Obstructive sleep apnea severity and prevalent atrial fibrillation in a sleep clinic cohort with versus without excessive daytime sleepiness.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF) in cardiac cohorts. Less is known regarding the magnitude of this association in a sleep clinic cohort with vs. without excessive daytime sleepiness (EDS). OBJECTIVES: To explore the association of OSA severity with AF in a sleep clinic cohort stratified by EDS. PATIENTS AND METHODS: All consecutive adults (n = 3814) admitted to the Skaraborg Hospital, Sweden between Jan 2005 and December 2011 were registered in a local database, and the follow-up ended in December 2018. OSA was defined as an apnea-hypopnea index (AHI) ≥5 events/h. Mild OSA was defined as AHI ≥5 & AHI<15 events/h; moderate OSA as AHI ≥15 & AHI<30 events/h; and severe OSA as AHI ≥30 events/h. EDS was defined as an Epworth Sleepiness Scale score ≥11. We conducted cross-sectional analyzes of the prevalent AF across the OSA severity categories and logistic regression analyzes stratified by EDS. RESULTS: In all, 202 patients (5.3%) had AF at baseline, 1.6% in no-OSA, 3.9% in mild OSA, 5.2% in moderate OSA, and 7.6% in severe OSA, respectively (p < 0.001). The stratified analyzes revealed that patients with severe OSA without EDS had an increased risk for prevalent AF (OR 2.54, 95% CI 1.05-6.16; p = 0.039) independent of the confounding factors. CONCLUSIONS: There was an independent dose-response relationship between OSA and prevalent AF among the non-sleepy phenotype in this sleep clinic cohort. Since adherence to OSA treatment is challenging in the absence of EDS, these patients may have increased risk for adverse cardiovascular outcomes.

Adherence to CPAP Treatment and the Risk of Recurrent Cardiovascular Events: A Meta-Analysis.

Importance: The effect of continuous positive airway pressure (CPAP) on secondary cardiovascular disease prevention is highly debated. Objective: To assess the effect of CPAP treatment for obstructive sleep apnea (OSA) on the risk of adverse cardiovascular events in randomized clinical trials. Data Sources: PubMed (MEDLINE), EMBASE, Current Controlled Trials: metaRegister of Controlled Trials, ISRCTN Registry, European Union clinical trials database, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov databases were systematically searched through June 22, 2023. Study Selection: For qualitative and individual participant data (IPD) meta-analysis, randomized clinical trials addressing the therapeutic effect of CPAP on cardiovascular outcomes and mortality in adults with cardiovascular disease and OSA were included. Data Extraction and Synthesis: Two reviewers independently screened records, evaluated potentially eligible primary studies in full text, extracted data, and cross-checked errors. IPD were requested from authors of the selected studies (SAVE [NCT00738179], ISAACC [NCT01335087], and RICCADSA [NCT00519597]). Main Outcomes and Measures: One-stage and 2-stage IPD meta-analyses were completed to estimate the effect of CPAP treatment on risk of recurrent major adverse cardiac and cerebrovascular events (MACCEs) using mixed-effect Cox regression models. Additionally, an on-treatment analysis with marginal structural Cox models using inverse probability of treatment weighting was fitted to assess the effect of good adherence to CPAP (≥4 hours per day). Results: A total of 4186 individual participants were evaluated (82.1% men; mean [SD] body mass index, 28.9 [4.5]; mean [SD] age, 61.2 [8.7] years; mean [SD] apnea-hypopnea index, 31.2 [17] events per hour; 71% with hypertension; 50.1% receiving CPAP [mean {SD} adherence, 3.1 {2.4} hours per day]; 49.9% not receiving CPAP [usual care], mean [SD] follow-up, 3.25 [1.8] years). The main outcome was defined as the first MACCE, which was similar for the CPAP and no CPAP groups (hazard ratio, 1.01 [95% CI, 0.87-1.17]). However, an on-treatment analysis by marginal structural model revealed a reduced risk of MACCEs associated with good adherence to CPAP (hazard ratio, 0.69 [95% CI, 0.52-0.92]). Conclusions and Relevance: Adherence to CPAP was associated with a reduced MACCE recurrence risk, suggesting that treatment adherence is a key factor in secondary cardiovascular prevention in patients with OSA.

Cardiovascular Outcomes in Adults with Coronary Artery Disease and Obstructive Sleep Apnea with versus without Excessive Daytime Sleepiness in the RICCADSA Cinical Trial.

Rationale: Recent randomized controlled trials did not show cardiovascular benefits of continuous positive airway pressure (CPAP) in adults with coronary artery disease (CAD) and obstructive sleep apnea (OSA) in intention-to-treat analyses. It has been argued that exclusion of patients with OSA with excessive daytime sleepiness (EDS), who may be most likely to benefit from CPAP treatment, may be a reason for the null results. Objectives: We addressed 1) the effect of concomitant EDS on adverse outcomes in patients with CAD and OSA; and 2) whether the cardiovascular benefit of CPAP adherence differs between individuals with versus without EDS. Methods: This was a secondary analysis of the RICCADSA (Randomized Intervention with CPAP in CAD and Obstructive Sleep Apnea) trial, conducted in Sweden between 2005 and 2013. Data were analyzed from 155 patients with CAD with OSA (apnea-hypopnea index ⩾ 15/h) and EDS (Epworth Sleepiness Scale score ⩾ 10), who were allocated to CPAP and 244 patients without EDS (ESS < 10), who were randomized to CPAP or no CPAP. Patients who were allocated to no CPAP or were nonadherent (CPAP usage < 4 h/night) were compared with adherent patients (CPAP usage ⩾ 4 h/night) at 1-year follow-up. Inverse probability of treatment weighting was applied to mimic randomization of EDS. The primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Results: The median follow-up was 52.2 months. The incidence of the primary endpoint did not differ significantly between the EDS versus no-EDS groups in the entire cohort. Within the adherent group, patients without EDS had a significantly decreased risk compared with patients with EDS (adjusted hazard ratio, 0.41; 95% confidence interval, 0.20-0.85; P = 0.02). Conclusions: Adverse cardiovascular outcomes did not differ by degrees of EDS for patients with CAD with OSA who were untreated or nonadherent to treatment. CPAP use, at least 4 h/night, was associated with reduced adverse outcomes in participants without EDS. Clinical trial registered with www.clinicaltrials.gov (NCT00519597).

Postoperative Atrial Fibrillation in Adults with Obstructive Sleep Apnea Undergoing Coronary Artery Bypass Grafting in the RICCADSA Cohort.

Postoperative atrial fibrillation (POAF) occurs in 20−50% of patients with coronary artery disease (CAD) after coronary artery bypass grafting (CABG). Obstructive sleep apnea (OSA) is also common in adults with CAD, and may contribute to POAF as well to the reoccurrence of AF in patients at long-term. In the current secondary analysis of the Randomized Intervention with Continuous Positive Airway Pressure (CPAP) in Coronary Artery Disease and Obstructive Sleep Apnea (RICCADSA) trial (Trial Registry: ClinicalTrials.gov; No: NCT 00519597), we included 147 patients with CABG, who underwent a home sleep apnea testing, in average 73 ± 30 days after the surgical intervention. POAF was defined as a new-onset AF occurring within the 30 days following the CABG. POAF was observed among 48 (32.7%) patients, occurring within the first week among 45 of those cases. The distribution of the apnea-hypopnea-index (AHI) categories < 5.0 events/h (no-OSA); 5.0−14.9 events/h (mild OSA); 15.0−29.9 events/h (moderate OSA); and ≥30 events/h (severe OSA), was 4.2%, 14.6%, 35.4%, and 45.8%, in the POAF group, and 16.2%, 17.2%, 39.4%, and 27.3%, respectively, in the no-POAF group. In a multivariate logistic regression model, there was a significant risk increase for POAF across the AHI categories, with the highest odds ratio (OR) for severe OSA (OR 6.82, 95% confidence interval 1.31−35.50; p = 0.023) vs. no-OSA, independent of age, sex, and body-mass-index. In the entire cohort, 90% were on ß-blockers according to the clinical routines, they all had sinus rhythm on the electrocardiogram at baseline before the study start, and 28 out of 40 patients with moderate to severe OSA (70%) were allocated to CPAP. During a median follow-up period of 67 months, two patients (none with POAF) were hospitalized due to AF. To conclude, severe OSA was significantly associated with POAF in patients with CAD undergoing CABG. However, none of those individuals had an AF-reoccurrence at long term, and whether CPAP should be considered as an add-on treatment to ß-blockers in secondary prevention models for OSA patients presenting POAF after CABG requires further studies in larger cohorts.

Effect of Obstructive Sleep Apnea and CPAP Treatment on Cardiovascular Outcomes in Acute Coronary Syndrome in the RICCADSA Trial.

We aimed to address the impact of OSA and its treatment with continuous positive airway pressure (CPAP) on major adverse cardiovascular and cerebrovascular events (MACCE) in patients with acute coronary syndrome (ACS). In this current analysis of the revascularized ACS subgroup (n = 353) of the Randomized Intervention with CPAP in Coronary Artery Disease and Obstructive Sleep Apnea (RICCADSA) trial (Trial Registry: ClinicalTrials.gov; No: NCT00519597), participants with non-sleepy OSA (apnea-hypopnea-index [AHI] ≥ 15 events/h on a home sleep apnea testing, and Epworth Sleepiness Scale [ESS] score < 10; n = 171) were randomized to CPAP (n = 86) or no-CPAP (n = 85). The sleepy OSA patients (AHI ≥ 15 events/h and ESS ≥ 10) who were offered CPAP, and the ones with no-OSA (AHI < 5 events/h) were included in the observational arm. A post-hoc analysis was done to compare untreated OSA (no-CPAP; n = 78) and nonadherent sleepy/non-sleepy OSA (n = 96) with the reference group without OSA (n = 81). The primary endpoint (the first event of repeat revascularization, myocardial infarction, stroke or cardiovascular mortality) during a median 4.7-year follow-up was evaluated in time-dependent Cox proportional hazards models adjusted for confounding factors. The incidence of MACCE did not differ significantly in intention-to-treat population. On-treatment analysis showed a significant risk reduction in those who used CPAP for ≥4 vs. <4 h/day or did not receive treatment (adjusted hazard ratio [HR] 0.17; 95% confidence interval [CI] 0.03-0.81; p = 0.03). Compared with the reference group, nonadherent/untreated OSA was associated with an increased cardiovascular risk (adjusted HR 1.97, 95% CI 1.03-3.77; p = 0.04). We conclude that OSA is an independent risk factor for adverse cardiovascular outcomes in patients with ACS. CPAP treatment may reduce this risk, if the device is used at least 4 h/day.

Outcomes in coronary artery disease patients with sleepy obstructive sleep apnoea on CPAP.

Coronary artery disease (CAD) patients with obstructive sleep apnoea (OSA) have increased risk for major adverse cardiovascular and cerebrovascular events (MACCEs) compared with CAD patients without OSA. We aimed to address if the risk is similar in both groups when OSA patients are treated.This study was a parallel observational arm of the RICCADSA randomised controlled trial, conducted in Sweden between 2005 and 2013. Patients with revascularised CAD and OSA (apnoea-hypopnoea index (AHI) ≥15 events·h-1) with daytime sleepiness (Epworth Sleepiness Scale score ≥10) were offered continuous positive airway pressure (CPAP) (n=155); CAD patients with no OSA (AHI <5 events·h-1) acted as controls (n=112), as a randomisation of sleepy OSA patients to no treatment would not be ethically feasible. The primary end-point was the first event of MACCEs. Median follow-up was 57 months.The incidence of MACCEs was 23.2% in OSA patients versus 16.1% in those with no OSA (adjusted hazard ratio 0.96, 95% CI 0.40-2.31; p=0.923). Age and previous revascularisation were associated with increased risk for MACCEs, whereas coronary artery bypass grafting at baseline was associated with reduced risk.We conclude that the risk for MACCEs was not increased in CAD patients with sleepy OSA on CPAP compared with patients without OSA.

CPAP Does Not Reduce Inflammatory Biomarkers in Patients With Coronary Artery Disease and Nonsleepy Obstructive Sleep Apnea: A Randomized Controlled Trial.

Objectives: Obstructive sleep apnea (OSA) and enhanced vascular inflammation coexist in patients with coronary artery disease (CAD). Continuous positive airway pressure (CPAP) is first-line treatment for OSA with daytime sleepiness. This analysis of data from the RICCADSA (Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnea) trial investigated the effects of CPAP on inflammatory markers in patients with CAD and nonsleepy OSA. Methods: This single-center, randomized, controlled, open-label trial enrolled consecutive revascularized patients with nonsleepy OSA (apnea-hypopnea index >15/h; Epworth Sleepiness Scale score <10). Levels of high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) were measured in blood samples taken at baseline (median 94 days after revascularization) and after 1 year of follow-up in patients randomized to CPAP or no-CPAP. Results: A total of 220 patients with analyzable blood samples at baseline and 1 year were included. Baseline IL-6 levels were significantly lower in the CPAP versus no-CPAP group (median 3.1 pmol/L [interquartile range 1.3-5.7] vs. 4.2 pmol/L [2.0-8.9], respectively; p = .005). At 1-year follow-up, median IL-6 levels were significantly reduced in both groups (to 2.2 pmol/L [1.2-3.9] in the CPAP group and to 2.2 [1.2-4.7] in no-CPAP group; both p < .001 vs. baseline). IL-8, hs-CRP, and TNF-α did not change significantly from baseline. There was no association between CPAP adherence and changes in inflammatory marker levels. Conclusions: In patients with stable CAD and nonsleepy OSA, inflammatory biomarkers did not change significantly over time except for IL-6 levels, which reduced to the same extent in the CPAP and no-CPAP groups. Clinical Trial Registration: ClinicalTrials.gov, ID: NCT00519597; researchweb.org, VGSKAS-4731.

Effect of CPAP on diastolic function in coronary artery disease patients with nonsleepy obstructive sleep apnea: A randomized controlled trial.

BACKGROUND: Obstructive sleep apnea (OSA) has been associated with worse diastolic function in patients with coronary artery disease (CAD). This analysis determined whether continuous positive airway pressure (CPAP) treatment would improve diastolic function in CAD patients with nonsleepy OSA. METHODS: Between December 2005 and November 2010, 244 revascularized CAD patients with nonsleepy OSA (apnea-hypopnea index (AHI) ≥15/h, Epworth Sleepiness Scale [ESS] score<10) were randomly assigned to CPAP or no-CPAP. Echocardiographic measurements were obtained at baseline, and after 3 and 12months. RESULTS: A total of 171 patients with preserved left ventricular ejection fraction (≥50%), no atrial fibrillation or severe valve abnormalities, and technically adequate echocardiograms at baseline and follow-up visits were included (CPAP, n=87; no-CPAP, n=84). In the intention-to-treat analysis, CPAP had no significant effect on echocardiographic parameters of mild (enlarged left atrium or decreased diastolic relaxation velocity) or worse (increased E/é filling index [presumed elevated left ventricular filling pressure]) diastolic function. Post-hoc analysis revealed a significant association between CPAP usage for ≥4h/night and an increase in diastolic relaxation velocity at 12months' follow-up (odds ratio 2.3, 95% confidence interval 1.0-4.9; p=0.039) after adjustment for age, sex, body mass index, and left atrium diameter at baseline. CONCLUSIONS: CPAP did not improve diastolic dysfunction in CAD patients with nonsleepy OSA. However, good CPAP adherence was significantly associated with an increase in diastolic relaxation velocity after one year.

Effect of Positive Airway Pressure on Cardiovascular Outcomes in Coronary Artery Disease Patients with Nonsleepy Obstructive Sleep Apnea. The RICCADSA Randomized Controlled Trial.

RATIONALE: Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), many of whom do not report daytime sleepiness. First-line treatment for symptomatic OSA is continuous positive airway pressure (CPAP), but its value in patients without daytime sleepiness is uncertain. OBJECTIVES: To determine the effects of CPAP on long-term adverse cardiovascular outcome risk in patients with CAD with nonsleepy OSA. METHODS: This single-center, prospective, randomized, controlled, open-label, blinded evaluation trial was conducted between December 2005 and November 2010. Consecutive patients with newly revascularized CAD and OSA (apnea-hypopnea index ≥15/h) without daytime sleepiness (Epworth Sleepiness Scale score <10) were randomized to auto-titrating CPAP (n = 122) or no positive airway pressure (n = 122). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Median follow-up was 57 months. The incidence of the primary endpoint did not differ significantly in patients who did versus did not receive CPAP (18.1% vs. 22.1%; hazard ratio, 0.80; 95% confidence interval, 0.46-1.41; P = 0.449). Adjusted on-treatment analysis showed a significant cardiovascular risk reduction in those who used CPAP for ≥4 versus <4 hours per night or did not receive treatment (hazard ratio, 0.29; 95% confidence interval, 0.10-0.86; P = 0.026). CONCLUSIONS: Routine prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse cardiovascular outcomes in the intention-to-treat population. There was a significant reduction after adjustment for baseline comorbidities and compliance with the treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).

Increased inflammatory activity in nonobese patients with coronary artery disease and obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD). Enhanced vascular inflammation is implicated as a pathophysiologic mechanism but obesity is confounding. We aimed to address the association of OSA with inflammatory biomarkers in a nonobese cohort of revascularized patients with CAD and preserved left ventricular ejection fraction. DESIGN: Cross-sectional analysis of baseline investigations of a randomized controlled trial. SETTING: Clinic-based. PARTICIPANTS: There were 303 nonobese patients with CAD, of whom 213 with OSA (apnea-hypopnea index [AHI] ≥15 events/h) and 90 without OSA (AHI < 5 events/h). Obese patients with CAD and OSA (N = 105) were chosen as an additional control group. INTERVENTIONS: None. MEASUREMENTS: Circulating levels of high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, and tumor necrosis factor-α were assessed in relation to OSA diagnosis based on AHI ≥ 15 events/h as well as oxygen desaturation index (ODI) ≥ 5 events/h. RESULTS: Nonobese patients with OSA had significantly higher levels of hs-CRP and IL-6 than those without OSA. The values did not differ significantly between obese and nonobese patients with OSA. In bivariate regression analysis, AHI ≥ 15 events/h was associated with all four biomarkers but not so in the multivariate model after adjustment for confounders. ODI ≥ 5 events/h was associated with hs-CRP (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.13-1.99) and IL-6 (OR 1.30; 95% CI 1.05-1.60) in multivariate analysis. CONCLUSIONS: OSA with ODI ≥ 5 was independently associated with increased inflammatory activity in this nonobese CAD cohort. The intermittent hypoxemia, rather than the number of apneas and hypopneas, appears to be primarily associated with enhanced inflammation.

Obstructive sleep apnea is independently associated with worse diastolic function in coronary artery disease.

BACKGROUND: Diastolic dysfunction is common in patients with coronary artery disease (CAD). We hypothesize that patients with CAD and preserved left ventricular ejection fraction (LVEF) and obstructive sleep apnea (OSA) will have worse diastolic function than similar patients without OSA. MATERIAL AND METHODS: We analyzed sleep-study recordings and echocardiographic measurements obtained at baseline in a randomized controlled trial (RICCADSA) of revascularized patients with CAD who had LVEF of at least 50%. OSA was defined as an apnea-hypopnea-index (AHI) ≥15 events/h, and, no OSA, as an AHI <5. Worse diastolic function was defined as assumed elevated left ventricular filling pressure based on peak flow velocity in early diastole/Tissue Doppler of early diastolic ventricular filling (E/é) of >13 (or >9 in patients with an enlarged left atrial diameter [≥39 mm for women and ≥40 mm for men]). RESULTS: Data from 431 patients were evaluated (mean age: 63.7 ± 8.8 y; men: 82.5%; OSA: n = 331). Worse diastolic function was more common among the patients with OSA than those without (54.4% vs 41.0%, p = 0.019). In multivariate analysis, OSA was associated with worse diastolic function (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.13; 3.18) adjusted for female sex (OR 2.28, 95% CI 1.28; 4.07), hypertension (OR 1.84, 95% CI 1.20; 2.82), and diabetes mellitus (OR 2.45, 95% CI 1.42; 4.23). Age ≥60 years, obesity, and current smoking were nonsignificant. CONCLUSIONS: In this cohort with CAD and preserved LVEF, OSA was associated with worse diastolic function independent of the traditionally recognized risk indicators.

Occurrence and predictors of obstructive sleep apnea in a revascularized coronary artery disease cohort.

BACKGROUND: Knowledge about the prevalence of obstructive sleep apnea (OSA) in coronary artery disease (CAD) is insufficient. The aim of the current report was to evaluate the occurrence and predictors of OSA among revascularized patients with CAD within the framework of a randomized controlled trial (Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnea [RICCADSA]), evaluating the impact of continuous positive airway pressure on cardiovascular outcomes in CAD patients with OSA. MATERIAL AND METHODS: All patients undergoing percutaneous coronary intervention or coronary artery bypass grafting between September 2005 and November 2010 (n = 1,291) were invited to participate. Anthropometrics and medical history were obtained, ambulatory sleep recording was performed, and all subjects completed the Epworth Sleepiness Scale (ESS) questionnaire. RESULTS: In total, 662 patients participated in the sleep study. OSA, defined as an apnea-hypopnea index equal to or greater than 15/hour, was found among 422 (63.7%). The prevalence of hypertension was 55.9%; obesity (body mass index ≥ 30 kg/m²), 25.2%; diabetes mellitus, 22.1%; and current smoking, 18.9%. The patients with CAD who did not participate in the study demonstrated an almost similar anthropometric and clinical profile compared with the studied group. The majority (61.8%) of the patients with OSA were nonsleepy (ESS score < 10). Patients with OSA had a higher prevalence of obesity, hypertension, diabetes mellitus, and history of atrial fibrillation, whereas current smoking was more common in the non-OSA group. Age, male sex, body mass index, and ESS score, but not comorbidities, were independent predictors of OSA. CONCLUSIONS: The occurrence of unrecognized OSA in this revascularized CAD cohort was higher than previously reported. We suggest that OSA should be considered in the secondary prevention protocols in CAD.

Rationale and design of the Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnoea--RICCADSA trial.

RATIONALE: Obstructive sleep apnoea (OSA) is common in coronary artery disease (CAD) and a possible cause of increased mortality. To date, there is a lack of randomized controlled trials to draw the conclusion that all CAD patients should be investigated for OSA and subsequently be treated with continuous positive airway pressure (CPAP). OBJECTIVE: The Randomized Intervention with CPAP in CAD and OSA (RICCADSA) trial is designed to address if CPAP treatment reduces the combined rate of new revascularization, myocardial infarction, stroke and cardiovascular mortality over a 3-year period in CAD patients with OSA. Secondary outcomes include cardiovascular biomarkers, cardiac function and maximal exercise capacity at 3-month- and 1-year follow-ups. PATIENTS AND METHODS: A sample of 400 CAD patients (100 non-sleepy OSA patients randomized to CPAP, 100 to non-CPAP; 100 sleepy OSA patients on CPAP, and 100 CAD patients without OSA) will be included. So far, 240 patients have been enrolled in the trial since December 31, 2005. CONCLUSION: The RICCADSA trial will contribute to defining the impact of CPAP on prognosis of CAD patients with OSA.