Can We Impact on COPD?

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1 Can We Impact on COPD? Dr. Roland Leung Specialist in Respiratory Medicine MBBS MD FRACP FCCP FHKCP FHKAM(Med)

2 Hot Off the Press The Burden of Lung Disease Project Organizers: Sponsor: Hong Kong Thoracic Society American College of Chest Physicians (HK & Macau Chapter) Hong Kong Lung Foundation

3 The Significant Findings In 2005, respiratory disease was ranked as the top cause of mortality and hospitalization in Hong Kong. Respiratory diseases accounted for 16% of all inpatient bed-days. Although there has been a slow decline in respiratory mortality rate in the past decade, there has been no change in respiratory hospitalization rates. Respiratory diseases, therefore, have accounted for the largest share of the health-care burden locally.

4 Hong Kong: Mortality & In-Patient Days 30.0% 28.7% 26.1% 25.0% Percentage 20.0% 15.0% 16.0% 11.6% 10.0% 5.0% 0.0% Mortality In-Patient Days Repiratory Diseases 28.7% 16.0% Cardiovascular Diseases 26.1% 11.6%

5 Mortality of Respiratory Diseases In 2005, deaths due to Respiratory Diseases (163/ ) Overall Male Female Respiratory Infection Respiratory Caner COPD

6 Respiratory Diseases in 2005 In-patient % of Resp Diseases Mortality Hospitalization bed days Respiratory infection Lung Cancer COPD Tuberculosis Bronchiectasis Asthma Pneumoconiosis OSA Others

7 COPD No. 2 No.2 in Hospitalization (14.6%) No.3 in Respiratory Death (17.9%) Rate of Mortality & Hospitalization from Correlated with Rate of Smoking since 1980 Male 32% to 15%, female 3% to 4% Better Treatment of COPD COPD still under-diagnosed Lung Function study: (Ip et al) 24.9% smokers had COPD 12.8% Stage II or above

8 1. World Health Organization. COPD: burden. ( 2. World Health Organization. Asthma: scope. ( 3. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report ( COPD is a growing burden to society and patients 1 COPD is estimated to cause almost 3 million deaths per year, 15 times more than are caused by asthma. 1,2 Of all the major chronic diseases, COPD is the only one with an increasing death rate. 3

9 COPD is a growing burden to society and patients 1 By 2020, COPD is expected to be the third largest cause of chronic disease mortality worldwide. 2 Leading causes of mortality and disability 2 1. World Health Organization. COPD: burden. ( 2. Murray CJL, Lopez AD. Lancet 1997; 349:

10 慢阻肺病之死亡率比糖尿病高 3 倍比乳癌高 6 倍比哮喘高 11 倍 10

11 慢阻肺病在香港發病率極高較中國大陸更嚴重慢阻肺病在亞洲地區的發病率僅次日本 : 中國大陸香港日本南韓台灣泰國發病率 8.2% 8.9% 10.9% 7.8% 2.5% 7.1% 11

12 慢阻肺病之健康推廣宣傳嚴重不足慢阻肺病與其他慢性疾病的健康教育項目比較 : 只及高血壓的 10% 只及哮喘的 7% 只及糖尿病的 4% 只及乳癌的 3% 哮喘乳癌慢阻肺病糖尿病高血壓健康推廣宣傳 6,019 14, ,395 4,479 (2006 年 8 月 30 日至 2007 年 8 月 30 日, 在世界疾病認知推廣月份的報導文章數目 ) 12

13 SCMP 17-Nov-08

14 AM Nov-08

15 What are the PROBLEMS IN COPD that clinicians are faced with? Symptoms Quality of Life Exacerbations Health care utilisation hospitalisation Mortality Lung function decline

16 Prospective RCTs in COPD TORCH INSPIRE UPLIFT Objective To investigate the longterm effects of Salm/FP 50/500 µg BID, Salm50 µg BID and FP 500 µg on the survival of subjects over 3 years To compare the effectiveness of Salm/FP 50/500 with Tiotropium in reducing the rate of moderate and/or severe exacerbation in subjects with severe to very severe COPD To determine whether treatment with tiotropium 18 µg daily reduces the rate of decline of FEV 1 over time in patients with COPD Duration 3 years 2 years 4 years Patient Numbers 6,112 1,323 5,993 Treatment (a) Salm/FP 50/500 BID (b) FP 500 BID (c) Salm 50 BID (d) Placebo (a) Salm/FP 50/500 BID (b) Tiotropium 18 µg (a) Tiotropium 18 µg (b) Placebo + Usual Care

17 Primary Endpoint Secondary Endpoint TORCH All-cause mortality in the 3 years postrandomization amongst all subjects randomized to treatment Rate of moderate COPD exacerbation and severe COPD exacerbation Effects on HRQoL COPD related mortality On treatment mortality Severe COPD exacerbation/ltot/on treatment mortality Clinic post-bronchodilator FEV 1 No. of withdrawals from treatment Health status using EQ- 5D / SGRQ Healthcare resource utilisation INSPIRE Rate of *healthcare Utilisation(HCU) COPD Exacerbations over 2 years * defined as treatment with oral corticosteroids, antibiotics or hospitalisation The yearly rate of decline in FEV 1 (trough and post-dose) from steady state until end of the treatment period (4 years) Rate of COPD exacerbation requiring OCC/antibiotics Time to first/each/next HCU exacerbation Post-dose FEV 1 (2h after) Effects on HRQoL Rate of symptom-defined exacerbations Time to first/each/next symptom-defined exacerbation Difference in rate of HCU and symptom-defined exacerbations Time to withdrawal UPLIFT The yearly rate of decline in FEV 1 (trough and post-dose) from steady state until after 1 month off treatment Rate of decline in FEV 1 after 1 month Rate of decline of FVC and SVC HRQoL St. George s Respiratory Questionnaire Exacerbations Hospitalizations due to exacerbations Mortality (respiratory and allcause) Tertiary Lung function decline over the 3-years Mortality

18 When do patients present? Lung function deterioration without symptoms Symptoms generally develop only after a significant drop in FEV 1 (to less than 50%) has occurred Severe FEV 1 (%of predicted) Asymptomatic Lung function normal Lung function reduced Axis of progression Symptoms Mild 1. Sutherland ER et al. N Eng J Med 2004; 350 (26):

COPD Relax bronchial airways smooth muscle and

19 Bronchodilators in Stable COPD Bronchodilator medications are central to symptom management in COPD Relax bronchial airways smooth muscle and expand bronchial air passages Inhaled therapy is preferred

20 Naïve COPD patients: trough FEV 1 response over 1 year Tiotropium (n=119) Placebo (n=78) Difference from baseline (L) * * * -0.1 Day 1 Day 8 Day 92 Day 344 *P<0.001 versus placebo Adams, Anzueto and Kesten. Resp. Med 2006

21 Naïve COPD patients: dyspnea score response over 1 Year 2.0 Tiotropium (n=113) Placebo (n=76) TDI Focal score * * * *P<0.05 versus placebo Adams, Anzueto and Kesten. Resp. Med Day

22 Naïve COPD patients: SGRQ over 1 year Tiotropium (n=120) Placebo (n=77) 0 Difference from baseline in SGRQ Total score Improvement * 344 Day *P<0.05 versus placebo Adams, Anzueto and Kesten. Resp. Med 2006

23 Casaburi, et al Chest 2005 SPIRIVA demonstrates superior improvements in breathlessness post rehab Combined rehab with SPIRIVA results in extended, superior outcomes in breathlessness compared with rehab alone

25 Co-Primary Endpoints Co-primary endpoints: Yearly rate of decline in trough (pre-bronchodilator) FEV 1 from steady state until end of the treatment period Yearly rate of decline in FEV 1 measured 90 minutes after inhalation of study drug and ipratropium (30 minutes after inhalation of salbutamol) from steady state until end of the treatment period

26 Secondary Endpoints Key Secondary Endpoints Time to 1 st exacerbation Time to 1 st hospitalization Other Secondary endpoints FEV 1, FVC, and SVC at all time points Decline in FVC and SVC COPD exacerbations & related hospitalizations HRQoL (St. George s Respiratory Questionnaire) Mortality (all cause, lower respiratory) On-treatment On-treatment + vital status follow-up

27 Vital status Study Design Run in Treatment period 2 weeks 4 years (48 month) 30 days follow-up Tiotropium qd All previously prescribed respiratory medications permitted (except inhaled anticholinergics) Stop: Tiotropium qd Start: Ipratropium qid Placebo qd Screening Day 1 Randomization Day 30 Every 6 months 4 years End of trial End of follow up Spirometry Spirometry + SGRQ Spirometry Spirometry + SGRQ Spirometry + SGRQ Spirometry

28 Clinic Visit Spirometry Pre dose Spirometry Ipratropium (total: 80 µg) Salbutamol (total 400 µg) Post dose Spirometry Day 1, Randomization 1 hour 30 min Time Maximizing bronchodilation Study drug Pre dose followed by Spirometry Ipratropium Salbutamol Post dose Spirometry 1 hour 30 min Day 30 and every 6 months during 4 year study Time

29 Worldwide Distribution of UPLIFT Study Centers Argentina France Lithuania Portugal Taiwan Australia Germany Malaysia Russia Thailand Austria Greece Mexico Singapore Turkey Belgium Hong Kong Netherlands Slovakia United Kingdom Brazil Hungary New Zealand Slovenia US Czech Republic Ireland Norway South Africa Denmark Italy Philippines Spain Finland Japan Poland Switzerland

30 Baseline Characteristics Characteristic Tiotropium (n = 2986) Control (n = 3006) Male (%) Age (yrs)* 64.5 ± ± 8.5 Body Mass Index* 26.0 ± ± 5.1 Smoking status Current smoker (%) Smoking history (pack-yrs)* 49.0 ± ± 27.9 Duration of COPD (yrs)* 9.9 ± ± 7.4 GOLD stage (II / III / IV) (%) 46 / 44 / 8 45 / 44 / 9 SGRQ total score (units)* 45.7 ± ± 17.2 *Mean±SD

31 Baseline Spirometry Pre-Bronchodilator Post-Bronchodilator Tiotropium (n = 2986) Control (n = 3006) Tiotropium (n = 2986) Control (n = 3006) FEV 1 (L) 1.10 ± ± ± ± 0.44 FEV 1 (% predicted) 39.5 ± ± ± ± 12.6 FVC (L) 2.63 ± ± ± ± 0.90 FEV 1 /FVC 42.4 ± ± ± ± 10.7 SVC 2.80 ± ± ± ± 0.90 Mean±SD

32 Baseline and On Treatment + Respiratory Medications Medication (% of patients) Baseline Tiotropium (n = 2986) On Treatment + Baseline Control (n = 3006) On Treatment + Any respiratory medication Short-acting anticholinergic Short-acting beta-agonist Long-acting beta-agonist* Inhaled steroid* Theophylline Systemic steroids Mucolytics Leukotriene receptor antagonists Supplemental O at any time during treatment, incl. short-term treatment of exacerbations *Used alone or in combination

33 Pre- and Post-bronchodilator FEV 1 Mean values at each time point FEV 1 (L) * * * * * * * * Tiotropium Control * * * * * * * * * * (n=2516) (n=2374) (n=2494) Post-Bronch FEV 1 = ml 1.00 (n=2363) Pre-Bronch FEV 1 = ml Day 30 (steady state) Month *P< vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV 1 (observed mean) = (trough), (peak). Patients with 3 acceptable PFTs after day 30 were included in the analysis.

34 COPD has a significant impact on patients everyday activities Percentages of patients who have daily activities affected by COPD World Health Organization. COPD: burden. ( 2. Rennard S, et al. EurRespirJ 2002; 20:

35 SGRQ Total Score Mean values at each time point Improvement SGRQ Total Score (Units) * * Tiotropium (n = 2478) Control (n = 2337) * * * * * * SGRQ Total Score = 2.3 units Month *P< vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline SGRQ Total Score (observed mean) = Patients with 2 acceptable SGRQ Total Scores after month 6 were included in the analysis.

36 Percentage of Patients With 4-Unit Improvement in SGRQ Total Score* Patients (%) Tiotropium Control year 2 years 3 years 4 years All p-values <0.001; *compared to Day 1

37 Increased frequency of COPD exacerbations are related to increased disease progression Donaldson GC et al. Thorax 2002; 57: Seemungal TAR et al. Am J Respir Crit Care Med 1998; 157: Spencer S et al. Eur Respir J 2004; 23:

38 COPD exacerbations are related to an increased risk of mortality 1-5 Outcomes of COPD exacerbations in various patient groups 6-9 Up to 43% of COPD patients die within 1 year of an exacerbationrelated hospital admission Seemungal TAR et al. Am J Respir Crit Care Med 1998; 157: Spencer S et al. Eur Respir J 2004; 23: Groenewegen KH et al. Chest 2003; 124: Connors AF et al. Am J Respir Crit Care Med 1996; 154(4): Soler-Cataluna JJ et al. Thorax 2005; 60: Seneff MG et al. JAMA 1995; 274: Murata GH et al. Ann Emerg Med 1991; 20: Adams SG et al. Chest 2000; 117: Patil SP et al. Arch Intern Med 2003; 163:

39 Probability of COPD Exacerbation Probability of exacerbation (%) Tiotropium Control Hazard ratio = 0.86, (95% CI, 0.81, 0.91) p < (log-rank test) Month

40 Exacerbations Tiotropium Mean (SE) Control Mean (SE) Risk Ratio 95% CI P-value # exacerbations per patient-year # exacerbation days per patientyear 0.73 (0.02) 0.85 (0.02) , 0.91 < (0.32) 13.6 (0.35) , 0.95 < Hazard ratio was estimated using Cox regression. Log-rank test was used for p-value. Wald statistics was used for CI. Randomized patients taking 1 dose of study medication were included in the analysis. Number of exacerbations per patient year and the ratio between tiotropium and placebo were estimated using Poisson regression corrected for treatment exposure and overdispersion. Randomized patients with 1 dose of study medication were included in the analysis.

41 Reduced Mortality with Tiotropium On-Treatment 20 Probability of death from any cause (%) % Reduction in Risk Hazard ratio = 0.84, (95% CI, 0.73, 0.97) P=0.016 (log-rank test) Months Tiotropium Control

42 Reduced Risk of Mortality On treatment Protocol-Defined End of Treatment (Day 1440) 30-Day Follow-Up Period (Day 1470)* 16% Reduced risk of mortality P= % Reduced risk of mortality P= % Reduced risk of mortality P=0.086 NS On-treatment analysis Intention-to-treat analyses 16% lower mortality risk with tiotropium while patients received study medication Effect extended to end of treatment period (day 1440), as defined by protocol Effect became non-significant within the 30-day follow-up period (day 1470), when according to protocol, patients were discontinued from their study medication

43 TORCH: study design TORCH (TOwards a Revolution in COPD Health) is a landmark study investigating the effectiveness of SFC on all-cause mortality, that included over 6000 patients 2 week run-in SFC 50/500 mcg Fluticasone propionate 500 mcg Salmeterol 50 mcg Placebo group n=1,533 n=1,534 n=1,521 n=1, Calverley PMA et al. New Eng J Med 2007; 356:

44 1. Calverley PMA et al. New Engl J Med 2007; 356 (8): Seretide may improve patient survival 1 Comparison of death rate over 3 years with Seretide and placebo 1 In the TORCH study, Seretide reduced the risk of death by 17.5% over three years compared with placebo although this missed statistical significance (p=0.052)

45 IMPACT OF SMOKING CESSATION PROGRAMME ON MORTALITY FROM THE LUNG HEALTH STUDY (LHS) Proportion of patients with no event 1.00 Special intervention group Usual care group % Time since LHS baseline (years) Anthonisen et al. Ann Intern Med 2005

46 The magnitude of the mortality reduction is comparable to other interventions In COPD smoking cessation programs reduce mortality by 15% at 15 years Effect of statins on all-cause mortality in patients with coronary heart disease Meta-analysis of 17 trials n = 40,974 Mean/median follow up years Relative Risk Reduction = 16% Absolute Risk Reduction = 1.8% 1. Anthonisen NR, Skeans MA, Wise RA, et al. Ann Intern Med 2005; 142: Wilt et al. Arch Intern Med 2004; 164:

47 NATURAL HISTORY OF COPD FEV 1 (% of value at age 25) Smoked regularly and susceptible to its effects Disability Death Age (years) Never smoked or not susceptible to smoke Stopped at 45 Stopped at 65 Fletcher et al., 1977

48 Pre- and Post-bronchodilator FEV 1 Mean values at each time point FEV 1 (L) * * * * * * * * Tiotropium Control * * * * * * * * * * (n=2516) (n=2374) (n=2494) Post-Bronch FEV 1 = ml 1.00 (n=2363) Pre-Bronch FEV 1 = ml Day 30 (steady state) Month *P< vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV 1 (observed mean) = (trough), (peak). Patients with 3 acceptable PFTs after day 30 were included in the analysis.

49 Rate of Decline in FEV 1 Mean slope from day 30 until completion of double-blind treatment treated set with 3 post-randomization measurements Tiotropium (ml/yr) Control (ml/yr) Tio - Con P-value* n Mean (SE) n Mean (SE) Mean (SE) Pre-bronch (1) (1) 0 (2) 0.95 Post-bronch (1) (1) 2 (2) 0.20 *unadjusted p-value

50 Rate of Decline in FEV 1 by GOLD Stage Post-bronchodilator FEV 1 GOLD Stage Tiotropium (ml/yr) Control (ml/yr) Tio - Con P-value n Mean (SE) n Mean (SE) Mean (SE) II (2) (2) 6 (3) 0.02 III (2) (2) 0 (3) 0.87 IV (5) (5) -9 (7) 0.24 P-value for subgroup by treatment interaction = 0.07

51 Rate of Decline in FEV 1 No Baseline LABA or ICS Mean slope from day 30 until completion of double-blind treatment treated set with 3 post-randomization measurements Tiotropium (ml/yr) Control (ml/yr) P-value n Mean (SE) n Mean (SE) Pre-bronch (2) (3) Post-bronch (3) (3) 0.048

52 Annual Decline in Post-Bronchodilator FEV 1 in Major Long Term COPD Trials Study (Duration) (order: year of publication) Current smokers Baseline FEV 1 % predicted Study drug Study drug Annual decline in FEV 1 (ml/year) Placebo only Placebo*+ EUROSCOP (3 years) 100% ~ 79% Budesonide ISOLDE (3 years) 36 39% ~ 50% Fluticasone LHS II (3.3 years) 90% ~ 68% Triamcinolone BRONCUS (3 years) 41-51% ~ 57% NAC TORCH (3 years) post hoc analysis 43% ~ 48% S / F / SFC 42 / 42 / UPLIFT (3 years) 30% ~ 47% Tiotropium UPLIFT (4 years) 30% ~ 47% Tiotropium * All respiratory medications permitted throughout the trial, other than inhaled anticholinergics

53 Most Common Adverse Events (>3%) Incidence Rate*: tiotropium>control Tiotropium n=2986 Control n=3006 Rate Ratio (Tio/Con) 95 % CI Abdominal pain , 1.43 Arthralgia , 1.62 Benign Prostatic Hyperplasia , 1.54 Constipation , 1.61 Cough , 1.24 Depression , 1.62 Diarrhoea , 1.33 Dizziness , 1.58 Headache , 1.47 Insomnia , 1.75 Mouth dry , 2.36 Nasopharyngitis , 1.24 Oedema , 1.31 Sinusitis , 1.39 Urinary tract infections , 1.28 *per 100 patient years

54 Stroke N with Event Tiotropium (n = 2986) Rate / 100 pt-yrs N with event Control (n = 3006) Rate / 100 pt-yrs Risk Ratio Tio/Con 95% CI Adverse Event , 1.29 Serious adverse Event , 1.37 Fatal (on treatment) , 2.05 Fatal (on-treatment, adjudicated) , 1.87 Fatal (vital status, day 1470) , 1.66 Rate per 100 person-years of time at risk to tiotropium or control

55 Myocardial Infarction N with Event Tiotropium (n = 2986) Rate / 100 pt-yrs Control (n = 3006) N with event Rate / 100 pt-yrs Risk Ratio Tio/Con 95% CI Adverse Event , 1.00 Serious Adverse Event , 0.99 Fatal (on treatment) , 1.15 Fatal (on-treatment, adjudicated) , 2.69 Fatal (vital status, day 1470, adjudicated) , 2.30 Rate per 100 person-years of time at risk to tiotropium or control

56 SAE Incidence (per 100 pt-yrs) Reported By >1% in Any Treatment Group** Tiotropium n=2986 Control n=3006 Rate Ratio (Tio/Con) 95% CI Cardiac SOC , 0.98 * Angina , 2.26 Atrial fibrillation , 1.33 Cardiac failure , 1.87 Cardiac failure congestive , 0.96 * Coronary artery disease , 1.01 Myocardial infarction , 0.99 * Respiratory (lower) SOC , 0.92 * Bronchitis , 1.98 COPD exacerbation , 0.94 * Dyspnea , 0.94 * Pneumonia , 1.11 Respiratory failure , 0.92 * *p<0.05; **excluding lung cancer (multiple different terms)

57 Respiratory Failure Hazard ratio (95% CI) n Hazard Ratio Adverse Events (0.65, 0.999)* Serious Adverse Events Fatal Events UPLIFT 29 Trials UPLIFT (0.50, 1.27) (0.62, 0.98)* (0.41, 1.13) (0.48, 1.01) (0.16, 1.88) 29 Trials UPLIFT 29 Trials * p < 0.05 Tiotropium lower risk Control lower risk

58 Summary A Landmark 4-year COPD Trial (UPLIFT) proved that tiotropium have favourable impact on the clinical course of COPD through: Significantly sustained improvements in lung function ( ml, p<0.001) Significantly sustained improvement in health-related quality of life Significant reduction in the no. of exacerbations per patient year (14%, p<0.001) Significant reduction in mortality (16%, p=0.016)

59 Summary Evidence for reduced cardiac morbidity No increased risk for stroke or myocardial infarction Reduced lower respiratory morbidity Decreased risk for respiratory failure

60 GOLD Recommendations Rabe K et al GOLD 2007 Am J Respir Crit Care Med 2007; 176:

61 COPD AT THE TIPPING POINT Symptom control

62 COPD AT THE TIPPING POINT Preventing exacerbations Symptom control

63 COPD AT THE TIPPING POINT Reducing mortality Preventing exacerbations Symptom control