BACKGROUND: This systematic review assesses the likelihood of developing dementia and cognitive impairment in patients with atrial fibrillation (AF) receiving non-vitamin K antagonist oral anticoagulants (NOACs) as opposed to vitamin K antagonists (VKAs). METHODS: We performed a systematic review with meta-analysis and trial sequential analysis (TSA), which encompassed both randomized controlled trials (RCTs) and observational studies. The objective was to assess the impact of NOACs and VKAs on the incidence of dementia in individuals diagnosed with AF. RESULTS: Out of 1914 studies that were screened, 31 studies were included in the final analysis, which consisted of nine RCTs or their subsequent post-hoc analyses, in addition to 22 observational studies. The meta-analysis shows that NOACs were associated with a decreased probability of developing dementia of any cause [Rate Ratio (RR): 0.88; 95 % confidence interval (95 % CI): 0.82-0.94], especially in patients below the age of 75 (RR: 0.78; 95 % CI: 0.73-0.84). Consistent patterns were observed across all forms of dementia and cognitive function decline. The overall evidence indicates notable variability in the outcome with a moderate-to-low degree of certainty. The TSA suggests that the total sample size of the included trials (155,647 patients) was significantly smaller than the required information size of 784,692 patients to discern the true effect of NOAC versus VKA in terms of reducing dementia risk. CONCLUSION: NOACs may reduce the likelihood of developing dementia in patients with AF, particularly in those under the age of 75. This review highlights the urgent necessity for thorough research to determine the efficacy of NOACs in safeguarding cognitive health.
INTRODUCTION: There is a paucity of real-world studies examining the risks of stroke/systemic embolism (SE) and major bleeding (MB) among non-valvular atrial fibrillation (NVAF) patients switching from warfarin to a direct oral anticoagulant (DOAC). This retrospective study was conducted to compare the stroke/SE and MB risks between patients switched from warfarin to apixaban, dabigatran, or rivaroxaban in real-world clinical practice. MATERIALS AND METHODS: This study used data from four United States commercial claims databases from January 1, 2012 to June 30, 2019. The study population included NVAF patients initially treated with warfarin and switched to apixaban, dabigatran, or rivaroxaban within 90 days of their warfarin prescription ending. Patients were matched 1:1 between the DOACs in each database using propensity scores and then pooled for the final analysis. Cox proportional hazards models were used to calculate the risk of stroke/SE and MB. RESULTS AND CONCLUSIONS: The final population consisted of 2,611 apixaban-dabigatran, 12,165 apixaban-rivaroxaban, and 2,672 dabigatran-rivaroxaban pairs. Apixaban vs. dabigatran was associated with a lower risk of stroke/SE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.39-0.96) and MB (HR: 0.67; 95% CI: 0.50-0.91). Apixaban vs. rivaroxaban was associated with a similar risk of stroke/SE (HR: 0.88; 95% CI: 0.73-1.07) and a lower risk of MB (HR: 0.60; 95% CI: 0.52-0.68). There was no significant difference in either risk between dabigatran and rivaroxaban. These results provide important insights into how the risks of stroke/SE and MB for NVAF patients vary when switching from warfarin to different DOACs.
BACKGROUND: The reason for higher incidence of atrial fibrillation (AF) in Europe compared with East Asia is unclear. We aimed to investigate the association between modifiable lifestyle factors and lifetime risk of AF in Europe and East Asia, along with race/ethnic similarities and disparities. METHODS: 1:1 propensity score matched pairs of 242,763 East Asians and 242,763 White Europeans without AF were analyzed. Modifiable lifestyle factors considered were blood pressure, body mass index, cigarette smoking, diabetes, alcohol consumption, and physical activity, categorized as non-adverse or adverse levels. Lifetime risk of AF was estimated from the index age of 45 years to the attained age of 85 years, accounting for the competing risk of death. RESULTS: The overall lifetime risk of AF was higher in White Europeans than East Asians (20.9% vs 15.4%, p < 0.001). The lifetime risk of AF was similar between the two races in individuals with non-adverse lifestyle factor profiles (13.4% vs 12.9%, p = 0.575), whereas it was higher in White Europeans with adverse lifestyle factor profiles (22.1% vs 15.8%, p < 0.001). The difference in the lifetime risk of AF between the two races increased as the burden of adverse lifestyle factors worsened (1 adverse lifestyle factor; 4.3% to ≥ 3 adverse lifestyle factors; 11.2%). Compared with East Asians, the relative risk of AF in White Europeans was 23% and 62% higher for one (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.16-1.29) and ≥ 3 adverse lifestyle factors (HR 1.62, 95% CI 1.51-1.75), respectively. CONCLUSIONS: The overall higher lifetime risk of AF in White Europeans compared with East Asians might be attributable to adverse lifestyle factors. Adherence to healthy lifestyle factors was associated with the lifetime risk of AF of about 1 in 8 regardless of race/ethnicity.
Atrial Fibrillation , Life Style , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Atrial Fibrillation/epidemiology , Biological Specimen Banks , Cohort Studies , Longitudinal Studies , Republic of Korea/epidemiology , Risk Factors , UK Biobank , United Kingdom/epidemiology , White People , East Asian People
INTRODUCTION: There is currently no guidance on how to assess the calibration of multistate models used for risk prediction. We introduce several techniques that can be used to produce calibration plots for the transition probabilities of a multistate model, before assessing their performance in the presence of random and independent censoring through a simulation. METHODS: We studied pseudo-values based on the Aalen-Johansen estimator, binary logistic regression with inverse probability of censoring weights (BLR-IPCW), and multinomial logistic regression with inverse probability of censoring weights (MLR-IPCW). The MLR-IPCW approach results in a calibration scatter plot, providing extra insight about the calibration. We simulated data with varying levels of censoring and evaluated the ability of each method to estimate the calibration curve for a set of predicted transition probabilities. We also developed evaluated the calibration of a model predicting the incidence of cardiovascular disease, type 2 diabetes and chronic kidney disease among a cohort of patients derived from linked primary and secondary healthcare records. RESULTS: The pseudo-value, BLR-IPCW, and MLR-IPCW approaches give unbiased estimates of the calibration curves under random censoring. These methods remained predominately unbiased in the presence of independent censoring, even if the censoring mechanism was strongly associated with the outcome, with bias concentrated in low-density regions of predicted transition probability. CONCLUSIONS: We recommend implementing either the pseudo-value or BLR-IPCW approaches to produce a calibration curve, combined with the MLR-IPCW approach to produce a calibration scatter plot. The methods have been incorporated into the "calibmsm" R package available on CRAN.
BACKGROUND: Although early rhythm control (ERC) in patients with atrial fibrillation (AF) reduces the risk of stroke, there is no evidence thus far on whether ERC reduces the risk of developing dementia in patients with AF and prior stroke. OBJECTIVES: This study sought to evaluate whether ERC reduces the risk of developing dementia in patients with new-onset AF and prior stroke. METHODS: Using the Korean nationwide claims database, we identified patients with new-onset AF and prior stroke between 2010 and 2016. Patients who received rhythm control therapy within 1 year after AF onset were defined as the ERC group, otherwise patients were categorized as the usual care group. A propensity score weighting method was used to balance the 2 groups. Incident dementia defined by relevant diagnostic codes was evaluated. RESULTS: A total of 41,370 patients were included (mean age 70 ± 11 years; mean CHA2DS2-VASc score 5.3±1.6): 10,213 in the ERC group and 31,157 in the usual care group. Compared with usual care, ERC was associated with lower risks of all dementia, Alzheimer's dementia, and vascular dementia (weighted HRs [95% CIs], 0.825 [0.776-0.876], 0.831 [0.774-0.893], and 0.800 [0.702-0.913], respectively, all P < 0.001). The benefit of ERC was slightly accentuated in the younger age group (<65 years). The beneficial effect of ERC in reducing the risk of dementia was consistent regardless of the characteristics of prior stroke. CONCLUSIONS: ERC might be beneficial in the prevention of dementia in patients with AF and prior stroke. To prevent the progression of cognitive dysfunction, ERC should be considered in this population.
Stroke confers a severe global healthcare burden, hence exploring risk factors for stroke occurrence and prognosis is important for stroke prevention and post-stroke management strategies. Endogenous fibrinolysis is a spontaneous physiological protective mechanism that dissolves thrombus to maintain vascular patency. Recently, impaired endogenous fibrinolysis has been considered as a potential novel cardiovascular risk factor, but its link with ischaemic stroke in the past has been underappreciated. In this review, we summarize the latest mechanisms of endogenous fibrinolysis, review the current evidence and data on endogenous fibrinolysis in ischemic stroke. It includes the structure of thrombus in ischemic stroke patients, the effect of fibrin structure on the endogenous fibrinolytic efficiency, and the association between intravenous thrombolytic therapy and endogenous fibrinolysis in ischemic stroke. It also includes the single factors (tissue plasminogen activator, urokinase plasminogen activator, plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, complement component 3, complement component 5, alpha-2-antiplasmin, plasmin-alpha-2-antiplasmin complex, and lipoprotein[a]), and the global assessments of endogenous fibrinolysis status (thromboelastography, rotational thromboelastometry, and global thrombosis test), and their potential as predictors to identify occurrence or unfavorable functional outcomes of ischemic stroke. All of these assessments present advantages and limitations, and we suggest that the global thrombosis test may be more appropriate for detecting impaired endogenous fibrinolysis status in ischemic stroke patients.
BACKGROUND: The aim of this study was to evaluate the impact of educational status (ES) on the clinical course of Asian patients with atrial fibrillation (AF). METHODS: We used data from the prospective APHRS-AF Registry. ES was classified as follows: low (primary school), medium (secondary), and high (University). The primary outcome was a composite of all-cause death, thromboembolic events, acute coronary syndrome, and heart failure. Secondary outcomes were each component of the primary outcome, cardiovascular death, and major bleeding. The one-year risk of primary and secondary outcomes was assessed through Cox-regressions. Adherence to the Atrial fibrillation Better Care (ABC) pathway was assessed. RESULTS: Among 2697 AF patients (69±12 years, 34.8% females), 34.6% had low ES; 37.3% had medium ES; and 28.1% had high ES. Compared to patients with medium-high ES, patients with low ES were older, more often females, with a higher prevalence of cardiovascular risk factors, and a lower ABC pathway adherence (30.4% vs. 40.2%, P<0.001). On multivariable analysis, low ES was associated with a higher risk for the primary outcome (HR 1.52,95%CI 1.11-2.06) and all-cause death (HR 1.76,95%CI 1.10-2.83) than medium-high ES. A significant interaction was found for the risk of composite outcome among the different age strata, with the higher risk in the elderly (P for int=0.008), whereas the beneficial effect of the ABC pathway was irrespective of ES (P for int=0.691). CONCLUSIONS: In Asian AF patients, low ES is associated with high mortality. Efforts to improve education and include ES evaluation in the integrated care approach for AF are necessary to reduce the cardiovascular burden in these patients.
Background: In light of high burden of heart failure (HF) in China, studies of prognostic implication of HF stages are important. We aimed to evaluate the relationship between HF stages and mortality risk in Chinese community populations. Methods: Nationwide representative populations aged ≥35 years (n = 23,284, mean age 56.9 years, women 53.2%) were enrolled from 2012 to 2016. According to the international HF guidelines, participants were divided into stage A, B and C, and those who did not qualify these stages were categorized as apparently-healthy group. Association between HF stages and all-cause, cardiovascular [CV] and non-CV death was evaluated using multivariable-adjusted Cox proportional regression analysis. Findings: During a median follow-up of 4.7 years (109,902.8 person-years), 1314 deaths occurred. Age-adjusted incidence rate of all-cause death was 5.3 in apparently-healthy, 7.8 in stage A, 8.6 in stage B and 24.6 in stage C groups per 1000 person-years. In reference to apparently-healthy group, adjusted hazard ratio for all-cause death was 1.90 (95% CI: 1.47-2.45), 2.43 (95% CI: 1.89-3.13) and 6.40 (95% CI: 4.56-8.99) for stage A, B and C. Advancing HF stages were associated with increasing risks for all-cause, CV and non-CV death (P-trend <0.05). For all-cause death, population attributable fraction due to stage A, B and C were 21.2%, 33.4% and 4.9%, accounting for 1,933,385, 3,045,993 and 446,867 deaths in China in 2018. Interpretation: Advancing HF stages were associated with increasing risk mortality. Development and implementation of early screening and targeted interventions are urgently needed to reduce HF burdens in China. Funding: This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant 2017-I2M-1-004), the Projects in the Chinese National Science & Technology Pillar Program during the Twelfth Five-year Plan Period (No.: 2011BAI11B01), and the Project Entrusted by the National Health Commission of the People's Republic of China (NHC2020-609).
Valproate is the most effective treatment for idiopathic generalised epilepsy. Current guidance precludes its use in women of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to men. New guidance will limit use both in men and women aged <55 years, resulting in withdrawal of valproate from men already taking it, as occurs for women. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for men or women on valproate, meaning clinicians cannot reliably counsel either sex when discussing valproate withdrawal with them, despite that this concern may be at the forefront of patients' and clinicians' minds. We assessed whether there are any morbidity or mortality risks associated with valproate withdrawal in young men and women. We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were men and women aged 16-54 years with ≥1 epilepsy disease or symptom code between 01/12/2017-01/12/2018 and ≥2 valproate prescriptions over the preceding two years (01/01/2015-30/11/2017). 5-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining on vs. withdrawn from valproate during the 01/12/2017-01/12/2018 recruitment period, regardless of whether switched to another antiseizure medication. Survival analysis was undertaken using Cox-proportional hazard models, generating hazard ratios (HRs) with 95% confidence intervals (CIs). 8,991 men and 5,243 women taking valproate were recruited. 28% of men and 36% of women were subsequently withdrawn from valproate. Valproate withdrawal was associated with significantly increased risks of emergency department attendance (HRs overall: 1.236 (CI 1.159-1.319), men: 1.181 (CI 1.083-1.288), women: 1.242 (CI 1.125-1.371)), hospital admission (HRs overall: 1.160 (CI 1.081-1.246), men: 1.132 (CI 1.027-1.249), women: 1.147 (CI 1.033-1.274)), falls (HRs overall: 1.179 (CI 1.041-1.336), men: 1.298 (CI 1.090-1.546)), injuries (HRs overall: 1.095 (CI 1.021-1.174), men: 1.129 (CI 1.029-1.239)), burns (HRs overall: 1.592 (CI 1.084-2.337)), and new-onset depression (HRs overall 1.323 (CI 1.119-1.565), women: 1.359 (CI 1.074-1.720)). The risk of these outcomes occurring was 1-7% higher in those withdrawn from valproate than in those remaining on valproate. Overall, valproate withdrawal was not associated with increased mortality. These results may help patients and clinicians have a more informed discussion about personal safety when considering valproate withdrawal.
Background: Air pollution (AP) is linked up to 20% of cardiovascular deaths. The aim of this nationwide study was to investigate subpopulations vulnerable to AP for non-ST- (NSTEMI) and ST-elevation myocardial infarction (STEMI) incidence. Methods: We analysed short- (lags up to seven days) and mid-term (0-30 days moving average) influence of particulate matter (PM2.5), sulphur dioxide (SO2), nitrogen dioxide (NO2) and benzo(a)pyrene (BaP) on hospitalizations due NSTEMI and STEMI in 2011-2020. Data on AP concentrations were derived using GEM-AQ model. Study included residents of five voivodeships in eastern Poland, inhabited by over 8,000,000 individuals. Findings: Higher NO2 and PM2.5 concentrations increased mid-term risk of NSTEMI in patients aged < 65 years by 1.3-5.7%. Increased SO2 and PM2.5 concentration triggered STEMI in the short- (SO2, PM2.5) and mid-term (PM2.5) amongst those aged ≥ 65 years. In the short- and mid-term, women were more susceptible to PM2.5 and BaP influence resulting in increased STEMI incidence. In rural regions, STEMI risk was triggered by SO2, PM2.5 and BaP. Income-based stratification showed disproportions regarding influence of BaP concentrations on NSTEMI incidence based on gross domestic product (up to 1.4%). Interpretation: There are significant disparities in the influence of air pollution depending on the demographic and socio-economic factors. AP exposure is associated with the threat of a higher risks of NSTEMI and STEMI, especially to younger people, women, residents of rural areas and those with lower income. Funding: National Science Center and Medical University of Bialystok, Poland.
Objectives: To review the evidence on the effectiveness and safety of low-dose-rivaroxaban 2.5 mg twice daily (LDR) in patients with coronary artery disease (CAD) and/or peripheral artery disease (PAD) taking antiplatelets. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Efficacy endpoints were cardiovascular events (CVEs), myocardial infarction, stroke, all-cause, and cardiovascular death. Any, major, fatal bleeding, and intracranial hemorrhage (ICH) were safety endpoints. Numbers needed to treat (NNT), and numbers needed to harm (NNH) were also calculated. Results: Seven RCTs were included with 45,836 patients: 34,276 with CAD and 11,560 with PAD. Overall, 4247 CVEs and 3082 bleedings were registered. LDR in association with either any antiplatelet drug or aspirin (ASA) alone reduced the risk of CVEs (hazard ratio [HR] 0.86, 95% confidence interval [95%CI] 0.78-0.94) and ischemic stroke (HR 0.68, 95%CI 0.55-0.84). LDR + ASA increased the risk of major bleeding (HR 1.71, 95%CI 1.38-2.11) but no excess of fatal bleeding or ICH was found. The NNT to prevent one CVE for LDR + ASA was 63 (43-103) and the NNH to cause major bleeding was 107 (77-193). Conclusions: The combination of LDR with either antiplatelet drugs or low-dose aspirin reduces CVEs and ischemic stroke in patients with CAD/PAD. There was an increased risk of major bleeding but no excess of fatal or ICH was found. LDR seems to have a favorable net clinical benefit compared to ASA treatment alone.
BACKGROUND: There are limited data regarding the combined effect of early rhythm control (ERC) and healthy lifestyle (HLS) behaviors on the risk of ischemic stroke in patients with atrial fibrillation (AF). OBJECTIVES: This study sought to evaluate how the combination of ERC and HLS behaviors affects the risk of ischemic stroke in patients with AF. METHODS: Using the Korean National Health Insurance database, we included patients with new-onset AF between 2009 and 2016 (n = 208,662). Patients who received rhythm control therapy within 2 years after AF diagnosis were defined as the ERC group. Patients with ≥2 HLS behaviors were defined as the HLS group. Patients were categorized into 4 groups: group 1, without ERC and without HLS (n = 46,972); group 2, with HLS alone (n = 110,479); group 3, with ERC alone (n = 15,133); and group 4, with both ERC and HLS (n = 36,078). The primary outcome was ischemic stroke. RESULTS: Compared to group 1, group 2 and group 3 were associated with a lower risk of stroke (HR: 0.769 [95% CI: 0.728-0.881] and HR: 0.774 [95% CI: 0.703-0.852], respectively). Group 4 showed the lowest risk of stroke (HR: 0.575; 95% CI: 0.536-0.617). After propensity score weighting, the incorporation of additional ERC alongside HLS was associated with a relative risk reduction of 22% for stroke, and additional HLS alongside ERC were associated with a relative risk reduction of 27% for stroke. CONCLUSIONS: Each of ERC and HLS might reduce the risk of ischemic stroke in patients with new-onset AF. The presence of both ERC and HLS is associated with an enhanced benefit for stroke prevention in this population.
BACKGROUND: Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. METHODS: The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. RESULTS: Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. CONCLUSIONS: In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. PLAIN LANGUAGE SUMMARY: Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.
BACKGROUND: Bleeding events are often reported among patients with atrial fibrillation (AF), irrespective of antithrombotic use. This study is to determine clinical outcomes of patients with AF who survived from bleeding event. METHODS: We analyzed data from COOL-AF (Cohort of Antithrombotic Use and Optimal International Normalized Ratio Levels in Patients with Atrial Fibrillation) Thailand registry. Outcomes of patients who experienced any bleeding were compared with patients who had never bleed. Time updated multivariate Cox-proportional hazard models were used to estimate the risk for clinical outcomes of patients with and without bleeding. RESULTS: Of total 3,405 patients (mean age: 67.8 ± 11.3 years; 41.9% female) in COOL-AF registry, 609 patients (17.9%) reported bleeding event occurs and 568 patients (93.3%) survived though hospital discharge. Patients who survived major bleeding (n = 126) were at increased risk for both death (adjusted hazard ratio [HR]: 4.44, 95% confidence interval [CI]: 2.91-6.75, p < 0.001) and stroke/systemic embolism (adjusted HR: 4.49, 95% CI: 2.19-9.24, p < 0.001). Minor bleeding also increased subsequent death (adjusted HR: 2.13, 95% CI: 1.56-2.90, p < 0.001). Up to 30% of patients who survived major bleeding and 6.3% of minor bleedings discontinued oral anticoagulation. Discontinuation was associated with very high death rate (42.1%), whereas patients who resumed oral anticoagulation after bleeding had lower mortality (10%). The most common causes of death in patients who survived a bleeding event were not related to cardiovascular causes nor bleeding. CONCLUSION: Patients with AF who have bleeding events have an increased risk for subsequent death and stroke and systemic embolism. These patients should be identified as vulnerable clinically complex patients and require a holistic approach to their AF management.
BACKGROUND: In older adults, obstructive sleep apnea (OSA) has been associated with several cardiovascular complications. Whether young patients diagnosed with OSA also are at higher risk of developing subsequent cardiovascular disease is uncertain. We aimed to estimate the risk of developing an incident cardiovascular event among young patients diagnosed with OSA. METHODS AND RESULTS: We linked nationwide Danish health registries to identify a cohort of patients aged ≤50 years with OSA using data from 2010 through 2018. Cases without OSA from the general population were matched as controls (1:5). The main outcome was any cardiovascular event (including hypertension, diabetes, atrial fibrillation, ischemic heart disease, ischemic stroke, heart failure, and venous thromboembolism). All-cause mortality was a secondary outcome. The study included 20 240 patients aged ≤50 years with OSA (19.6% female; mean±SD age 39.9±7.7 years) and 80 314 controls. After 5-year follow-up, 31.8% of the patients with OSA developed any cardiovascular event compared with 16.5% of the controls, with a corresponding relative risk (RR) of 1.96 (95% CI, 1.90-2.02). At 5-year follow-up, 27.3% of patients with OSA developed incident hypertension compared with 15.0% of the controls (RR, 1.84 [95% CI, 1.78-1.90]). Incident diabetes occurred in 6.8% of the patients with OSA and 1.4% of controls (RR, 5.05 [95% CI, 4.60-5.54]). CONCLUSIONS: Similar to older adults, young adults with OSA demonstrate increased risk of developing cardiovascular events. To prevent cardiovascular disease progression, accumulation of cardiovascular risk factors, and mortality, risk stratification and prevention strategies should be considered for these patients.
Cardiovascular Diseases , Diabetes Mellitus , Hypertension , Sleep Apnea, Obstructive , Young Adult , Humans , Female , Aged , Male , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/complications , Risk Factors , Sleep Apnea, Obstructive/complications , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea, Obstructive/epidemiology , Hypertension/complications , Heart Disease Risk Factors
AIMS: To evaluate the efficacy and cardiovascular outcomes of combination pioglitazone with either a glucagon-like peptide-1 receptor agonist (GLP-1RA) or a sodium-glucose cotransporter-2 (SGLT2) inhibitor in individuals with type 2 diabetes (T2D) by conducting a systematic review, meta-analysis, and analysis of a large international real-world database. METHODS: We searched MEDLINE, SCOPUS and Web of Science to identify relevant articles for inclusion (PROSPERO [CRD: 42023483126]). Nineteen studies assessing pioglitazone + SGLT2 inhibitors or GLP-1RAs versus controls were identified, 16 of which were randomized controlled trials. Risk of bias was assessed using Cochrane-endorsed tools and quality of evidence was assessed using GRADE. We additionally performed a retrospective cohort study of all individuals aged 18 years or over with T2D, using the TriNetX platform. We included propensity-score-matched individuals who were treated for at least 1 year with pioglitazone and a GLP-1RA or pioglitazone and an SGLT2 inhibitor, compared against GLP-1RA and SGLT2 inhibitor monotherapy. Outcomes were all-cause mortality, heart failure, chronic kidney disease and composite stroke and transient ischaemic attack. RESULTS: The average follow-up in the included studies ranged from 24 to 52 weeks. Combination of pioglitazone with a GLP-1RA reduced glycated haemoglobin (HbA1c) and weight greater than in controls: mean differences -1% (95% confidence interval [CI] -1.27, -0.74) and -1.19 kg (95% CI -1.80, -0.58), respectively. There was no statistically significant difference in systolic blood pressure (SBP) or mortality between groups: mean difference - 1.56 mmHg (95% CI -4.48, 1.35; p = 0.30) and relative risk (RR) 0.29 (95% CI 0.07-1.15; p = 0.08), respectively. Combination of pioglitazone with SGLT2 inhibitors reduced HbA1c, weight and SBP to a greater extent than control treatment: mean differences -0.48% (95% CI -0.67, -0.28), -2.3 kg (95% CI -2.72, -1.88) and -2.4 mmHg (95% CI -4.1, -0.7; p = 0.01), respectively. There was no statistically significant difference in mortality between groups (RR 1.81, 95% CI 0.30-10.97; p = 0.52). The included trials demonstrated a reduction in risk of heart failure with combination treatment. Similarly, from the real-world database (n = 25 230 identified), pioglitazone and SGLT2 inhibitor combination therapy was associated with reduced risk of heart failure compared to monotherapy alone (hazard ratio 0.50, 95% CI 0.38-0.65; p < 0.001). CONCLUSION: Both our systematic review/meta-analysis and the real-world dataset show that combination of pioglitazone with either GLP-1RAs or SGLT2 inhibitors is associated with increased weight loss and reduced risk of heart failure compared with monotherapy.
