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Age-related macular degeneration and risk of total and cause-specific mortality over 15 years
Maturitas 84 (2016) 63–67
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Age-related macular degeneration and risk of total and cause-specific mortality over 15 years Bamini Gopinath ∗ , Gerald Liew, George Burlutsky, Paul Mitchell Centre for Vision Research, Department of Ophthalmology, Westmead Millennium Institute, The University of Sydney, Sydney, Australia
a r t i c l e
i n f o
Article history: Received 28 September 2015 Received in revised form 30 October 2015 Accepted 2 November 2015 Keywords: Age-related macular degeneration Blue Mountains Eye Study Mortality Cardiovascular disease Ischemic heart disease
a b s t r a c t Objective: We aimed to investigate the independent association between AMD and risk of ischemic heart disease (IHD), stroke, and cardiovascular (CVD) mortality, and all-cause mortality over 15 years. Methods: 3654 participants aged 49+ years at baseline were followed over 15 years. AMD was assessed from retinal photographs. Deaths and cause of death were confirmed by data linkage with the Australian National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were assessed using Cox models. Results: 71.4% (n = 162) and 34.6% (n = 1037) of participants with any AMD and no AMD, respectively, died over 15 years. After multivariable-adjustment, no significant associations were observed between AMD and total- and cause-specific mortality in the overall cohort. However, among men, late AMD at baseline was associated with an increased risk of all-cause mortality (n = 22; 95.7%), 15 years later: multivariableadjusted HR, 1.80 (95% CI 1.04–3.11). Women with late AMD had 2-fold increased risk of stroke mortality (n = 15; 28.9%), HR 2.10 (95% CI 1.08–4.06). Early-stage AMD was not associated with mortality risk. Conclusion: Late AMD independently predicted all-cause mortality in men and stroke mortality in women, over 15 years. Although underlying mechanisms are unclear, these findings indicate that late AMD is a marker of biological aging. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Age-related macular degeneration (AMD) is a progressive, chronic disease of the central retina, and is a leading cause of blindness and low vision among older adults [1]. AMD has both early and late stages. Early AMD is usually not associated with loss of vision. Vision loss in late AMD is caused either by neovascular disease, with growth of new blood vessels that leak and scar underneath the central retina, or by geographic atrophy in which an area of the retina in the macula atrophies. Neovascular or wet AMD is responsible for most AMD-related severe visual loss [2–9]. The most important risk factor for any stage of AMD is old age. Pooled data from seven population-based studies showed that the prevalence of geographic atrophy in the United States was 0.3% in 60–64 year olds, 0.5% in 65–69 year olds, 0.9% in 70–74 year olds, 1.8% in 75–79 year olds, and 6.9% in those 80 or older [5]. The respective rates for neovascular disease were 0.4%, 0.6%, 1.2%, 2.2%, and 8.2%. Therefore, as life expectancy improves with advances in medicine and
∗ Corresponding author at: Centre for Vision Research, University of Sydney, Westmead Millennium Institute, Westmead, NSW 2145, Australia. Fax: +61 2 86273099. E-mail address: [email protected] (B. Gopinath). http://dx.doi.org/10.1016/j.maturitas.2015.11.001 0378-5122/© 2015 Elsevier Ireland Ltd. All rights reserved.
public health, the number of patients affected by AMD is also likely to increase [5,10]. Several studies have attempted to establish whether persons with AMD are at increased risk of death, particularly resulting from vascular causes, but results have been equivocal [11–15]. This inconsistency in findings is speculated to be due to AMD being associated with other systemic conditions that are risk factors for mortality, so that controlling for these risk factors nullified the association between AMD and mortality in some [15,16] but not all studies [11–14]. Differences in study design, age-sex population distribution, and follow-up duration could also explain these differences [11]. It was suggested in one study that longer follow-up (i.e., at least 15 years) would be needed to establish the relationship between AMD and mortality risk [11,13]. To best of our knowledge, only the recent Study of Osteoporotic Fractures [11] has looked at the relationship between AMD and mortality risk over 15 years. This study showed that women aged 80+ years with any AMD had increased risk of death from any cause or cardiovascular disease (CVD). However, the results of this study are not applicable to all older adults, given that this study did not examine AMD and 15-year mortality risk in men. Therefore, in this report we aimed to enhance current understanding of whether AMD is a useful prognostic indicator in
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identifying older adults at risk of poorer survival. Specifically, we assessed the association between AMD (any, early or late) and allcause and cause-specific mortality (CVD; ischemic heart disease, IHD; and stroke mortality) 15 years later, independent of the effects of various potential confounders (e.g., age, sex, smoking, body mass index, diabetes, hypertension, cancer, angina, myocardial infarction, walking disability and self-rated health). 2. Methods
2.3. Assessment of mortality
2.1. Study population The Blue Mountains Eye Study (BMES) is a population-based cohort study of common eye diseases and other health outcomes in a suburban Australian population located west of Sydney. Study methods and procedures have been described elsewhere [17]. Baseline examinations of 3654 residents aged >49 years were conducted during 1992–4 (BMES-1; 82.4% participation rate). Surviving baseline participants were invited to attend examinations after 5- (1997–9, BMES-2), 10- (2002–4, BMES-3), and 15 years (2007–9, BMES-4) at which 2334 (75.1% of survivors), 1952 participants (75.6% of survivors) and 1149 (55.4% of survivors) were re-examined, respectively. For the current report we have analyzed data from BMES-1 through to BMES-3. The University of Sydney and the Western Sydney Area Human Ethics Committees approved the study, and written, informed consent was obtained from all participants at each examination. 2.2. Assessment of AMD For the current analyses, the primary study factor was the presence/absence of early and late AMD at baseline i.e., BMES-1. We took two 30◦ stereoscopic color retinal photographs of the macula of both eyes, which were graded for presence of early and late AMD using the Wisconsin AMD Grading System [7,18]. Inter- and intragrader reliability showed good agreement for grading of specific AMD lesions with quadratic weighted kappa values ranging from 0.64 to 0.93 and 0.54–0.94 respectively [2]. The detailed methodology of AMD ascertainment in this population has been previously reported [7,18]. Early AMD was defined as the absence of late AMD and presence of either: (1) large (>125-m diameter) indistinct soft or reticular drusen or (2) both large distinct soft drusen and Table 1 Baseline characteristics of Blue Mountains Eye Study participants stratified by gender (n = 3654). Variable
Women (n = 2072)
Men (n = 1582)
P-value
Age, years Tertiary education Smoking status Never smoked Former smoker Current smoker
66.4 (9.9) 1016 (52.4)
65.9 (9.5) 970 (65.5)
0.16 <0.0001 <0.0001
1215 (61.3) 488 (24.6) 278 (14.0)
485 (32.3) 772 (51.3) 247 (16.4)
1254 (63.1) 292 (14.7) 440 (22.2) 26.1 (5.0) 170 (8.2) 78 (3.8) 986 (48.0) 132 (6.9) 200 (9.7) 231 (11.2) 134 (6.5) 52 (2.5)
638 (42.2) 313 (20.7) 562 (37.1) 26.2 (3.8) 96 (6.1) 62 (4.0) 659 (41.9) 149 (10.3) 110 (7.0) 223 (14.2) 204 (13.0) 23 (1.5)
Alcohol consumption <1 Drink/week 1–4 Drinks/week >4 Drinks/week Body mass index kg/m2 Walking disability Low self-rated health Hypertension Diabetes Cancer Angina Myocardial infarction Stroke
retinal pigmentary abnormalities (hyperpigmentation or hypopigmentation) in either eye [18]. Similarly, late AMD was defined as the presence of neovascular AMD or geographic atrophy in either eye [18]. Any AMD was defined as having early or late AMD. A retinal specialist (P.M.) adjudicated all uncertain retinal pathology and confirmed all late AMD cases. Patients and their physicians were informed by mail if they were diagnosed with AMD through these photographs.
All data are presented as mean (SD) or n (%).
Mortality data since baseline (15 years) were obtained via data linkage with the Australian National Death Index (NDI). Information provided by family members during follow-up was also included if the participant was reported to have died on or before December 2007. The International Classification of Diseases, 9th and 10th Revision [19] cause of death codes were obtained. Validity of NDI data has been reported to have high sensitivity and specificity for cardiovascular mortality (92.5% and 89.6%, respectively) [20]. The census cut-off point for mortality was end of December 2007 (i.e., a 15-year period from the baseline examination). 2.4. Assessment of covariates At face-to-face interviews with trained interviewers, a comprehensive medical history that included information about demographic factors, socio-economic characteristics and lifestyle factors like smoking was obtained from all participants. For the current analyses, we used covariate information that was obtained at baseline (BMES-1) only. History of smoking was defined as never, past, or current smoking. Current smokers included those who had stopped smoking within the past year. Alcohol intake was assessed by questions about the frequency of consuming alcoholic drinks (days per week), and consumption was split into 3 groups (<1 drink/week; 1–4 drinks/week; >4 drinks/week). A history of angina, myocardial infarction, diabetes mellitus, hypertension, stroke, or cancer at baseline was determined by responses to questions starting with “Has a doctor advised you that you have . . . ?” Fasting blood samples were processed on the same day for serum lipids, plasma glucose concentrations, white blood cell count, and fibrinogen at the Westmead Hospital Clinical Pathology laboratory, in western Sydney, Australia. Diabetes was defined either from history or by fasting blood glucose ≥7.0 mmol/L. Body mass index (BMI) was calculated from measured weights and heights (kg/m2 ). Disability in walking at baseline was assessed as present if the participant was observed by a trained examiner to have walking difficulties or used walking aids or a wheelchair. Self-rated health was assessed by asking, “For somebody your age, would you say your health is excellent, very good, good, fair, or poor?” Low self-rated health was defined as fair/poor. 2.5. Statistical analysis
<0.0001
0.72 0.01 0.99 0.0003 0.001 0.004 0.01 <0.0001 0.03
SAS (SAS Institute, Cary NC) version 9.2 was used for analyses. The association between presence of AMD and total and causespecific mortality was examined with Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI). Because risk of AMD and mortality are strongly associated with increasing age, age was used as the time scale in the Cox proportional hazards regression, allowing the models to compare risk for people of comparable age (instead of length of follow-up) [12]. Covariates adjusted for in mortality analyses were those previously shown to be associated with total and cause-specific mortality in the BMES: age, sex, educational status (tertiary qualified or not), current smoking, alcohol consumption, BMI, walking disability, doctor-diagnosed history of cancer, angina, acute myocardial
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Table 2 Association between age-related macular degeneration (AMD) and 15-year total mortality, cardiovascular disease (CVD) and ischemic heart disease (IHD) mortality, presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI)a in the Blue Mountains Eye Study (n = 3654). AMD status All-cause mortality (n = 1473)
No AMD Any AMD Early AMD Late AMD
CVD mortalityl (n = 882)
IHD mortalityl (n = 611)
Stroke mortalityl (n = 402)
No. of cases/no. at risk
Adjusted HR (95% No. of cases/no. CI) at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
1406/3569 162/227 95/152 67/75
1.0 (Reference) 1.07 (0.87–1.32) 1.02 (0.80–1.31) 1.08 (0.79–1.49)
1.0 (Reference) 0.95 (0.73–1.25) 0.82 (0.58–1.16) 1.20 (0.82–1.75)
577/3569 73/227 39/152 34/75
1.0 (Reference) 1.07 (0.78–1.46) 0.90 (0.61–1.32) 1.41 (0.90–2.19)
382/3572 46/227 26/152 20/75
1.0 (Reference) 0.87 (0.57–1.34) 0.75 (0.43–1.32) 1.15 (0.66–2.03)
836/3572 98/227 52/152 46/75
a Adjusted for age, sex, qualifications, body mass index, smoking status, alcohol consumption, poor self-rated health, walking disability, presence of hypertension and/or diabetes, doctor-diagnosed history of cancer, angina, stroke and/or acute myocardial infarction.
Table 3 Association between age-related macular degeneration (AMD) and 15-year total mortality, cardiovascular disease (CVD) and ischemic heart disease (IHD) mortality, presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI)a among men (n = 1582). AMD status
No AMD Any AMD Early AMD Late AMD
All-cause mortality (n = 735)
CVD mortality (n = 426)
IHD mortality (n = 312)
Stroke mortality (n = 180)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
713/1555 67/87 45/64 22/23
1.0 (Reference) 1.22 (0.89–1.65) 1.06 (0.75–1.52) 1.80 (1.04–3.11)
413/1555 34/87 21/64 13/23
1.0 (Reference) 0.99 (0.64–1.53) 0.89 (0.53–1.51) 1.12 (0.54–2.30)
299/1555 33/87 20/64 13/23
1.0 (Reference) 1.27 (0.82–1.98) 1.04 (0.61–1.78) 2.04 (0.99–4.22)
175/1555 11/87 6/64 5/23
1.0 (Reference) 0.49 (0.19–1.30) 0.46 (0.11–1.95) 0.58 (0.18–1.90)
a Adjusted for age, qualifications, body mass index, smoking status, alcohol consumption, poor self-rated health, walking disability, presence of hypertension and/or diabetes, doctor-diagnosed history of cancer, angina, stroke and/or acute myocardial infarction.
Table 4 Association between age-related macular degeneration (AMD) and 15-year total mortality, cardiovascular disease (CVD) and ischemic heart disease (IHD) mortality, presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI)a among women (n = 2072). AMD status
No AMD Any AMD Early AMD Late AMD
All-cause mortality (n = 738)
CVD mortality (n = 456)
IHD mortality (n = 299)
Stroke mortality (n = 222)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
693/2016 95/140 50/88 45/52
1.0 (Reference) 1.01 (0.76–1.35) 1.05 (0.74–1.49) 0.96 (0.64–1.43)
423/2017 64/140 31/88 33/52
1.0 (Reference) 1.03 (0.72–1.47) 0.79 (0.50–1.26) 1.55 (0.98–2.46)
278/2016 40/140 19/88 21/52
1.0 (Reference) 0.96 (0.62–1.50) 0.83 (0.46–1.48) 1.22 (0.68–2.21)
207/2017 35/140 20/88 15/52
1.0 (Reference) 1.36 (0.83–2.22) 1.08 (0.57–2.04) 2.10 (1.08–4.06)
a Adjusted for age, qualifications, body mass index, smoking status, alcohol consumption, poor self-rated health, walking disability, presence of hypertension and/or diabetes, doctor-diagnosed history of cancer, angina, stroke and/or acute myocardial infarction.
infarction, stroke, diabetes mellitus and hypertension, and low self-rated health. Age was included in the final model as a linear covariate; and in addition the Cox regression models were also stratified by age (given that the effects of age on might be non-linear). We used Martingale-based residuals method to test proportionality assumptions of the hazard ratios for each covariate. After using age strata we found that proportionality assumptions were satisfied. We also tested for a statistically significant interaction between AMD and sex by adding a product term in the final multivariable model. We defined an interaction if the association between the joint variable of AMD and sex departed from the multiplicative scale of the association between each factor alone, confirmed by a statistically significant interaction term. However, there was no significant interaction term between AMD and sex on all-cause or cause-specific mortality risk (all values were P > 0.05). However, there is extensive published evidence to support sexspecific differences in mortality rates [21–23], hence, we also chose to stratify our analyses by men and women. Significance was taken as P < 0.05. 3. Results Table 1 shows the study characteristics of participants at baseline stratified by gender. Women compared to men were more likely to consume less than 1 drink per week, and to have a walk-
ing disability, hypertension, stroke and cancer. However, women versus men were less likely to have tertiary qualifications, diabetes, angina, and acute myocardial infarction (Table 1). Over the 15 years, 1473 participants had died. Of those with any AMD, early or late AMD at baseline, 162 (71.4%), 95 (62.5%) and 67 (89.3%) had died 15 years later, respectively (Table 2). The mean age of all-cause mortality for men and women was 79.0 (8.7) and 81.6 (9.6) years, respectively (p < 0.0001). Significant differences were also observed in mean age of CVD, IHD and stroke mortality for men and women: 80.2 and 83.6 (p < 0.0001); 80.3 and 83.1 (p < 0.0001); and 80.8 and 84.3 (p < 0.0001), respectively. The mean time to death from all causes, CVD, IHD, and stroke for men and women was: 7.5 versus 8.1 years (p = 0.01); 8.1 versus 8.6 (p = 0.09), 8.4 versus 8.9 (p = 0.13) and 7.3 and 8.4 (p = 0.01), respectively. After multivariable adjustment, no significant associations were observed between AMD status at baseline and risk of all-cause and cause-specific mortality 15 years later (Table 2) among all persons. Table 3 shows that men with late AMD at baseline, had increased risk of 15-year all-cause mortality multivariable-adjusted HR 1.80 (95% CI 1.04–3.11). A marginally significant association (p = 0.05) between late AMD and IHD mortality was also observed in men, HR 2.04 (95% CI 0.99–4.22). Among women, late AMD was associated with 2-fold increased risk of death from stroke 15 years later (Table 4), multivariable-adjusted HR 2.10 (95% CI 1.08–4.06).
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4. Discussion This cohort study extends the existing published literature by showing that late AMD is a significant and independent predictor of 15-year all-cause mortality in men, and stroke mortality in women. Men or women with early AMD were not at a higher risk of dying compared to persons without AMD. These epidemiological data add to the existing evidence-base that late AMD could be a marker of biological aging and poorer survival in older adults. Our findings reiterate data from previous studies which have shown that older adults with early AMD are not more likely to die than their peers who have no AMD [12]. The most likely reason that late AMD rather than early AMD independently predicts mortality risk in older adults is that early AMD is usually not associated with the loss of vision. Whereas, vision loss in late AMD is caused either by neovascular disease, with growth of new blood vessels that leak and scar underneath the central retina, or by geographic atrophy in which an area of the retina in the macula atrophies. Neovascular AMD is responsible for most AMD-related severe visual loss [7]. Hence, late AMD could accelerate the aging process through poorer vision and greater frailty, leading to more accidents, falls and fractures, misuse of medication, and difficulty attending doctors, all of which could contribute to a higher risk of all-cause death [11,24,25]. Alternatively, the link between late AMD and reduced overall survival could reflect some, as yet undetermined, systemic pathophysiologic features indicative of physiological aging [12]. For instance, persons with late AMD might have a greater propensity to survive to old age and then biologically succumb to vascular dysfunction at a faster rate than those survivors of comparable age without AMD. On the other hand, persons with early AMD have other health conditions that place them at risk of dying at the same rate as their counterparts of similar age who do not have AMD [12,14]. Given that we found marginally significant associations between late AMD and IHD mortality in men and increased stroke mortality risk in women with late AMD; the current study support the hypothesis that AMD and vascular disease could share common antecedents [26]. A recent systematic review [26] supports our findings, as it showed that when late AMD manifests first, it might serve as a useful indicator of a higher risk for future vascular events. These findings also have implications for long-term treatment of late AMD with anti-VEGF agents which some [27], though not all [28], studies suggest may have a small effect on increased risk of CVD. Atherosclerosis, inflammation and oxidative stress, implicated in the pathogenesis of both AMD and vascular disease [29,30], could be potential mechanistic links between these two diseases. Moreover, lipid metabolism has been shown to have a possible role in AMD [31], which could be another potential mechanism that underlies its link with CVD. Recent research indicates that C-reactive protein, a marker of systematic inflammation and independent risk factor for CVD, is associated with AMD as well [26]. Variants in the complement factor H gene have recently been identified to predict AMD risk [32], and complement activation may also increase risk of stroke [14] and CVD [33]. Further, smoking is strong risk factor for both AMD and stroke [34,35]. However, the relationship between AMD and vascular mortality is likely to be more complex than a single shared risk factor or even a single shared biological pathway, and more work is clearly needed [26]. Reasons for the sex-specific associations observed in the current study are unclear. There is increasing interest in whether this might be linked to e.g., sex differences in cerebrovascular events [36] particularly for neovascular AMD, where women have higher rates at older ages (as cerebrovascular mortality may have already occurred in men) [37,38]. Moreover, it has been shown that stroke tended to be more severe in women, with a 1-month case fatality of 24.7% compared with 19.7% for men [37]. This concurs with our finding
of a significant association between late AMD and stroke mortality in women but not men. Conversely, significant associations were observed between late AMD and total mortality in men but not women. This could be because men, as a result of less healthy lifestyles (e.g., men compared to women were more likely to be current smokers in the BMES; 16% versus 14%), have a greater predisposition to late AMD, and hence, may also be the group which is likely to have increased risk of mortality due to these lifestyle risk factors. Moreover, putative AMD risk factors may reflect differential distribution of underlying health profiles based on distinct exposures experienced by different birth cohorts [12] or men and women over their lifetime[12]. Our study has some noteworthy strengths, first, ours is a prospective study with longer duration of follow-up, and thus, there is likely to be sufficient time for increased risk of mortality to become manifest. Additionally, we adjusted for a wide range of potentially confounding factors and used standardized procedures for AMD and mortality ascertainment. However, our study findings also needed to be interpreted with caution as it is not without its limitations. First, our finding that late AMD predicts mortality risk was based on relatively small numbers (particularly in the case of sex-stratified analyses) and hence, should be interpreted cautiously. Second, we cannot exclude the effects of unknown or poorly measured confounding factors or residual confounding attributable to other mortality risk factors which could have influenced the observed associations between AMD and risk of death in the BMES. 5. Conclusion In summary, we found that the presence of late AMD independently predicted an increased risk of all-cause mortality in men, and stroke mortality in women, 15 years later. The sex-specific associations observed with total- and cause-specific mortality in the BMES, warrants further investigation by other prospective studies with longer duration of follow-up and larger sample size. While underlying mechanisms are unclear, these findings suggest that late AMD is a marker of biological aging. Funding The Blue Mountains Eye Study was funded by the Australian National Health and Medical Research Council (Grant Nos. 974159, 991407, 211069, 262120, 457349), and Westmead Millennium Institute. Bamini Gopinath is supported by a Blackmores Dr Paul Beaumont and Macular Disease Foundation of Australia Fellowship. Author’s contributions All authors contributed significantly to the conduct of the study, analysis and manuscript preparation. Study concept and design: BG and PM. Acquisition of subjects and data: PM. Analysis and interpretation of data: BG, GL, GB, PM. Preparation of Manuscript: BG. Important critical revision: BG, GL, GB, PM. Competing interest None to declare. Ethical approval The University of Sydney and the Western Sydney Area Human Ethics Committees approved the study, and written, informed consent was obtained from all participants at each examination.
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Maturitas journal homepage: www.elsevier.com/locate/maturitas
Age-related macular degeneration and risk of total and cause-specific mortality over 15 years Bamini Gopinath ∗ , Gerald Liew, George Burlutsky, Paul Mitchell Centre for Vision Research, Department of Ophthalmology, Westmead Millennium Institute, The University of Sydney, Sydney, Australia
a r t i c l e
i n f o
Article history: Received 28 September 2015 Received in revised form 30 October 2015 Accepted 2 November 2015 Keywords: Age-related macular degeneration Blue Mountains Eye Study Mortality Cardiovascular disease Ischemic heart disease
a b s t r a c t Objective: We aimed to investigate the independent association between AMD and risk of ischemic heart disease (IHD), stroke, and cardiovascular (CVD) mortality, and all-cause mortality over 15 years. Methods: 3654 participants aged 49+ years at baseline were followed over 15 years. AMD was assessed from retinal photographs. Deaths and cause of death were confirmed by data linkage with the Australian National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were assessed using Cox models. Results: 71.4% (n = 162) and 34.6% (n = 1037) of participants with any AMD and no AMD, respectively, died over 15 years. After multivariable-adjustment, no significant associations were observed between AMD and total- and cause-specific mortality in the overall cohort. However, among men, late AMD at baseline was associated with an increased risk of all-cause mortality (n = 22; 95.7%), 15 years later: multivariableadjusted HR, 1.80 (95% CI 1.04–3.11). Women with late AMD had 2-fold increased risk of stroke mortality (n = 15; 28.9%), HR 2.10 (95% CI 1.08–4.06). Early-stage AMD was not associated with mortality risk. Conclusion: Late AMD independently predicted all-cause mortality in men and stroke mortality in women, over 15 years. Although underlying mechanisms are unclear, these findings indicate that late AMD is a marker of biological aging. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Age-related macular degeneration (AMD) is a progressive, chronic disease of the central retina, and is a leading cause of blindness and low vision among older adults [1]. AMD has both early and late stages. Early AMD is usually not associated with loss of vision. Vision loss in late AMD is caused either by neovascular disease, with growth of new blood vessels that leak and scar underneath the central retina, or by geographic atrophy in which an area of the retina in the macula atrophies. Neovascular or wet AMD is responsible for most AMD-related severe visual loss [2–9]. The most important risk factor for any stage of AMD is old age. Pooled data from seven population-based studies showed that the prevalence of geographic atrophy in the United States was 0.3% in 60–64 year olds, 0.5% in 65–69 year olds, 0.9% in 70–74 year olds, 1.8% in 75–79 year olds, and 6.9% in those 80 or older [5]. The respective rates for neovascular disease were 0.4%, 0.6%, 1.2%, 2.2%, and 8.2%. Therefore, as life expectancy improves with advances in medicine and
∗ Corresponding author at: Centre for Vision Research, University of Sydney, Westmead Millennium Institute, Westmead, NSW 2145, Australia. Fax: +61 2 86273099. E-mail address: [email protected] (B. Gopinath). http://dx.doi.org/10.1016/j.maturitas.2015.11.001 0378-5122/© 2015 Elsevier Ireland Ltd. All rights reserved.
public health, the number of patients affected by AMD is also likely to increase [5,10]. Several studies have attempted to establish whether persons with AMD are at increased risk of death, particularly resulting from vascular causes, but results have been equivocal [11–15]. This inconsistency in findings is speculated to be due to AMD being associated with other systemic conditions that are risk factors for mortality, so that controlling for these risk factors nullified the association between AMD and mortality in some [15,16] but not all studies [11–14]. Differences in study design, age-sex population distribution, and follow-up duration could also explain these differences [11]. It was suggested in one study that longer follow-up (i.e., at least 15 years) would be needed to establish the relationship between AMD and mortality risk [11,13]. To best of our knowledge, only the recent Study of Osteoporotic Fractures [11] has looked at the relationship between AMD and mortality risk over 15 years. This study showed that women aged 80+ years with any AMD had increased risk of death from any cause or cardiovascular disease (CVD). However, the results of this study are not applicable to all older adults, given that this study did not examine AMD and 15-year mortality risk in men. Therefore, in this report we aimed to enhance current understanding of whether AMD is a useful prognostic indicator in
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identifying older adults at risk of poorer survival. Specifically, we assessed the association between AMD (any, early or late) and allcause and cause-specific mortality (CVD; ischemic heart disease, IHD; and stroke mortality) 15 years later, independent of the effects of various potential confounders (e.g., age, sex, smoking, body mass index, diabetes, hypertension, cancer, angina, myocardial infarction, walking disability and self-rated health). 2. Methods
2.3. Assessment of mortality
2.1. Study population The Blue Mountains Eye Study (BMES) is a population-based cohort study of common eye diseases and other health outcomes in a suburban Australian population located west of Sydney. Study methods and procedures have been described elsewhere [17]. Baseline examinations of 3654 residents aged >49 years were conducted during 1992–4 (BMES-1; 82.4% participation rate). Surviving baseline participants were invited to attend examinations after 5- (1997–9, BMES-2), 10- (2002–4, BMES-3), and 15 years (2007–9, BMES-4) at which 2334 (75.1% of survivors), 1952 participants (75.6% of survivors) and 1149 (55.4% of survivors) were re-examined, respectively. For the current report we have analyzed data from BMES-1 through to BMES-3. The University of Sydney and the Western Sydney Area Human Ethics Committees approved the study, and written, informed consent was obtained from all participants at each examination. 2.2. Assessment of AMD For the current analyses, the primary study factor was the presence/absence of early and late AMD at baseline i.e., BMES-1. We took two 30◦ stereoscopic color retinal photographs of the macula of both eyes, which were graded for presence of early and late AMD using the Wisconsin AMD Grading System [7,18]. Inter- and intragrader reliability showed good agreement for grading of specific AMD lesions with quadratic weighted kappa values ranging from 0.64 to 0.93 and 0.54–0.94 respectively [2]. The detailed methodology of AMD ascertainment in this population has been previously reported [7,18]. Early AMD was defined as the absence of late AMD and presence of either: (1) large (>125-m diameter) indistinct soft or reticular drusen or (2) both large distinct soft drusen and Table 1 Baseline characteristics of Blue Mountains Eye Study participants stratified by gender (n = 3654). Variable
Women (n = 2072)
Men (n = 1582)
P-value
Age, years Tertiary education Smoking status Never smoked Former smoker Current smoker
66.4 (9.9) 1016 (52.4)
65.9 (9.5) 970 (65.5)
0.16 <0.0001 <0.0001
1215 (61.3) 488 (24.6) 278 (14.0)
485 (32.3) 772 (51.3) 247 (16.4)
1254 (63.1) 292 (14.7) 440 (22.2) 26.1 (5.0) 170 (8.2) 78 (3.8) 986 (48.0) 132 (6.9) 200 (9.7) 231 (11.2) 134 (6.5) 52 (2.5)
638 (42.2) 313 (20.7) 562 (37.1) 26.2 (3.8) 96 (6.1) 62 (4.0) 659 (41.9) 149 (10.3) 110 (7.0) 223 (14.2) 204 (13.0) 23 (1.5)
Alcohol consumption <1 Drink/week 1–4 Drinks/week >4 Drinks/week Body mass index kg/m2 Walking disability Low self-rated health Hypertension Diabetes Cancer Angina Myocardial infarction Stroke
retinal pigmentary abnormalities (hyperpigmentation or hypopigmentation) in either eye [18]. Similarly, late AMD was defined as the presence of neovascular AMD or geographic atrophy in either eye [18]. Any AMD was defined as having early or late AMD. A retinal specialist (P.M.) adjudicated all uncertain retinal pathology and confirmed all late AMD cases. Patients and their physicians were informed by mail if they were diagnosed with AMD through these photographs.
All data are presented as mean (SD) or n (%).
Mortality data since baseline (15 years) were obtained via data linkage with the Australian National Death Index (NDI). Information provided by family members during follow-up was also included if the participant was reported to have died on or before December 2007. The International Classification of Diseases, 9th and 10th Revision [19] cause of death codes were obtained. Validity of NDI data has been reported to have high sensitivity and specificity for cardiovascular mortality (92.5% and 89.6%, respectively) [20]. The census cut-off point for mortality was end of December 2007 (i.e., a 15-year period from the baseline examination). 2.4. Assessment of covariates At face-to-face interviews with trained interviewers, a comprehensive medical history that included information about demographic factors, socio-economic characteristics and lifestyle factors like smoking was obtained from all participants. For the current analyses, we used covariate information that was obtained at baseline (BMES-1) only. History of smoking was defined as never, past, or current smoking. Current smokers included those who had stopped smoking within the past year. Alcohol intake was assessed by questions about the frequency of consuming alcoholic drinks (days per week), and consumption was split into 3 groups (<1 drink/week; 1–4 drinks/week; >4 drinks/week). A history of angina, myocardial infarction, diabetes mellitus, hypertension, stroke, or cancer at baseline was determined by responses to questions starting with “Has a doctor advised you that you have . . . ?” Fasting blood samples were processed on the same day for serum lipids, plasma glucose concentrations, white blood cell count, and fibrinogen at the Westmead Hospital Clinical Pathology laboratory, in western Sydney, Australia. Diabetes was defined either from history or by fasting blood glucose ≥7.0 mmol/L. Body mass index (BMI) was calculated from measured weights and heights (kg/m2 ). Disability in walking at baseline was assessed as present if the participant was observed by a trained examiner to have walking difficulties or used walking aids or a wheelchair. Self-rated health was assessed by asking, “For somebody your age, would you say your health is excellent, very good, good, fair, or poor?” Low self-rated health was defined as fair/poor. 2.5. Statistical analysis
<0.0001
0.72 0.01 0.99 0.0003 0.001 0.004 0.01 <0.0001 0.03
SAS (SAS Institute, Cary NC) version 9.2 was used for analyses. The association between presence of AMD and total and causespecific mortality was examined with Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI). Because risk of AMD and mortality are strongly associated with increasing age, age was used as the time scale in the Cox proportional hazards regression, allowing the models to compare risk for people of comparable age (instead of length of follow-up) [12]. Covariates adjusted for in mortality analyses were those previously shown to be associated with total and cause-specific mortality in the BMES: age, sex, educational status (tertiary qualified or not), current smoking, alcohol consumption, BMI, walking disability, doctor-diagnosed history of cancer, angina, acute myocardial
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Table 2 Association between age-related macular degeneration (AMD) and 15-year total mortality, cardiovascular disease (CVD) and ischemic heart disease (IHD) mortality, presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI)a in the Blue Mountains Eye Study (n = 3654). AMD status All-cause mortality (n = 1473)
No AMD Any AMD Early AMD Late AMD
CVD mortalityl (n = 882)
IHD mortalityl (n = 611)
Stroke mortalityl (n = 402)
No. of cases/no. at risk
Adjusted HR (95% No. of cases/no. CI) at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
1406/3569 162/227 95/152 67/75
1.0 (Reference) 1.07 (0.87–1.32) 1.02 (0.80–1.31) 1.08 (0.79–1.49)
1.0 (Reference) 0.95 (0.73–1.25) 0.82 (0.58–1.16) 1.20 (0.82–1.75)
577/3569 73/227 39/152 34/75
1.0 (Reference) 1.07 (0.78–1.46) 0.90 (0.61–1.32) 1.41 (0.90–2.19)
382/3572 46/227 26/152 20/75
1.0 (Reference) 0.87 (0.57–1.34) 0.75 (0.43–1.32) 1.15 (0.66–2.03)
836/3572 98/227 52/152 46/75
a Adjusted for age, sex, qualifications, body mass index, smoking status, alcohol consumption, poor self-rated health, walking disability, presence of hypertension and/or diabetes, doctor-diagnosed history of cancer, angina, stroke and/or acute myocardial infarction.
Table 3 Association between age-related macular degeneration (AMD) and 15-year total mortality, cardiovascular disease (CVD) and ischemic heart disease (IHD) mortality, presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI)a among men (n = 1582). AMD status
No AMD Any AMD Early AMD Late AMD
All-cause mortality (n = 735)
CVD mortality (n = 426)
IHD mortality (n = 312)
Stroke mortality (n = 180)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
713/1555 67/87 45/64 22/23
1.0 (Reference) 1.22 (0.89–1.65) 1.06 (0.75–1.52) 1.80 (1.04–3.11)
413/1555 34/87 21/64 13/23
1.0 (Reference) 0.99 (0.64–1.53) 0.89 (0.53–1.51) 1.12 (0.54–2.30)
299/1555 33/87 20/64 13/23
1.0 (Reference) 1.27 (0.82–1.98) 1.04 (0.61–1.78) 2.04 (0.99–4.22)
175/1555 11/87 6/64 5/23
1.0 (Reference) 0.49 (0.19–1.30) 0.46 (0.11–1.95) 0.58 (0.18–1.90)
a Adjusted for age, qualifications, body mass index, smoking status, alcohol consumption, poor self-rated health, walking disability, presence of hypertension and/or diabetes, doctor-diagnosed history of cancer, angina, stroke and/or acute myocardial infarction.
Table 4 Association between age-related macular degeneration (AMD) and 15-year total mortality, cardiovascular disease (CVD) and ischemic heart disease (IHD) mortality, presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI)a among women (n = 2072). AMD status
No AMD Any AMD Early AMD Late AMD
All-cause mortality (n = 738)
CVD mortality (n = 456)
IHD mortality (n = 299)
Stroke mortality (n = 222)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
No. of cases/no. at risk
Adjusted HR (95% CI)
693/2016 95/140 50/88 45/52
1.0 (Reference) 1.01 (0.76–1.35) 1.05 (0.74–1.49) 0.96 (0.64–1.43)
423/2017 64/140 31/88 33/52
1.0 (Reference) 1.03 (0.72–1.47) 0.79 (0.50–1.26) 1.55 (0.98–2.46)
278/2016 40/140 19/88 21/52
1.0 (Reference) 0.96 (0.62–1.50) 0.83 (0.46–1.48) 1.22 (0.68–2.21)
207/2017 35/140 20/88 15/52
1.0 (Reference) 1.36 (0.83–2.22) 1.08 (0.57–2.04) 2.10 (1.08–4.06)
a Adjusted for age, qualifications, body mass index, smoking status, alcohol consumption, poor self-rated health, walking disability, presence of hypertension and/or diabetes, doctor-diagnosed history of cancer, angina, stroke and/or acute myocardial infarction.
infarction, stroke, diabetes mellitus and hypertension, and low self-rated health. Age was included in the final model as a linear covariate; and in addition the Cox regression models were also stratified by age (given that the effects of age on might be non-linear). We used Martingale-based residuals method to test proportionality assumptions of the hazard ratios for each covariate. After using age strata we found that proportionality assumptions were satisfied. We also tested for a statistically significant interaction between AMD and sex by adding a product term in the final multivariable model. We defined an interaction if the association between the joint variable of AMD and sex departed from the multiplicative scale of the association between each factor alone, confirmed by a statistically significant interaction term. However, there was no significant interaction term between AMD and sex on all-cause or cause-specific mortality risk (all values were P > 0.05). However, there is extensive published evidence to support sexspecific differences in mortality rates [21–23], hence, we also chose to stratify our analyses by men and women. Significance was taken as P < 0.05. 3. Results Table 1 shows the study characteristics of participants at baseline stratified by gender. Women compared to men were more likely to consume less than 1 drink per week, and to have a walk-
ing disability, hypertension, stroke and cancer. However, women versus men were less likely to have tertiary qualifications, diabetes, angina, and acute myocardial infarction (Table 1). Over the 15 years, 1473 participants had died. Of those with any AMD, early or late AMD at baseline, 162 (71.4%), 95 (62.5%) and 67 (89.3%) had died 15 years later, respectively (Table 2). The mean age of all-cause mortality for men and women was 79.0 (8.7) and 81.6 (9.6) years, respectively (p < 0.0001). Significant differences were also observed in mean age of CVD, IHD and stroke mortality for men and women: 80.2 and 83.6 (p < 0.0001); 80.3 and 83.1 (p < 0.0001); and 80.8 and 84.3 (p < 0.0001), respectively. The mean time to death from all causes, CVD, IHD, and stroke for men and women was: 7.5 versus 8.1 years (p = 0.01); 8.1 versus 8.6 (p = 0.09), 8.4 versus 8.9 (p = 0.13) and 7.3 and 8.4 (p = 0.01), respectively. After multivariable adjustment, no significant associations were observed between AMD status at baseline and risk of all-cause and cause-specific mortality 15 years later (Table 2) among all persons. Table 3 shows that men with late AMD at baseline, had increased risk of 15-year all-cause mortality multivariable-adjusted HR 1.80 (95% CI 1.04–3.11). A marginally significant association (p = 0.05) between late AMD and IHD mortality was also observed in men, HR 2.04 (95% CI 0.99–4.22). Among women, late AMD was associated with 2-fold increased risk of death from stroke 15 years later (Table 4), multivariable-adjusted HR 2.10 (95% CI 1.08–4.06).
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4. Discussion This cohort study extends the existing published literature by showing that late AMD is a significant and independent predictor of 15-year all-cause mortality in men, and stroke mortality in women. Men or women with early AMD were not at a higher risk of dying compared to persons without AMD. These epidemiological data add to the existing evidence-base that late AMD could be a marker of biological aging and poorer survival in older adults. Our findings reiterate data from previous studies which have shown that older adults with early AMD are not more likely to die than their peers who have no AMD [12]. The most likely reason that late AMD rather than early AMD independently predicts mortality risk in older adults is that early AMD is usually not associated with the loss of vision. Whereas, vision loss in late AMD is caused either by neovascular disease, with growth of new blood vessels that leak and scar underneath the central retina, or by geographic atrophy in which an area of the retina in the macula atrophies. Neovascular AMD is responsible for most AMD-related severe visual loss [7]. Hence, late AMD could accelerate the aging process through poorer vision and greater frailty, leading to more accidents, falls and fractures, misuse of medication, and difficulty attending doctors, all of which could contribute to a higher risk of all-cause death [11,24,25]. Alternatively, the link between late AMD and reduced overall survival could reflect some, as yet undetermined, systemic pathophysiologic features indicative of physiological aging [12]. For instance, persons with late AMD might have a greater propensity to survive to old age and then biologically succumb to vascular dysfunction at a faster rate than those survivors of comparable age without AMD. On the other hand, persons with early AMD have other health conditions that place them at risk of dying at the same rate as their counterparts of similar age who do not have AMD [12,14]. Given that we found marginally significant associations between late AMD and IHD mortality in men and increased stroke mortality risk in women with late AMD; the current study support the hypothesis that AMD and vascular disease could share common antecedents [26]. A recent systematic review [26] supports our findings, as it showed that when late AMD manifests first, it might serve as a useful indicator of a higher risk for future vascular events. These findings also have implications for long-term treatment of late AMD with anti-VEGF agents which some [27], though not all [28], studies suggest may have a small effect on increased risk of CVD. Atherosclerosis, inflammation and oxidative stress, implicated in the pathogenesis of both AMD and vascular disease [29,30], could be potential mechanistic links between these two diseases. Moreover, lipid metabolism has been shown to have a possible role in AMD [31], which could be another potential mechanism that underlies its link with CVD. Recent research indicates that C-reactive protein, a marker of systematic inflammation and independent risk factor for CVD, is associated with AMD as well [26]. Variants in the complement factor H gene have recently been identified to predict AMD risk [32], and complement activation may also increase risk of stroke [14] and CVD [33]. Further, smoking is strong risk factor for both AMD and stroke [34,35]. However, the relationship between AMD and vascular mortality is likely to be more complex than a single shared risk factor or even a single shared biological pathway, and more work is clearly needed [26]. Reasons for the sex-specific associations observed in the current study are unclear. There is increasing interest in whether this might be linked to e.g., sex differences in cerebrovascular events [36] particularly for neovascular AMD, where women have higher rates at older ages (as cerebrovascular mortality may have already occurred in men) [37,38]. Moreover, it has been shown that stroke tended to be more severe in women, with a 1-month case fatality of 24.7% compared with 19.7% for men [37]. This concurs with our finding
of a significant association between late AMD and stroke mortality in women but not men. Conversely, significant associations were observed between late AMD and total mortality in men but not women. This could be because men, as a result of less healthy lifestyles (e.g., men compared to women were more likely to be current smokers in the BMES; 16% versus 14%), have a greater predisposition to late AMD, and hence, may also be the group which is likely to have increased risk of mortality due to these lifestyle risk factors. Moreover, putative AMD risk factors may reflect differential distribution of underlying health profiles based on distinct exposures experienced by different birth cohorts [12] or men and women over their lifetime[12]. Our study has some noteworthy strengths, first, ours is a prospective study with longer duration of follow-up, and thus, there is likely to be sufficient time for increased risk of mortality to become manifest. Additionally, we adjusted for a wide range of potentially confounding factors and used standardized procedures for AMD and mortality ascertainment. However, our study findings also needed to be interpreted with caution as it is not without its limitations. First, our finding that late AMD predicts mortality risk was based on relatively small numbers (particularly in the case of sex-stratified analyses) and hence, should be interpreted cautiously. Second, we cannot exclude the effects of unknown or poorly measured confounding factors or residual confounding attributable to other mortality risk factors which could have influenced the observed associations between AMD and risk of death in the BMES. 5. Conclusion In summary, we found that the presence of late AMD independently predicted an increased risk of all-cause mortality in men, and stroke mortality in women, 15 years later. The sex-specific associations observed with total- and cause-specific mortality in the BMES, warrants further investigation by other prospective studies with longer duration of follow-up and larger sample size. While underlying mechanisms are unclear, these findings suggest that late AMD is a marker of biological aging. Funding The Blue Mountains Eye Study was funded by the Australian National Health and Medical Research Council (Grant Nos. 974159, 991407, 211069, 262120, 457349), and Westmead Millennium Institute. Bamini Gopinath is supported by a Blackmores Dr Paul Beaumont and Macular Disease Foundation of Australia Fellowship. Author’s contributions All authors contributed significantly to the conduct of the study, analysis and manuscript preparation. Study concept and design: BG and PM. Acquisition of subjects and data: PM. Analysis and interpretation of data: BG, GL, GB, PM. Preparation of Manuscript: BG. Important critical revision: BG, GL, GB, PM. Competing interest None to declare. Ethical approval The University of Sydney and the Western Sydney Area Human Ethics Committees approved the study, and written, informed consent was obtained from all participants at each examination.
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