TORCH: and Propionate and Survival in COPD April 19, 2007 Justin Lee Pharmacy Resident University Health Network Outline Overview of COPD Pathophysiology Pharmacological Treatment Overview of the TORCH Trial Critical appraisal Discussion What is COPD? COPD is a respiratory disorder largely caused by smoking that is characterized by: progressive, partially reversible airway obstruction systemic manifestations increasing frequency and severity of exacerbations Pathophysiology Inflammation Small Airway Disease Parenchymal Destruction (Chronic Bronchitis) (Emphysema) Airway inflammation Loss of alveolar attachments Airway remodeling Decrease of elastic recoil Airway Obstruction O Donnell DE et al. Can Respir J 2003: 10(Suppl A): 11A-33A. Adapted from GOLD Guidelines 2006 Pharmacotherapy Principles Treatment Ladder Improve lung function Provide symptomatic relief With exception to smoking cessation, no intervention has been proven to: Slow disease progression Prevent mortality Stepwise increase in treatment based on degree of symptoms and airflow limitation O Donnell DE et al. Can Respir J 2003: 10(Suppl A): 11A-33A.
Pharmacotherapy Ideal vs. Actual (FEV 1 60-79%) (FEV 1 40-59%) (FEV 1 < 40%) Adapted from O Donnell DE et al. Can Respir J 2003: 10(Suppl A): 11A-33A. O Donnell DE et al. Can Respir J 2003: 10(4): 181-5. Unanswered Question Should regular treatment with long-acting bronchodilators and / or inhaled corticosteroids be initiated at an earlier stage of the disease? Inhaled Corticosteroid Debate Traditional School of Thought COPD is characterized by neutrophilic inflammation Asthma is characterized by eosinophilic inflammation Since ICS inhibit eosinophilic NOT neutrophilic inflammation, their use is different in COPD and asthma Recommended in mild to moderate asthma Reserved for moderate to severe COPD Inhaled Corticosteroid Debate Inhaled Corticosteroid Debate Chronic systemic inflammation may explain link between COPD and co-existing systemic disease Some retrospective and population-based cohort studies suggest ICS may have beneficial effects on: Frequency of exacerbations COPD-related mortality Cardiovascular disease and lung cancer mortality Rabe KF. N Engl J Med. 2007; 356: 851-4. Sin et al. Am J Respir Crit Care Med. 2001; 164: 580-4. Soriano et al. Eur Respir J. 2002; 20: 819-25. Sin et al. Thorax. 2005; 60: 992-7. ISOLDE study vs. placebo (3 yr) 751 COPD patients 40 to 75 years old FEV 1 < 50% of predicted No difference in rate of FEV 1 decline exacerbation frequency Slower in health status Trend towards improved survival on post-hoc analysis Burge PS et al. BMJ. 2000; 320: 1297-1303.
Inhaled Corticosteroid Debate Several RCTs have shown that use of ICS + LABA combinations (for up to 1 year) Reduced frequency of exacerbation Improved trough and peak FEV 1 Improved dyspnea Improved health status and QOL Mahler DA et al. Am J Respir Crit Care Med. 2002; 166: 1084-91. Hanania NA et al. Chest. 2003; 124: 834-43. Caverley PMA et al. Eur Respir J. 2003; 22: 912-9. Calverley PMA et al. Lancet. 2003; 361: 449-56. Anzueto AR et al. Chest. 2004: 126(Suppl): 808S. Towards a Revolution in COPD Health (TORCH) and Propionate and Survival in Trial Overview Calverly PMA, Anderson JA, Celli B et al. N Engl J Med 2007; 356: 775-89. Question Does the combination of salmeterol and fluticasone reduce mortality in COPD patients compared with placebo, salmeterol or fluticasone alone? Study Design Multi-national (42 countries) Multi-center (444 sites) Prospective Double-blinded -controlled Randomized Parallel-group Superiority trial Interventions 2 week run-in period All treatment with ICS or LABA was stopped Other COPD medications could continue Patients randomized to 4 treatment arms 50 µg + 500 µg BID 50 µg BID 500 µg BID Measures of Outcome Primary Endpoint Time to death from any cause up to 3 years Secondary Endpoints Frequency of exacerbations Health status Spirometric values
Inclusion Criteria Current or former smokers with 10-pack-year history 40-80 years old diagnosis of COPD pre-bronchodilator FEV 1 < 60% of predicted value FEV 1 increase with use of 400 µg albuterol < 10% of predicted value Pre-bronchodilator FEV 1 / FVC ratio 0.7 Exclusion Criteria Diagnosis of asthma, non-copd respiratory disorders Other conditions likely to interfere with the study or cause death within 3 years Previous lung-volume reduction surgery and/or lung transplantation A requirement for long-term ( 12 h per day) oxygen therapy Evidence of alcohol, drug or solvent abuse Known or suspected hypersensitivity to any of the study medications Known α-1 anti-trypsin deficiency Current use of oral corticosteroid therapy Received an investigational drug in previous 4 weeks Patients who had an exacerbation requiring systemic oral corticosteroid therapy and/or hospitalization during the run-in period Results Primary Endpoint Combination treatment with fluticasone and salmeterol failed to demonstrate a significant difference in the mortality rate of COPD patients over three years Results Secondary Endpoints Combo regimen significantly improved all secondary endpoints compared to placebo Annual rate of exacerbation Moderate or severe RR = 0.75 (95% CI 0.69-0.81, p < 0.001) Requiring systemic corticosteroids RR = 0.57 (95% CI 0.51-0.64, p < 0.001) Severe requiring hospitalization RR = 0.83 (95% CI 0.72-0.90, p = 0.03) Health status St. George s Respiratory Questionnaire = -3.1 (95% CI -4.1 to -2.1, p < 0.001) Spirometry Post-bronchodilator FEV 1 = 0.092 (95% CI 0.075 to 0.108, p < 0.001) Results - Safety COPD exacerbation was most common adverse event No significant differences in adverse events thought to be associated with the use of LABAs No significant differences in major adverse events thought to be associated with the use of ICS Bone mineral density Fracture rate Incidence of cataracts Are the results of the study valid? In patients receiving medications containing fluticasone, Expected candidiasis and dysphonia Unexpected pneumonia
Was the assignment of patients to treatments randomized? Yes - Computer allocation system randomized patients to one of four treatment arms using 1:1:1:1 ratio Treatment stratified according to country and smoking status Were all patients who entered the trial properly accounted for and attributed at its conclusion? Yes - 8554 recruited 2370 (27.7%) withdrew during run-in period 1638 did not meet inclusion criteria 6184 randomized to treatment 72 excluded from efficacy analysis 5 centres failed to meet standards for good clinical and ethical practice Inclusion of these patients did not change outcome in posthoc analysis Was follow-up complete? Yes - All patients were followed for 3 years from the start of treatment regardless of whether they continued to take the study medication Patient Enrollment and Completion 8554 Recruited 2370 (27.7%) During Run-In Period 6184 Randomized 72 (1.2%) Excluded - Unacceptable Research Practices 1524 1521 1534 + 1533 673 (44.2%) 561 (36.9%) 587 (38.3%) 522 (34.1%) 851 960 947 1011 Adapted from Calverly PMA et al. N Engl J Med 2007; 356: 775-89. Were patients analyzed in the groups to which they were randomized? In the placebo and fluticasone groups, # of randomized patients does not equal # of patients in safety population 1 patient in placebo group received fluticasone for more than half of the study period As per intention-to-treat, patient analyzed in: Efficacy population of the placebo group Safety population of the fluticasone group All randomized patients included in the safety analysis 72 patients excluded from efficacy analysis Why? 5 centres did not meet research standards Were patients, health workers, and study personnel blind to treatment? Yes patients and investigators were blinded Dosing schedule and inhaler devices were identical in each treatment arm Dry powder inhalation BID via Accuhaler device Independent blinded committee determined the primary cause of death and whether it was related to COPD
Were the groups similar at the start of the trial? Yes No significant differences were noted between treatment arms Population Characteristics 57 73 years old 75 % Males Various ethnic origins > 50% already on ICS Moderate to severe COPD Aside from the experimental intervention, were the groups treated equally? Yes - all patients were: Followed for 3 years regardless of whether they continued to take the study medication Allowed to continue any concomitant medication for COPD except for ICS, LABA and long-term oral steroids Offered salbutamol as reliever Seen q12wk to confirm vital status and record any adverse events Seen q24wk to assess health status and spirometry Was the study adequately powered to detect the primary endpoint? Controversial! Based on ISOLDE trial, TORCH assumed 17% mortality rate in placebo arm 1510 patients in each arm were required Powered to detect reduction in mortality of 4.3% (or ~25% relative reduction) in the combo group compared to placebo α = 0.05 with 90% power In the TORCH trial, Mortality rate in the placebo arm was only 15.2% Sample size was increased after 2 years of enrolment Patient Enrollment and Completion 8554 Recruited 2370 (27.7%) During Run-In Period 6184 Randomized 72 (1.2%) Excluded - Unacceptable Research Practices + 1524 1521 1534 1533 673 (44.2%) 561 (36.9%) 587 (38.3%) 522 (34.1%) 851 960 947 1011 Adapted from Calverly PMA et al. N Engl J Med 2007; 356: 775-89. Was the study adequately powered to detect the primary endpoint? Statistical power of the trial was diluted by large number of drop outs from all treatment arms Intervention Arm Combo Early Withdrawal 673 (44.2%) 522 (34.1%) 561 (36.9%) What are the results? How large was the treatment effect and how precise was the estimate? 587 (38.3%)
Death From Any Cause Death From Any Cause Intervention Death From Any Cause (3 year) 15.2% ARR - RRR - + 12.6% 2.6% 17.1% 16.0% -0.8% -5.3% 13.5% 1.7% 11.2% None of the treatments demonstrated significant mortality benefit vs. placebo Inferred benefit ladder, Combo = > COPD-Related Death Rate of Exacerbations Combo showed 25% reduction in exacerbation frequency NNT to prevent 1 exacerbation in 1 year = 4 None of the treatments demonstrated significant mortality benefit vs. placebo Inferred benefit ladder, Combo = > * Combo significant better than all treatment arms Inferred Benefit Ladder: Combo > = > Rate of Exacerbations Requiring Hospitalization Health Status and Postbronchodilator FEV 1 Health Status FEV 1 Combo showed 17% reduction in hospitalizations NNT to prevent 1 exacerbation in 1 year = 32 Combo superior to all Combo superior to all Combo significant better than placebo Inferred Benefit Ladder: Combo = = = -4 is clinically relevant
Adverse Events Significant increase in the incidence of pneumonia in patients receiving medications containing fluticasone Treatment Incidence ARR NNH Will the results help me in caring for my patients? 12.3 - - 13.3 1.0 100 Combo 18.3 (p < 0.001) 19.6 (p < 0.001) 6.0 7.3 17 14 Can the results be applied to my patients? TORCH population 40 to 80 years of age moderate to severe COPD (FEV 1 < 60% of predicted) Variable ethnicities Be cautious in extrapolating to patients with mixed features of COPD and asthma E,g. mixed inflammatory patterns with eosinophils Are the likely treatment benefits worth the potential harm and costs? For every 100 patients treated with combo, Prevent 25 exacerbations in a year Prevent 3 hospitalizations Cause 7 pneumonias Important to note that pneumonia did not appear to translate into death Results support CTS and GOLD recommendations to use ICS + LABA in patients who experience frequent exacerbations despite optimal bronchodilator treatment Strengths and Limitations Large long term assessment Selection bias in patient population given risk of placebo treatment? Dilutional effect of statistical power given drop out rate? Be cautious interpreting secondary endpoints Conclusions Be cautious in recommending ICS monotherapy Monotherapy with LABAs is reasonable Combination therapy with ICS + LABA should be reserved for severe COPD with frequent exacerbations Several advantages over monotherapy Trial results indicate no significant mortality benefit, but difficult to interpret given high drop out rates Clinical significance of risk of pneumonia is unclear
Discussion & Questions