) | 19% overall. 48% (severe), 6% (non-severe). increased risk of poor outcome RR 8.0 [3.8, 16.8] | – |
| Prodromos et al. [36] | 25 (NR) | No TDP or related deaths with HCQ + AZT. Found to substantially decrease arrhythmias. | – |
| Malaty et al. [29] | 23 (4911) | 6.9% with. HCQ, CQ, AZ. ventricular arrhythmias (VT, VF), atrial arrhythmias (AF, Afl, AT), brady-arrhythmias (AV block, sinus bradycardia). | 14.2% overall. 15.9% DILQTS with AZ + HCQ/CQ, 11.44% DILQTS with HCQ or CQ or AZ |
| Martins-Filho et al. [33] | 6 (1141) | Risk for mortality RR 4.9 [1.2, 10.9] | – |
| Michaud et al. [35] | 38 (NR) | – | High to moderate risk of LQTS for CQ, HCQ, Favipiravir, Remdesivir, and LPV/r. Not for AZ. |
| Shoar et al. [32] | 12 (3257) | Risk for mortality OR 22.4 [1.8, 283.6] | – |
| Vakili et al. [61] | 30 (6389) | 16.6% | – |
| Ladapo et al. [37] | 5 (5577) | 1/936 in HCQ group versus 1/469 control (1/4 reporting study). 0% in 3/4 reporting studies | No HCQ associated LQT reported |
| Hessami et al. [66] | 56 (29056) | Incidence- 11% (overall), 33% (severe Patients). Associated with ICU admission (OR: 22.2, 95%CI 4.5-110.0) | – |
| Zeng et al. [54] | 17 (5726) | CI vs non-CI groups RR 5.7 [0.7, 47.0] | – |
| Hamam et al. [22] | 9 (1445) | 19.7% | – |
| Tleyjeh et al. [42] | 19 (5652) | 0.3% (overall). 5% incidence of discontinuation of CQ or HCQ due to prolonged QTc or arrhythmias (13 studies of 4334 patients) | 9% QTc change form baseline of ≥ 60 ms or QTc ≥ 500 ms, 5% discontinuation of CQ or HCQ due to prolonged QTc or arrhythmias (13 studies of 4334 patients). |
| Takla et al. [41] | 24 (NR) | 44% with HCQ and/or CQ, 44% found no evidence of a significant difference, and 11% mixed results | 44% greater incidence |
| Sardinha et al. [27] | 12 (3316) | 1.77%. (AF most common) | – |
| Thakkar et al. [26] | 101 | 44% | – |
[i] TDP: Torsade de Pointes, OR: odds ratio, RR: relative risk, HCQ: Hydroxychloroquine, CQ: Chloroquine, AZ: Azithromycin, ICU: Intensive care unit, VT: Ventricular tachycardia, VF: Ventricular fibrillation, AF: Atrial fibrillation, Afl: Atrial flutter, AT: Atrial tachycardia, AV block: Atrioventricular block, LPV/r: Lopinavir/Ritonavir, CI: cardiac injury.
Table 5
Myocarditis and COVID-19.
| SOURCE | STUDIES/(SAMPLE SIZE) | FREQUENCY/AGE (MEAN RANGE)/PRE-EXISTING DISEASE | CLINICAL SYMPTOMS | ECG | IMAGING – ECHO AND CMRI | INVESTIGATIONS – OTHER | ELEVATED BIOMARKERS | THERAPEUTICS |
|---|---|---|---|---|---|---|---|---|
| Sawalha et al. [48] | 14 case reports (14) | 100%, 21 to 78 years CVD 8%, HTN 33% | Dyspnea 71%, Shock 58%, Chest pain 57%, Cough 67%, fever 75% | diffuse ST-segment elevation 25%, ST-segment depression 25%, T-wave inversion 25%, arrythmias 17% | Reduced LVEF 50%, pericardial effusion 42%, cardiac tamponade 20%, diffuse hypokinesis 30%. Diffuse gadolinium enhancement 100% | CT angiography 17%, invasive coronary angiography 25%, endomyocardial biopsy 7% | Trop. 86%, CKMB 17%, NT-BNP 50%, CRP 100%, IL6 100% | Glucocorticoids, Ig, colchicine. For cytokine storm – Tocilizumab, INF. ECMO (14%) |
| Kariyana et al. [49] | 11 (NR) | 12% to 100%, 21 to 74 years | Dyspnea 82%, chest pain/tightness 55%, fever 55%, cough 55% | ST elevation 56%, T wave inversion 33% | Reduced LVEF 67%, pericardial effusion 33%, cardiomegaly 67%. Diffuse gadolinium enhancement 100% | Endomyocardial biopsies | Trop. T 100%, CKMB 100%, NT-BNP 100% | Corticosteroides, LPV/r, HCQ, Ig, tzp, inotropes, vasopressor |
| Shafi et al. [24] | 61 (NR) | 12% to 100%, 8 to 79 years | – | – | – | – | – | Steroids, LPV/r, Tocilizumab |
| Thakkar et al. [26] | 101 (NR) | 19%–28%, NR | – | – | – | – | – | – |
[i] ECHO: Electrocardiogram, LVEF: Left ventricular ejection fraction, CMRI: Cardiac magnetic resonance imaging, CT angiography: computed tomography angiography, CK-MB: Creatine kinase-MB, pro-BNP: pro Brain Natriuretic Peptide, IL-6: inteleuking-6, CRP:C-reactive protein, LPV/r: Lopinavir Ritonavir, HCQ: Hydroxychloroquine, Ig: Immunoglobulin, tzp: piperacillin/tazobactam, ECMO: extracorporeal membrane oxygenation, INF: interferon.
Table 6
Risks associated to the use of RAAS inhibitors in COVID-19 patients.
| SOURCE | ACEI/ARB-TESTING COVID-19 POSITIVE | ACEI/ARB-HOSPITALIZATION | ACEI/ARB-SEVERE DISEASE | ACEI/ARB-LENGTH OF HOSPITALIZATION | ACEI/ARB-MORTALITY | ||
|---|---|---|---|---|---|---|---|
| Asiimwe et al. [67] | OR 1.01 [0.93, 1.10] | OR 1.16 [0.80, 1.68] | OR 1.04 [0.76, 1.42] | MD-0.45 | OR 0.86 [0.64, 1.15] | ||
| Xu et al. [74] | aOR 1.00 [0.94, 1.05] | – | aOR 0.95 [0.73, 1.24] | – | aOR 0.87 [0.66, 1.14] | ||
| Beressa et al. [68] | – | – | RR 0.92 [0.74, 1.14] | WMD -2.33 [5.60, 0.75] | RR 0.73 [0.63, 0.85] | ||
| De Almeida-Pititto et al. [69] | – | – | OR 0.76 [0.39, 1.49] | – | – | ||
| Baral et al. [70] | – | – | OR 0.833 [0.605, 1.148] | – | OR 0.650 [0.356, 1.187] | ||
| Barochiner et al. [76] | – | – | RR 0.81 [0.63-1.04] | – | RR 0.81 [0.63-1.04] | ||
| Bezabih et al. [77] | – | – | OR 0.84 [0.73, 0.96] | – | OR 0.84 [0.73, 0.96] | ||
| Flacco et al. [71] | – | – | OR 1.00 [0.84, 1.18] | – | OR 0.85 [0.81, 1.03] | ||
| Garg et al. [78] | – | – | OR 1.18 [0.91, 1.54] | – | OR 1.03 [0.69, 1.55] | ||
| Zhang et al. [72] | OR 0.93 [0.85, 1.02] | – | aOR 0.76 [0.52, 1.12] | – | aOR 0.97 [0.77, 1.23] | ||
| Ssentongo et al. [75] | OR 0.93 [0.85, 1.02] | – | – | – | RR 0.65 [0.45, 0.94] | ||
| Kaur et al. [79] | – | OR 2.1 [1.09, 4.05] | OR 1.08 [0.79, 1.46] | – | OR 0.91 [0.65, 1.26] | ||
| Liu X et al. [73] | OR 0.95 [0.89, 1.05] | – | OR 0.75 [0.59, 0.96] | – | OR 0.52 [0.35, 0.79] | ||
| Bin Abdulhak et al. [80] | – | – | – | – | aOR 0.33 [0.22, 0.49] | ||
| REF. NO. | ACEI- TESTING POSITIVE | ARB- TESTING POSITIVE | ACEI- HOSPITALIZATION, ARB- HOSPITALIZATION | ACEI- SEVERE DISEASE | ARB- SEVERE DISEASE | ACEI- MORTALITY | ARB- MORTALITY |
| Asiimwe et al. [67] | aOR 0.97 [0.87, 1.09] | aOR 0.90 [0.65, 1.24] | aOR 0.78 [0.47, 1.28], aOR 1.09 [0.67, 1.77] | aOR 0.72 [0.46, 1.13] | aOR 1.12 [0.69, 1.82] | aOR 0.80 [0.46, 1.38] | aOR 1.11 [0.94, 1.32] |
| Xu J et al. [74] | aOR 0.95 [0.88, 1.02] | aOR 0.97 [0.82, 1.14] | – | aOR 0.81 [0.61, 1.08] | aOR 1.09 [0.76, 1.55] | aOR 0.51 [0.23, 1.12] | aOR 1.63 [0.61, 4.35] |
| Bezabih et al. [77] | – | – | – | OR 0.77 [0.63, 0.93] | OR 1.13 [0.95, 1.35] | OR 0.77 [0.63, 0.93] | OR 1.13 [0.95, 1.35] |
| Flacco et al. [71] | – | – | – | OR 0.90 [0.65, 1.26] | OR 0.92 [0.75, 1.12] | OR 0.90 [0.65, 1.26] | OR 0.92 [0.75, 1.12] |
| Garg et al. [78] | – | – | – | OR 1.34 [0.96, 1.87] | OR 1.25 [0.93, 1.67] | OR 1.07 [0.37, 3.05] | OR 1.07 [0.81, 1.43] |
| Zhang et al. [72] | aOR 0.90 [0.79, 1.04] | OR 1.12 [0.96, 1.32] | – | OR 0.93 [0.59, 1.48] | OR 0.91 [0.71, 1.17] | – | – |
| Ssentongo et al. [75] | – | – | – | – | – | RR 0.65 [0.32, 1.30] | – |
[i] ACEI: Angiotensin Converting Enzyme Inhibitors, ARB: Angiotensin Receptor Blockers, OR: odds ratio, aOR: adjusted odds ratio, RR: relative risk, WMD: weighted mean difference.