Study [Ref.] | Participants | Design | Data source | Duration weeks | Participants included | ICS exposure | Ascertainment of ICS exposure | Outcomes | Outcome ascertainment | Risk estimates ICS (versus controls) with outcomes | Bias and limitations |
Fan 38 | 2654 ICS users, 5398 non-users | PC | US VA DB | 78 | 1. Outpatient visit or hospitalisation
with ICD-9 diagnosis of COPD.2. Using at least one pulmonary prescription
during 90 days before index visit.3. Age >45 yrs.4. Participant
in the ACQUIP RCT for ≥1 yr. | Becl (44%), triam (45%),
fluni (6%), flu (5%) | Prescription for inhalers, subdivided
by 90-day exposure periods.“User” if prescription filled for >80%
of each 90 days. | Death | Records date of death for veterans whose
families file for the benefit. | HR of death ICS versus controls.Low
dose (HR 0.96; 95% CI 0.69–1.33); medium/high doses (HR
0.86; 95% CI 0.67–1.10)Adjusted for distance from hospital,
pulmonary prescriptions, prior hospitalisations, comorbidity. | Significant baseline differences in age,
marital status, race, comorbidity, COPD clinic visits and hospitalisations,
respiratory prescription use.Assumes VA system provides records on all prescriptions
and patients compliant.No ascertainment of death by checking, DB known to
identify 98.8% of deaths among Medicare-eligible patients. |
Huiart 39 | 371 cases, 1864 controls | Nested CC | Canadian Health Insurance DB in Saskatchewan | 130 | New patients with COPD.1. At least 3 inhaler
prescriptions.2. Age >55 yrs with no previous use or ICS in 5 yrs.3.
Register in health plan for 5 yrs.4. Entry time 3rd prescription between
Jan 1990–Dec 1997.Matched for age, duration and frequency of exacerbations.Excluded
lengthy hospital admissions. | Becl or bud | Exposed if recently received ICS prescription
in 12 months prior to index date. | MI | Discharge diagnosis from the hospital
DB, and death from vital statistics.Compared to medical charts, diagnostic
agreement in hospital DB as high as 97%. | RR for AMI with ICS:crude RR 0.86 (95%
CI 0.68–1.09); adjusted RR 0.83 (95% CI, 0.63–1.08),adjusted
for AMI risk factors and severity of COPD: sex, HTN, DM, HLD, CV disease,
number of COPD exacerbations and respiratory prescription. | Important baseline differences: sex,
risk factors and history of CVD, hospitalisations in past 3 months.No
dose information available; duration of exposure extrapolated from quantity
dispensed, rather than compliance. Matching for COPD severity inaccurate as
relied on co-prescription exposure.Limited data on smoking. |
Lee 4 | 32130 cases, 320501 controls for mortality (3159
cases, 31534 controls for CV death) | Nested CC | US VA, CMS and NDI | 260 | 1. Age >45 yrs of US VA care
for >1 yr. 2. ICD-9 diagnosis of COPD between Oct 1, 1999 and Sept.
2003 at two or more outpatient visits within 12 months or primary diagnosis
of COPD. | NA | Any exposure to respiratory prescription
in the 180 days before index date. No details on accuracy of pharmacy
data. | Death, CVD | DB captures approximately 98%
of veteran deaths. Random sample of 40% with CV death: IHD disease,
cardiomyopathy, cardiac arrest, or arrhythmias. | Adjusted OR for ICS: all-cause death
0.80 (95% CI 0.78– 0.83); CVD 0.80 (95%
CI 0.72–0.88), adjusted for respiratory and cardiac prescriptions,
exacerbations, and presence of CV disease. | Imbalances in comorbid cardiac conditions
and cardiac prescription use, and COPD exacerbations. Confounding by indication.
Did not ascertain COPD severity or smoking status. Unlikely to find significant
differences due to low rates of exposure. |
| | | | | Matched on sex, age, region, and year
of diagnosis. | | | | | | Immortal time bias. Uncertain accuracy
of diagnosis of CVD. |
Macie 5 | 1629 ICS users, 2393 non-users | Cohort, nested CC | Manitoba Population Health Research Repository (Canada) | 39 | 1. Discharged from hospital with primary
ICD code of COPD between Apr 1996–Mar 2000.2. Age >35 yrs.3.
Resident of the province ≥1 yr prior and 1 yr post-discharge
until death.Patient who died within 90 days of hospital discharge excluded. | NA | Provincial retail pharmacies capture
all dispensing of prescriptions except for in-patient drugs.DB has anonymous
recipient IDs and information about the prescription dispensed. | Death, CVD | Death from any cause in the 275 days
after hospital discharge. Analysis of death certificates for: COPD, asthma;
CV and other causes. | Adjusted HR for death with ICS within
90 days of discharge.Aged >65 yrs, 0.75 (0.61–0.91).Note:
absolute mortality among age >65 yrs: 11.7% in ICS users;
13.1% in non-users.ICSs reduced the risk of death by 23% (95%
CI 6–37%) and CV deaths by 38% (95% CI
11–57%) compared to bronchodilators. | Significant baseline differences: age,
Charlson score, respiratory prescriptions. Confounding exists.No prescription
data while hospitalised so patients admitted in first 90 days of study
received less ICS and likely to be high mortality group.Difficulty in judging
actual drug usage, and cause of death. |
Mapel 40 | 786 ICS users, 397 SABA users | RC | Two regional MCOs in the USA | 96 | 1. Aged >40 yrs.2. Had >90-day
use of an ICS or SABA.3. At least two outpatient visits or one hospital admission
with relevant ICD-9 code between 1995–2000.Follow-up 1st day following
90-day period to death or disenrolment. | NA | Pharmacy claims for ≥90-day cumulative
of: 1) ICS alone, 2) LABA alone, or 3) ICS + LABA. | Death | Death obtained from state vital statistics
records and matched on name, SSN and DOB. | HR for mortality: ICS versus
SABA 0.59 (95% CI 0.46–0.78). | Significant baseline differences: age,
sex, presence of asthma, disease severity. Confounding by indication.No ascertainment
of exposure, compliance or use.Misclassification bias in COPD diagnosis (asthma).Uncertain
risk of immortal time bias. |
Mapel 41 | 742 ICS users, 1832 SABA users | RC, nested CC | Four US integrated HMOs | 156 | At least one in-patient or two outpatient
visits for COPD based on ICD-9 codes from Sep 2000 to Sep 2001.Matched on
sex, age, data survival follow-up. | Flu/sal, any ICS | Pharmacy records of prescriptions using
National Drug Codes. Duration extrapolated from units dispensed. Prescriptions
reviewed for missing data. | Death | Death during study period Sept 2000–Sept
2003 ascertained through local vital statistic registers, matched by name,
sex DOB and SSN. | HR for mortality ICS versus
SABA 0.76 (0.61–0.95).HR for mortality in propensity matched
cohort: ICS versus SABA 0.75 (0.58–0.97).RR for death
with ICS in nested CC RR 0.86 (95% CI 0.46–0.96). | Significant baseline differences: age,
hospitalisation for COPD, comorbidities. Discrepancy between prescription
and actual use.Duration extrapolated.Industry funded. |
Sin 43 | 11481 ICS users, 11139 non-users | RC | CIHI hospital discharge DB in Ontario (Canada) | 52 | 1. ICD-9 code for at least one hospitalisation
with main discharge diagnosis of COPD between April 1, 1992 and March 31,
1997.2. Aged >65 yrs.3. Survive ≥30 days after discharge. | Becl, bud, triam, fluni | Ontario Drug Benefit database. | Death | Captures all decedents of Ontario, including
date of death. | Adjusted RR for death with ICS use (within
90 day post-discharge RR 0.71 (95% CI, 0.65 to 0.78),
adjusted for age, sex, Charlson score exacerbations and co-medication. Stratified
analysis on Charlson score, sex, and age did not change association. | Significant baselines differences: age,
Charlson index, prescriptions and emergency visits.Confounding by indication.No
verification of actual medication usage. Risk of immortal time bias. |
Sin 42 | 3343 ICS users, 3397 non-users | RC | CIHI hospital discharge in Alberta (Canada) | 128 | 1. ICD-9 code for at least one hospitalisation
with main discharge diagnosis of COPD between April 1, 1994 and March 31,
1998.2. Aged >65 yrs.3. Excluded those with primary diagnosis of
asthma. | ICS | Crosschecked with Alberta Blue Cross
DB with record of quantity and date dispensed.Doses imputed. | Death | Vital statistics with electronic file
of all deceased persons in Alberta, including dates of death. | All cause death for ICS users versus non-users.Crude RR 0.61 (95% CI 0.56–0.66). Adjusted
RR 0.75 (95% CI 0.68–0.82), adjustments for age, sex,
comorbid conditions, ICU stay and use of other pulmonary prescription. | Significant baseline differences in age,
Charlson comorbidity score and use of prescriptions.Unclear, which ICS studied,
and what doses.No verification of actual use.Unclear risk of immortal time
bias. |
Soriano 45 | 431 ICS users, 3620 non-users | RC | UK GPRD | 156 | 1. Newly diagnosed COPD between 1990–1999.2.
Aged >50 yrs.3. Received ≥3 prescriptions over 6 months.4.
Alive for 6 months after entry. | Flu | Prescriptions in 90 days post-hospital
discharge. | Death | Date of death identified with Specific
OMIS code. | HR for fluticasone (3 yr
death).HR 0.62 (95% CI 0.45–0.85), Adjusted for
age, sex, year of entry, smoking, comorbid conditions and oral steroid use. | Significant baseline differences: age,
sex, prescription use, comorbidity.No verification of actual use.Risk of immortal
time bias.Industry funded. |
Soriano 44 | 3049 ICS users, 627 SABA users | RC | UK GPRD 1990–1999 | 52 | 1. Newly diagnosed COPD.2. Aged >50 yrs.3.
1st hospitalisation for COPD related condition.4. At least 1 prescription
for respiratory condition in first 90 days after discharge. | Beclo, bud, flu | Based on prescription by GP in 90 days
post-discharge. | Death | NA | Death rate in 1 yr 17.1%
in ICS users versus 24.3% in control group. | Significant baseline differences in age,
smoking prescription, and hospitalisation.Confounding by indication.Ascertainment
of mortality.Unclear risk of immortal time bias.Drug dosage unclear.Actual
use may differ.Industry funded. |
| | | | | 5. Excluded if died or re-admitted within
30 days. | | | | | | |
Tkacova 46 | 55 ICS users, 90 non-users | RC | Slovakian university hospital | 52 | 1. Documented outpatient clinic visit
or an in-patient hospitalisation with primary diagnosis of COPD.2. At least
one bronchodilator before the index visit or hospitalisation date.3. LTOT
prescription between 1996–2002.4. Stable condition at the time of LTOT
initiation.Prescribing physician recorded details of prescription at time
of initiation of O2. | Becl (n = 45),
flu (n = 6), bud (n = 4) | Whether patients were or were not receiving
ICS at time of LTOT initiation. | Death | Survival data from records of home O2 vendors captured death. | HR for death with ICS use.HR 0.38 (95%
CI 0.18–0.79). Adjusted HR 0.46 (95% CI 0.21–0.98),
adjusted for age, sex, co-medication, Pa,O2
and Pa,CO2.ICS users had significantly greater
1-yr survival (46/55 or 84%) than non-users (54/90
or 60%).(Log-rank statistics p<0.05). | Significant baselines differences in
use of SABA, arterial hypertension and severity of COPD.Misclassification
as exposure status based on single time-period, and patients may have started
on ICS after that.Risk of confounding as no adjustment for risk factors. |
Vollmer 47 | 863 regular ICS users, 996 irregular
ICS users, and 1043 non-users | RC | US Kaiser Permanente | 208 | 1. Aged >50 yrs as of Jan 2000.2.
Enroled between 1998–1999.3. Outpatient or ED visit with ICD-9 COPD
code.4. ≥6 prescriptions of respiratory drugs, with ≥1 prescription
dispensed Sept–Dec 1999. | NA | EMR.One or more dispensing event during
each of the three preceding 2 months. | Death | Vital statistics registers of Oregon
and Washington. 29.5% had incomplete follow-up. | RR for death (no asthma): never
smokers: 0.47 (0.19–1.16, p = 0.10);
ex-smokers: 0.76 (0.56–1.02, p = 0.07);
current smokers 1.09 (0.65–1.83, p = 0.74);
adjusted for age, sex, comorbidity, use of home O2, pulmonologist,
COPD hospitalisation or ED care, and propensity to use ICS. | Significant baselines differences: smoking,
co-existing asthma, pulmonologist care, ED care.No verification of compliance.Incomplete
follow-up.Industry funded. |