American Journal of Respiratory and Critical Care Medicine

From the Authors:

We appreciate the correspondence from Drs. Lucas M. Donovan and Sanjay R. Patel about our study recently published in the Journal (1). On the basis of real-life clinical data from the Pays de la Loire Sleep Cohort linked to health administrative data, we demonstrated an inverse dose–response relationship between positive airway pressure (PAP) adherence and incident major adverse cardiovascular (CV) events (MACEs; composite outcome of mortality, stroke, and cardiac diseases), after adjustment for major confounding factors including CV active drug adherence.

The first comment from Donovan and Patel concerns the finding of our subgroup analysis showing a stronger impact of PAP on lowering the relative risk of MACEs in patients without overt CV disease compared with those with prior history of CV events (P value for interaction < 0.0001). This finding is consistent with a post hoc analysis of the ISAACC (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) trial. The effect of intervention with CPAP shows that among patients with nontreated obstructive sleep apnea (OSA) and recent acute coronary syndrome, only those with no previous heart disease on admission had an increased risk of a recurrent CV event compared with the non-OSA group (2). It may contribute to explaining the lack of association between PAP therapy and CV outcomes in randomized controlled trials focusing on secondary prevention (36). However, as we mentioned in the discussion section, subgroup analyses should be interpreted with caution because of unbalanced sample sizes. Among 5,138 patients included in our study, only 647 had a prior history of CV events and were therefore in secondary prevention. The remaining 4,491 patients with no overt CV disease belonged to the primary prevention group. To better evaluate the potential CV benefit of PAP therapy in both primary and secondary prevention, Donovan and Patel suggest considering not only the relative risk reduction but also the absolute risk reduction (ARR). In the overall population, the overall incidence density rate of MACEs was 30.1 events per 1,000 person-years (95% confidence interval, 28.2–32.1). As expected, the incidence of MACEs was markedly lower in the primary prevention group (24.4 events per 1,000 person-years [22.4–26.7]) than in the secondary prevention group (84.0 events per 1,000 person-years [74.3–95.0]). Table 1 shows the incidence of MACEs according to PAP daily usage in patients without and with a history of CV diseases. Among patients with no overt CV disease, the incidence of MACEs was 25.6 events per 1,000 person-years (22.1–29.4) in the nonadherent group (PAP use less than 4 h per night) and 24.0 events per 1,000 person-years (21.9–26.2) in adherent users (PAP use 4 h or more per night) resulting in a raw ARR of 1.6 events per 1,000 person-years (1.4–1.7) in the adherent group. Among patients with prior history of CV diseases, the incidence of MACEs was 96.1 events per 1,000 person-years (73.3–122.6) in the nonadherent group and 80.6 events per 1,000 person-years (69.8–92.9) in adherent users, resulting in a raw ARR of 15.5 events per 1,000 person-years (13.7–17.6) in the adherent group.

Table 1. Incidence of Major Adverse Cardiovascular Events According to Positive Airway Pressure Daily Usage in Patients without and with Prior History of Cardiovascular Diseases

  Incidence Density Rate (95% CI), Events per 1,000 Person-Years
n0–4 h4–6 h6–7 h⩾7 h
History of CVD     
 No4,49125.6 (22.1–29.4)24.3 (21.0–28.1)20.8 (17.3–25.0)25.9 (22.5–29.6)
 Yes64796.1 (75.3–122.6)76.9 (59.4–99.4)75.3 (55.6–101.9)86.0 (69.9–105.8)

Definition of abbreviations: CI = confidence interval; CVD = cardiovascular diseases.

Real-world observational data represent a promising method for overcoming the sample selection biases that have been recently described in randomized controlled trials of CV endpoints in the context of OSA (3, 7). The second comment from Donovan and Patel concerns the healthy adherer effect and the interpretation of E-values in our study. The healthy adherer effect arises when patients who adhere to preventive therapy are more likely to engage in other healthy behaviors than their nonadherent counterparts. This phenomenon can result in biased estimates of the effect of adherence on clinical outcomes (8). We completely agree with Donovan and Patel that the healthy adherer effect is particularly relevant to comparisons between patients with OSA who are adherent and those who are nonadherent to PAP therapy. This is why we have made the effort to capture the healthy adherer effect by adjusting for chronic CV active drug adherence as assessed by the Medication Possession Ratio, which is considered a valuable proxy (9). Several measures that are particularly relevant to the assessment of CV outcomes in the context of PAP use, such as alcohol intake, tobacco consumption, and socioprofessional status, were also taken into account. Moreover, we applied the recently described E-value to quantify the potential for unmeasured confounding to negate observed treatment effects (10). However, there is no simple way to control for all biases using healthcare datasets (8). We agree with Donovan and Patel that adherence to chronic CV active drugs does not fully capture the healthy adherence effect and that concern for residual confounding remains. Further studies are needed to fully explore the healthy adherer effects in the context of PAP adherence and CV outcomes in patients with OSA.

1. Gervès-Pinquié C, Bailly S, Goupil F, Pigeanne T, Launois S, Leclair-Visonneau L, et al.; Pays de la Loire Sleep Cohort Study Group. Positive airway pressure adherence, mortality and cardio-vascular events in sleep apnea patients. Am J Respir Crit Care Med 2022;206:13931404.
2. Zapater A, Sánchez-de-la-Torre M, Benítez ID, Targa A, Bertran S, Torres G, et al.; Spanish Sleep Network. The effect of sleep apnea on cardiovascular events in different acute coronary syndrome phenotypes. Am J Respir Crit Care Med 2020;202:16981706.
3. Reynor A, McArdle N, Shenoy B, Dhaliwal SS, Rea SC, Walsh J, et al. Continuous positive airway pressure and adverse cardiovascular events in obstructive sleep apnea: are participants of randomized trials representative of sleep clinic patients? Sleep 2021;45:zsab264.
4. McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, et al.; SAVE Investigators and Coordinators. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med 2016;375:919931.
5. Peker Y, Glantz H, Eulenburg C, Wegscheider K, Herlitz J, Thunström E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA randomized controlled trial. Am J Respir Crit Care Med 2016;194:613620.
6. Sánchez-de-la-Torre M, Sánchez-de-la-Torre A, Bertran S, Abad J, Duran-Cantolla J, Cabriada V, et al.; Spanish Sleep Network. Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial. Lancet Respir Med 2020;8:359367.
7. Pack AI, Magalang UJ, Singh B, Kuna ST, Keenan BT, Maislin G. Randomized clinical trials of cardiovascular disease in obstructive sleep apnea: understanding and overcoming bias. Sleep. 2021;44:zsaa229.
8. Shrank WH, Patrick AR, Brookhart MA. Healthy user and related biases in observational studies of preventive interventions: a primer for physicians. J Gen Intern Med 2011;26:546550.
9. Kapur VK, Psaty BM. Obtaining valid estimates of the effect of CPAP therapy: reducing healthy adherer and other biases in observational studies. Chest 2022;161:14441445.
10. VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med 2017;167:268274.
*Corresponding author (e-mail: ).

Author Contributions: All authors were substantially involved in drafting the manuscript and critically revised the manuscript and approved the final version of the article.

Originally Published in Press as DOI: 10.1164/rccm.202208-1534LE on August 16, 2022

Author disclosures are available with the text of this letter at www.atsjournals.org.

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