OBJECTIVES: To investigate healthcare system–driven variation in general characteristics, interventions, and outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the ICU within one Western European region across three countries. DESIGN: Multicenter observational cohort study. SETTING: Seven ICUs in the Euregio Meuse-Rhine, one region across Belgium, The Netherlands, and Germany. PATIENTS: Consecutive COVID-19 patients supported in the ICU during the first pandemic wave. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline demographic and clinical characteristics, laboratory values, and outcome data were retrieved after ethical approval and data-sharing agreements. Descriptive statistics were performed to investigate country-related practice variation. From March 2, 2020, to August 12, 2020, 551 patients were admitted. Mean age was 65.4 ± 11.2 years, and 29% were female. At admission, Acute Physiology and Chronic Health Evaluation II scores were 15.0 ± 5.5, 16.8 ± 5.5, and 15.8 ± 5.3 ( p = 0.002), and Sequential Organ Failure Assessment scores were 4.4 ± 2.7, 7.4 ± 2.2, and 7.7 ± 3.2 ( p < 0.001) in the Belgian, Dutch, and German parts of Euregio, respectively. The ICU mortality rate was 22%, 42%, and 44%, respectively ( p < 0.001). Large differences were observed in the frequency of organ support, antimicrobial/inflammatory therapy application, and ICU capacity. Mixed-multivariable logistic regression analyses showed that differences in ICU mortality were independent of age, sex, disease severity, comorbidities, support strategies, therapies, and complications. CONCLUSIONS: COVID-19 patients admitted to ICUs within one region, the Euregio Meuse-Rhine, differed significantly in general characteristics, applied interventions, and outcomes despite presumed genetic and socioeconomic background, admission diagnosis, access to international literature, and data collection are similar. Variances in healthcare systems’ organization, particularly ICU capacity and admission criteria, combined with a rapidly spreading pandemic might be important drivers for the observed differences. Heterogeneity between patient groups but also healthcare systems should be presumed to interfere with outcomes in coronavirus disease 2019.
Although male Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients have higher Intensive Care Unit (ICU) admission rates and a worse disease course, a comprehensive analysis of female and male ICU survival and underlying factors such as comorbidities, risk factors, and/or anti-infection/inflammatory therapy administration is currently lacking. Therefore, we investigated the association between sex and ICU survival, adjusting for these and other variables. In this multicenter observational cohort study, all patients with SARS-CoV-2 pneumonia admitted to seven ICUs in one region across Belgium, The Netherlands, and Germany, and requiring vital organ support during the first pandemic wave were included. With a random intercept for a center, mixed-effects logistic regression was used to investigate the association between sex and ICU survival. Models were adjusted for age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, comorbidities, and anti-infection/inflammatory therapy. Interaction terms were added to investigate effect modifications by sex with country and sex with obesity. A total of 551 patients (29% were females) were included. Mean age was 65.4 ± 11.2 years. Females were more often obese and smoked less frequently than males (p-value 0.001 and 0.042, respectively). APACHE II scores of females and males were comparable. Overall, ICU mortality was 12% lower in females than males (27% vs 39% respectively, p-value < 0.01) with an odds ratio (OR) of 0.62 (95%CI 0.39–0.96, p-value 0.032) after adjustment for age and APACHE II score, 0.63 (95%CI 0.40–0.99, p-value 0.044) after additional adjustment for comorbidities, and 0.63 (95%CI 0.39–0.99, p-value 0.047) after adjustment for anti-infection/inflammatory therapy. No effect modifications by sex with country and sex with obesity were found (p-values for interaction > 0.23 and 0.84, respectively). ICU survival in female SARS-CoV-2 patients was higher than in male patients, independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country. Sex-specific biological mechanisms may play a role, emphasizing the need to address diversity, such as more sex-specific prediction, prognostic, and therapeutic approach strategies.
Background: The leading global risk factor for cardiovascular-disease-related morbidity and mortality is hypertension. In the past decade, attention has been paid to increase females’ representation. The aim of this study is to investigate whether the representation of females and presentation of sex-stratified data in studies investigating the effect of antihypertensive drugs has increased over the past decades. Methods: After systematically searching PubMed and Embase for studies evaluating the effect of the five major antihypertensive medication groups until May 2020, a scoping review was performed. The primary outcome was the proportion of included females. The secondary outcome was whether sex stratification was performed. Results: The search resulted in 73,867 articles. After the selection progress, 2046 studies were included for further analysis. These studies included 1,348,172 adults with a mean percentage of females participating of 38.1%. Female participation in antihypertensive studies showed an increase each year by 0.2% (95% CI 0.36–0.52), p < 0.01). Only 75 (3.7%) studies performed sex stratification, and this was the highest between 2011 and 2020 (7.2%). Conclusion: Female participation showed a slight increase in the past decade but is still underrepresented compared to males. As data are infrequently sex-stratified, more attention is needed to possible sex-related differences in treatment effects to different antihypertensive compounds.
Aims: In the prevention of cardiovascular morbidity and mortality, early recognition and adequate treatment of hypertension are of leading importance. However, the efficacy of antihypertensives may be depending on sex disparities. Our objective was to evaluate and quantify the sex-diverse effects of beta-blockers (BB) on hypertension and cardiac function. We focussed on comparing hypertensive female versus male individuals. Methods and results: A systematic search was performed for studies on BBs from inception to May 2020. A total of 66 studies were included that contained baseline and follow up measurements on blood pressure (BP), heart rate (HR), and cardiac function. Data also had to be stratified for sex. Mean differences were calculated using a random-effects model. In females as compared to males, BB treatment decreased systolic BP 11.1 mmHg (95% CI, −14.5; −7.8) vs. 11.1 mmHg (95% CI, −14.0; −8.2), diastolic BP 8.0 mmHg (95% CI, −10.6; −5.3) vs. 8.0 mmHg (95% CI, −10.1; −6.0), and HR 10.8 beats per minute (bpm) (95% CI, −17.4; −4.2) vs. 9.8 bpm (95% CI, −11.1; −8.4)), respectively, in both sexes’ absolute and relative changes comparably. Left ventricular ejection fraction increased only in males (3.7% (95% CI, 0.6; 6.9)). Changes in left ventricular mass and cardiac output (CO) were only reported in males and changed −20.6 g (95% CI, −56.3; 15.1) and −0.1 L (95% CI, −0.5; 0.2), respectively. Conclusions: BBs comparably lowered BP and HR in both sexes. The lack of change in CO in males suggests that the reduction in BP is primarily due to a decrease in vascular resistance. Furthermore, females were underrepresented compared to males. We recommend that future research should include more females and sex-stratified data when researching the treatment effects of hypertensives.
Background Hypertension is one of the leading global risk factors for cardiovascular disease-related morbidity and mortality. Females have historically been underrepresented in clinical trials resulting in presumed sex-related disparities in antihypertensive treatment effects. The past decade, widespread attention has been paid to this shortcoming aiming at increasing females' representation in clinical trials. Purpose To investigate whether in studies investigating the effect of antihypertensive drugs 1) the representation of females and 2) presentation of sex-stratified data has increased over the past decades. Methods We performed a scoping review after systematically searching PubMed and Embase for studies evaluating the effects of the five major groups of antihypertensive medication from inception (1945) until May 2020. The review was registered in Prospero database. Studies were only included if they 1) investigated one class of the five main groups of antihypertensive medications (beta-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics, 2) human studies, 3) investigated adults ≥18 years of age, 4) were written in English or Dutch. We excluded articles if 1) only abstract was available and full report was not found, 2) unsuitable study design, 3) no reference group included, 4) outcome not related to cardiovascular health, 5) no registration of specific dose and duration information. The primary outcome was the proportion of included females over time, stratified per decade. The secondary outcome was whether sex-stratification was reported. Linear regression analysis with beta coefficient (β) and 95% CI was performed to explore the associations between the percentage of females included in the studies over time. Results The search strategy resulted in 73,867 potential articles. After study selection based on title/abstract and full text, 2,079 original studies were eligible for our study. These included 1,395,264 adults of which the mean percentage of females participating in all included studies was 27.9% (Figure 1, Table 1). The percentage of females participating in antihypertensive studies showed a slight increase each year by 0.4% (95% CI 0.36–0.53, P<0.01). The yearly increase was the highest between 2001 and 2010 being 0.52% (95% CI 0.076–0.954) and in the most recent decade (between 2011 and 2020) 38.7% of included participants were female. Sex-stratification was performed in 76 (3.7%) studies and was the highest between 2011 and 2020 (7.3%). Conclusion Despite yearly increase in female participation in antihypertensive studies, females still only account for only one third of the study population. Moreover, less than 10% of studies report sex stratified data. Considering the global burden of hypertension, more differentiated sex-specific attention remains critically needed. Funding Acknowledgement Type of funding sources: None.
Cardiovascular disease (CVD) is the number one cause of death worldwide, with hypertension as the leading risk factor for both sexes. As sex may affect responsiveness to antihypertensive compounds, guidelines for CVD prevention might necessitate divergence between females and males. To this end, we studied the effectiveness of calcium channel blockers (CCB) on blood pressure (BP), heart rate (HR) and cardiac function between sexes. We performed a systematic review and meta-analysis on studies on CCB from inception to May 2020. Studies had to present both baseline and follow-up measurements of the interested outcome variables of interest and present data in a sex-stratified manner. Mean differences were calculated using a random-effects model. In total, 38 studies with 8202 participants were used for this review. In females as compared to males, systolic BP decreased by −27.6 mmHg (95%CI −36.4; −18.8) (−17.1% (95%CI −22.5;−11.6)) versus −14.4 mmHg (95%CI −19.0; −9.9) (−9.8% (95%CI −12.9;−6.7)) (between-sex difference p < 0.01), diastolic BP decreased by −14.1 (95%CI −18.8; −9.3) (−15.2%(95%CI −20.3;−10.1)) versus −10.6 mmHg (95%CI −14.0; −7.3) (−11.2% (95%CI −14.8;−7.7)) (between-sex difference p = 0.24). HR decreased by −1.8 bpm (95%CI −2.5; −1.2) (−2.5% (95%CI −3.4; −1.6)) in females compared to no change in males (0.3 bpm (95% CI −1.2; 1.8)) (between-sex difference p = 0.01). In conclusion, CCB lowers BP in both sexes, but the observed effect is larger in females as compared to males.
Background Hypertension is the leading risk factor for cardiovascular disease (CVD) and is the most substantial and neglected health burden in women. While treatment of high blood pressure is essential in the global prevention strategies of CVD it is assumed that effectiveness of pharmacological treatment may be hampered by sex differences. However, it is still not known whether sex differences exist in the effect of the antihypertensive medications. Purpose To evaluate sex-stratified effects for angiotensin receptor blockers (ARBs) on blood pressure (BP) and cardiac function in female compared to male hypertensive participants. Methods A series of systematic reviews and meta-analysis was performed. PubMed and EMBASE were systematically searched for studies evaluating the effects of the five major groups of antihypertensive medication from 1945 to May 2020. Randomized control trials and observational studies in humans (≥18 years) were included investigating beta-blockers (BB), angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and diuretics. In this study data on ARB's was analyzed. Studies had to present both baseline and follow-up measurements of at least one of the outcome variables of interest and present their data in a sex-stratified manner. Data on BPand cardiac function where retrieved from studies. Risk of bias was assessed using the Cochrane risk of bias tool. Results The search strategy resulted in 73,867 hits. After first screening based on title and abstract, 15,130 articles where suitable for full test screening. After excluding all studies that matched the exclusion criteria, 205 studies with 15,570 participants where eligible for analysis for the five antihypertensive drugs. Studies investigating ARB's (n=17) where used in this review. Seven trials (41%) had a low risk of bias. ARB decreased BP significantly and comparably in both women and men. Systolic BP −18.2 mmHg (95% CI, −24.8 to −11.5) vs −20.1 mmHg (95% CI, −26.7 to −13.6) and diastolic BP −11.6 mmHg (95% CI, −14.7 to −8.4) vs −12.3 mmHg (95% CI, −16.4 to −8.1). LVEF did not change significantly in either group. LV mass was only reported in males and did not change significantly −11.8 g (95% CI, −25.6 to 1.9). Conclusion Our meta-analysis shows that based on the current studies, no sex differences exists in the effect of ARB on blood pressure or cardiac function. Funding Acknowledgement Type of funding sources: None.
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