Pulmonary Year in Review

Transcription

1 Pulmonary Year in Review Rachel Givelber, MD University of Pittsburgh SOM Pulmonary, Allergy, Critical Care and Sleep Medicine Rachel Givelber, MD Assistant Professor of Medicine PACCM, UPSOM

2 Disclosures No financial disclosures Firm fixed belief that clinical trials are helpful in the practice of medicine Longstanding desire that all physicians consider how study design and patient selection criteria impact their ability to use clinical trial data

3 Smoking Cessation

4 Smoking Cessation Smoking Cessation Smoking is still highly prevalent High school: 24.6% 9.2% cigarettes 13.4% e-cigarettes 9.4% hookah Adults: 21.3% (17.8 cigarettes) Leading cause of preventable death: 480, million $ in health care/productivity loss US PHS Office of Surgeon General, 2014 MMWR 2015

5 Smoking Cessation Survival Probabilities Current versus Never Smokers Women Never Smoker Men Never Smoker Current Smoker 11 yr Current Smoker 12 yr Jha P et al. N Engl J Med 2013;368:

6 Smoking Cessation Nicotine Patch vs. Varenicline vs. Combination Nicotine Replacement Therapy 3-arm unblinded randomized trial 12 weeks of open-label pharmacotherapy All groups offered 6 counseling sessions 26 week abstinence (4, 12, 52 weeks) 1086 subjects 15% from cohort study of smokers 85% from community Baker et al. JAMA 2016;315:

7 Smoking Cessation Nicotine, Varenicline, C-NRT Inclusion Criteria > 5 cigarettes (mean 17) Serious psych or medical disease No e-cigarettes or burpropion Patient Characteristics 67% white, 28% black Mean age 48 years 52% women Baker et al. JAMA 2016;315:

8 Smoking Cessation Patch, Varenicline, C-NRT Mix of in-person and telephone calls Abstinence confirmed by exhaled CO levels Initial Abstinence Patch Varenicline C-NRT 73% 68.2% 80.5% 26 weeks 22.8% 23.6% 26.8% 52 weeks (84% f/u) 20.8% 19.1% 20.2% Baker et al. JAMA 2016;315:

9 Smoking Cessation Patch, Varenicline, C-NRT Varenicline and C-NRT reduced cravings and withdrawal symptoms more. Varenicline: more insomnia, sleepiness, vivid dreams and nausea Patch and C-NRT: more itching / hives Baker et al. JAMA 2016;315:

10 Smoking Cessation Conclusions: Patch, Varenicline, C-NRT No significant differences between 3 arms Quit rates were lower than in prior RCT and meta-analyses Efficacy study your mileage may vary Baker et al. JAMA 2016;315:

11 Smoking Cessation Gradual vs. Abrupt Smoking Cessation Randomized controlled non-inferiority trial Abrupt vs. cutting down by 75% over 2 weeks Behavioral support by nurses Nicotine replacement (patch plus short-acting ) 697 patients, primary care clinics in England 4 week abstinence (26-week) Lindson-Hawley et al. Ann Intern Med 2016;164:

12 Non-Inferiority Trial Randomized, controlled trial designed to show new treatment is NO WORSE than standard therapy New therapy: cheaper, less toxic, easier Standard therapy: previously superior to placebo Caution in design and interpretation Margin of acceptable difference is key Sloppy or small study favors non-inferiority Intention to treat and per-protocol analysis

13 Non-Inferiority Trial Schumi and Wittes. Trials 2011;12: 106

14 Smoking Cessation Gradual vs. Abrupt Smoking Cessation Inclusion Criteria > 15 cigarettes/day (median 20) Quit Date: 2 weeks after enrollment Gradual: cut in half each week Abrupt: identify difficult times of day Patient characteristics Mean age 49 years 50% women 94% white 51% preference for gradual cessation Lindson-Hawley et al. Ann Intern Med 2016;164:

15 Smoking Cessation Gradual vs. Abrupt Smoking Cessation Abrupt: Superior quit rates Smokers who preferred abrupt cessation had higher quit rates, irrespective of group 4-week abstinence 26-week abstinence Gradual Abrupt 39.2% 49% Not non-inferior 15.5% 22% Non-inferior Superior Lindson-Hawley et al. Ann Intern Med 2016;164:

16 Smoking Cessation Smoking Cessation Conclusions Remains a major public and individual health hazard Quit rates low ~ 22% at 6 months with any pharmacotherapy Abrupt strategy preferable E-cigarettes associated with lower quit rates Meta-analysis, Lancet Resp Med 2016; 4:

17 COPD Management COPD 3 rd most common cause of death in US > 50 billion $ in costs in 2010 Exacerbations predict adverse outcomes Loss of lung function Decline in QOL Hospitalization Mortality Exacerbation: inclusion criteria and outcome of clinical trials

18 COPD Management COPD Practice Guidelines: Global Initiative for Chronic Obstructive Lung Disease (GOLD) Long Acting Beta Agonist (LABA) + inhaled corticosteroid (ICS) Long Acting Muscarinic Agonist (LAMA) Newer delivery devices and combination therapies Fewer puffs Breath activated

19 COPD Management FLAME Trial: LABA + LAMA vs. LABA + ICS 1 year randomized, placebo controlled noninferiority trial Indacaterol-glycopyrronium qd vs. salmeterolfluticasone BID Multicenter, multinational Funded and designed by Novartis Annual rate of COPD exacerbations Wedzicha et al. NEJM 2016;374:

20 COPD Management FLAME Trial Inclusion criteria FEV % predicted, FEV 1 / FVC < mild or severe exacerbation in 1 year steroids and/or antibiotics, ± hospitalization Non-inferiority margin: 15% Correspond to RR 0.86 c/w placebo Modified intention-to-treat Randomized, one-dose of drug, no major protocol violations before unblinding Efficacy analyses while on therapy Wedzicha et al. NEJM 2016;374:

21 COPD Management FLAME Trial 5328 Screened 4942 Run-in 3362 Randomized 1680 LABA-LAMA 1682 LABA-ICS wks wks 1675 Mod ITT 1528 per-protocol 1679 Mod ITT 1556 per-protocol Wedzicha et al. NEJM 2016;374:

22 COPD Management FLAME Trial Characteristic LABA-LAMA LABA-ICS Age, yr 64.6 ± ± 7.7 Male sex, % Current smoker ICS at screening, % FEV1, % predicted 44.0 ± ± 9.4 Wedzicha et al. NEJM 2016;374:

23 COPD Management FLAME Trial: Results Wedzicha et al. NEJM 2016;374:

24 COPD Management FLAME Trial: Results Wedzicha et al. NEJM 2016;374:

25 COPD Management FLAME Trial: Results No baseline patient characteristics predicted response Similar adverse events: 19% serious Less pneumonia with LAMA (3.2 vs 4.8, p = 0.02) 24 deaths (1.4%) in each group No indication that withdrawal from ICS led to higher exacerbations Wedzicha et al. NEJM 2016;374:

26 COPD Management FLAME Trial: Caveats In US indacaterol-glycopyrronium is approved at lower dose BID (qd in this trial) Overall high rates of exacerbation (electronic diary), favors non-inferiority Pharmaceutical designed and funded Wedzicha et al. NEJM 2016;374:

27 COPD Management Effectiveness of Fluticasone Furoate- Vilanterol in Clinical Practice Efficacy: clinical trial Strict entrance criteria Close monitoring Effectiveness: real world More representative Closer to usual practice Randomized controlled trial Moderate or severe exacerbations in 1 year Vestbo et al. NEJM 2016;375:

28 COPD Management Effectiveness of Fluticasone Furoate-Vilanterol Salford, England: one hospital and EHR 75 general practices Inclusion criteria Age > 40 COPD, 1 or more exacerbations in 3 years Inhaler therapy (LABA, ICS, LAMA) No spirometry requirements Exclusion criteria: oral glucocorticoids, exacerbation w/in 2 weeks Vestbo et al. NEJM 2016;375:

29 COPD Management Effectiveness of Fluticasone Furoate-Vilanterol Randomized: FF-V vs. continue usual care Stratified by exacerbation in 1 year If on triple therapy, continued LAMA No extra visits Called at 3, 6, 9 months Clinic at 12 months Outcomes assessed from EHR, verified by GP or research staff Sponsored by GSK, designed collaboratively Vestbo et al. NEJM 2016;375:

30 COPD Management LABA-ICS vs Usual Care 3161 Screened 2799 Randomized 1403 Usual Care 1396 LABA-ICS 1309 Completed 1291 Completed 1056 Completed 1051 Completed Primary Effectiveness Wedzicha et al. NEJM 2016;374:

31 COPD Management LABA-ICS vs Usual Care Characteristic Usual Care N = 1403 FF-V N = 1396 Age, yr 67 ± ± 10 Female sex, % Current smoker Coexisting Condition, % Any Cardiac Vascular Diabetes Vestbo et al. NEJM 2016;375:

32 COPD Management Effectiveness of Fluticasone Furoate-Vilanterol Therapy at Baseline LABA, LAMA, both ICS, ICS + LABA, ICS + LAMA Triple therapy Vestbo et al. NEJM 2016;375:

33 COPD Management Effectiveness of Fluticasone Furoate-Vilanterol Vestbo et al. NEJM 2016;375:

34 COPD Management Effectiveness of Fluticasone Furoate-Vilanterol Moderate-severe exacerbations in entire trial 1.5/year in FF-V, 1.64 in usual care Tolearability: FF-V, 24% changed meds, 4% for worse control Usual Care, 11% changed meds, 8% for worse control No differences in hospitalization, contact with medical system, safety Vestbo et al. NEJM 2016;375:

35 COPD Management COPD Summary Endobrochial Coiling does not improve exercise tolerance and is associated with excess pneumonia (data not shown) Many new inhalers on the market Once daily dosing Breath activated With or without capsule Patient education remains crucial

36 COPD Management COPD Summary LABA-LAMA combination appears as safe as LABA-ICS and more efficacious Once daily inhaler used in trial not available in US LABA-ICS superior to usual care in novel EFFECTIVENESS trial These medications remain unaffordable for many patients

37 OSA and CVD Obstructive Sleep Apnea and CV disease Vulnerable Airway Ventilatory Control OSA: breathing cessation desaturation/resaturation sleep fragmentation sympathetic outflow Stroke Hypertension?? MECHANISMS?? Congestive Heart Failure Glucose Intolerance

38 OSA and CVD Obstructive Sleep Apnea and CV disease CPAP improves CV risk factors in RCT Blood pressure Endothelial function Insulin sensitivity CPAP associated with improved outcomes in observational studies Mortality CV complications Dose response effect

39 OSA and CVD Sleep Apnea Cardiovascular Endpoints (SAVE) Multicenter, randomized, open label Patients with OSA and CVD Secondary prevention CPAP + usual care vs. usual care alone Blinded outcome assessment Composite endpoint death from CVD, MI, stroke, hospitalization for angina, CHF or TIA Funded by Australian NHMRC and Philips Respironics McEvoy et al. NEJM 2016;375:

40 OSA and CVD Sleep Apnea Cardiovascular Endpoints (SAVE) Inclusion Criteria Age Moderate to severe OSA, RDI > 12 CAD, cerebrovascular disease Excluded Severe sleepiness Severe hypoxemia (<80% for 10% of recording) Cheyne-Stokes respiration Use of sham CPAP < 3h during 1 week run-in McEvoy et al. NEJM 2016;375:

41 OSA and CVD SAVE Trial 15,325 assessed 5844 eligible before sleep testing 3246 entered run-in 2717 randomized 1359 CPAP + usual care 1284 followed 4 years 1358 usual care 1256 followed 4 years McEvoy et al. NEJM 2016;375:

42 OSA and CVD SAVE Trial Characteristic CPAP Group N = 1346 Usual Care N = 1341 Age, yr 61 ± ± 7.9 Male sex, % Race Asian/white/other 64/24/11 63/25/12 BMI, kg/m ± ± 4.4 CAD/CVD, % 51/49 51/49 Diabetes, % Oxygen desaturation index 28.1 ± ± 13.5 Epworth 7.3 ± ± 3.6 McEvoy et al. NEJM 2016;375:

43 OSA and CVD SAVE Trial CPAP adherence Run-in 5.2 h First month 4.4 h 12-months 3.5 h No differences between groups in medications, smoking, weight during study McEvoy et al. NEJM 2016;375:

44 OSA and CVD SAVE Trial McEvoy et al. NEJM 2016;375:

45 OSA and CVD SAVE Trial CPAP associated with Less sleepiness Improved health-related QOL Mood Attendance at work Hint that more adherent patients had some benefit in CVD: Hazard ratio 0.80 ( , p=0.13) McEvoy et al. NEJM 2016;375: