Table 4—

Characteristics of observational studies of inhaled corticosteroids(ICS) and cardiovascular (CV) events or mortality

Study [Ref.]ParticipantsDesignData sourceDuration weeksParticipants includedICS exposureAscertainment of ICS exposureOutcomesOutcome ascertainmentRisk estimates ICS (versus controls) with outcomesBias and limitations
Fan 382654 ICS users, 5398 non-usersPCUS VA DB781. 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.DeathRecords 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 39371 cases, 1864 controlsNested CCCanadian Health Insurance DB in Saskatchewan130New 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 budExposed if recently received ICS prescription in 12 months prior to index date.MIDischarge 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 432130 cases, 320501 controls for mortality (3159 cases, 31534 controls for CV death)Nested CCUS VA, CMS and NDI2601. 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.NAAny exposure to respiratory prescription in the 180 days before index date. No details on accuracy of pharmacy data.Death, CVDDB 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 51629 ICS users, 2393 non-usersCohort, nested CCManitoba Population Health Research Repository (Canada)391. 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.NAProvincial retail pharmacies capture all dispensing of prescriptions except for in-patient drugs.DB has anonymous recipient IDs and information about the prescription dispensed.Death, CVDDeath 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 40786 ICS users, 397 SABA usersRCTwo regional MCOs in the USA961. 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.NAPharmacy claims for ≥90-day cumulative of: 1) ICS alone, 2) LABA alone, or 3) ICS + LABA.DeathDeath 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 41742 ICS users, 1832 SABA usersRC, nested CCFour US integrated HMOs156At 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 ICSPharmacy records of prescriptions using National Drug Codes. Duration extrapolated from units dispensed. Prescriptions reviewed for missing data.DeathDeath 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 4311481 ICS users, 11139 non-usersRCCIHI hospital discharge DB in Ontario (Canada)521. 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, fluniOntario Drug Benefit database.DeathCaptures 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 423343 ICS users, 3397 non-usersRCCIHI hospital discharge in Alberta (Canada)1281. 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.ICSCrosschecked with Alberta Blue Cross DB with record of quantity and date dispensed.Doses imputed.DeathVital 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 45431 ICS users, 3620 non-usersRCUK GPRD1561. Newly diagnosed COPD between 1990–1999.2. Aged >50 yrs.3. Received ≥3 prescriptions over 6 months.4. Alive for 6 months after entry.FluPrescriptions in 90 days post-hospital discharge.DeathDate 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 443049 ICS users, 627 SABA usersRCUK GPRD 1990–1999521. 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, fluBased on prescription by GP in 90 days post-discharge.DeathNADeath 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 4655 ICS users, 90 non-usersRCSlovakian university hospital521. 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.DeathSurvival 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 47863 regular ICS users, 996 irregular ICS users, and 1043 non-usersRCUS Kaiser Permanente2081. 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.NAEMR.One or more dispensing event during each of the three preceding 2 months.DeathVital 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.
  • PC: prospective cohort; VA: Veterans Affairs; DB: database; ICD: International Statistical Classification of Diseases and Related Health Problems; COPD: chronic obstructive pulmonary disease; ACQUIP: Ambulatory Care Quality Improvement Project; RCT: randomised controlled trial; Becl: beclometasone; triam: triamcinolone; fluni: flunisolide; flu: fluticasone; HR: hazard ratio; CC: case–control; bud: budesonide; MI: myocardial infarction; RR: relative risk; AMI: acute myocardial infarction; HTN: hypertension; DM: diabetes mellitus; HLD: hyperlipidaemia; CVD: cardiovascular disease; CMS: Center for Medicaid Services; NDI: National Death Index; NA: not available; IHD: ischaemic heart disease; ID: identification; SABA: short-acting β-agonist; MCO: managed care organisation; LABA: long-acting β-agonist; RC: retrospective cohort; SSN: social security number; DOB: date of birth; HMO: health maintenance organisation; Sal: salmeterol; CIHI: Canadian Institute of Health Information; ICU: intensive care unit; GPRD: General Practitioner Research Database; OMIS: Oxford Medical Information Systems; GP: general practitioner; LTOT: long-term oxygen therapy; Pa,O2: arterial oxygen tension; Pa,CO2: arterial carbon dioxide tension; ED: emergency department; EMR: Electronic Medical Record.