Editor’s Note: Commentary based on Gottlieb DJ, Craig SE, Lorenzi-Filho G et al. Sleep Apnea Cardiovascular Clinical Trials-Current Status and Steps Forward: The International Collaboration of Sleep Apnea Cardiovascular Trialists. Sleep 2013;36:975-980.

Background

Sleep apnea is a common chronic disease that is associated with coronary heart disease, stroke, heart failure and mortality, although the ability of sleep apnea treatment to reduce cardiovascular morbidity and mortality has not been demonstrated.

Methods

A search of major worldwide clinical trials registry databases, including all registries contributing data to the World Health Organization Clinical Trials Registry Platform, and included all trials submitted to the registry as of November 2012. The search was designed to return all studies including the key words “sleep apnea” plus any of the following terms: cardiovascular, cerebrovascular, stroke, or vascular.

Results

Most of the available data on the long-term cardiovascular outcomes of OSA treatment comes from observational trial. There are multiple challenges in conducting Randomized Controlled Trials (RCTs) on the effect of sleep apnea management in reducing cardiovascular morbidity and mortality. Current RCTs enrolled small numbers of patients with a short follow-up period and inconsistent outcomes. The International Collaboration of Sleep Apnea Cardiovascular Trialists (INCOSACT) was established to help in promoting new research projects and overcoming all potential challenges that may limit conducting these trials.

Conclusion

Despite all potential challenges that come with conducting RCTs on the impact of Sleep apnea management on cardiovascular outcomes, ongoing efforts including the International Collaboration of Sleep Apnea Cardiovascular Trialists (INCOSACT) will help in getting more data that can help in guiding our therapy.

Commentary/Perspective

There is increased evidence of association between OSA and cardiovascular diseases, including coronary artery disease, hypertension, left ventricular dysfunction, and arrhythmias.^1,2 Several observational studies showed that untreated obstructive sleep Apnea (OSA) patients had a higher risk of cardiovascular disease than those treated with CPAP.^3,4 Furthermore, some of these trials demonstrated that CPAP treatment was associated with lower incidence of death from cardiovascular disease.⁵ However, retrospective observational design is subject to selection bias and unmeasured confounding that may very well affect outcomes.

Although RCTs are the definitive way to control for treatment-selection bias, only few RCTs compared the effect of OSA treatment on cardiovascular outcomes. Also, most of these trials were conducted for short period of time and did not check for long-term cardiovascular morbidity and mortality outcomes. Gottlieb et al⁶ explained the challenges that face conducting these needed studies. The first challenge is mainly related to the lack of standardization in the definition, diagnosis techniques and criteria classification of OSA. There is no universal consensus on the criteria used to define and recognize the severity of sleep apnea. Also, there is no consensus on the appropriate diagnostic techniques used to make this diagnosis. The latter factor can be very limiting as traditionally the diagnosis of OSA is usually made by the use of polysomnography, which is an expensive technique and limited to specialized facilities. More patients in the US are diagnosed now by limited channel, home-based sleep apnea testing, measuring airflow, respiratory effort, and pulse oximetry, this technique can be very helpful in facilitating the diagnosis of OSA and therefore enrollment of patients in clinical trials, but it is not well validated. Another challenge facing clinical trials in sleep apnea is the ethical and technical issues related to placebo effects used to compare with CPAP. The ethical dilemma is related to the fact that even though the long term cardiovascular outcomes CPAP is not well established. CPAP is known to cause a considerable symptomatic improvement which can make randomizing severely symptomatic patients to the non-CPAP arm ethically questionable. That resulted in randomizing either asymptomatic or minimally symptomatic patient, which may bias the results by including a lower risk population. Furthermore, even if the use of placebo was ethical in OSA patient, the choice of appropriate non-therapeutic comparator can be challenging as well. Currently, used comparators include sham CPAP, subtherapeutic CPAP, placebo pills, nasal dilator strips, or a non-treatment control group without placebo. The only validated placebo, which is sham CPAP was associated with a decreased enthusiasm of patients and providers for enrollment as well as high drop right at six months.⁷ Another important challenge in conducting a long-term RCT on the outcomes of OSA treatment is the expected high incidence of non-adherence in CPAP use over the minimum period required to show a significant difference in cardiovascular morbidity and mortality. As CPAP adherence can definitely be harder to achieve, maintain and monitor.⁶

Despite all of these challenges, multiple RCTs were conducted within the last few years. Gottlieb et al⁶ identified 40 RCTs of sleep apnea treatment initiated after 2000 with a target enrollment of at least 50 subjects and endpoints of blood pressure, cardiac function, functional status following stroke, or composite cardiovascular disease endpoints. Thirteen of these trials were already completed with a study population of 2,859 patients whereas the remaining 27 on-going trials are expected to enroll 11,236 subjects.⁶

Even with available results of the completed trials, the main question of the impact of OSA treatment on long-term cardiovascular outcomes is not answered. That is partially secondary to the focus of early trials on blood pressure as the main outcome. Blood pressure was chose as the expected impact was easier to demonstrate in a relatively shorter period of time, with fewer subjects and at lower cost than what would be required for studies with endpoints like myocardial infarction or stroke. Another factor is that even trials that looked for endpoints like myocardial infarction or stroke had a small enrollment size with average of 200 patient per RCT and that will not be sufficient to clearly demonstrate cardiovascular risk reduction following sleep apnea treatment. Even larger trials such as The Spanish Sleep and Breathing Network Trial that included 723 non-sleepy patients and the Multicentre OSA Interventional Cardiovascular Trial (MOSAIC) that included 391 minimally symptomatic patients failed to show a statistically significant reduction in cardiovascular risk.^8,9

Ongoing trials are more promising as they include a larger population. Current ongoing RCTs on the impact of sleep apnea treatment on CHF patients are comparing more clinically relevant outcomes as mortality and CHF hospitalizations, which include the Adaptive Servoventilation for Treatment of OSA and CSA in Heart Failure (ADVENT-HF) study and the Treatment of Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients With Heart Failure (SERVE-HF). Other trials like the Sleep Apnea Cardiovascular Endpoints (SAVE) study are comparing combined vascular events and mortality in patients with minimally symptomatic OSA and ischemic heart disease or cerebrovascular disease.⁶

To overcome the challenges of designing RCT in this population that was faced in previous and current era, the National Institutes of Health are funding three grants: the Heart Biomarker Evaluation in Apnea Treatment (HeartBEAT, NCT01086800), Best Apnea Interventions in Research (BestAIR, NCT01261390), and the Sleep Apnea in TIA/Stroke (SleepTight, NCT01446913) trial with the goal to evaluate and improve design approaches. These trials are expected to provide an insight on the effectiveness of various recruitment strategies, methods for optimizing adherence, use of control treatments, intermediate endpoints most responsive to intervention, and the use of oxygen as an alternative to CPAP.⁶

Another major achievement was the establishment of the International Collaboration of Sleep Apnea Cardiovascular Trialists (INCOSACT). The main aim of this consortium is promoting new research ideas, helping researchers obtaining funding, providing a credible framework to support the conduct of clinical trials, facilitating the sharing of expertise, standardizing the methodology used for diagnosis, treatment and monitoring of participants, and helping investigators to negotiate the complex regulatory landscape that confronts international clinical trials. In addition to focusing on conducting large RCT, this consortium will also promote conducting meta-analyses of data collected in smaller clinical trials and will welcome ideas for collaboration on mechanistic research trials that can be embedded as sub-studies within larger research frameworks and trying to support basic research especially on genetic and biomarker assessments that might otherwise be prohibitively expensive.⁶

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References

1. Gami AS. SV. Sleep apnea and cardiovascular disease. In: DP Z, editor Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine 8th edition. Philadelphia, PA: Saunders, 2007.
2. Somers VK, White DP, Amin R et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol 2008;52:686-717.
3. Milleron O, Pilliere R, Foucher A et al. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J 2004;25:728-34.
4. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046-53.
5. Doherty LS, Kiely JL, Swan V, McNicholas WT. Long-term effects of nasal continuous positive airway pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest 2005;127:2076-84.
6. Gottlieb DJ, Craig SE, Lorenzi-Filho G et al. Sleep Apnea Cardiovascular Clinical Trials-Current Status and Steps Forward: The International Collaboration of Sleep Apnea Cardiovascular Trialists. Sleep 2013;36:975-980.
7. Kushida CA, Nichols DA, Holmes TH et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2012;35:1593-602.
8. Barbe F, Duran-Cantolla J, Sanchez-de-la-Torre M et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA 2012;307:2161-8.
9. Craig SE, Kohler M, Nicoll D et al. Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial. Thorax 2012;67:1090-6.

Keywords: Cardiovascular System, Disease Management, Sleep Apnea Syndromes

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