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Update on ATS news in pneumology for 2016

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Florin Mihălțan

Given that few Romanian lung physicians manage to reach American Thoracic Society (ATS) congresses in the USA, I consider necessary to share some of the presentations about different diseases, traditionally performed at manifestation. In this article I will present the latest news reported in some diseases such as COPD and sleep breathing disorders.

Keywords: COPD, sleep breathing disorders

Every year, the ATS Congress has an important moment for participants: 4 days of “Clinical Year in Review”, when opinion leaders are presenting the most challenging and actual scientific information about dif-ferent topics published in the previous year.

At the same time, all these presentations are pub-lished in a booklet of the American Thoracic Society (ATS)(1), whose chapters covering: new tools to support acute respiratory failure, general critical care, the brain and critical care, sleep disorders breathing, ILD, COPD, pulmonary vascular diseases, tuberculosis and nontu-berculosis mycobacteria infections, the host microbiome in lung disease, bronchiectasis, lung transplantation, thoracic oncology, thoracic imaging, health disparities and paliative care.

Out of this concentrated information intensively distributed in these days, I will try to summarise some chapters (on more prevalent diseases, such as COPD and sleep disordered breathing), for the Romanian pneu-mologists who couldn’t attend this congress.

Sleep disordered breathing (SDB)

Wang Y et al. made an analysis of comorbidities of SDB and asthma, starting from the common risk factors and comorbidities usualy found in these diseases(2). This prospective study evaluated the incidence of asthma exacerbations over a period of one year in a cohort of patients with this obstructive disease, and the preva-lence of sleep apnoea syndrom (OSA) associated with asthma and another group of control without asthma.

The prevalence of OSA was 19.2% in asthma patients and 9.6% in the control group, and a 14-fold increase in asthma exacerbations was reported in those with OSA. This frequency of asthma exacerbations was correlated with IAH level and overnight hypoxemia. There are two important conclusions of the researchers: OSA is a risk factor for asthma and asthma exacerbations, and common mechanisms are related to OSA hypoxia and oxidative stress, elevations in leptin levels with immu-nomodulation, on the one hand, and to OSA-related alterations in parasympathetic – sympathetic balance on the other hand.

Another debate in 2016 concerned the protection offered by CPAP for the prevention of cardiovascular events. McEvoy R.D. et al. participated in SAVE trial (Sleep Apnea Cardiovascular Endpoints), evaluating the role of CPAP for secondary prevention of cardiovascular diseases. On 2717 patients with moderate to severe OSA and existing cardiovascular diseases (CVD)(3), followed-up for 3.7 years, with an average of 3.3 hours per night of CPAP, they didn’t find any significant differences between the CPAP group and control group regarding composite or individual cardiovascular endpoint, but a decresead sleepness, anxiety, and depression scores, fewer missed work days and improved quality of life were found. There is a lower risk of stroke if patients are adherent to CPAP (hazard ratio: 0.56) and a benefit on cerebrovascular diseases.

In 2016, another important study analysed the ben-efits of CPAP on patients with coronary artery disease(4). The RICCADSA (Randomized Intervention with CPAP in CAD and OSA), a prospective, randomised controlled trial looking at the benefits of CPAP versus non-CPAP in patients with apnoea/hypopnea index (AHI) >15 and Epworth Sleepiness Scale score <10 (without sleepiness) associated with a recent coronary artery revascularization procedure demonstrated that after 2 years the CPAP adherence is low among non-sleepy patients with coronary artery diseases (for those with more than 4 hours per night it was found a significant reduction of cardiovascular events compared to those who were non-adherent). The incidence results of a composite cardiovas-cular primary endpoint (revascularization, myocardial infarction and cardiovascular mortality) were not very significant (18.1% in the CPAP group and 22.1% in the control group).

Heart failure and sleep apnea is another important topic with many pro/con discussions. S. Javaheri et al.(5) reported the results of a prospective trial on older men with sleep disordered breathing (SDB) (mean age: 76 years old) fol-lowed-up for 7.3 years, looking at the risk of developing incident or decompensated heart failure. 11% of the home polysomnography diagnosis patients had an elevated cen-tral apnea index (>5) (CSA) or Cheyne Stokes Respiration (CSR), and 45% had an obstructive apnea index >15. CSA and CSR were associated with a significantly increased incidence of incident heart failure and even after adjusting for confounders (odds ratio: 1.55-2.29) was stronger for CSR. One possible explanation is that the increased sympathetic nervous activity associ-ated to CSA/CSR contributed to adverse cardiac reac-tions. That’s why many researchers are looking for new therapies of this central sleep apnea. M.R. Constanzo et al., starting from the SERVE-HF trial(1,6) results (which found that adaptive servo-ventilation used in CSA patients with heart failure with reduced ejection fraction [<45%] was associated with increased cardiovascular mortality), evalu-ated after 6 months the benefits of phrenic nerve stimula-tion, another promising therapy, in a prospective multicenter randomised trial, using a transvenous phrenic stimulator. On 151 patients with an AHI>20 (>50% central events) at 6 months, the AHI was reduced to >50% of the baseline values in 51% of the treated group versus 11% of the control group. At 12 months, 8% of the treatament group had serious adverse events associated with the pro-cedure. This study proves that transvenous neuro-stimulation of the phrenic nerve is inducing significant reductions of AHI (without normalizing this index), but similar with the magnitude of improvements reported after CPAP.

Pregnancy and sleep apnea were another important topic reported in the ATS congress. In a multicenter pro-spective cohort study of 3705 nulliparous women studied in early and late pregnancy, Fl. Facco et al. found SDB in 3.6% of early pregnant women (IAH>5) and 8.3% of late pregnancy women(7). A two-fold increased prevalence of preeclampsia and 3.5-fold increased prevalence of diabe-tes was also found in this SDB cohort of women. The conclusion of the authors was: SDB incidence is increas-ing from early to late pregnancy and the prevalence of hypertensive disorders and gestational diabetes increases with the rising of SDB severity.

COPD

For COPD, three important chapters were dissected at the ATS updates conference. The first analysis was on COPD patients screening. The report of U.S. Preventive Services Task Force (USPSTF) for 2016 in comparison with 2008 recommendation is against the screening of “asymptomatic” adults (lack of evidence of the benefits on short or long term)(8) (even if it’s well known that this kind of patients are false asymptomatic because they selfrestrict their activity to minimize symptoms). At the same time, the task force recommen-dation assumes that medical treatments for COPD reduce symptoms and exacerbations, but do not alter history or reduce mortality in these patients. Regarding sympto-matic smokers with preserved spirometry, things are different. P.G. Woodruff et al.(9) performed an analysis on the “Spiromics” cohort and found that among current or former smokers with preserved pulmonary function, those who were symptomatic, with CAT≥10, had a higher rate of respiratory exacerbations (0.27 vs. 0.08 events per year), a shorter 6-minute walk distance and greater airway thickening on chest CT in comparison with unob-structed asymptomatic smokers. In the future, this can change the actual GOLD classification because it remains uncertain whether these patients represent­ a transitional pre-COPD phase or a sepa-rated clinical entity. Another question raised by this article is coming from CAT score, which seems to be a better predictor for future exacerbations than post-bronchodilator FEV1.

An important chapter of the ATS update in COPD con-cerned the therapeutic aspects. The greate debate regarding supplemental oxygen in mild to moderate hypoxemic COPD was clarified by the study of Long-Term Oxygen Treatment Trial Research Group(10). They randomized this cohort of patients to receive long-term supplemental oxygen (24-hour oxygen for those with resting desaturation and during exer-cise and sleep for those with exercise desaturation) versus no long-term supplemental oxygen. They found no difer-ences in rates of hospitalization, COPD exacerba-tions, quality of life, lung function or 6-minute walk distance. Also, they found no differences in time to event analysis between supplemental and no supple-mental oxygen group, and also in death rate or first hospitalization.

Dual bronchodilators (LABA/LAMA) (long-acting beta agonist/long-acting muscarinic antagonist) and also com-binations of inhaling corticosteroid/long-acting beta ago-nist (ICS/LABA) were analysed in more studies as other drugs. Even if there is an increase of the number of inhal-ers, the role of dual bronchodilators versus ICS/LABA is less clear. There are now many critics to Flame study(1,11), beginning from the changes realised by the results of Flame in the updated GOLD 2017. It seems that cutoffs of 2% in blood eosinophils can make the difference in favor of indacaterol/glycopyrronium versus salmeterol/flutica-sone group, but in posthoc analysis of Widsom study(1) the withdrawal of inhaled corticosteroids increased the rate of moderate and severe exacerbations among individuals with a blood eosinophil count of 4% or higher or an abso-lute eosinophil count of at least 300 cells per microliter. At the same time, using the electronic diary can influence the rate and types of reported exacerbations (the diary triggered usually an alarm for the patient to contact the site). For cutting the indications of LABA/LAMA, we still need data on longer term outcomes and to iden-tify subgroups who might experience greater ben-efits from this treatment(1). In this open competition of dual bronchodilators – ICS/LABA, there are also other possible questions regarding the influence of the latter combinations on cardiovascular mortality in COPD or in a “real world settings”. The answers are coming from two studies with the combination of vilanterol/fluticasone furoat(12,13). SUMMIT study(12), a double-blind randomized clinical trial performed on more than 16.000 patients comparing this combination versus fluticasone furoate alone, vilanterol alone and placebo, showed no differ-ences in all cause mortality in any of the treatment arm (no differences in risk of pneumonia or cardio-vascular events). However, in prespecified secondary analysis, the rate of FEV1 decline was reduced by ICS/ LABA therapy by 8 ml/per year (results almost identical to those seen in posthoc subgroup analysis of GOLD 2 patients in the UPLIFT study comparing tiotropium to

placebo). Real-world studies like Salford Lung Study are seldom. This study was randomized, open label, compar-ing once daily fluticasone furoate - vilanterol to usual care in an unrestricted COPD patient population recruited from clinics in Salford and South Manchester, a unique community served by a single hospital. The authors found, on more than 2700 patients, a lower rate of moderate and severe exacerbation by 8.4% over one-year peri-od, compared to usual care(13). In the fluticasone furo-ate/vilanterol arm of the study, 22% of the patients switched back to prior treatment, versus 11% in the usual care group, and the outcomes were influenced by bias introduced by the unblinded nature of the trial, and the reduction of exacerbation frecquency seen in the treat-ment arm may be due to once daily frequence of the medi-cation(1). It seems that this competition, LABA/LAMA versus ICS/LABA, remains open.

References

  1. ATS International Conference, Clinical Year in Review, 2017, p. 1-56.
  2. Wang Y., Liu K., Yang J. Li Z., Nie M. Dong Y., Huang H., Chen J. Impact of obstructive sleep apnea on severe asthma exacerbations. Sleep Med. 2016; 26,1-5.
  3. McEvoy R.D., Antic N.A., Heeley E., Luo Y., Ou Q., Zhang X., Mediano O., Chen R., Drager L.F., Liu G., Chen Z., Du B., McArdle N., Mukherjee S., Tripathi M., Billot L., Li Q., Lorenzi Filho G., Barbe F., Redline S., Wang J., Arima H., Neal B., White D.P., Grunstein R.R., Zhong N., Anderson C.S. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N. Engl. J. Med, 2016, 375, 919-31.
  4. Peker Y., Glantz H., Eulenburg C., Wegscheider K., Herlitz J., Thunstrom E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea, The RICCADSA randomised controlled trial, Am J. Respir. Crit. Care Med.,2016,194(5), 613-20.
  5. Javaheri S., Blackwell T. Ancoli-Israel S., Ensrud K.E., Stone K.L., Redline S. Sleep disordered breathing an incident heart failure in older men, Am. J. Respir. Crit. Care Med., 2016, 193, 561-8.
  6. Constanzo R., Ponikowski J., Javaheri S., Augostini R., Goldberg L., Holcomb R., Kao A., Khayat R.N., Oldenburg O., Stellbrink C., Abraham W.T. Transvenous neurostimulation for central sleep apnoes, A randomised controlled trial, Lancet 2016, 388, 974-82.
  7. Facco F.L., Parker C.B., Reddy U.M., Silver R.M., Koch M.A., Louis J.M., Basner R.C., Chung J.H., Nhan-Chang C.L., Pien G.W., Redline S., Brobman W.A., Wing D.A., Simhan H.N., Haas D.M., Mercer B.M., Parry S., Mobley D., Hunter S., Saade G.R., Shubert F.P., Zee P.C. Association between sleep disordered breathing and hypertensive disorders of pregnancy and gestational diabetes mellitus. Obstetrics abd gynecology 2017, 129, 31-41.
  8. Siu AL., Bibbins-Domingo K., Grossman D.C., Davidson K.W., Epling J.W., Garcia F.A., Gillman M., Kemper A.R., Krist A.H., Kurth A.E., Landefeld C.S., Mangione C.M., Harper D.M., Phillips W.R., Phipps M.G., Pignone M.P. Screening for chronic obstructive pulmonary disease: US Preventive Services Task Force Recommendation Statement. JAMA 2016, 315, 1372-7.
  9. Woodruff P.G., Barr R.G., Bleecker E., Christenson S.A., Couper D., Curtis J.L., Gouskova N.A., Hansel N.N., Hoffman E.A., Anner R.E., Kleerup E., Lazarus S.C., Martinez F.J., Paine R., Rennard S., Taskin D.P., Han M.K. for the SPIROMICS Research Group. Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function, N. Engl. J. Med. 2016, 374,1811-21.
  10. Long-Term Oxygen Treatment Trial Research Group. A randomized trial of Long Term Oxygen for COPD with moderate desaturation, N. Engl. J. Med. 2016, 375(17), 1617-26.
  11. Wedzicha J.A., Banerji D., Chapman K.R., Vestbo J., Roche N., Ayers R.T., Thach C., Fogel R., Patalano F., Vogelmeier C.F., for the Falme Investigators. Indacaterol-Glycopyrronium versus Salmeterol-Fluticason in COPD, N. Engl. J. Med 2016, 374, 2222-34.
  12. Vestbo J., Anderson J.A., Brook R.D., Calverley P.M., Celli B.R., Crim C., Martinez F., Yates J., Newby D.E. for the SUMMIT Investigators. Fluticaone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial-Lancet 2016,387,1817-26.
  13. Vestbo J., Leather D., Diar Bakerly N., New J., Gibson J.M., McCorkindale S., Collier S., Crawford J., Frith L., Harvey C., Svedsater H., Woodcock A. for the Salford Lung Study Investigators. Effectivenes of Fluticasone Furoate – Vilanterol for COPD in Clinical Practice, N. Engl J. Med 2016, 375, 1253-60.

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