ByDr. Marjan Minou, M.D., Anesthesiologist andDr. Navideh Fahim, M.D., Pshychiatrist2014

Clinical Project Director: Pr. Peivand Pirouzi,Ph.D., M.B.A., C.C.P.E.

Receptors on heart vs. Receptorson lungAct in opposite mannerWhat makes heart calm ,

aggravate lung issuesWhat makes lung relax, stresses on

heart

stimulation of cardiac beta‐adrenoceptors asdone by B2A may have deleteriouscardiovascular effects particularly in patientswith cardiac risk factors

Tachycardia and arrhythmias are well‐knownside effects of B2A

Differences in pathophysiological aspectsbetween asthma and COPD

In asthma patients, B2A (SABA and LABA) arethe preferred bronchodilative compounds andMA are more used in combination with B2A ifadditional bronchodilation is required.

In COPD patients, usage of MA and B2A areeach recommended starting in Step 2 withLABA (long‐acting bronchodilation)

Several observational studies have been performed on the associationbetween the usage of inhaled B2A and the occurrence of AMI

However, these studies have produced conflicting results

Reasons for this variation are numerous:

>. small number of events (AMI) leading to poor precision of riskestimate

>. potential misclassification of potential cardiac events versusairway‐related events due to similar clinical complaints,

>. differences in populations of drug users,

>. measurement of drug exposure,

>. background risk of AMI

There are several studies evaluating the efficacy of LABA inpatients suffering from asthma. Unfortunately, side effectsare only reported in some of these studies in a more or lessstructured way

none of these studies AMI has been reported as a (serious)adverse event ((S)AE) but some of the reported AE’s (chesttightness, chest pain) could be associated with an ischemiccardiovascular event.

these symptoms might also be associated with a lackingefficacy in treating asthma and therefore a cleardiscrimination between cardiac‐ or airway‐relatedness cannotbe made.

Due to the small number of reported AEs in large RCTs a finalstatement regarding the risk for AMI in asthmatic patientsusing LABA is still missing.

COPD patients are high‐risk patients regarding ischemicevents due to high prevalence of smoking and increasedage.

Therefore, much higher rates of (S)AEs affecting the heartare reported in the respective RCTs

While in several reviews published regarding analyzing therisks and benefits of LABA in treating patients sufferingfrom COPD shows no increase the risk of cardiovascularadverse events in comparison to placebo.

Most reviews focus on efficacy, but data regarding sideeffects are limited.

Data regarding cardiac side effects are missing

The Developing standards to decrease thediscrepancies in results from different studiesin the future

Increase the usefulness, validity, andreliability of these studies for benefit‐riskassessment in the EU.

This protocol gives guidelines for conductingstudies from 5 database in UK, Spain, Germany,Denmark and Netherland across 3 designs

cohort,

nested case‐control,

case‐cross‐over

on the association between inhaled LABA use andAMI

The main focus is to evaluate the impact of study design population database characteristics on the association between inhaled LABA and

AMI.

all patients included in the period of validdata collection.

The study period is Jan 1st 2002 ‐ Dec 31st2009.

Study group ; inhaled LABA Control group; inhaled LAMA or

SAMA orSABA

First step; whole population of study Second step;1. Asthma patients2. Copd patients3. Asthm+ copd

1. Prevalence of inhaled DRUG use overall by age andsex for the 8 year period (2002‐2009).

2. Prevalence of drug use stratified by indication onlyfor the 8 year period (2002‐2009).( asthma, copd,as+copd, none)

3. Period prevalence (per year) of inhaled DRUGever used in that year (2002‐2009) stratified bynumber of prescriptions (categories: 1 only, >1 &<5, 5‐11, 12‐23, >23).

4. Prevalence of the lifetime AMI by age and sex overthe first year

5. (Cumulative) Incidence of the first AMI in databaseby age and gender, per year (e.g. 2003 if previousmeasure of prevalence was computed over 2002).

In the second step, measurementsconsidered in 1.), 3.), 4.), 5.) of the firststep will be separately performed for thethree patients’ strata:

i.) patients with asthma only,ii.) patients with COPD only andiii.) patients with COPD and asthma (if

available in the database).

All patients, who received at least oneprescription of an inhaled LABA and/or inhaledSABA and/or inhaled LAMA and/or inhaledSAMA and with coded diagnosis of asthmaand/or COPD during the study period, will beincluded in the studyExclusion;1. previous MI2. Not asthma or COPD

The cases are the patients in the cohortstudy who have developed an AMI. Thecontrols are a random selection fromamongst all patients in the cohort study whohaven’t had an AMI at the time when thecase has had its AMI. Follow‐up time, age,sex and indication will be matched fordefining control patients

In the case‐crossover study each case acts as itsown control.All patients of the cohort study, who havedeveloped a myocardial infarction are included.

Case window is 24 hours for the AMI. Control window ; for each patient the exposure

data are compared between the case windowand multiple control windows.The control windows are the same weekdays as

the case window during the past twelve months.

1. Diagnosis (asthma, copd )2. Lethal outcome of MI can not be traced3. Our analyses are only based on prescription data.4. the severity of asthma and COPD has to be considered in our

analysis as an influence on MI risk5. Information on important confounders such as socioeconomic

status and alcohol and tobacco dependence are not recorded inmost databases.

6. since patients on a mild asthma (step 1) use only relievermedication on an irregular basis, a 3 months periods

might be not appropriate for these patients.7. only patients with an AMI within one year before the index date.8. several coding methods are used for the coding of diseases .9. regarding the definition of patients’ strata, we simplify the clinicalreality to some extent.