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Rebuttal From Drs Punjabi and Gottlieb

2022; Elsevier BV; Volume: 161; Issue: 3 Linguagem: Inglês

10.1016/j.chest.2021.12.032

1931-3543

Naresh M. Punjabi, Daniel J. Gottlieb,

Cardiovascular and Diving-Related Complications

Drs Mehra and Orbea1Mehra R. Orbea C.P. POINT: Should Asymptomatic OSA Be Treated in Patients With Significant Cardiovascular Disease? Yes.Chest. 2022; 161: 605-607Google Scholar present several fundamental points in their perspective of the reason that patients with asymptomatic OSA with cardiovascular disease should be treated with positive airway pressure (PAP) therapy. Their first point is that OSA is a proven causal factor for increased BP through its effects on vascular function; thus, PAP treatment is warranted. There can be no rebuttal on their recommendation because the randomized controlled trial data have provided the necessary justification for instituting positive PAP therapy in those patients with coexistent OSA and hypertension. The second point that is proposed is that poor adherence in those patients who are asymptomatic may be the underlying cause that studies may have failed to demonstrate efficacy with PAP therapy for cardiovascular events. This too is a very reasonable argument. However, given the lack of data on cardiovascular efficacy in the asymptomatic patient with OSA, it is difficult to justify starting PAP therapy based solely on an inferential conclusion that it may be a benefit for cardiovascular risk because it benefits sleepiness or BP. Empiric data should guide therapeutic recommendations; it should not be inferred that treatment has a beneficial effect on cardiovascular risk simply because it has a beneficial effect on other outcomes (eg, sleepiness or hypertension). The third point they raise is that “most trials did not include those patients with cardiovascular risk.” Although this is also correct, the largest trial to date (eg, Sleep Apnea Cardiovascular Endpoints2McEvoy R.D. Antic N.A. Heeley E. et al.CPAP for prevention of cardiovascular events in obstructive sleep apnea.N Engl J Med. 2016; 375: 919-931Google Scholar) focused on patients with cardiovascular risk and failed to show efficacy on the primary end point of cardiovascular events. Their final point is that benefits of PAP therapy on endothelial dysfunction,3Kohler M. Craig S. Pepperell J.C.T. et al.CPAP improves endothelial function in patients with minimally symptomatic OSA: results from a subset study of the MOSAIC trial.Chest. 2013; 144: 896-902Google Scholar even in the asymptomatic patient, rationalize its use in the asymptomatic patient with cardiovascular disease. Although there is no countering the evidence on the effects of PAP therapy on endothelial function, it has to be noted that improvements in intermediary end points, which have pathophysiologic relevance, do not guarantee that there will be improvements in downstream effects on cardiovascular events. In fact, a recent example of how a novel therapy that targets a putative intermediate step can alter levels of a biologically relevant biomarker, but may not change clinical scores, is semorinemab, an anti-tau antibody, for Alzheimer disease. The phase 2 Tauriel study showed that, in people with prodromal-to-mild Alzheimer disease, there is a dose-dependent decrease in cerebrospinal fluid tau levels. However, in that study, no changes in neurodegeneration were observed.4Mullard A. Failure of first anti-tau antibody in Alzheimer disease highlights risks of history repeating.Nat Rev Drug Discov. 2021; 20: 3-5Google Scholar In a follow-up trial, semorinemab failed to lower the rate of clinical decline as compared with placebo.5Terry M. Mixed Bag in Phase II Alzheimer’s Trial. 2021.https://www.biospace.com/article/ac-immune-and-genentech-semorinemab-shows-mixed-results-in-phase-ii-alzheimer-s-trial/Google Scholar Although much excitement still remains in that area, it serves as an example to understand that targeting causal pathways does not guarantee a win easily for clinical efficacy. Nevertheless, it is highly relevant that effects of intermediate biomarkers not be dismissed. Take cholesterol for example. There is no argument that lowering low-density lipoprotein cholesterol has relevance for cardiovascular events. All of these arguments notwithstanding, we are in complete agreement with Drs Mehra and Orbea that “…caution is recommended against treatment solely upon absence of symptoms….” As previously stated, starting PAP therapy is a shared decision between the treating physician and the patient and should incorporate prevalent comorbidity along with a careful survey of symptoms that may not be evident to the patient. It will need to be the approach until more certainty is gained on the relevance of PAP therapy in the asymptomatic patient with cardiovascular disease. There is, of course, one certainty: more research is needed on the effects of PAP therapy in various OSA phenotypes to determine the added value for different subsets of patients with OSA. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. COUNTERPOINT: Should Asymptomatic OSA Be Treated in Patients With Significant Cardiovascular Disease? NoCHESTVol. 161Issue 3PreviewThe year 2021 marked the 40th anniversary since the original description of positive airway pressure (PAP) for the treatment of OSA.1 In the four decades that have followed, empirical evidence on the health implications of untreated OSA has grown substantially, particularly for cardiovascular disease.2,3 There is now irrefutable evidence that treating OSA with PAP is associated with improvements in measures of objective and subjective sleepiness, quality of life, and BP.4,5 Given the sizeable body of available data on the favorable effects of PAP on the reduction of BP, it is no surprise that OSA was identified as a secondary cause of hypertension in the 2003 report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Full-Text PDF POINT: Should Asymptomatic OSA Be Treated in Patients With Significant Cardiovascular Disease? YesCHESTVol. 161Issue 3PreviewOSA is estimated to afflict >1 billion individuals worldwide1 and is associated with the development of adverse cardiovascular outcomes and increased mortality rates, based upon meta-analyses of thousands of individuals.2 Clinical trials designed to investigate impact of positive airway pressure (PAP) treatment of OSA on various outcomes, however, have been challenging to interpret, given inherent limitations that include suboptimal treatment adherence. The third edition of the International Classification of Sleep Disorders by the American Academy of Sleep Medicine recommends CPAP treatment for the following conditions: (1) apnea hypopnea index > 5 with one or more symptoms (eg, sleepiness, fatigue, insomnia, snoring) or an associated medical or psychiatric disorder (eg, hypertension, coronary artery disease, atrial fibrillation) or (2) apnea hypopnea index > 15, irrespective of symptoms or associated conditions. Full-Text PDF Rebuttal From Drs Mehra and Pena OrbeaCHESTVol. 161Issue 3PreviewWe appreciate the comments of our esteemed colleagues, Drs Punjabi and Gottlieb,1 who have taken the position of recommending against treatment of asymptomatic OSA in patients with significant cardiovascular disease. As in most scenarios, we find several areas of agreement; however, several points are worthy of further discussion to pave our path forward. To state that, in the absence of evidence-based indications for positive airway pressure (PAP) therapy, use in asymptomatic patients with cardiovascular risk is not justified, as indicated by our colleagues, has far-reaching implications. Full-Text PDF