Article

Hospitalized Cardiovascular Diseases in Neovascular Age-Related Macular Degeneration

The Degge Group, Ltd, Arlington, Virginia, USA.
Archives of ophthalmology (Impact Factor: 4.4). 09/2008; 126(9):1280-6. DOI: 10.1001/archopht.126.9.1280
Source: PubMed

ABSTRACT

To compare the incidence rate of hospitalized myocardial infarctions (MIs) and cerebrovascular accidents (CVAs) in subjects with and without neovascular age-related macular degeneration (AMD).
A retrospective database cohort study was performed in subjects with neovascular AMD and controls matched for age, sex, geography, and enrollment duration. Healthcare claims for the study period from January 1, 2002, to June 30, 2005, were used to identify subjects and outcomes. Incidence of hospitalized MI and CVA events and rate ratios adjusted for 11 risk factors were calculated.
In 7203 subjects with neovascular AMD and 20,208 controls, the rate of MI was 16.2 events per 1000 subjects with neovascular AMD and 23.1 events per 1000 controls. The adjusted rate ratio for MI was 0.58 (95% confidence interval, 0.48-0.72; P < .001) for subjects with neovascular AMD vs controls. The rate of CVA was 14.3 events per 1000 subjects with neovascular AMD and 22.1 events per 1000 controls. The adjusted rate ratio for CVA was 0.56 (95% confidence interval, 0.45-0.70; P < .001).
Rates of MI or CVA were significantly lower in subjects with neovascular AMD than in controls. These findings could not be explained by systematic differences in case selection, health care use, or comorbidities, although other possible biases cannot be ruled out.

Full-text

Available from: Emily West Gower
EPIDEMIOLOGY
Hospitalized Cardiovascular Diseases in Neovascular
Age-Related Macular Degeneration
Bao-Anh Nguyen-Khoa, PharmD, MPH; Earl L. Goehring Jr, BA; Winifred Werther, PhD;
Emily W. Gower, PhD; Diana V. Do, MD; Judith K. Jones, MD, PhD
Objective: To compare the incidence rate of hospital-
ized myocardial infarctions (MIs) and cerebrovascular ac-
cidents (CVAs) in subjects with and without neovascu-
lar age-related macular degeneration (AMD).
Methods: A retrospective database cohort study was per-
formed in subjects with neovascular AMD and controls
matched for age, sex, geography, and enrollment dura-
tion. Healthcare claims for the study period from Janu-
ary 1, 2002, to June 30, 2005, were used to identify sub-
jects and outcomes. Incidence of hospitalized MI and CVA
events and rate ratios adjusted for 11 risk factors were
calculated.
Results: In 7203 subjects with neovascular AMD and
20 208 controls, the rate of MI was 16.2 events per 1000
subjects with neovascular AMD and 23.1 events per 1000
controls. The adjusted rate ratio for MI was 0.58 (95%
confidence interval, 0.48-0.72; P.001) for subjects with
neovascular AMD vs controls. The rate of CVA was 14.3
events per 1000 subjects with neovascular AMD and 22.1
events per 1000 controls. The adjusted rate ratio for CVA
was 0.56 (95% confidence interval, 0.45-0.70; P.001).
Conclusions: Rates of MI or CVA were significantly lower
in subjects with neovascular AMD than in controls. These
findings could not be explained by systematic differ-
ences in case selection, health care use, or comorbidi-
ties, although other possible biases cannot be ruled out.
Arch Ophthalmol. 2008;126(9):1280-1286
A
GE-RELATED MACULAR DE-
generation (AMD) is the
leading cause of blind-
ness in people 65 years and
older in the United
States.
1,2
Neovascular AMD represents an
advanced form of AMD in which choroi-
dal neovascularization develops, and it is
associated with severe vision loss if un-
treated. Population estimates have placed
the prevalence of neovascular AMD at 1.3%
in adults older than 40 years and 9.3% in
people 80 years or older.
3
The 10-year in-
cidence of neovascular AMD is 4.1% in
persons older than 75 years.
4
Several stud-
ies have shown atherosclerotic diseases to
be a risk factor preceding AMD.
5-7
Con-
versely, 2 studies have prospectively
examined the development of new car-
diovascular events subsequent to a neo-
vascular AMD diagnosis; neither study
identified sufficient subjects with neo-
vascular AMD to provide generalizable
results.
8,9
Two larger studies in the Medi-
care population have yielded mixed re-
sults.
10,11
In this study, a large insurance
database was used to estimate and com-
pare incidence rates of myocardial infarc-
tion (MI) and cerebrovascular accident
(CVA) events in subjects with and with-
out neovascular AMD.
METHODS
DATA SOURCE
The Ingenix LabRx Database (LabRx) con-
tains administrative claims data for an em-
ployed, commercially insured population in the
United States who are enrolled in 11 health in-
surance plans affiliated with the United-
Health Group. The health plans have con-
tracts with a network of more than 400 000
physicians and more than 50% of all hospitals
in the United States to provide health care ser-
vices. The health plans are geographically di-
verse, with the largest proportion of patients
in the Midwest. Plan members are predomi-
nantly from employer-based groups offering
plans that include preferred provider organi-
zations, point of service arrangements, or man-
aged indemnity programs. Medical and phar-
macy claims are submitted by health care
providers to receive payment from the plans
for covered services. These claims records are
later patient deidentified and aggregated into
the research database (LabRx). LabRx con-
Author Affiliations: The Degge
Group, Ltd, Arlington, Virginia
(Drs Nguyen-Khoa and Jones
and Mr Goehring); Genentech
Inc, South San Francisco,
California (Dr Werther); and
Wilmer Eye Institute, Johns
Hopkins University School of
Medicine, Baltimore, Maryland
(Drs Gower and Do).
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tains the covered health care experience of approximately 14
million patients annually and is widely used for pharmacoepi-
demiologic, health quality, health outcomes, and economic re-
search. Longitudinal claims data in LabRx date back to 1993
and are cross-linked by 4 categories: membership data, medi-
cal claims, pharmacy claims, and health professional data.
12
Com-
plete pharmacy and medical claims data (including Medicare
and Medicaid) were available for all subjects in this study.
STUDY DESIGN
A retrospective cohort analysis of subjects with neovascular AMD
and their matched controls was conducted to determine the in-
cidence of MI and CVA, separately. The study period covered
January 1, 2002, through June 30, 2005.
STUDY POPULATION
Subjects With Neovascular AMD
Patients were classified as subjects with neovascular AMD if
they had an International Classification of Diseases, Ninth Revi-
sion, Clinical Modification (ICD-9-CM) diagnosis of 362.52 (exu-
dative senile macular degeneration) that was coded at least twice
on separate dates of service (
Figure 1). Retinal specialists were
responsible for 94% of the AMD diagnoses coded in this study.
The index date was defined as the date of the first neovascular
AMD diagnosis coded following a minimum of 183 days of ob-
servation. Subjects were included if they were at least 50 years
of age at the index date. Since only the year of birth was pro-
vided by LabRx, the midpoint (July 1) of the birth year was
used as the date of birth for each subject (
Figure 2).
Control Subjects
A set of controls frequency-matched on sex, region, enroll-
ment duration, and age at enrollment was identified at approxi-
mately an 11:1 ratio of controls to subjects with neovascular
AMD. Enrollment duration was matched within 6-month in-
tervals, while age was matched within 10-year intervals. Con-
trol subjects were excluded if they were coded at any time dur-
ing the study period for a diagnosis of neovascular AMD or other
types of macular degeneration (ICD-9-CM code 362.50 macu-
lar degeneration [senile], unspecified; 362.51 nonexudative se-
nile macular degeneration; or 362.57 drusen [degenerative]).
From this pool of potential matched controls, 3 subjects were
randomly selected without replacement for each subject with
neovascular AMD to create the final comparator cohort. Each
control subject for a subject with neovascular AMD was as-
signed the same index date as the corresponding subject with
neovascular AMD.
OUTCOMES
Events occurring after the index date were identified using in-
patient claims as defined by the variables “place of service” and
“health care cost category.” Outcome events with admission
and discharge dates that fell on the same day were excluded.
Adjacent hospital claims with the same provider identification
were counted as a single hospitalization if they were not sepa-
rated by at least 1 day.
The study outcomes, acute MI and CVAs, were analyzed sepa-
rately. These outcomes were defined using ICD-9-CM codes for
MI (410.xx) and CVA (431.xx, 432.xx, 433.x1, 434.x1, and
436.xx). Outcomes were based on definitions used by the An-
tiplatelet Trialists’ Collaboration.
8
Subjects were censored at the
first event.
To test the positive predictive value (PPV) for the out-
comes criteria, 2 hospital physicians working with the re-
search team evaluated 200 (100 subjects with neovascular AMD
and 100 controls) randomly selected claims profiles of pa-
tients identified with an outcome event. The physicians were
shown the specific outcome event claim and then used all avail-
able inpatient and outpatient diagnosis, procedural, and phar-
macy claims data to determine if the outcome was valid. Re-
viewers were blinded to the study design and all claims for eye
disorders or procedures were redacted from the profiles to re-
move any possibility of bias based on the inclusion criteria.
Where their conclusions differed, a third physician (J.K.J.) evalu-
ated those profiles to make a final decision. Sensitivity analy-
ses were then performed on the results of the discordant claims
to obtain a PPV range. The PPV was 71% for MI (range, 47%-
75%) and 66% (range, 47%-85%) for CVA. The percentage of
agreement between reviewers was 72% (95% confidence inter-
2005
183 d
Must have
2 neovascular AMD diagnoses
between July 1, 2002, and June 30, 2005
End of eligibility/
end of study period
Sample patient
Observation period for MI/CVA events (3.5 y)
2002
JUL2004JUL
X
1
X
2
E
1
2003JUL JUL
Figure 1. “Exudative senile macular degeneration” claims had to be coded at
least twice on separate dates of service. The neovascular age-related macular
degeneration (AMD) index date (X
1
) had to have been preceded by a
minimum of 183 days of continuous enrollment. Follow-up was censored at
either disenrollment or the end of the study period. X
2
indicates the sample
subsequent neovascular AMD diagnosis; E
1
, the sample event; MI,
myocardial infarction; CVA, cerebrovascular accident.
In neovascular
AMD data set
15
046
Excluded 6526 subjects (43%) with only
1 neovascular AMD diagnosis
(ICD-9-CM code 362.52)
Excluded 373 subjects (3%) younger than
50 years at index neovascular AMD diagnosis
Excluded 59 subjects (<
1%) where controls
could not be matched
Excluded 885 subjects (6%) without sufficient
enrollment history or without at least
183 days of enrollment history prior to
the index neovascular AMD diagnosis
(ICD-9-CM code 362.52)
In neovascular
AMD study cohort
7203
Subjects
remaining after
exclusion criterion
8520
Subjects
remaining after
exclusion criterion
7635
Subjects
remaining after
exclusion criterion
7262
Figure 2. Neovascular age-related macular degeneration (AMD) study cohort
identification. The original data set contained 15 046 subjects with
neovascular AMD, after 4 exclusion criteria were applied; the remaining 7203
subjects were included in the study. Forty-three percent of original subjects
with neovascular AMD were retained; 15 046 was used as the denominator to
calculate the percentages. ICD-9-CM indicates International Classification of
Diseases, Ninth Revision, Clinical Modification.
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val [CI], 63%-81%) and 62% (95% CI, 51%-71%) for MI and
CVA, respectively.
DATA ANALYSIS
For each subject, MI or CVA events were recorded along with
time to event, end of eligibility, or end of study period ex-
pressed to the nearest day. Event rates and 95% CIs were cal-
culated for each outcome by age and sex as the number of events
per 1000 persons. Time to event was calculated for each pa-
tient as the time from the index date to the outcome date, the
date at the end of their eligibility period, or the date at the end
of the study period. The detection of either outcome after the
index date was counted as an event. Initial data evaluation was
performed using SAS software version 9.1 (SAS Institute, Cary,
North Carolina).
Cox regression was performed to analyze the difference in
time to outcome events between subjects with neovascular AMD
and controls (R version 2.4.1; R Foundation for Statistical Com-
puting, Vienna, Austria). Adjustments were made for the pres-
ence of risk factors for MI and CVA during the 183-day period
preceding the index date, with all covariates included in the
model. These risk factors included history of MI or CVA in the
6-month period prior to the index date, congestive heart fail-
ure (inpatient only), diabetes mellitus, cardiac arrhythmia (in-
patient only), other cerebrovascular diseases, hypertension, hy-
perlipidemia, heart disease (coronary artery disease), and angina.
In addition, the Charlson comorbidity score, a weighted index
that takes into account the seriousness of the comorbid con-
ditions, was used to assess comorbidities in the analysis. The
Charlson Comorbidity Index was developed as a method for
estimating the risk of death from comorbid disease.
13
In this
study, a comorbidity score was calculated by modifying the
Charlson Comorbidity Index to include corresponding ICD-
9-CM codes for most comorbid conditions while excluding codes
for MI and CVA. This comorbidity score was included as a con-
tinuous variable in the regression model. Rate ratios (RRs) with
95% CIs were reported.
RESULTS
After applying the selection criteria, 7203 subjects with
neovascular AMD with 11 128 person-years (PY) and
20 208 controls with 28 407 PY were identified for analy-
sis. The average enrollment duration was 2.8 and 2.9 years
for subjects with neovascular AMD and controls, respec-
tively, with the largest proportion of follow-up time found
in patients aged 70 to 89 years. The mean age was 75 years
and the ratio of women to men was 3 to 2. Subjects with
neovascular AMD had slightly more comorbidities than
controls, as indicated by comorbidity scores of 2 or higher
for 42.6% and 37.9% of subjects with neovascular AMD
and controls, respectively. In the 183-day period prior
to the index date, the common comorbid conditions iden-
tified in both groups were essential hypertension, disor-
ders of lipid metabolism, diabetes mellitus, and osteoar-
thritis. A higher proportion of each condition was found
in the neovascular AMD cohort than in the control co-
hort (
Table 1).
In general, concomitant drug use in the preindex and
postindex periods was similar in subjects with neovas-
cular AMD and controls. Among the top 10 drug classes
in both groups were 3-hydroxy-3-methylglutaryl coen-
zyme A (HMG-CoA) reductase inhibitors, antihyperten-
sive agents, opioid analgesics, proton pump inhibitors,
and cyclooxygenase isoenzyme 2 inhibitors. The pro-
portion of users within any drug class was higher in the
neovascular AMD group than in controls (Table 1).
INCIDENCE OF MI: OVERALL RATES
The rate of MI events was lower in the neovascular AMD
cohort than in controls. There were 117 MI events in the
neovascular AMD group, for a rate of 16.2 MI events per
1000 persons (95% CI, 13.5-19.4). In the control group,
467 subjects had MI events, for a rate of 23.1 events per
1000 persons (95% CI, 21.1-25.2).
Table 1. Baseline Measurements of Subjects
With Neovascular AMD and Their Matched Controls
(July 1, 2002-June 30, 2005)
a
Overall Subjects
Neovascular
AMD
(n=7203)
Control
(n=20 208)
P
Value
b
Enrollment duration, y
Mean (SD) 2.9 (0.9) 2.8 (0.8)
Median (SD) 3.5 3.1
Age group, y, No. (%)
50-59 531 (7.4) 1579 (7.8)
60-69 1082 (15.0) 3221 (15.9)
70-79 2448 (34.0) 7069 (35.0)
80-89 2702 (37.5) 7090 (35.1)
90 440 (6.1) 1249 (6.2)
Age, y, mean (SD) 76.5 (9.9) 75.4 (10.2)
Sex
F 4282 (59.4) 11 873 (58.8)
M 2921 (40.6) 8335 (41.2)
Region, No. (%)
Northeast 1059 (14.7) 2614 (12.9)
South 2675 (37.1) 7983 (39.5)
Midwest 2927 (40.6) 8262 (40.9)
West 537 (7.5) 1339 (6.6)
Other 5 (0.1) 10 (0)
Charlson Comorbidity Index
score, No. (%)
0 4133 (57.4) 12 545 (62.1) .001
1 1527 (21.2) 3840 (19.0) .001
2 1543 (21.4) 3823 (18.9) .001
Select comorbidities, No. (%)
Essential hypertension 3533 (49.0) 8140 (40.3) .001
Disorders of lipoid
metabolism
2551 (35.4) 5365 (26.5) .001
Diabetes mellitus 1186 (16.5) 3137 (15.5) .06
Osteoarthrosis and allied
disorders
1032 (14.3) 2542 (12.6) .001
History of acute MI 73 (1.0) 212 (1.0) .80
History of CVA 153 (2.1) 653 (3.2) .001
Select drug classes, No. (%)
HMG-CoA reductase
inhibitors
2036 (28.3) 4810 (23.8) .001
Narcotic analgesic
combinations
2027 (28.1) 4938 (24.4) .001
Cardioselective -blockers 1726 (24.0) 4067 (20.1) .001
Proton pump inhibitors 1271 (17.6) 3201 (15.8) .001
COX-2 inhibitors 924 (12.8) 2250 (11.1) .001
Abbreviations: AMD, age-related macular degeneration; COX, cyclooxygenase
2; CVA, cerebrovascular accident; HMG-CoA, 3-hydroxy-3-methylglutaryl
coenzyme A; MI, myocardial infarction.
a
Percentages may not equal 100 because of rounding.
b
2
.
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Rates of MI were lower in subjects with neovascular
AMD than in controls for both sexes. Compared with con-
trols, the risk of MI was 32% lower in men with neovas-
cular AMD and 28% lower in women. Within either group,
rates were higher in men than in women. Rates of MI were
higher in patients older than 75 years compared with
younger subjects; about 70% of both cohorts were older
than 75 years (
Figure 3).
After adjustment for risk factors and comorbidity
scores, the rate of MI events after the index date was 42%
lower in the neovascular AMD group than in controls (ad-
justed RR, 0.58; 95% CI, 0.48-0.72; P .001). The diag-
noses of diabetes, hypertension, heart disease, and an-
gina were significant positive predictors of MI in the
regression model. However, the presence of hyperlipid-
emia was inversely associated with MI (adjusted RR, 0.81;
95% CI, 0.67-0.97; P =.02) (
Table 2).
INCIDENCE OF CVAs: OVERALL RATES
The rate of CVA events was also higher in controls than
in the neovascular AMD cohort. There were 103 CVA
events in the neovascular AMD group, for a rate of 14.3
CVA events per 1000 persons (95% CI, 11.7-17.3). In the
control group, there were 446 CVA events, for a rate of
22.1 events per 1000 persons (95% CI, 20.1-24.2). The
data were stratified by the history of CVA in the 183-
day period preceding the index date. Relatively few sub-
jects in either group had a history of CVA.
The rates of CVA were also lower in the neovascular
AMD group for both sexes. In particular, the risk of CVA
in subjects with neovascular AMD was 37% and 34% lower
for men and women, respectively. Again, rates of CVA
were higher in patients older than 75 years than in younger
subjects (
Figure 4).
After adjustment for risk factors, the rate of CVA events
after the index date was 44% lower in the neovascular
AMD group than in controls (adjusted RR, 0.56; 95% CI,
0.45-0.70; P .001). Positive predictors in the regres-
sion model included history of CVA, diabetes, hyperten-
sion, and increasing Charlson score. As with the acute
MI outcome, the presence of hyperlipidemia was in-
versely associated with the development of CVA (ad-
justed RR, 0.70; 95% CI, 0.57-0.86; P=.001) (
Table 3).
For both outcomes, few subjects in either cohort had
multiple events. A sensitivity analysis excluding these sub-
jects was conducted and results were generally not dif-
ferent from the overall analysis.
COMMENT
In this retrospective database study, the adjusted risk of
MI and CVA showed a significantly lower rate of events
as defined by claims for inpatient health care use in pa-
tients with neovascular AMD compared with controls.
40.0
30.0
35.0
25.0
10.0
15.0
20.0
5.0
0.0
MI Events/1000 Persons
Neovascular AMD (n
=
7203)
Control (n
=
20
208)
16.2
23.1
Men
18.1
26.5
Women
14.9
20.7
Age
<
75 y
9.4
10.3
Age
75 y
20.0
32.7
Figure 3. Myocardial infarction (MI) events per 1000 persons in subjects
with and without neovascular age-related macular degeneration (AMD) ( July
1, 2002-June 30, 2005). Values are given as mean (95% confidence
interval).
Table 2. Adjusted Rate Ratio for the Development of MI
in Subjects With and Without Neovascular AMD
(July 1, 2002-June 30, 2005)
a
Reference Exposure Rate Ratio (95% CI) P Value
Neovascular AMD
Unadjusted 0.70 (0.57-0.86)
Adjusted 0.58 (0.48-0.72) .001
Covariate
Angina 1.62 (1.17-2.25) .004
Cardiac arrhythmia 1.03 (0.69-1.53) .89
Charlson score 1.06 (0.99-1.12) .08
Congestive heart failure 1.26 (0.86-1.87) .24
Diabetes mellitus 1.99 (1.62-2.44) .001
Heart disease 1.66 (1.36-2.03) .001
History of acute MI
b
1.53 (0.92-2.54) .10
History of CVA
b
1.30 (0.88-1.92) .19
Hyperlipidemia 0.81 (0.67-0.97) .02
Hypertension 1.35 (1.13-1.61) .001
Other cerebrovascular disease 0.86 (0.49-1.53) .61
Abbreviations: AMD, age-related macular degeneration; CI, confidence
interval; CVA, cerebrovascular accident; MI, myocardial infarction.
a
Outcome adjusted for presence of angina, cardiac arrhythmia, Charlson
score, congestive heart failure, diabetes, heart disease, history of acute MI,
history of CVA, hyperlipidemia, hypertension, and other cerebrovascular
disease.
b
History of acute MI and CVA use the outcome codes to identify events in
the 183 days prior to the index event.
40.0
30.0
35.0
25.0
10.0
15.0
20.0
5.0
0.0
CVA Events/1000 Persons
Neovascular AMD (n
=
7203)
Control (n
=
20
208)
All Subjects
14.3
22.1
Men
14.4
22.8
Women
14.2
21.6
Age
<
75 y
5.9
9.1
Age
75 y
18.9
31.7
Figure 4. Cerebrovascular accidents (CVAs) per 1000 persons in subjects
with and without neovascular age-related macular degeneration (AMD)
( July 1, 2002-June 30, 2005). Values are given as mean (95% confidence
interval).
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These results were consistent within age groups, sex, and
history of the defined outcomes. In addition, the results
were sustained after adjustments for risk factors. A greater
difference in event rates was seen in subjects older than
75 years, who composed a majority of both cohorts. This
may be an indicator of the overall health of the 2 co-
horts; however, the sample size of subjects younger than
75 years provides low power for interpretation of these
results. Biologically, the results appear unexpected given
that atherosclerosis has been a proposed antecedent for
neovascular AMD, MI, and CVA.
5,14,15
The health status of the neovascular AMD cohort ap-
pears to be comparable with the general population of a
similar age group. Hypertension was found in 49.0% vs
52.4% nationally and diabetes, in 16.5% vs 17.3% na-
tionally (Table 1).
16
The prevalence was lower in the con-
trol group where 40.3% had hypertension and 15.5% had
diabetes. This difference in the rate of chronic diseases
is also reflected in the lower comorbidity scores of the
control group.
It is possible that the subjects with neovascular AMD
received more general medical care because of their eye
condition or because they had more chronic disease (sup-
ported by higher modified Charlson comorbidity scores
in the neovascular AMD group). We examined the fre-
quency of nonophthalmology office visits during the 183-
day preindex period and found that 32% of subjects with
neovascular AMD made office visits 3 or more times in
this period vs 48% of controls. Thus, the control group
sought more medical care even though they had lower
Charlson scores. Subjects with neovascular AMD also may
have received more drug treatment for the risk factors
of MI and CVA. But pharmacy claims showed only mi-
nor differences in the use of cholesterol medications, an-
tihypertensives, antidiabetics, or antiplatelet agents. How-
ever, the possibility that the AMD group may have
benefited from better drug therapy management cannot
be ruled out (ie, rigorous monitoring and adjustment for
compliance, appropriate dosing, or better safety assess-
ment).
In this study, the covariate hyperlipidemia was in-
versely related to the development of MI or CVA in the
neovascular AMD group (Table 2 and Table 3). This may
reflect a yet unexplained relationship; however, some evi-
dence suggests AMD is associated with elevated high-
density lipoprotein cholesterol levels, a protective factor
against MI and CVA.
15,17
Hyman and colleagues
17
re-
ported that high high-density lipoprotein cholesterol lev-
els were 2.3 times more likely to be present in patients with
neovascular AMD than controls. Both cohorts received
lipid-lowering medication at about the same proportion.
For example, HMG-CoA use was 22.1% in subjects with
neovascular AMD and 19.5% of controls in the preindex
period. But the claims data do not reveal the relative im-
pact of the treatments; thus, the AMD group may have been
subject to more effective lipid lowering and possibly have
fewer cardiovascular events. Laboratory measures were not
available in the database to examine the possible effect of
cholesterol on the outcomes.
Wong and colleagues
9,18
published 2 studies looking
at the risk of CVA and coronary heart disease in patients
with AMD. The 10-year risk for developing either out-
come was higher in subjects with early AMD than in con-
trols. However, the study identified only 10 and 15 sub-
jects with late AMD in each study, making interpretation
difficult for this group.
Duan and colleagues
10
conducted a cross-sectional co-
hort study using Medicare data involving 32 788 subjects
with neovascular AMD and yielded different results than
our study. Subjects without a prior MI were followed up
for 2 years for incident MI events. Subjects with neovas-
cular AMD were 26% more likely to develop MI events than
subjects without AMD (95% CI, 1.20-1.33). There were a
number of differences compared with our study. The in-
clusion criteria for neovascular AMD and the definition of
an MI were less specific, and no adjustments were made
for differential follow-up time between the cohorts or mul-
tiple confounding risk factors.
Another study using Medicare data found no differ-
ence in the rates of cardiovascular or cerebrovascular
events in subjects with neovascular AMD and controls.
Alexander and colleagues
11
evaluated 15 771 subjects with
new-onset neovascular AMD against controls matched
for age, race, sex, and follow-up time. No difference was
found in overall rates of inpatient MI, ischemic stroke,
or combined strokes. This study differed from ours in that
it selected subjects with new-onset neovascular AMD
while the current study included subjects with new and
existing neovascular AMD. No adjustments were made
for risk factors to the outcome in this study.
Several limitations should be considered when inter-
preting the study results. Subject selection was made using
a specific ICD-9-CM code for neovascular AMD. How-
ever, a nondifferential misclassification is possible in the
selection of cohorts or identification of outcomes, which
may bias the results toward the null. Efforts were made
to minimize this possibility through the requirement of
Table 3. Adjusted Rate Ratio for the Development of CVAs
in Subjects With and Without Neovascular AMD
(July 1, 2002-June 30, 2005)
a
Reference Exposure Rate Ratio (95% CI) P Value
Neovascular AMD
Unadjusted 0.65 (0.53-0.81)
Adjusted 0.56 (0.45-0.70) .001
Covariate
Angina 0.90 (0.55-1.44) .65
Cardiac arrhythmia 1.31 (0.86-2.00) .22
Charlson score 1.08 (1.01-1.15) .02
Congestive heart failure 0.87 (0.53-1.40) .56
Diabetes mellitus 1.44 (1.16-1.80) .001
Heart disease 1.06 (0.85-1.34) .59
History of acute MI
a
0.89 (0.41-1.95) .77
History of CVA
a
3.02 (2.24-4.09) .001
Hyperlipidemia 0.70 (0.57-0.86) .001
Hypertension 1.49 (1.24-1.79) .001
Other cerebrovascular disease 1.43 (0.92-2.22) .11
Abbreviations: See Table 2.
a
Outcome adjusted for presence of angina, cardiac arrhythmia, Charlson
score, congestive heart failure, diabetes, heart disease, history of acute MI,
history of CVA, hyperlipidemia, hypertension, and other cerebrovascular
disease.
b
History of acute MI and CVA use the outcome codes to identify events in
the 183 days prior to the index event.
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the presence of 2 claims for ICD-9-CM code 362.52, which
carries high specificity for neovascular AMD and is not
shared with any other eye condition. In addition, nearly
all diagnoses (94%) were made by a specialist. Control
patients were also excluded if other macular disorders
that may progress to neovascular AMD were diagnosed.
Variables such as race/ethnicity, smoking, exercise, or
diet were not available for analysis. In particular, smok-
ing has been linked to neovascular AMD, heart disease,
and stroke.
19-23
Other studies have shown a higher preva-
lence of neovascular AMD among white individuals than
black individuals, but black individuals were more likely
to develop MI or CVA.
3
According to the 2005 US Cen-
sus Bureau, about 81.5% of people older than 45 years
were white.
24
Among individuals without diabetes older
than 50 years, Centers for Disease Control and Preven-
tion data from the 2002 National Health Interview Sur-
vey show that 74.4% (95% CI, 60.8%-88.1%) of patients
with macular degeneration were white.
25
Thus, the ob-
served and expected proportions are not remarkably dif-
ferent and variations in race distribution between pa-
tients with neovascular AMD and controls are not likely
to have a significant impact on the outcomes. Smoking,
exercise, or dietary habits may be different between the
cohorts in this study and the impacts of these variables
on the outcomes are unknown.
As with all claims studies, limitations exist in the re-
liability of the ICD-9-CM codes selected to detect events.
In published analyses of ICD-9-CM–coded MI events,
PPVs of 87% to 97% have been reported when validated
by medical record reviews, denoting a high specificity of
the outcome when it is coded.
26-31
Cerebrovascular acci-
dent–coded events in the literature have shown a wider
PPV range from 62% to 92%.
27,32-36
The claims profile re-
view in this study resulted in PPVs of 71% for MI and
66% for CVA. Claims profiles and not medical records
were reviewed by 3 physicians in this study. Lower PPVs
and interrater agreement are expected since claims data
do not contain clinical notes or laboratory and diagnos-
tic results that aid in the confirmation of the outcomes
(ie, cardiac enzymes, electrocardiogram, imaging stud-
ies, angiography). The greater variability in the CVA group
may be because of the use of different ICD-9-CM code
groups to define CVA, which would cause a change in
the sensitivity and specificity of case ascertainment. Lastly,
only hospitalized events were included as outcomes to
improve the reliability of detecting a true outcome.
Event rates for MI or CVA in this study are limited by
the ability to detect these events through hospitaliza-
tion. Events that occur outside the hospital setting may
not have been counted, such as those resulting in death
prior to admission. The mortality rate is not known in
our sample. Loss of events because of preadmission deaths
or nonhospitalized events could result in an underesti-
mate of event rates for both groups. Although the mag-
nitude and direction of missed events on the outcome is
unknown, if undetected MI and CVA were to occur se-
lectively more often in the neovascular AMD group, then
this could explain some of the difference. Finally, the re-
liability of event rates in this study is supported by their
similarity to those in the Cardiovascular Health Study
(CHS). The CHS evaluated 5288 participants 65 years or
older and reported the incidence of MI and CVA at 13.7
per 1000 PY and 11.5 per 1000 PY, respectively. The in-
cidence rates in our study were similar to that of the CHS
at 11.3 MIs per 1000 PY and 9.7 CVAs per 1000 PY.
37
Few studies have been conducted in a large sample
of subjects with a diagnosis of neovascular AMD describ-
ing and comparing the rates of cardiovascular out-
comes. Two recent studies on the association of neovas-
cular AMD to MI or CVA outcomes have yielded mixed
results. In the current study, the risk of hospitalized MI
and CVA was found to be inversely associated with the
diagnosis of neovascular AMD. The relationship be-
tween neovascular AMD and cardiovascular disease re-
mains unclear and warrants further study.
Submitted for Publication: March 19, 2007; final revi-
sion received February 19, 2008; accepted February 20,
2008.
Correspondence: Bao-Anh Nguyen-Khoa, PharmD,
MPH, 1616 N Fort Myer Dr, Ste 1430, Arlington, VA 2220
(bnguyen@deggegroup.com).
Author Contributions: The Degge Group had full ac-
cess to all of the data in the study and takes responsibil-
ity for the integrity of the data and the accuracy of the
data analyses. Dr Werther provided feedback in the con-
ception and design of the study, participated in critical
revision of the manuscript for important intellectual con-
tent, and provided supervision of the internal manu-
script review process.
Financial Disclosure: Dr Jones is president of The Degge
Group. Dr Nguyen-Khoa and Mr Goehring are employ-
ees of The Degge Group. Dr Werther is an employee of
Genentech Inc.
Funding/Support: The Degge Group received funding for
the conduct of this study from Genentech, Inc. Dr Wer-
ther, senior epidemiologist at Genentech Inc, repre-
sents the study sponsor.
Role of the Sponsor: Neither Genentech Inc nor any rep-
resentative of the sponsor took part in the collection, man-
agement, analysis, or interpretation of the data. Study re-
sults were shared with the study sponsor.
Additional Contributions: Varinder P. Singh, MS, per-
formed data management and analysis and John C. Pez-
zullo, PhD, performed statistical analysis.
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  • Source
    • "In the Australian Heart Eye Study (AHES)[50], researchers reported that the severity of coronary stenosis and the presence of stenotic lesions of CAD were independently associated with early AMD but showed no associations with late AMD. However, an inverse association was reported between nAMD and cardiovascular disease requiring hospitalization in a large casecontrol study[51], which was in accordance with our results. We found that CAD conferred an increased risk for PCV (OR 3.381, 95%CI 1.377–8.302) "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose: To investigate the effect of genetic variants in the high-density lipoprotein (HDL) metabolic pathway and risk factors on neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in China. Methods: A total of 742 Chinese subjects, including 221 controls, 230 cases with nAMD, and 291 cases with PCV, were included in the present study. Five single nucleotide polymorphisms (SNPs) from three genes in the HDL metabolic pathway (HDLMP) including cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC) and lipoprotein lipase (LPL) were genotyped in all study subjects with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Risk factors including gender, hypertension, hyperlipidemia, diabetes mellitus, and coronary artery disease were identified. Chi-square tests or Fisher's exact tests were applied to discover associations between SNPs and risk factors for PCV and nAMD. Gene-gene interactions and gene-environment interactions were evaluated by the multifactor-dimensionality reduction (MDR) method. Results: CETP rs3764261 were significantly associated with an increased risk for PCV (odds ratio (OR) = 1.444, P = 0.0247). LIPC rs1532085 conferred an increased risk for PCV (OR = 1.393, P = 0.0094). We found no association between PCV and LPL rs12678919, LIPC rs10468017 or CETP rs173539. No association was found between five SNPs with nAMD. Regarding risk factors, females were found to have significantly decreased risks for both PCV and nAMD (P = 0.006 and 0.001, respectively). Coronary artery disease (CAD) was a risk factor in PCV patients but played a protective role in nAMD patients. Hyperlipidemia was associated with PCV but not with nAMD. Neither hypertension nor diabetes mellitus was associated with PCV or nAMD. The MDR analysis revealed that a three-locus model with rs12678919, rs1532085, and gender was the best model for nAMD, while a five-locus model consisting of rs10468017, rs3764261, rs1532085, gender, and hyperlipidemia was best for PCV. Conclusion: Our large-sample study suggested that CETP rs3764261 conferred an increased risk for PCV. We also first found the association between rs1532085 and PCV. The result of present study also showed that gender and CAD are associated with PCV and nAMD. Significant association was found between hyperlipidemia and PCV but not nAMD.
    Full-text · Article · Dec 2015 · PLoS ONE
  • Source
    • "Of the 13 unique studies that met the inclusion criteria, 5 were retrospective cohort studies2627282930 using healthcare claims databases and 8 were prospective cohort studies [22,31323334353637 (Figure 1). The 13 studies included 2 from Asia, 1 from Europe, 1 from Australia and 9 from North America. "
    [Show abstract] [Hide abstract] ABSTRACT: Research has indicated some shared pathogenic mechanisms between age-related macular degeneration (AMD) and cardiovascular disease (CVD). However, results from prior epidemiologic studies have been inconsistent as to whether AMD is predictive of future CVD risk. To systematically review population-based cohort studies of the association between AMD and risk of total CVD and CVD subtypes, coronary heart disease (CHD) and stroke. A systematic search of the PubMed and EMBASE databases and reference lists of key retrieved articles up to December 20, 2012 without language restriction. Two reviewers independently extracted data on baseline AMD status, risk estimates of CVD and methods used to assess AMD and CVD. We pooled relative risks using random or fixed effects models as appropriate. Thirteen cohort studies (8 prospective and 5 retrospective studies) with a total of 1,593,390 participants with 155,500 CVD events (92,039 stroke and 62,737 CHD) were included in this meta-analysis. Among all studies, early AMD was associated with a 15% (95% CI, 1.08-1.22) increased risk of total CVD. The relative risk was similar but not significant for late AMD (RR, 1.17; 95% CI, 0.98-1.40). In analyses restricted to the subset of prospective studies, the risk associated with early AMD did not appreciably change; however, there was a marked 66% (95% CI, 1.31-2.10) increased risk of CVD among those with late AMD. Whereas the results from all cohort studies suggest that both early and late AMD are predictive of a small increase in risk of future CVD, subgroup analyses limited to prospective studies demonstrate a markedly increased risk of CVD among people with late AMD. Retrospective studies using healthcare databases may have inherent methodological limitations that obscure such association. Additional prospective studies are needed to further elucidate the associations between AMD and specific CVD outcomes.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "This retrospective and nonrandomized study found that systemic adverse events occurred in 7 of the 503 patients (1.4%) in the bevacizumab group and in 3 of the 199 patients in the ranibizumab group (1.5%); this was not a significant difference. The event rates that we observed are similar to previously reported findings (13-15). Although the 2 groups in our study differed with respect to age and concomitant diseases such as diabetes mellitus and dyslipidemia, they were similar in terms of systemic adverse events even after adjusting for these factors. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to compare the incidence of systemic adverse events in patients treated with intravitreal injections of bevacizumab or ranibizumab, and to evaluate whether compared to ranibizumab administration, bevacizumab constitutes a higher risk for systemic adverse events. A retrospective review was conducted for 916 consecutive patients treated with at least 1 intravitreal injection of bevacizumab or ranibizumab. Cox regression was performed to assess whether a variable had predictive value for occurrence of new systemic adverse events and to account for different follow-up times. A total of 702 patients were analyzed; 503 patients received bevacizumab alone, and 199 patients received ranibizumab alone. Systemic adverse events occurred in 10 of 702 patients (1.4%): 7 in the bevacizumab group (7/503; 1.4%) and 3 in the ranibizumab group (3/199; 1.5%). This difference was not statistically significant (Fisher's exact test, P = 0.573). Cox proportional hazards analysis of 4 models did not reveal a covariate that significantly changed the hazard for systemic adverse events. In conclusion, compared to ranibizumab, bevacizumab may not increase the risk of systemic adverse events in patients receiving intravitreal injections.
    Full-text · Article · Dec 2012 · Journal of Korean medical science
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