Randomised vitamin E supplementation and risk of chronic lung disease in the Women’s Health Study Anne H Agler, Tobias Kurth, J Michael Gaziano, Julie E Buring, Patricia A Cassano Thorax 2011;66:320e325 R1 Seon-Hye Kim Journal conference

 Chronic obstructive pulmonary disease (COPD) characterized by progressive irreversible airflow limitation and comprises a significant public health burden Prevalence of COPD in the US adult population : 3~4 % 5 th leading cause of death in the USA in 2001 expected to be 3rd leading cause of death by 2020, due to population ageing and increasing cumulative exposure to cigarette smoke. Contributing factors to rising COPD incidence obesity, dietary patterns, environmental & occupational exposures, and improved diagnostic and screening programmes. Introduction Introduction

 Hypothesis : diet or nutritional supplements plays a role in etiology of COPD.  Previous observational studies & randomized trials of diet or nutritional supplements → investigated the relation btw antioxidants (notably vitamin E) & lung outcomes. → higher intake of nutrients with antioxidant properties ∝ better pulmonary outcomes → but causal inferences are limited by concerns about confounding and other biases. Introduction Introduction

Limitation of previous studies 1)an incomplete understanding of potential to benefit 2)short duration of studies 3)Very few large randomized studies of non-diseased individuals have been completed. Introduction Introduction

Heart Protection Study (HPS)coronary disease, other occlusive arterial disease or DM vitamin E supplementsno effect of occurrence of respiratory- related death, on COPD/asthma hospitalization rates or on pulmonary function Alpha-Tocopherol and Beta- Carotene (ATBC) study male cigarette smokers α -tocopherolno effect of incidence of chronic bronchitis or COPD symptoms Women’s Health Study (WHS)healthy women (aged >45 yrs) Hypothesis : supplementation with 600 IU α-tocopherol EOD decreases the rate of occurrence of chronic lung disease (CLD)

METHODS METHODS Study design Randomized double-blind placebo controlled two-by-two factorial trial (39,876 women enrolled between April 1993 and January 1996 ) End of trial : 31 March 2004 Objective : risks & benefits of vit. E (600IU EOD) and/or aspirin supplements Inclusion criteria : age ≥ 45 years, healthcare professional in the USA no previous history of CAD, CVD and cancer, adverse aspirin effects less than weekly use of vit. E, A or b-carotene supplements

RESULTS RESULTS Figure 1 Flow diagram of the vitamin E component of the Women’s Health Study chronic lung disease (CLD) analysis. Total # = women

METHODS METHODS Outcomes Mailed questionnaires collected baseline data at the beginning : anthropometric, demographic, lifestyle & clinical characteristics Follow-up questionnaires : completed twice during the first yr & annually thereafter : supplement compliance, new disease occurrence & diagnosis date, personal characteristics & habits, non-study aspirin, vitamin & NSAIDs use and side effects CLD(Chronic Lung Disease) ascertainment : self-reported doctor-diagnosed CLD was ascertained on questionnaires beginning 12 months after study enrollment

RESULTS RESULTS Table 1-A Baseline characteristics of participants in the Women’s Health Study by vitamin E randomization

RESULTS RESULTS Table 1-B. Baseline characteristics of participants in the Women’s Health Study by vitamin E randomization

RESULTS RESULTS Figure 2. Cumulative incidence of chronic lung disease during the randomised component of the Women’s Health Study. 4.4% 3.9%

RESULTS RESULTS Figure 3 Effect modification of the vitamin E/chronic lung disease effect in the Women’s Health Study.

Discussion Discussion Maintenance Immunosuppression Mino Heart Protection Study (HPS) Woman’s Health Study (WHS) Alpha-Tocopherol and Beta-Carotene (ATBC) study Cardiovascular disease OXX Cigarette smokersPartial all Gender ratioM: F = 3:1M:F= 0:1M:F = 1:0 Study duration5 yrs10 yrs4 yrs Supplement formulation Vit. A, C & E (600IU) combined Vit. E (600IU) alone Vit. E (5omg) and/or Vit. A Outcome of pulmonary function no effect of hospitalization, respiratory related death Reduced the risk of occurrence of new CLD (approximately 10%) no effect of incidence of COPD or COPD symptoms

Discussion Discussion Limitations 1) outcome ascertainment was based solely on self-reported doctor diagnosis, a concern that is partly mitigated by the fact that participants were female health professionals clinical characteristics 2)if the outcome is misclassified (either by undercounting cases or by including false positives), the misclassification is likely to affect both arms of the trial equally and the HR may therefore be an underestimate of the true effect size.

Discussion Discussion Proposed mechanisms Vitamin E transport to the type II cells is hypothesized to occur via high density lipoproteins(HDL) because type II cells have no physical contact with plasma and interact only with interstitial fluid lipoproteins, which are predominantly HDL lipoproteins. The concentration of HDL cholesterol in the plasma & in the interstitial fluid predicts the amount of vitamin E available to the lung compartment to combat oxidative stress. Thus, a higher HDL cholesterol level is hypothesized to deliver a greater effective dose of vitamin E to the lung compartment.

Discussion Discussion Proposed mechanisms Given that HDL cholesterol levels are 20~25% higher in women than in men of all age groups, differences in the biologically effective dose of vitamin E may contribute to the difference in findings between women in the WHS and the predominantly male participants in the HPS and ATBC. Alcohol intake (threshold of ≥ 1 alcoholic drink /day) is associated with both higher HDL cholesterol levels. The preventive effect of vitamin E on CLD was greatest in women consuming the highest level of alcohol (≥ 1 drink/day).

Discussion Discussion Efficacy and safety considerations  The efficacy and safety of vitamin E supplementation 1)potential harmful effects include an increased risk of all cause mortality, susceptibility to bleeding and hemorrhagic stroke. 2) a recent paper suggested that vitamin E has beneficial effects on the risk of ischemic stroke. Thus, the design of future vitamin E supplementation trials must carefully consider information about risks and benefits, and recommendations may need to be tailored to specific populations.

CONCLUSIONS CONCLUSIONS Female health professionals taking 600 IU vitamin E supplements EOD were 10% less likely to report a new CLD diagnosis. Any decisions about use of vitamin E as a preventive must consider information about vitamin E-associated risks and bioavailability. There are few prevention strategies for emphysema and chronic bronchitis, so further study of vitamin E in relation to COPD is needed for relieving public health burden.