Relationship Between Azithromycin and Cardiovascular Outcomes in Unvaccinated Patients With COVID-19 and Preexisting Cardiovascular Disease.

Background Empiric antimicrobial therapy with azithromycin is highly used in patients admitted to the hospital with COVID-19, despite prior research suggesting that azithromycin may be associated with increased risk of cardiovascular events. Methods and Results This study was conducted using data from the ISACS-COVID-19 (International Survey of Acute Coronavirus Syndromes-COVID-19) registry. Patients with a confirmed diagnosis of SARS-CoV-2 infection were eligible for inclusion. The study included 793 patients exposed to azithromycin within 24 hours from hospital admission and 2141 patients who received only standard care. The primary exposure was cardiovascular disease (CVD). Main outcome measures were 30-day mortality and acute heart failure (AHF). Among 2934 patients, 1066 (36.4%) had preexisting CVD. A total of 617 (21.0%) died, and 253 (8.6%) had AHF. Azithromycin therapy was consistently associated with an increased risk of AHF in patients with preexisting CVD (risk ratio [RR], 1.48 [95% CI, 1.06-2.06]). Receiving azithromycin versus standard care was not significantly associated with death (RR, 0.94 [95% CI, 0.69-1.28]). By contrast, we found significantly reduced odds of death (RR, 0.57 [95% CI, 0.42-0.79]) and no significant increase in AHF (RR, 1.23 [95% CI, 0.75-2.04]) in patients without prior CVD. The relative risks of death from the 2 subgroups were significantly different from each other (Pinteraction=0.01). Statistically significant association was observed between AHF and death (odds ratio, 2.28 [95% CI, 1.34-3.90]). Conclusions These findings suggest that azithromycin use in patients with COVID-19 and prior history of CVD is significantly associated with an increased risk of AHF and all-cause 30-day mortality. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT05188612.

Sex differences and disparities in cardiovascular outcomes of COVID-19.

AIMS: Previous analyses on sex differences in case fatality rates at population-level data had limited adjustment for key patient clinical characteristics thought to be associated with coronavirus disease 2019 (COVID-19) outcomes. We aimed to estimate the risk of specific organ dysfunctions and mortality in women and men. METHODS AND RESULTS: This retrospective cross-sectional study included 17 hospitals within 5 European countries participating in the International Survey of Acute Coronavirus Syndromes COVID-19 (NCT05188612). Participants were individuals hospitalized with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from March 2020 to February 2022. Risk-adjusted ratios (RRs) of in-hospital mortality, acute respiratory failure (ARF), acute heart failure (AHF), and acute kidney injury (AKI) were calculated for women vs. men. Estimates were evaluated by inverse probability weighting and logistic regression models. The overall care cohort included 4499 patients with COVID-19-associated hospitalizations. Of these, 1524 (33.9%) were admitted to intensive care unit (ICU), and 1117 (24.8%) died during hospitalization. Compared with men, women were less likely to be admitted to ICU [RR: 0.80; 95% confidence interval (CI): 0.71-0.91]. In general wards (GWs) and ICU cohorts, the adjusted women-to-men RRs for in-hospital mortality were of 1.13 (95% CI: 0.90-1.42) and 0.86 (95% CI: 0.70-1.05; pinteraction = 0.04). Development of AHF, AKI, and ARF was associated with increased mortality risk (odds ratios: 2.27, 95% CI: 1.73-2.98; 3.85, 95% CI: 3.21-4.63; and 3.95, 95% CI: 3.04-5.14, respectively). The adjusted RRs for AKI and ARF were comparable among women and men regardless of intensity of care. In contrast, female sex was associated with higher odds for AHF in GW, but not in ICU (RRs: 1.25; 95% CI: 0.94-1.67 vs. 0.83; 95% CI: 0.59-1.16, pinteraction = 0.04). CONCLUSIONS: Women in GW were at increased risk of AHF and in-hospital mortality for COVID-19 compared with men. For patients receiving ICU care, fatal complications including AHF and mortality appeared to be independent of sex. Equitable access to COVID-19 ICU care is needed to minimize the unfavourable outcome of women presenting with COVID-19-related complications.

Sex beyond cardiovascular risk factors and clinical biomarkers of cardiovascular disease.

In recent years, increasing attention has been reserved to the analysis of sex-related differences in pathophysiology and prognosis of ischemic heart disease (IHD). The traditional conventional cardiovascular risk factors (hypertension, hypercholesteremia, diabetes mellitus and cigarette smoking) are still considered the major risk factors for IHD in both sexes. Nevertheless, recent studies show that they may interact with male and female coronary anatomy in a different manner. The path to sex-specific risk stratification of IHD is also supported by differences in inflammation and necrosis biomarkers (such as C-reactive protein and troponins, respectively). Indeed, large cohort studies often show different mean values of these markers in men and women. The current review summarizes the state-of-art knowledge on sex-related differences in cardiovascular risk factors and cardiac biomarkers with a prognostic value.

Smoking and sex differences in first manifestation of cardiovascular disease.

BACKGROUND AND AIMS: An increasing proportion of women believe that smoking few cigarettes daily substantially reduces their risk of developing cardiovascular (CV) related disorders. The effect of low intensity smoking is still largely understudied. We investigated the relation among sex, age, cigarette smoking and ST segment elevation myocardial infarction (STEMI) as initial manifestation of CV disease. METHODS: We analyzed data of 50,713 acute coronary syndrome patients with no prior manifestation of CV disease from the ISACS-Archives (NCT04008173) registry. We compared the rates of STEMI in current smokers (n = 11,530) versus nonsmokers (n = 39,183). RESULTS: In the young middle age group (<60 years), there was evidence of a more harmful effect in women compared with men (RR ratios: 1.90; 95% CI: 1.69-2.14 versus 1.68; 95% CI: 1.56-1.80). This association persisted even in women who smoked 1 to 10 packs per year (RR ratios: 2.02; 95% CI: 1.65 to 2.48 versus 1.38; 95% CI: 1.22 to 1.57). In the older group, rates of STEMI were similar for women and men (RR ratios: 1.36; 95% CI: 1.22-1.53 versus 1.39; 95% CI: 1.28-1.50). STEMI was associated with a twofold higher 30-day mortality rate in young middle age women compared with men of the same age (odds ratios, 5.54; 95% CI, 3.83-8.03 vs. 2.93; 95% CI, 2.33-3.69). CONCLUSIONS: Low intensity smoking provides inadequate protection in young - middle age women as they still have a substantially higher rate of STEMI and related mortality compared with men even smoking less than 10 packs per year. This finding is worrying as more young - middle age women are smoking, and rates of smoking among young-middle age men continue to fall.

Gender Differences in Non-Obstructive Coronary Artery Disease.

Subjects affected by ischemic heart disease with non-obstructive coronary arteries constitute a population that has received increasing attention over the past two decades. Since the first studies with coronary angiography, female patients have been reported to have non-obstructive coronary artery disease more frequently than their male counterparts, both in stable and acute clinical settings. Although traditionally considered a relatively infrequent and low-risk form of myocardial ischemia, its impact on clinical practice is undeniable, especially when it comes to infarction, where the prognosis is not as benign as previously assumed. Unfortunately, despite increasing awareness, there are still several questions left unanswered regarding diagnosis, risk stratification and treatment. The purpose of this review is to provide state of the art update on the current evidence available on gender differences in clinical characteristics, management and prognosis of ischemic heart disease with non-obstructive coronary arteries, both in the acute and stable clinical settings.

Sex Differences in Modifiable Risk Factors and Severity of Coronary Artery Disease.

Background It is still unknown whether traditional risk factors may have a sex-specific impact on coronary artery disease (CAD) burden. Methods and Results We identified 14 793 patients who underwent coronary angiography for acute coronary syndromes in the ISACS-TC (International Survey of Acute Coronary Syndromes in Transitional Countries; Clini​calTr​ials.gov, NCT01218776) registry from 2010 to 2019. The main outcome measure was the association between traditional risk factors and severity of CAD and its relationship with 30-day mortality. Relative risk (RR) ratios and 95% CIs were calculated from the ratio of the absolute risks of women versus men using inverse probability of weighting. Estimates were compared by test of interaction on the log scale. Severity of CAD was categorized as obstructive (≥50% stenosis) versus nonobstructive CAD. The RR ratio for obstructive CAD in women versus men among people without diabetes mellitus was 0.49 (95% CI, 0.41-0.60) and among those with diabetes mellitus was 0.89 (95% CI, 0.62-1.29), with an interaction by diabetes mellitus status of P =0.002. Exposure to smoking shifted the RR ratios from 0.50 (95% CI, 0.41-0.61) in nonsmokers to 0.75 (95% CI, 0.54-1.03) in current smokers, with an interaction by smoking status of P=0.018. There were no significant sex-related interactions with hypercholesterolemia and hypertension. Women with obstructive CAD had higher 30-day mortality rates than men (RR, 1.75; 95% CI, 1.48-2.07). No sex differences in mortality were observed in patients with nonobstructive CAD. Conclusions Obstructive CAD in women signifies a higher risk for mortality compared with men. Current smoking and diabetes mellitus disproportionally increase the risk of obstructive CAD in women. Achieving the goal of improving cardiovascular health in women still requires intensive efforts toward further implementation of lifestyle and treatment interventions. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT01218776.

Coronary No-Reflow Phenomenon in Clinical Practice.

Timely delivered coronary revascularization with no residual anatomical stenosis does not always lead to prompt restoration of anterograde coronary flow and complete myocardial reperfusion. This condition is known as coronary no-reflow and is associated with major clinical adverse events and poor prognosis. The pathophysiology of no-reflow phenomenon is still poorly understood. Proposed mechanisms include distal microembolization of thrombus and plaque debris, ischemic injury, endothelial dysfunction and individual susceptibility to microvascular dysfunction/obstruction. Older age, diabetes, hypercholesterolemia, prolonged ischemic time, hemodynamic instability, high thrombus burden, complex angiographic lesions and multivessel disease are frequently reported to be associated with the no-reflow phenomenon. There is no general consensus on the correct prevention and management of no-reflow. Non-pharmacological measures such as distal embolic protection devices and manual thrombus aspiration did not result in improved flow or reduction of infarct size. Current preventive measures include reduction of time from symptoms onset to reperfusion therapy, and intracoronary administration of vasodilators such as adenosine, verapamil or nitroprusside.