ISAACC: No Effect of CPAP on CV Outcomes in OSA

Stephanie Edwards

February 20, 2020

Continuous positive airway pressure (CPAP) treatment did not significantly reduce cardiovascular events among patients with previous acute coronary syndrome (ACS) and obstructive sleep apnea (OSA) but without daytime sleepiness, in a randomized, controlled study.

A nonsignificant difference in the primary endpoint, a composite of first cardiovascular events including cardiovascular death, acute myocardial infarction, nonfatal stroke, heart failure, angina or transient ischemic attack, was seen after a median 3.35 years' follow-up, the researchers found.

"The CPAP had no significant effect on the individual components of the primary cardiovascular events, revascularization procedures, all-cause death, atrial fibrillation or other arrhythmias, or newly diagnosed diabetes," Manual Sánchez-de-la-Torre, MD, Translational Research in Respiratory Medicine, Hospital Universitari Arnau de Vilanova-Santa Maria, Lleida, Spain, and Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Madrid, Spain, said in a statement.

The study was published online in The Lancet Respiratory Medicine.

Significant Impact on Population

More than 1 million patients in the United States have ACS, and although prognosis after diagnosis has improved, morbidity and mortality remain, the researchers say. In addition, OSA affects 20% to 30% of the population and has been associated with many health problems that could potentially lead to cardiovascular disease (CVD), and patients with coronary artery disease also have a high prevalence of OSA.

Randomized trials have shown CPAP is associated with reductions in blood pressure, left ventricular mechanical overload, and arrhythmia, factors that can affect prognosis in patients with coronary artery disease, the authors note. Other studies, however, have shown no reduction in CV outcomes or death in patients with sleep apnea with CPAP, nor is it effective as secondary cardiovascular prevention.

Against a background of these varying findings, the authors designed a secondary prevention trial to evaluate if CPAP treatment for OSA had any effect on the prevalence of cardiovascular events (CVE) in patients with ACS.

The Impact of Sleep Apnea Syndrome in the Evolution of Acute Coronary Syndrome. Effect of Intervention with CPAP (ISAACC) study was a multicenter, open-label, parallel-group, randomized controlled trial of patients with ACS at 15 hospitals throughout Spain.

Eligible patients were men and women age 18 years and older who had been admitted to the hospital for ACS and had an Epworth Sleepiness Scale (EES) score of ≤ 10; that is, patients who despite their OSA, did not have excessive daytime sleepiness. Patients with previous treatment with CPAP for OSA, sleep disorders, presence of Cheyne-Stokes respiration, chronic disease or medical history that could interfere with study objectives, limited life expectancy, and cardiogenic shock were excluded, the authors note.

All patients admitted to hospital underwent respiratory polygraphy during the first 24 to 72 hours of hospitalization. Patients with OSA, defined as an apnea-hypopnea index (AHI) ≥ 15/h, were randomly assigned to CPAP therapy plus usual care (CPAP group) or usual care only (UC group). Patients without OSA were randomly selected for the reference group.

Patients were monitored, and follow-up was a minimum of 1 year. Examinations occurred at the time of inclusion; 1, 3, 6, 12, 18, 24, 30, and 36 months, and every 12 months after.

Of the 2834 patients who had respiratory polygraphy, 2551 were enrolled in the study. Of those with ACS and OSA, 629 participants were assigned to the CPAP group and 626 to the UC group. Participants with ACS but not OSA were randomly excluded (n = 684) or were placed in the reference group (n = 603). The mean age was 60 years, and 84% were male.

The number of patients who completed the 1-year follow-up was 552 (88%) in the CPAP group, 549 (88%) in the UC group, and 511 (86%) in the reference group. The median follow-up period was 3.35 years. Mean AHI was 36 events per hour, and mean EES scale was 5.32.

The results showed that patients who experienced a CVE during follow-up was not significantly different between the CPAP group and the UC group.

ISAACC: Cardiovascular Events During Follow-Up by Treatment Group
Endpoint CPAP Group Usual Care Hazard Ratio (95% Confidence Interval) P value
Prevalence of Cardiovascular Death or Nonfatal Events After 1 Year [n (%)] 98 (16) 108 (17) 0.89 (0.68 - 1.17) .40

The annual event rate for cardiovascular events in the CPAP group was 7.18 per 100 person-years compared with 7.78 per 100 person-years in the UC group (relative risk [RR], 0.92; 95% confidence interval [CI], 0.74 - 1.15; P = .47).

In comparison, 102 (17%) patients from the UC group and 90 (15%) from the reference group had a cardiovascular event during follow-up (hazard ratio, 1.01; 95% CI, 0.76 - 1.35; P = .93). The annual event rate of cardiovascular events was 7.62 per 100 person-years in the UC group and 6.56 per 100 person-years in the reference group (RR, 1.16; 95% CI, 0.92 - 1.47; P = .66).

Mean CPAP adherence was 2.78 h/night (SD, 2.73) and median was 2.2 h/night. Patients were divided into a poor adherence group (mean adherence < 4 h/night) or a good adherence group (≤ 4 h/night) and compared with the UC group.

CPAP adherence did not influence the results, that for patients with ACS and OSA, CPAP treatment did not reduce the prevalence of CVE.

Cardiovascular Events Per Subgroup by CPAP Adherence
Adherence CV Events [n (%)] vs Usual Care [Hazard Ratio (95% Confidence Interval)] P value
Poor Adherence 102/607 (17%) 0.88 (0.63 - 1.22) .46
Good Adherence 56/377 (15%) 0.94 (0.65 - 1.36) .76
Usual Care 41/277 (18%)    

Among various secondary endpoints, CPAP treatment showed an association with an improved EES and blood pressure. It was also associated with a greater increase in body-mass index and waist circumference when compared with the follow-up of those in the UC group.

The results of the ISAACC study were similar to those of the Sleep Apnea Cardiovascular Endpoints (SAVE) study published in 2016 in the New England Journal of Medicine. The SAVE study also showed no reduction in cardiovascular events during the follow-up period, and both studies found a positive effect of CPAP treatment on clinical symptoms. One notable difference between the studies was that patients in SAVE had chronic coronary artery or cerebrovascular disease, while those in ISAACC were in acute phase of coronary disease, the authors note.

Some limitations reported by the researchers include the exclusion of patients with severe ACS and very poor expectations for short-term outcomes, and those with the most severe OSA and daytime sleepiness. Participants were predominately male and white, so results for women and other ethnicities or races are unknown.

The authors note that using respiratory polygraphy could underestimate the severity of OSA. In addition, patients in acute phase could be given pharmacological treatment that could potentially influence the results of a sleep study by increasing AHI. Lastly, low compliance to CPAP treatment could underestimate the effect of sustained well-conducted CPAP.

Expanding Criteria for Analysis

In an accompanying editorial, Raphael Heinzer, Centre for Investigation and Research in Sleep, Lausanne University Hospital (CHUV); Pulmonary Department, CHUV, Lausanne, Switzerland, and Danny Eckert, Adelaide Institute for Sleep Health, Flinders University, Bedford Park, Australia, suggest that a relationship between OSA and CPAP treatment to prevent cardiovascular diseases should not be ruled out.

They note that the ISAACC study, and others like it, provide insight only in secondary prevention since participants already had established CVD, and they suggest that applying CPAP to prevention rather than reversal of disease may yield better results.

"Reversing an altered vascular structure might be more difficult than preventing it, and these studies do not rule out a possible effect of OSA treatment as a primary prevention," the editorialists write. They note, however, the difficulties such a study would present, such as an increased participant population and length follow-up period.

This study included patients without major daytime sleepiness, but the authors note that including patients with excessive daytime sleepiness could also affect results.

Heinzer and Eckert add that including participants based on their AHI might not "reflect the complexity of OSA," noting that many sleep specialists now use AHI as a "generic marker of OSA severity and that additional, more specific biomarkers should be used to identify patients with OSA who are susceptible to OSA-related cardiovascular and metabolic outcomes."

They suggest that once predictors are identified, new trials should reassess the effect of OSA treatment on cardiovascular diseases.

This study was funded by ResMed (Australia), Fondo de Investigación Sanitaria (Fondo Europeo de Desarrollo Regional), the Spanish Respiratory Society, the Catalonian Cardiology Society, Esteve-Teijin, Oxigen Salud, and ALLER. Sánchez-de-la-Torre reported no competing interests. Heinzer reported being a member of the medical advisory board of Dreem and NightBalance-Philips, receiving a grant from the Ligue pulmonaire vaudoise, and speaker's fees from Nightbalance-Philips. Eckert reported grants from the National Health and Medical Research Council of Australia, grants and personal fees from Apnimed, and grants from Bayer and the Cooperative Research Centres, outside of the submitted work.

Lancet Resp. Published online December 12, 2019. Abstract, Editorial

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