Are anticholinergics associated with increased risks for

How safe are anticholinergics in COPD? Are anticholinergics associated with increased risks for cardiovascular

morbidity and mortality? Over a decade of controversy

Donald P. Tashkin, M.D. Emeritus Professor of Medicine

Division of Pulmonary/Critical Care Medicine

Effects of antimuscarinic agents on the heart • Large doses of atropine cause progressively increasing

tachycardia by blocking vagal effects on the S-A nodal pacemaker 2 mg atropine IM increases resting HR by ~35-40 beats (most

noticeable in healthy young adults in whom vagal tone is considerable)

• Atropine often causes cardiac arrhythmias (atrial arrhythmias and AV dissociation)

• Atropine may decrease AV conduction time and shorten the PR interval

Goodman & Gilman’s The Pharmacologic Basis of Therapeutics, 1980

Tertiary and Quaternary Ammonium Antimuscarinics

Lung Health Study • Early intervention 5-yr trial in subjects with mild to

moderate COPD (mean FEV1 75% predicted) to determine: The effectiveness of a state-of-the-art smoking cessation and

relapse prevention program in altering the natural hx of COPD when combined with maintenance bronchodilator therapy with either a short-acting anticholinergic bronchodilator (ipratropium [Atrovent®] 40 mcg qid) or placebo (primary endpoint)

• Subjects were randomly assigned to usual care (UC; no intervention) or special intervention (SI: smoking cessation program; random, double-blind allocation to inhaled ipratropium [SIA] or placebo [SIP])

Anthonisen et al. JAMA 1994; 272:1497-1505

Ipratropium (SIA) increases FEV1 but does not influence the rate of decline of FEV1

SIA

SIP

UC

Mean FEV1 (Post-BD) by Smoking History Group

2.02.12.22.32.42.52.62.72.82.93.0

0 1 2 3 4 5 6 7 8 9 10 11Year of Follow-up

Mea

n FE

V1 (L

iters

)

Sustained quittersIntermittent quittersContinuous smokers

Anthonisen et al. JAMA 1994; 272:1497-1505

Published 8 years later: Anthonisen, AJRCCM 2002

DAYS

From John Connett, PhD, LHS Data Coordinating Center

Lanes et al. AJRCCM 2003; 167:801-2

Cardiovascular morbidity and the use of inhaled bronchodilators

• Aim: Examine the relationship between use of inhaled respiratory drugs (BA, IB, ICS) in airways disease (COPD, asthma) & 1st hospitalization for CV event (SVT, MI, CHF, CVA) from 1996 thru 2000

• Methods: Used Manitoba Health data base to capture inpatient/outpatient, vital status, prescriptions

• Analysis: Nested case-control comparing patients with and without CV events with matching for gender, age Used conditional logistic regression in multivariate analysis

controlling for other respiratory (& CV) drugs, diagnosis (asthma, COPD), co-morbidities

Macie et al. Int J COPD 2008;3:1-7




Medication Safety in COPD Patients: The Risk of Mortality Associated with Treatment in Veterans

with Newly Diagnosed COPD

Todd A. Lee1,2, A. Simon Pickard1,3, David Au4,5, Brian Bartle1, Kevin B. Weiss1,2

1 CMC3, Hines VA Hospital 2 Northwestern University Feinberg School of Medicine

3 University of Illinois at Chicago 4 University of Washington

5 VA Puget Sound Health Care System

Sponsored by VA HSR&D IIR 03-307 Lee et al. Ann Intern Med 2008;149:380-390

Objective

• Determine mortality risk associated with exposure to respiratory medications in VA patients with newly diagnosed COPD Respiratory-related mortality Cardiovascular-related mortality All-cause mortality

Methods • Identified a cohort of VA patients with a new diagnosis of

COPD between Oct. 1, 1999 and Sept. 30, 2003

• Analysis conducted using VA & Medicare administrative datasets

• Patients followed from date of diagnosis until death or September 30, 2004

• Nested case control study of patients in the overall cohort Randomly sampled 40% of patients who died during the follow-up

period Potential cases matched to NDI plus data to identify cause of death

Cases & Controls • Cases

Persons with a respiratory-related or cardiovascular-related cause of death listed as underlying cause

• Respiratory-related – Diseases of respiratory system (J00 – J99); breathing abnormalities (R06)

• Cardiovascular-related – Ischemic heart disease (I20-I25); Cardiomyopathy, cardiac arrest &

arrhythmias (I42-I51) Persons who died of any cause during the follow-up period

• Controls

Patients from eligible cohort alive at case death date Individually matched (10:1) at random on sex, age, region of the

country and year of diagnosis Assigned end date equal to matched cases date of death

Exposure

• Identified all COPD-related prescriptions dispensed between COPD diagnosis date and death/end date

• Exposure defined based on 6 month period prior to end date • Exposure classifications:

Ever/Never Cumulative dose Average daily dose

Analysis • Analyses done separately for each group

• Conditional logistic regression to estimate risk of mortality

associated with medication exposure

• Adjusted models controlling for comorbidities, health services use and markers of COPD severity

• Odds ratios (ORs) and 95% confidence intervals used to quantify the risk of death

Mortality

• 32,130 patients died during follow-up period • 11,897 cases with cause of death data

Respiratory-related = 2,405 Cardiovascular-related = 3,159

Respiratory-related mortalitya

Cardiovascular-related mortalityb All-cause mortalityc

Adjusted OR [95% CI]

Adjusted OR [95% CI]

Adjusted OR[95% CI]

ICS 0.88 [0.79, 1.00] 0.80 [0.72, 0.88] 0.80 [0.78, 0.83]

IPRA 1.07 [0.96, 1.20] 1.34 [1.22, 1.47] 1.11 [1.08, 1.15]LABA 1.12 [0.97, 1.30] 0.97 [0.84, 1.11] 0.92 [0.88, 0.96]THEO 1.71 [1.46, 2.00] 1.16 [0.99, 1.37] 1.05 [0.99, 1.10]

From Lee et al. Ann Intern Med 2008;149:380-390

a Adjusted model includes systemic steroid use, inpatient exacerbations, outpatient exacerbations, CHF, number of SABA fills

b Adjusted model includes systemic steroid use, inpatient exacerbations, outpatient exacerbations, CHF, IHD, diabetes, number of SABA fills, exposure to following medications: digoxin, beta-blockers, alpha blockers, diuretics, calcium channel blockers, lipid lowering medications, ACE inhibitors, ARBs, insulin, oral hypoglycemics and NSAIDsc Adjusted model includes systemic steroid use, inpatient exacerbations, outpatient exacerbations, number of short-acting -agonist fills, chronic heart failure, ischemic heart disease, cancer, digoxin, -blockers, -blockers, diuretics, lipid-lowering medications, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), insulin, oral hypoglycemics, and nonsteroidal anti-inflammatory drugs

From Lee TA et. al. Ann Intern Med 2008;149:380-390

Singh S, et al., JAMA 2008;300:1439-50

Meta-analysis: Database • 17 randomized controlled trials • 14,783 COPD patients • Inhaled anticholinergics > 30 days • Number of trials:

12 tiotropium (long-acting); 5 ipratropium (short-acting)

• 9 placebo; 8 active controls • CVD data missing in most publications; obtained from

FDA and manufacturer trial register Singh S et al., JAMA 2008;300:1439-50

Cardiovascular Risks I -- CVD death, MI or stroke --

• Inhaled anticholinergics: 135/7,472 • Control therapy: 86/7,311 • RR = 1.58 (95% CI, 1.21 - 2.06), p = 0.0009

• CVD death (n = 88)* 1.80 (1.17 – 2.77) • MI (n = 111)** 1.53 (1.05 -2.23) • Stroke (n = 43): 1.46 (0.81 – 2.62)

*12 trials **11 trials

Cardiovascular Risks II -- CVD death, MI and Stroke --

Type of anticholinergic formulation Any RR = 1.58 (1.21 – 2.06) Short-acting RR = 1.70 (1.19 – 2.42) Long-acting RR = 1.43 (0.95 – 2.16)

Type of control agent Any (includes BA, ICS) RR = 1.58 (1.21 – 2.06) Placebo RR = 1.55 (1.15 – 2.10)

Active control RR = 1.64 (0.96 – 2.79) P for heterogeneity = 0.82

Cardiovascular Risks III -- Treatment Duration --

Long-term trials (> 6 mos) N = 5 RRall = 1.73 (1.27 – 2.36)

RRtio = 2.12 (1.22 – 3.67) Short-term trials (6 wks – 6 mos) N = 12 RRall = 1.16 (0.67 – 2.01)

Cardiovascular Risks IV -- Myocardial Infarction --

Inhaled anticholinergics: 68/5430 Control therapy 43/5168 RR = 1.53 (1.05-2.23)

Short-acting RR = 1.50 (0.96-2.33) Long-acting RR = 1.61 (0.77-3.29) Placebo RR = 1.48 (1.00-2.21) Active control RR = 1.70 (0.68-4.25)

Authors’ Conclusion:

• Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI or stroke among patients with COPD

UPLIFT Objective: Assess whether tiotropium 18 µg once daily is associated

with a decrease in the rate of decline of FEV1 over time in patients with COPD

Design: Randomized, double-blind, placebo-controlled, parallel-group Treatment duration: 4 years Sample size: 5,993 patients (450 centers, 37 countries)

Treatment: Patients randomized 1:1 to receive: tiotropium (18 µg) or placebo once daily

PLUS usual care – except inhaled anticholinergics

UPLIFT Primary Endpoints: • Rate of decline of FEV1 (trough and peak) over time in

patients with COPD (measured with standardized spirometry)

Secondary Endpoints: • St. George’s Respiratory Questionnaire • Exacerbations: mild (Rx at home); mod (visit with health

care provider, incl. ER); severe (hospitalization) • Hospitalizations due to exacerbations • Mortality (respiratory and all-cause)

Safety of Tiotropium in UPLIFT

Fatal Events: Definitions

• On-treatment 1st to last day of treatment + 30 days

• Vital status (VS) 4 years follow-up (day 1440) – VS 95% complete 4 years + 30 days follow-up (day 1470) – VS 75% complete

• Cause of death investigator mortality adjudication committee

Probability of Death from Any Cause On-Treatment

Tiotropium

Control

0 6 12 24 30 36 42 48 18

Hazard ratio = 0.84 95% CI: (0.73, 0.97) P = 0.016 (log-rank test)

20

15

10

5

0

Prob

abili

ty o

f dea

th fr

om a

ny c

ause

[%]

Months

Tiotropium

Control

0 6 12 24 30 36 42 48 18


20

15

10

5

0

Prob

abili

ty o

f dea

th fr

om a

ny c

ause

[%]

Months

Probability of Death from Any Cause On-Treatment + Vital Status – Day 1440

Tiotropium

Control

0 6 12 24 30 36 42 48 18


20

15

10

5

0

Prob

abili

ty o

f dea

th fr

om a

ny c

ause

[%]

Months

Probability of Death from Any Cause On-Treatment + Vital Status – Day 1470

Cardiovascular Events

Placebo Tiotropium Rate Ratio1 (95 % CI) N Rate2 N Rate2

UPLIFT Composite endpoint 246 2.89 208 2.25 0.78 (0.65, 0.94) Fatal composite 124 1.42 98 1.04 0.73 (0.56, 0.95)

1 rate ratio tio vs. placebo; 2per 100 person-years of time at risk to tiotropium or placebo

*SOC cardiac (fatal), SOC vascular (fatal), MI (fatal+nonfatal), stroke (fatal+nonfatal), sudden death, sudden cardiac death

Composite Endpoint* Used by Singh et al Applied to UPLIFT

“Because of the strength of the UPLIFT data, the absence of a strong signal related to stroke or cardiovascular events with tiotropium, and the potential limitations of the Singh meta-analysis, the FDA concluded that current data do not support the conclusion that there is an increased risk of stroke, heart attack, or death associated with tiotropium HandiHaler.”

Respimat device Slow Mist Inhaler

Singh et al. BMJ 2011 Posted on BMJ-webpage July 19, 2011

Meta-analysis of tiotropium in the Respimat and risk of mortality in COPD RCTs

Singh et al. BMJ 2011

Meta-analysis of tiotropium in the Respimat and risk of cardiovascular death in RCTs

Singh et al. BMJ 2011

Geometric mean TIO plasma concentration-time profiles following TIO in HH vs SMI

11.5*

8.49*

26.4*

*Cmax (pg/ml) Van Noord et al. Respir Med 2008

35.5% increase over TIO HH

Sensitivity analyses: risk ratios* (RR) with 95% confidence intervals (CI) – Mantel-Haenszel

All 6 studies 5 µg/placebo

All 6 studies (5+10 µg)/placebo

Cases N/N 70/53 90/53

RR fixed effects (95% CI)

1.32 (0.93, 1.88)

1.36 (0.97, 1.91)

RR random effects (95% CI)

1.33 (0.93, 1.90)

1.35 (0.95, 1.90)

Disse et al. BMJ 2011 (letter to editor) *adjusted for different exposures in Rx arms

Population-based observational study of mortality in users of TIO Respimat vs. Handihaler

• Source population derived from Dutch primary care longitudinal database (>400 GPs) 11,287 patiaents ≥40 yrs old with ≥1 yr F/U who were users of

TIO Handihaler (HH) or Respimat (Resp) • 496 patients died while exposed to HH or Resp • Cause of death assessed (hospital records, death certificate) • Cox proportional hazards regression analysis adjusted for

smoking, COPD severity (# exacerbations, GP visits for respiratory illness), COPD duration & all factors that changed the crude HR by >5% Verhmamme et al. ERJ 2013

Hazard ratios for all-cause mortality in users of TIO Respimat vs. users of TIO Handihaler

Verhmamme et al. ERJ 2013

HRs for cardio- & cerebrovascular mortality in users of TIO Respimat vs. users of TIO Handihaler

Verhmamme et al. ERJ 2013

Tiotropium Respimat Safety Study • “A rigorous investigation between the tiotropium Respimat and

Handihaler formulations in a well controlled large outcome study, including all-cause mortality, is warranted to investigate any pharmacological differences between the formulations and for a reliable determination of benefit and risk.”

• “TIOSPIR a large-scale, prospective, randomized outcome study comparing tiotropium Respimat 5 mcg, 2.5 mcg and Handihaler 18 mcg was designed to assess these factors.”

• “To date the exposure in this trial of more than 10,000 patient-years already exceeds the exposure reported in both, the BI/Pfizer and Singh et al. pooled analyses for tiotropium Respimat.”

Disse et al. BMJ 2011 (letter to editor)

Tiotropium Safety & Performance in Respimat (TIOSPIR)

• Countries: 50 • Sites/centres: 1202 • 1266 deaths needed for adequate power • Patients:

17,183 randomized 17,135 treated 77% completed 99.7% vital status follow up

• Enrollment: May 2010 – April 2011

• Trial completed: May 2013

Wise RA, et al. N Engl J Med. 2013

TIOSPIR Study Design

• Treatment time is 2-3 years dependent on fatal events observed*

*Event-driven trial designed to end when approximately 1266 deaths reported.

C, close of study once the planned 1266 events have been reached; COPD, chronic obstructive pulmonary disease; R, randomization

Weeks 0 6 12 and then every 12 weeks

for 2-3 years 30-day posttreatment follow-up

R C

Tiotropium Respimat® 5 μg once daily

Tiotropium Respimat® 2.5 μg once daily

Tiotropium HandiHaler® 18 μg once daily

Wise RA, et al. Respir Res. 2013;14:40.

TIOSPIR Endpoints • Two primary endpoints

Time to death (all-cause) Time to first COPD exacerbation

• Secondary endpoints Number of COPD exacerbations Time to first severe (hospitalized) COPD exacerbation Number of severe (hospitalized) COPD exacerbations Time to first MACE

• Safety endpoints Serious AEs AEs relating to study treatment or leading to treatment discontinuation

• MACE (major adverse cardiovascular event) • Stroke, transient ischaemic attack, MI, sudden death, sudden cardiac death, or cardiac

death


Inclusion Criteria • Diagnosis of COPD and airway obstruction

Post-bronchodilator FEV1 ≤70% predicted FEV1/FVC ≤70%

• Age ≥40 years • Smoking history ≥10 pack-years • Patients with concomitant cardiac disease can be included,

unless having: MI within 6 months Hospitalization for heart failure (NYHA Class III or IV) within 12

months Unstable or life-threatening arrhythmia requiring intervention or change

in drug therapy within 12 months


Exclusion Criteria • Significant diseases other than COPD that could put patient at risk or

influence study results • Recent history (≤6 months) of MI • Unstable or life-threatening cardiac arrhythmia requiring intervention or

change in drug therapy during the last year or hospitalization for heart failure (NYHA III/IV) in the last year

• Asthma, cystic fibrosis, clinically evidence bronchiectasis, interstitial lung disease, pulmonary thromboembolic disease or planned lung transplant or lung volume reduction surgery

• Respiratory infection or exacerbation of COPD in the 4 weeks prior to randomization

• History of malignancy in the last 5 years requiring treatment • Moderate to severe renal impairment, narrow angle glaucoma or

significant symptomatic prostatic hyperplasia or bladder-neck obstruction COPD, chronic obstructive pulmonary disease; MI, myocardial infarction

Concomitant Medication

• All classes of maintenance respiratory medications except for non-study drug inhaled anticholinergics were permitted Medications for other diseases including cardiac diseases were permitted throughout the trial

For potentially life-threatening COPD exacerbations, any and all therapies and interventions deemed medically necessary by the treating physician could be prescribed


• 77% completed the study (23% discontinued prematurely) in all treatment groups

• 90% of patients were compliant, using 80-120% of study medication, on average, throughout the study

• Vital status was known for 99.7% of patients (including those discontinuing study drug prematurely) at end of study

• Median treatment duration : 835 days for all 3 treatment groups

Discontinuation, Compliance and Exposure

Tiotropium Respimat®

2.5 µg


5 µg

Tiotropium HandiHaler®

18 µg

Study drug exposure, patient-years 11,405 11,343 11,337

• Study drug exposure

Patient Baseline Demographics

Characteristic Tiotropium

Respimat® 2.5 µg (N=5724)

Tiotropium Respimat® 5 µg

(N=5705)

Tiotropium HandiHaler® 18 µg

(N=5687) Male sex, % 71.1 72.5 71.0 Age, year 65.1±9.1 64.9±9.1 65.0±9.0 Body mass index 26.2±5.7 26.2±5.7 26.2±5.7 Smoking status Current smoker, % Smoking history, pack-year

37.9

43.6±24.6

38.7

44.1±25.0

37.7

43.7±24.7 Duration of COPD, years 7.4±6.1 7.4±6.2 7.5±6.2 Geographic region, % Europe/Africa/Australia/New Zealand Latin America North America Asia

55.9 5.8 24.5 13.8

56.8 5.7 23.9 13.6

56.2 6.0 23.8 14.0

Race, %* White Black Asian

81.8 1.3

14.2

81.5 1.6

14.1

81.4 1.5

14.3

Patient Baseline Characteristics

Characteristic Tiotropium

Respimat® 2.5 µg (N=5724)

Tiotropium Respimat® 5 µg

(N=5705)

Tiotropium HandiHaler® 18 µg

(N=5687) Spirometry, postbronchodilation FEV1, litres* FEV1, % of predicted value FVC, litres Ratio of FEV1 to FVC

1.328±0.481 48.0±13.9

2.696±0.848 0.498±0.115

1.352±0.481 48.5±13.8

2.726±0.843 0.501±0.114

1.338±0.473 48.4±13.9

2.716±0.843 0.498±0.114

GOLD stage, %†

FEV1 ≥80% 50% ≤FEV1 <80% 30% ≤FEV1 <50% FEV1 <30%

0.2

46.8 40.2 11.4

0.3

48.1 40.1 10.0

0.2

48.0 39.7 10.9

* P-value <0.05 for baseline FEV1 (litres); P-values are based on F-tests for the continuous variables and on Chi-Squared tests for the categorical variables †Data were missing for 43 patients in this category, 193 patients had FEV1/FVC at least 70%

Wise RA, et al. N Engl J Med. 2013..

Cardiac History

History of cardiac disorder, %


2.5 µg (N=5724)


5 µg (N=5705)


18 µg (N=5687)

Cardiac arrhythmia 10.6 10.8 10.7 Heart failure class None Class I Class II Class III Class IV

91.8 3.3 3.9 0.8 0.0

92.2 3.2 4.0 0.5 0.0

92.3 2.7 4.3 0.6 0.1

MI 5.9 5.9 6.1 Stroke 2.2 2.4 2.2 Ischaemic heart disease/ coronary artery disease

14.8 15.0 15.7

Wise RA, et al. N Engl J Med. 2013.

Baseline Concomitant CV Medications

Cardiovascular medication, %


2.5 µg (N=5724)


5 µg (N=5705)


18 µg (N=5687)

Any 51.7 50.9 50.8 β-blockers 14.5 14.1 14.6 CCBs 17.9 18.1 17.2 ACE inhibitors 20.9 21.0 20.2 ARBs 11.6 11.6 11.1 Nitrates 3.9 4.2 4.2 Acetylsalicylic acid 18.9 19.2 19.7

ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker


Baseline Concomitant Respiratory Medications (allowed to continue except anticholinergics)

Respiratory medication, %


2.5 µg (N=5724)


5 µg (N=5705)


18 µg (N=5687)

Any 90.8 90.3 90.7 Inhaled anticholinergics Short-acting‡

Long-acting

17.3 46.5

17.5 46.8

17.1 47.3

Inhaled β2-agonists Short-acting Long-acting‡

54.4 61.9

53.1 61.2

53.3 62.3

Corticosteroids Inhaled‡

Oral

58.9 5.0

58.8 4.3

59.4 4.7

Leukotriene receptor antagonists Mucolytics Supplemental oxygen

2.6 7.1 4.2

2.5 7.2 3.9

2.6 7.4 4.2

Xanthines 15.9 15.4 15.5 Phosphodiesterase-4 inhibitor 0.1 0.3 0.3

‡


Number at risk:

Tiotropium Respimat® 2.5 μg

5730 5480 5347 5239 5170 5070 4986 4899 4823 4727 4658 4599

Tiotropium Respimat® 5 μg 5711 5440 5310 5201 5122 5023 4942 4891 4803 4712 4647 4598

Tiotropium HandiHaler® 18 μg

5694 5457 5308 5202 5130 5053 4968 4884 4806 4714 4645 4600

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0 60 120 180 240 300 360 420 480 540 600 660

Prob

abili

ty o

f tre

atm

ent d

isco

ntin

uatio

n Tiotropium Respimat® 5 µg Tiotropium Respimat® 2.5 µg Tiotropium HandiHaler® 18 µg

Days since start of treatment

TIOSPIR No difference between groups in time to premature discontinuation


Number at risk:

Tiotropium Respimat® 2.5 μg

5730 5714 5694 5667 5637 5608 5582 5531 5499 5457 5423 5383 5157 4782 3575 1619 504

Tiotropium Respimat® 5 μg 5711 5696 5675 5653 5626 5595 5576 5556 5510 5469 5429 5405 5167 4811 3585 1618 467

Tiotropium HandiHaler® 18 μg

5694 5683 5660 5625 5601 5576 5544 5507 5471 5432 5388 5352 5097 4754 3544 1597 488

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 Days since start of treatment

Prob

abili

ty o

f dea

th fr

om a

ny c

ause

Tiotropium Respimat® 5 µg Tiotropium Respimat® 2.5 µg Tiotropium HandiHaler® 18 µg

TIOSPIR No difference between treatment groups in time to death from any cause (including vital status follow-up) (I)


No difference between treatment groups in time to death

from any cause (including vital status follow-up) (II)

0.87 1.00 1.14

0.84 0.96 1.09

0.8 0.9 1 1.1 1.2 1.3Hazard ratio δ1.25

Favours HandiHaler® Favours Respimat®

Tiotropium Respimat® 5 µg versus Tiotropium HandiHaler® 18 µg

Tiotropium Respimat® 2.5 µg versus Tiotropium HandiHaler® 18 µg

Noninferiority margin


Also, no ↑ risk of death in patients with previous cardiac arrhythmia: HR 0.81 (0.58-1.12) Respimat 5µg vs. 18µg HH

Incidence of death from any cause was similar across treatment groups

Variable


2.5 µg (N=5730)


5 µg (N=5711)


18 µg (N=5694)

Comparison HR (95% CI)

P-value

Mortality (vital status follow-up), n (%)

440 (7.7) 423 (7.4) 439 (7.7) Respimat® 5 µg versus

HandiHaler®

0.96 (0.84,1.10) *

Respimat® 2.5

µg versus HandiHaler®

1.00 (0.87,1.14) *

Rate of events (per 100 patient-years) 3.35 3.22 3.36

Mortality (on treatment), n (%)

359 (6.3) 326 (5.7) 357 (6.3) Respimat® 5 µg versus

HandiHaler®

0.91 (0.79,1.06)

Respimat® 2.5

µg versus HandiHaler®

1.00 (0.86,1.16)

*Test for noninferiority was statistically significant (P<0.05). Wise RA, et al. N Engl J Med. 2013.

MIs in patients receiving TIO SMI vs. TIO HH Outcome TIO

SMI 2.5 µg

TIO SMI 5 µg

Both SMI

groups

TIO HH 18 µg

SMI 2.5 µg vs HH

SMI 5 µg

vs HH

Both SMI grps vs. HH

Number of patients/total number

RR (95%CI; P value)

RR (95%CI; P value)

RR (95%CI; P value)

Adjudi- cated fatal MIs

10/5730 11/5711 21/ 11,441

3/5694 3.31 (0.91-12.0; p=07)

1.66 (1.02-13.1;

p=0.047)

1.48 (1.04- 11.7;

p=0.04)

Fatal and nonfatal MIs

70/5724 73/5705 143/ 11,429

52/5687 1.34 (0.94-1.19;

p=0.11)

1.40 (0.98-1.99;

p=0.07)

1.37 (1.00- 1.88;

p=0.05) Loke et al. NEJM 2014; 370:480-2

Why do the results of TIOSPIR differ from those of previous meta-analyses and data base studies?

• Better power: 10 times as many deaths in TIOSPIR (n=1302) as in the trials analyzed in meta-analyses (n=137)

• Meta-analyses could not adjust for the bias introduced by a higher discontinuation rate in the placebo arm Longer exposure in active Rx arm –↑ opportunity for death Placebo drop-outs at increased risk of dying after withdrawal

(these deaths not captured) • In observational data base studies, confounding by

indication (patients with more severe COPD and coexisting CV disease more likely prescribed Respimat), inability to adequately control for disease severity or smoking

Documents

Are anticholinergics associated with increased risks for