E FFECTS OF C ARDIOVASCULAR D RUGS ON M ORTALITY IN S EVERE C HRONIC O BSTRUCTIVE P ULMONARY D ISEASE A T IME -D EPENDENT A NALYSIS Magnus P. Ekstrom, Anna Bornefalk Hermansson, and Kerstin E. Strom Am J Respir Crit Care Med Vol 187, Iss. 7, pp 715–720, Apr 1, JAE HUN PARK

INTRODUCTION Beneficial effect on mortality for cardiovascular drugs angiotensin-converting enzyme inhibitors (ACEI) angiotensin receptor blockers(ARB) antiplatelet drugs b-blockers Statins Immortal time bias, Immeasurable time bias ? Study of the time-dependent effects of cardiovascular drugs on mortality in severe COPD, accounting for immortal and immeasurable time bias

METHODS National prospective multicenter study in Sweden between ~ >45 years long-term oxygen therapy (LTOT) for COPD Exclusion criterion : lung cancer before start PaO2, PaCO2, FEV1, FVC, BMI, smoking history, WHO performance status

S TATISTICAL A NALYSIS - D RUG EXPOSURE Dispensed prescribed drugs (prescriptions) assessed during each full 91-day period (quarter) from the quarter before baseline until end of follow- up for each individual patient The probability of drug exposure(E) for each quarter set to 1 if there was at least one prescription during the quarter set to 0 if there was no prescription during either this or the next quarter set to the proportion of the current quarter spent in the hospital for quarters with no prescription but with a prescription during the next quarter exposure at baseline : exposure probability > 0

S TATISTICAL A NALYSIS - T IME - DEPENDENT MODEL Treatment with ACEI/ARBs and antiplatelet drugs, b-blockers, statins Treatment with combination of LABA + ICS, oral glucocorticoids, tiotropium Comorbidities Anemia Renal failure Cardiovascular diseases cerebrovascular disease, heart failure, hypertension, ischemic heart disease, peripheral artery disease, pulmonary embolism

RESULTS Total 2,249 patients 1,328 (59%) women, 921 men No follow-up lost (median 1.1 years) 3,118.1 person-years at risk 1,129 (50%) patients died respiratory disease (68%) cardiovascular disease (20%) cancer (6%)

enalapril, losartan aspirin simvastatin

E FFECTS ON M ORTALITY

DISCUSSION In severe oxygen-dependent COPD patients Antiplatelet drugs > ACEI/ARBs, statins  improve survival b-blockers  decrease survival Previous & recent studies Statins reduced mortality single-center study of patients with COPD undergoing vascular surgery [van Gestel] no effect for ACEI/ARB [Rutten] ACEI/ARB, statins reduced mortality Cardioselective b-blockers safe and effective to use in mild to moderate COPD lower relative risk of mortality  publication bias?

DISCUSSION Limitations Dispensed prescriptions do not necessarily imply consumption possible confounding by indication owing to the lack of randomization

DISCUSSION The mechanism between ACEI/ARB and statins and reduced mortality effect on undiagnosed disease effect on the excess risk of cardiovascular morbidity and mortality that seems to be a systemic consequence of COPD Direct effects on the respiratory system ARB on emphysema, exercise capacity, and lung function [animal models] Simvastatin on smoke-induced pulmonary artery remodeling and emphysema [animal models] ARB - decrease the lung hyperinflation in patients with COPD

DISCUSSION Antiplatelet drug - improved survival systemic antithrombotic effect Oral glucocorticoids – increased mortaily? Causal relation or an association between taking oral steroids and more severe underlying disease and exacerbations b-blockers had no negative effects on respiratory symptoms or FEV1? [Cochrane review] Small number of studies & short follow-up Excluded heart failure and significant comorbidities b-blockers worsened the airway obstruction in COPD

CONCLUSION What mechanisms of increased mortality in b- blocker? lower for patients using LABA + ICS  long-acting bronchodilation counteracts some of the adverse respiratory effects of b-blockers? Antiplatelet drugs, and possibly ACEI/ARB and statins have beneficial effects on survival in oxygen-dependent COPD