Osler Journal ClubOsler Journal Club

Dan Munoz and Adnan Dan Munoz and Adnan MalikMalik

September 13, 2006September 13, 2006

BackgroundBackground

• Population-based case-control studyPopulation-based case-control study• Investigating association between ACE Investigating association between ACE

inhibitors and abdominal aortic inhibitors and abdominal aortic aneurysm (AAA) ruptureaneurysm (AAA) rupture

• Based on animal data suggesting that Based on animal data suggesting that ACE inhibition may prevent expansion ACE inhibition may prevent expansion and rupture of AAA’sand rupture of AAA’s

• AAA’s are common (4-8% of men > 50 AAA’s are common (4-8% of men > 50 yrs)yrs)

• Mortality of AAA rupture is 80-90%Mortality of AAA rupture is 80-90%

Study OutlineStudy Outline

• 15,326 consecutive patients, greater than 15,326 consecutive patients, greater than 65 in age, admitted with primary diagnosis 65 in age, admitted with primary diagnosis of ruptured or intact AAA over a 10 year of ruptured or intact AAA over a 10 year period (1992-2002)period (1992-2002)

• Data derived from four linked administrative Data derived from four linked administrative databases in Ontario, Canada:databases in Ontario, Canada:1. Ontario Drug Benefit database1. Ontario Drug Benefit database

2. Canadian Institute for Health Information Discharge 2. Canadian Institute for Health Information Discharge Abstract databaseAbstract database

3. Ontario Health Insurance Plan database3. Ontario Health Insurance Plan database

4. Ontario Registered Persons database4. Ontario Registered Persons database

Study OutlineStudy Outline• Analysis looks at association between Analysis looks at association between

ACE inhibitor use prior to admission ACE inhibitor use prior to admission and odds of admission for unruptured and odds of admission for unruptured vs. ruptured aneurysm (primary vs. ruptured aneurysm (primary diagnosis responsible for admission)diagnosis responsible for admission)

• Primary outcome = AAA rupturePrimary outcome = AAA rupture• Multivariable analysis performed to Multivariable analysis performed to

adjust for demographics, risk factors adjust for demographics, risk factors for aneurysm rupture, comorbidities, for aneurysm rupture, comorbidities, health care access and screeninghealth care access and screening

ResultsResults

• Table 1. Baseline characteristics of Table 1. Baseline characteristics of patients.patients.

• Cases=patients with AAA ruptureCases=patients with AAA rupture• Controls=patients with unruptured AAAControls=patients with unruptured AAA• Notable for higher rate of imaging, Notable for higher rate of imaging,

electrocardiography, and cholesterol electrocardiography, and cholesterol testing in control grouptesting in control group

• Other health measures, comorbidities Other health measures, comorbidities were similarwere similar

ResultsResults

• Patients receiving ACE-I before Patients receiving ACE-I before admission significantly less likely to admission significantly less likely to present with ruptured aneurysm, OR present with ruptured aneurysm, OR 0.82 (CI 0.74-0.90)0.82 (CI 0.74-0.90)

• Dosing and specific type of ACE Dosing and specific type of ACE inhibitor did not affect associationinhibitor did not affect association

• Table 2. Other antihypertensives Table 2. Other antihypertensives were were not not associated with lower associated with lower incidence of AAA ruptureincidence of AAA rupture

Implications

• Association between ACE-I use and reduced risk of aortic rupture in elderly population with underlying AA Dx

• Potentially unique effect of ACE-I among anti-hypertensives in imparting protection against rupture

• Animal models and this study suggest current role for ACE-I Rx in selected sub-populations, while we await more definitive clinical investigation

Strengths of Approach

• Rarity of condition (M 4-8%, F 0.5-1%, age >50) makes case-control design useful/practical

• Canadian HC system imparting uniformity of access to hospital care, physician services Rx drug coverage

– Use of national utilization databases

– Further attempts to control for case-mix: no obvious inherent health status differences between groups

• Selection of controls

– (+) Demonstrated unruptured aneurysms

– (-) Question of how coming to attention

• Findings not overstated

– Authors caution: association vs. causation

– Direction: non-surgical candidates, trials

Weaknesses of Approach

• Inherent to case-control design– Missed populations

• Ruptures not making it to medical attention• Silent, undiagnosed aortic aneurysms

• Absence of detailed info on smoking status– Major risk factor for AA enlargement

• 10 year experience– Uniformity of intervention/technique quality?

• Definition of ACE-I therapy (Rx record)– Adherence/administration difficult to verify

Discussion Points

• How might this study have been better designed? Do you agree with the case-control model here?

• What other primary endpoints would be clinically relevant in examining ACE-I benefits/effects?– Rate of enlargement, threshold size, etc.

• What would be next investigational step?– How might a RCT be feasibly designed?

References

• Hackam D, et al., “Angiotensin-converting enzyme inhibitors and aortic rupture: a population-based case-control study,” Lancet 2006, 368: 659-665

• Dr. Jeanne Clark, Division of GIM

Taxonomy of Clinical Research Designs

• Controlled Trials– Non-Randomized– Randomized

• Other Intervention Studies– Before vs After– External Controls– Historical Controls

• Prospective Cohort Study – Concurrent– Non-Concurrent

• Case-Control Study• Cross-Sectional Study• Other / Mixed / ?

Experimental Observational

Comparison of 4 Major Study Designs

• Estimate Prevalence F F F A+• Estimate Incidence B- A+ F F• Prove Causality A+ B+ B- D

• Generalizability B- A- A- A• Feasibility C B A A

Goal or Feature RCT PCS CC X-S

RCT=Randomized, controlled trial; PCS=Prospective cohort study; CC=Case-control study; X-S=Cross-sectional study

Case Control Studies• Ppts selected on disease

– Present = cases; Absent = controls– Look back at exposures

• Etiology– Is head injury more common in pts with Alzheimers?– Is MI more common in women on HRT?

• Outcomes– Is history of FOB testing less common in people with

colon CA?

Examples of Exposures & Outcomes in Clinical Research

• Traits & Behaviors• Genetic Variants• Infectious Agents• Environmental Toxins• Medications• Surgical Procedures• Behavior Modification• Screening Programs

• Death• Disease• Sub-clinical Indicators of

Disease• Health-Related Traits• Quality of Life• Physical Function• Costs

Exposures Outcomes