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Polyvascular Disease and Long-Term
Cardiovascular Outcomes in Older Patients With
Non–ST-Segment–Elevation Myocardial Infarction
Sumeet Subherwal, MD, MBA; Deepak L. Bhatt, MD, MPH; Shuang Li, MHS;
Tracy Y. Wang, MD, MHS; Laine Thomas, PhD; Karen P. Alexander, MD;
Manesh R. Patel, MD; E. Magnus Ohman, MD; W. Brian Gibler, MD;
Eric D. Peterson, MD, MPH; Matthew T. Roe, MD, MHS
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Background—The impact of polyvascular disease (peripheral arterial disease [PAD] and cerebrovascular disease [CVD])
on long-term cardiovascular outcomes among older patients with acute myocardial infarction has not been well studied.
Methods and Results—Patients with non–ST-segment–elevation myocardial infarction aged ≥65 years from the CRUSADE
(Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation
of the ACC/AHA Guidelines) registry who survived to hospital discharge were linked to longitudinal data from the
Centers for Medicare & Medicaid Services (n=34 205). All patients were presumed to have coronary artery disease
(CAD) and were classified into the following 4 groups: 10.7% with prior CVD (CAD+CVD group); 11.5% with prior
PAD (CAD+PAD); 3.1% with prior PAD and CVD (CAD+PAD+CVD); and 74.7% with no polyvascular disease (CAD
alone). Cox proportional hazards modeling was used to examine the hazard of long-term mortality and composite of
death or readmission for myocardial infarction or stroke (median follow-up, 35 months; interquartile range, 17–49
months). Compared with the CAD alone group, patients with polyvascular disease had greater comorbidities, were less
likely to undergo revascularization, and received less often recommended discharge interventions. Three-year mortality
rates increased with number of arterial bed involvement as follows: 33% for CAD alone, 49% for CAD+PAD, 52%
for CAD+CVD, and 59% for CAD+PAD+CVD. Relative to the CAD alone group, patients with all 3 arterial beds
involved had the highest risk of long-term mortality (adjusted hazard ratio [95% CI], 1.49 [1.38–1.61]; CAD+CVD, 1.38
[1.31–1.44]; CAD+PAD, 1.29 [1.23–1.35]). Similarly, the risk of long-term composite ischemic events was highest
among patients in the CAD+PAD+CVD group.
Conclusions—Among older patients with non–ST-segment–elevation myocardial infarction, those with polyvascular
disease have substantially higher long-term risk for recurrent events or death. Future studies targeting greater adherence
to secondary prevention strategies and novel therapies are needed to help to reduce long-term cardiovascular events in this
vulnerable population. (Circ Cardiovasc Qual Outcomes. 2012;5:541-549.)
Key Words: myocardial infarction ◼ peripheral vascular disease ◼ coronary diseasece ◼ rebrovascular disorders
◼ aged
A
therosclerotic involvement of extracardiac vascular
beds (ie, peripheral arterial disease [PAD], cerebrovascular disease [CVD]) is prevalent among older patients1–3
and is viewed as a marker of systemic atherosclerosis with a
resultant higher likelihood of subsequent ischemic events.4–8
Prior studies have shown that patients with non–ST-segment–
elevation myocardial infarction (NSTEMI) and polyvascular
disease (prior PAD or CVD in addition to coronary artery disease [CAD]) have worse in-hospital and intermediate-term
(6–12 months) outcomes following their acute myocardial
infarction (MI).9–13 Furthermore, there appears to be a gradation of risk with the number of affected arterial beds such
that patients with atherosclerotic involvement of all 3 arterial
beds have worse short-term and intermediate-term outcomes
compared with those with dual-bed involvement, whereas
those with coronary bed involvement alone have the lowest
risk.6,14,15 Despite these findings, the influence of polyvascular disease on the long-term outcomes of patients after MI has
Received October 13, 2011; accepted May 2, 2012.
From the Duke University Medical Center, Durham, NC (S.S., S.L., T.Y.W., L.T., K.P.A., M.R.P., E.M.O., E.D.P., M.T.R.); VA Boston Healthcare
System, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA (D.L.B.); and University of Cincinnati, Cincinnati, OH (W.B.G.).
This article was handled independently by Guest Editor Eric D. Peterson, MD. The Editors had no role in the evaluation of the article or the decision
about its acceptance.
The online-only Data Supplement is available at http://circoutcomes.ahajournals.org/lookup/suppl/doi:10.1161/CIRCOUTCOMES.111.964379/-/DC1.
Correspondence to Matthew T. Roe, MD, MHS, Duke Clinical Research Institute, DUMC Box 3850, 2400 Pratt St, Durham, NC 27705. E-mail
[email protected]
© 2012 American Heart Association, Inc.
Circ Cardiovasc Qual Outcomes is available at http://circoutcomes.ahajournals.org
541
DOI: 10.1161/CIRCOUTCOMES.111.964379
542 Circ Cardiovasc Qual Outcomes July 2012
not been widely studied. We therefore used the database of
the Can Rapid Risk Stratification of Unstable Angina Patients
Suppress Adverse Outcomes with Early Implementation of
the ACC/AHA [American College of Cardiology/American
Heart Association] Guidelines (CRUSADE) registry to
evaluate NSTEMI patients ≥65 years of age linked to longitudinal data from the Centers for Medicare and Medicaid
Services (CMS) to delineate the risk of long-term cardiovascular ischemic events following NSTEMI among older
patients with and without concomitant polyvascular disease
(defined as prior PAD or CVD).
WHAT IS KNOWN
• Prior
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studies have shown that patients with non–
ST-segment–elevation myocardial infarction and
polyvascular disease (prior peripheral arterial disease, cerebrovascular disease, or both in addition to
coronary artery disease) have worse in-hospital and
intermediate-term (6–12 months) outcomes following their acute myocardial infarction.
• There appears to be a gradation of risk with the number of affected arterial beds such that patients with
atherosclerotic involvement of all 3 arterial beds
have worse short-term and intermediate-term outcomes compared with those with dual-bed involvement, whereas those with coronary bed involvement
alone have the lowest risk.
WHAT THE STUDY ADDS
• The present analysis extends findings of prior stud-
ies to the long-term setting by demonstrating in a
contemporary cohort that older patients with non–
ST-segment–elevation myocardial infarction and
polyvascular disease have very high rates of mortality (>50% at 3 years) and composite ischemic end
points compared with patients without polyvascular
disease.
• The risk of long-term outcomes increases incrementally with increasing number of arterial beds
involved.
• Despite increased long-term risk associated with
polyvascular disease, the use of guidelines-based
recommended therapies is modest.
Methods
The CRUSADE Quality Improvement Initiative comprised a database of patients with high-risk unstable angina and NSTEMI admitted to US hospitals from November 2001 through December 2006.16
Inclusion criteria were chest pain or anginal equivalent at rest of at
least 10 minutes in duration and occurring <24 hours before presentation and at least one of the following: (1) ischemic ECG changes (STsegment depression or transient ST-segment elevation) or (2) elevated
levels of biomarkers of myocardial necrosis (creatine kinase-MB or
troponin) above the upper limits of normal of local laboratory assays.
Patients were ineligible if they were transferred into a participating hospital >24 hours after the last episode of ischemic symptoms.
Approximately 8800 patients with STEMI were also included in the
CRUSADE registry from 2003 to 2006. A detailed process of care
and in-hospital outcomes were collected through retrospective chart
review using a standardized data collection form. The institutional
review board of each center approved participation in CRUSADE.
Because data were collected anonymously, informed consent was not
required.
Study Population
This analysis focused on patients with NSTEMI aged ≥65 years
who were discharged alive from 514 CRUSADE hospitals between
February 2003 and December 2006 and who had detailed clinical
data linked to CMS longitudinal administrative data through 2008 using indirect identifiers, including site, age, admission date, discharge
date, and sex.17 Of the 48 479 patients enrolled in the CRUSADE registry and linked to the CMS administrative data set during this time
period, we excluded the following: patients with STEMI (n=2619)
because of the small sample size of this population (the variable was
added in a later time period, and sites were not mandated to include
all patients with STEMI), patients whose CMS records did not match
for sex (n=538), patients who were ineligible for fee for service during the CMS discharge month (n=2143) because their NSTEMI hospitalizations could not be matched with the CMS data, patients with
inconsistent death dates (n=27), patients who died during the index
hospitalization (n=2526 overall), patients with inconsistent stroke or
MI readmission dates (n=8), patients transferred out of the original
CRUSADE hospital (n=4290) because in-hospital and discharge
treatments could not be fully profiled in these patients, and patients
with missing PAD or stroke information (n=721) on the case report
form. We also excluded nonindex admissions for patients with multiple admissions (n=1402), keeping only the index admission. The
final analysis population thus comprised 34 205 patients.
Data Definitions
Prior PAD was defined as a history of any of the following conditions:
claudication (either with exertion or at rest), amputation for arterial
insufficiency, vascular reconstruction, bypass surgery or percutaneous intervention to the extremities, documented aortic aneurysm, or a
positive noninvasive test (eg, ankle brachial index <0.8). Prior CVD
was defined as a history of stroke. Given that the analysis was performed in an NSTEMI population, all patients were considered to
have current CAD.
Consequently, all these patients with CAD were initially divided
into the following 4 groups based on history of extracardiac vascular
bed involvement (ie, whether they had a history of PAD, CVD, both,
or neither): (1) CAD+PAD, (2) CAD+CVD, (3) CAD+PAD+CVD,
and (4) CAD alone (no history of PAD or CVD). Polyvascular disease was defined as having any additional extracardiac vascular bed
involvement (history of PAD, CVD, or both).
End Point Definitions
The primary end point of interest was all-cause death and a composite of all-cause death, readmission for MI, or readmission for ischemic stroke. Long-term, all-cause mortality was available through
CMS linkage data. Readmission for MI was defined as hospitalization for MI captured through the CMS linkage data defined using
International Classification of Diseases, Ninth Revision, primary
discharge diagnosis code 410.x1. Readmission for ischemic stroke
was defined using the primary discharge diagnosis codes 434.x1,
436, or 433.x1.
Statistical Analysis
Baseline demographics, clinical presentation, in-hospital procedures,
and discharge medications were described among the 4 groups.
Continuous variables were summarized using medians with interquartile ranges and compared with Kruskal-Wallis tests, whereas categorical variables were summarized using percentages and compared
with Pearson χ2 tests.
The primary outcome of interest was death and the composite
end point (death, readmission for MI, or readmission for ischemic
Subherwal et al Polyvascular Disease and Outcomes in the Elderly 543
Table 1. Baseline Clinical Characteristics
Polyvascular Disease
No Polyvascular
Disease (CAD Alone)
(n=25 537)
CAD+CVD
(n=3652)
CAD+PAD
(n=3946)
77 (71–83)
80 (73–85)
77 (72–83)
78 (73–83)
<0.0001
51.3
47.6
56.7
57.8
<0.0001
White
86.0
83.4
88.3
87.7
Black
7.2
9.9
6.4
7.6
Family history of CAD
27.0
22.3
29.6
29.0
<0.0001
History of hypertension
74.7
83.0
84.2
86.7
<0.0001
Diabetes mellitus
31.7
41.2
45.4
53.2
<0.0001
Current/recent smoker
11.9
9.8
17.7
16.7
<0.0001
Dyslipidemia
49.8
49.5
63.7
66.2
<0.0001
Prior MI
27.6
36.8
39.9
48.4
<0.0001
Prior PCI
19.8
19
27.6
26.8
<0.0001
Prior CABG
21.0
23.6
36.5
39.2
<0.0001
Prior CHF
19.3
30.3
31.9
40.8
<0.0001
Variable
CAD+PAD+CVD
(n=1070)
P Value
Demographics
Age, y
Male sex
Race
<0.0001
Medical history
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Presentation characteristics
Signs of CHF
27.2
37.6
38.5
44.7
<0.0001
83 (70–100)
86 (72–104)
87 (72–103)
88 (74–104)
<0.0001
145 (124–166)
143 (121–164)
144 (122–167)
140 (122–166)
0.001
30.8
31.0
33.8
33.4
<0.0001
CrCl, mL/min*
43 (31–57)
36 (26–49)
37 (26–50)
35 (25–48)
<0.0001
LDL, mg/dL
93(71–118)
89 (67–116)
84 (64–109)
83 (66–111)
<0.0001
Heart rate, beats/min
SBP, mm Hg
ST depression/transient
ST elevation
Lab results
Data are presented as median (interquartile range) or %. CAD indicates coronary artery disease; CVD, cerebrovascular
disease; PAD, peripheral arterial disease; MI, myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary
artery bypass graft; CHF, congestive heart failure; SBP, systolic blood pressure; CrCl, creatinine clearance; LDL, low-density
lipoprotein.
*CrCl calculated by Cockcroft-Gault equation.
stroke). Event rates and time-to-event distributions among the 4
groups were displayed using Kaplan-Meier analyses and compared
with the log-rank test. Cox proportional hazards modeling was used
to examine the post-NSTEMI hazard of long-term mortality and the
hazard of the composite end point among patients with polyvascular
disease (CAD+PAD, CAD+CVD, CAD+PAD+CVD) relative to patients without polyvascular disease (those with isolated CAD), after
adjustment for variables in the CRUSADE–CMS long-term mortality
model.18 The previously published long-term mortality model identifies variables associated with long-term mortality among admitted
patients with NSTEMI (c-index=0.75). The variables in the model
for risk adjustment included the following: age, initial serum creatinine level, initial systolic blood pressure, signs of heart failure on
presentation, initial heart rate, weight, prior heart failure, hyperlipidemia, initial hematocrit level (with knot at 35%), initial troponin
ratio (with two knots at 5 and 50), diabetes mellitus, male sex, family
history of CAD, prior MI, current or recent smoking, prior percutaneous coronary intervention, race, ECG changes (transient ST elevation, both [versus neither]), hypertension, and prior coronary artery
bypass graft.
All comparisons were 2 tailed, and P<0.05 was considered statistically significant. All analyses were performed using SAS version 9.2
(SAS Institute) statistical software.
Results
Baseline Characteristics
Baseline demographics and clinical presentations of the 4
subgroups are presented in Table 1. Overall, patients with
polyvascular disease had a higher prevalence of most ischemic risk factors (diabetes mellitus, hypertension, prior
MI, prior coronary artery bypass graft, and renal insufficiency) compared with patients without polyvascular
disease. There was an increasing trend of prevalence of
these risk factors going from 2–arterial bed involvement
(CAD+CVD or CAD+PAD) to 3–arterial bed involvement
(CAD+PAD+CVD).
In-Hospital Cardiac Procedures
Rates of early invasive management (catheterization within
48 hours) and in-hospital cardiac catheterization were lower
overall among patients with polyvascular disease, with less
use among those with CAD+PAD+CVD than among those
with CAD+PAD or CAD+CVD; those with single–arterial
544 Circ Cardiovasc Qual Outcomes July 2012
Table 2. In-Hospital Cardiac Procedures
No Polyvascular
Disease (CAD Alone)
(n=25 537)
Polyvascular Disease
CAD+CVD
(n=3652)
CAD+PAD
(n=3946)
CAD+PAD+CVD
(n=1070)
P Value
Cardiac catheterization
68.8
48.4
60.4
49.7
<0.0001
Catheterization <48 hours
of arrival
52.2
32.1
41.3
33.1
<0.0001
None
9.9
9.7
6.9
6.0
One
28.0
24.1
20.3
16.5
Two
28.0
27.8
26.8
25.6
Three
34.2
38.4
46.0
51.9
PCI
39.2
25.6
31.6
22.9
<0.0001
CABG
10.5
5.9
8.5
6.5
<0.0001
No. diseased vessels*
<0.0001
Revascularization procedures
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Data are presented as %. CAD indicates coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral
arterial disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft.
*Defined by sites as lesions >50% on angiogram in each of the 3 major coronary vessels.
bed involvement (CAD alone) had higher rates of invasive
management (Table 2). Patients with polyvascular disease
also had a greater number of diseased coronary vessels, with
patients with 3–arterial bed involvement having the greatest
rates of 3-vessel CAD. Similar findings were demonstrated for
the use of revascularization procedures.
Discharge Therapies
Use of guidelines-recommended medications at discharge
were modest for all groups (Table 3). Given that discharge
on warfarin therapy may influence prescription of clopidogrel
on discharge, the online-only Data Supplement Table shows
rates of warfarin at discharge among patients not discharged
on clopidogrel. Lifestyle modification interventions were used
less frequently among patients with polyvascular disease, particularly among those with CAD+PAD+CVD (Table 3).
Long-Term Outcomes
The individual components and composite outcome at 1,
2, and 3 years after the index NSTEMI event are shown
in Figure 1. The presence of polyvascular disease among
patients with NSTEMI was associated with 3-year mortality rates >50%, with the highest 3-year mortality rate among
those with CAD+PAD+CVD (58.7%) followed by those with
CAD+CVD (52.1%) and CAD+PAD (49.2%). Patients without prior extracardiac vascular disease had the lowest 3-year
mortality rate at 33.2%. Similar findings were demonstrated
for readmission for MI, readmission for ischemic stroke, and
the composite outcome.
The Kaplan-Meier mortality analyses demonstrate
an early and sustained separation of the curves, with
the highest long-term mortality rates observed in the
CAD+PAD+CVD group and similar observed long-term
mortality rates in the CAD+PAD and CAD+CVD groups
(Figure 2). Similar findings were seen with the composite
outcome (Figure 3).
The adjusted risk of long-term mortality was higher
among patients with 2 arterial beds involved (CAD+PAD
and CAD+CVD groups) than among those in the CAD alone
Table 3. Discharge Medications and Interventions*
No Polyvascular
Disease
(CAD Alone)
Polyvascular Disease
CAD+CVD
CAD+PAD
CAD+PAD+CVD
P Value
Discharge medications
Aspirin
94.3
92.6
93.6
93.1
0.002
β-blocker
91.9
92.1
93.6
92.1
0.008
Statin
76.2
72.9
77.8
76.7
<0.0001
ACE inhibitor or ARB
67.8
69.1
67.7
69.3
0.396
Clopidogrel
68.9
68.2
70.1
71.9
0.107
Smoking cessation counseling
78.0
73.6
77.0
64.8
0.0006
Cardiac rehabilitation referral
61.2
56.4
60.0
59.3
0.0002
Dietary counseling
80.4
76.7
80.4
77.1
<0.0001
Discharge interventions
Data are presented as %. CAD indicates coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral
arterial disease; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
*Determined for each medication class and intervention for patients without listed contraindications.
Subherwal et al Polyvascular Disease and Outcomes in the Elderly 545
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Figure 1. Long-term outcomes after non–ST-segment–elevation myocardial infarction by previous vascular bed involvement. A, Mortality.
B, Readmission rates for ischemic stroke. C, Readmission for myocardial infarction. D, Composite of death, readmission for myocardial
infarction, or readmission for stroke. Event rates estimated using Kaplan-Meier methods, which allow for variable patient follow-up and
censoring. CAD indicates coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral arterial disease.
group (Table 4). Meanwhile, patients with 3 arterial beds
involved (CAD+PAD+CVD) had the highest adjusted risk
of long-term mortality (adjusted hazard ratio, 1.49; 95% CI,
1.38–1.61). Similar findings were demonstrated with the
composite outcome. Additionally, in a sensitivity analysis
of patients who died in the hospital (CAD alone, 5.2%;
CAD+PAD, 7.1%; CAD+CVD, 7.9%; CAD+PAD+CVD,
9.0%), we found very similar results among the groups with
respect to adjusted risk of long-term mortality and composite
outcomes.
Figure 2. Kaplan-Meier estimates of mortality after
non–ST-segment–elevation myocardial infarction by
previous vascular bed involvement. CAD indicates
coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral arterial disease.
546 Circ Cardiovasc Qual Outcomes July 2012
Figure 3. Kaplan-Meier estimates of death, myocardial infarction readmission, or stroke readmission by degree of polyvascular disease. AMI
indicates acute myocardial infarction; CAD, coronary artery disease; CVD, cerebrovascular disease;
PAD, peripheral arterial disease.
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Discussion
To our knowledge, this study is the largest analysis of the
impact of polyvascular disease on long-term outcomes in older
patients with NSTEMI and yielded several important findings.
First, we demonstrated very high rates of long-term mortality
and composite cardiovascular outcomes among older patients
with polyvascular disease. Second, the risk of long-term outcomes appears to increase incrementally with increasing number of arterial beds involved (3 versus 2 extracardiac vascular
beds). Finally, guidelines-recommended therapies and procedures are used less frequently in higher-risk patients with
polyvascular disease.
Association of Polyvascular Disease with
Short- and Intermediate-Term Risk
Prior analyses have demonstrated that patients with acute
coronary syndrome (ACS) and a history of polyvascular disease are at increased risk of short-term and intermediate-term
Table 4. Adjusted Risk of Long-Term Outcomes After NSTEMI
by Previous Vascular Bed Involvement
End Point
HR (95% CI)
Long-term mortality*
CAD+PAD+CVD
1.49 (1.38–1.61)
CAD+CVD
1.38 (1.31–1.44)
CAD+PAD
1.29 (1.23–1.35)
Long-term composite of death, MI readmission,
or stroke readmission*
CAD+PAD+CVD
1.44 (1.34–1.55)
CAD+CVD
1.35 (1.30–1.42)
CAD+PAD
1.25 (1.20–1.31)
CAD+PAD indicates patients with NSTEMI with history of PAD; CAD+CVD,
patients with NSTEMI with history of CVD; CAD+PAD+CVD, patients with
NSTEMI with history of PAD and CVD. NSTEMI indicates non–ST-segment–
elevation myocardial infarction; HR, hazard ratio; CAD, coronary artery disease;
PAD, peripheral arterial disease; CVD, cerebrovascular disease; MI, myocardial
infarction.
*Adjusted for Centers for Medicare & Medicaid Services long-term mortality
model.18 Reference group is the CAD alone group.
mortality. This increased mortality may be related to an
increased severity of coronary atherosclerotic burden among
patients with polyvascular disease because extracardiac
arterial bed involvement is likely a marker for more-diffuse
atherosclerosis.9,13,19 Additionally, these earlier analyses
demonstrated a graded response of in-hospital ischemic
events with increasing vascular bed involvement such that
patients with 3–arterial bed involvement are at highest risk
of in-hospital mortality. Analyses from the GRACE (Global
Registry of Acute Coronary Events) registry; the PAMISCA
(Prevalence of Peripheral Arterial Disease in Patients with
Acute Coronary Syndrome) registry; and the Worchester,
Massachusetts, registry extended these observations to intermediate-term outcomes (6–12 months).12,14,20 In comparison,
the 6 months to 12 months Kaplan-Meier estimates of ischemic events from the present study of older patients with
NSTEMI are much higher than those of these other registries
(eg, our analysis demonstrates a near-30% rate of 6-month
composite outcome versus 21% in GRACE among patients
with 3–arterial bed involvement). Similarly, analyses from
clinical trial databases have demonstrated an increased risk
of short-term ischemic outcomes among patients with ACS
who have polyvascular disease.10,21 Thus, polyvascular disease has been determined to be an independent predictor
of risk among patients with ACS through at least 1 year of
follow-up.
Association of Polyvascular Disease With
Long-Term Risk
Although the aforementioned analyses described short- and
intermediate-term outcomes, studies exploring the association between a history of polyvascular disease and longterm outcomes among patients with ACS have been limited.
Prior analyses of long-term outcomes among patients with
polyvascular disease have included only patients with stable
CAD or those undergoing coronary bypass surgery or were
published before coronary stents were routinely used for percutaneous coronary intervention procedures.20,22–24 By comparison, the present study is, to our knowledge, the largest
contemporary long-term analysis of the risk associated with
Subherwal et al Polyvascular Disease and Outcomes in the Elderly 547
polyvascular disease among patients with ACS. We have
demonstrated that patients with NSTEMI without polyvascular disease had the lowest long-term mortality and composite ischemic rates followed by patients with 2–arterial bed
involvement (CAD+PVD or CAD+CVD), whereas those
with 3–arterial bed involvement (CAD+PVD+CVD) had the
highest mortality and composite ischemic rates. Importantly,
we have demonstrated 3-year mortality rates of >50% among
older patients with NSTEMI and polyvascular disease, with
a gradation of risk for 3– versus 2–vascular bed involvement
after adjustment. These findings indicate that not only does
polyvascular disease increase long-term risk, but also there is
a gradation of long-term risk associated with increasing burden of atherosclerosis (eg, increasing number of arterial beds
involved).
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Underuse of Guidelines-Recommended Treatments
Although both the unstable angina and NSTEMI guidelines and the PAD guidelines highlight the importance of
secondary prevention with antiplatelet therapies, hypertension control, and statin therapy,25–27 we found that the use
of these cardioprotective agents was suboptimal not only
among patients with a history of polyvascular disease, but
also among the entire older NSTEMI population. Further,
although aspirin and β-blocker prescription rates on discharge were relatively high, roughly 25% to 30% of all eligible patients (those with and without extracardiac vascular
disease) were not discharged on statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers,
or clopidogrel.
The suboptimal use of clopidogrel at discharge could
partly be explained by the fact that 22% to 28% of patients
with polyvascular disease not discharged on clopidogrel
were treated with warfarin, but a large percentage of patients
who could have benefited from clopidogrel therapy remains.
Similar findings were demonstrated with the use of lifestyle
modification interventions, such as smoking cessation counseling, diet modification counseling, and cardiac rehabilitation referral. This modest use of evidence-based therapies
among eligible patients becomes even more notable given the
high long-term mortality, particularly among patients with
3–arterial bed involvement. Increased use of these life-saving therapies has the potential to reduce long-term ischemic
events.
Additionally, although guidelines recommend an early
invasive approach to treat the high-risk NSTEMI population,
we found that compared with patients without extracardiac
vascular disease, eligible patients with polyvascular disease
were less likely to undergo catheterization within 48 hours of
arrival. Furthermore, patients with polyvascular disease had
lower rates of any in-hospital revascularization (percutaneous
coronary intervention and coronary artery bypass graft combined) than those without extracardiac vascular disease, with
the patients with 3–arterial bed involvement having the lowest
revascularization rates of all groups. The more-conservative
lower rates of revascularization may reflect that patients with
polyvascular disease may have advanced, nonrevascularizable
vascular disease, and this may contribute to higher mortality
rates among those with polyvascular disease. Furthermore,
patients with polyvascular disease or their clinicians may
favor a medical management approach given the additional
comorbidities and decreased quality of life associated with
stroke and advanced PAD.28–30
Limitations
The present analysis was an observational study limited
to patients aged >65 years. The long-term association
between history of extracardiac vascular disease and ischemic outcomes needs to be confirmed in a younger cohort;
however, it must be noted that PAD is more prevalent in
elderly persons, with a mean age of ≈65 to 70 years in most
real-world registries.31,32 The present analysis was limited to
in-hospital survivors. Other studies have demonstrated an
association between polyvascular disease and in-hospital
mortality among patients post ACS. The findings expand
earlier observations with long-term follow-up. With the
registry design, we could not confirm diagnosis of PAD
with repeat noninvasive testing. Similarly, we could not
stratify based on symptomatic versus asymptomatic PAD
status, even though these entities have different rates of
ischemic outcomes.12
Additionally, among patients with a history of MI, percutaneous coronary intervention, or coronary artery bypass
graft, we could not determine age at the time of their initial
CAD diagnosis. It is possible that polyvascular disease represents a global atherosclerotic process and, consequently,
is more likely present among patients who have had CAD
longer. Regardless, the findings are applicable in that patients
with polyvascular disease, particularly those with all vascular beds involved, are at the highest risk; therefore, greater
attention is needed to optimize in-hospital and secondary
prevention.
Another limitation to definition and identification of
patients relates to those with prior CVD. We did not include
patients with documented carotid artery disease without a
prior stroke and may have included patients without actual
atherosclerotic disease (eg, hemorrhagic or thromboembolic stroke). We identified stroke and MI with linkage to
the CMS database; consequently, these end points were not
adjudicated and relied solely on billing data. However, the
positive predictive value of patients with MI and stroke by
Medicare claims-based definition is high.33–35 Adjustments
for covariates in the present study were limited to those
in the data collection form. Further, the analysis was limited to patients with NSTEMI only because the CRUSADE
database included a small sample of patients with unstable
angina and STEMI.
Importantly, it is possible that our rate of use of evidencebased therapies, including early invasive strategy, revascularization, or discharge therapies, was relatively low because of
increased comorbidities among patients with polyvascular
disease (advanced and nonintervenable coronary disease,
other medical comorbidities such as malignancy or kidney disease, hospice care, etc). The database was limited to specific
patient characteristics captured by the data collection form.
To limit selection bias of therapies, data abstractors were
instructed to note contraindications on the collection form
if patients did not receive these evidence-based therapies;
548 Circ Cardiovasc Qual Outcomes July 2012
subsequently, the data on use of therapies reported here
likely represent rates of use among patients without
contraindications.
Finally, we did not have information on long-term medication adherence. Thus, we were unable to determine whether
patients were taking the cardioprotective medications throughout the follow-up time period.
Conclusions
Downloaded from http://circoutcomes.ahajournals.org/ by guest on June 16, 2017
We found that older patients with NSTEMI and polyvascular disease have very high rates of mortality and composite
ischemic end points compared with patients without polyvascular disease, in this largest contemporary analysis with the
longest follow-up to our knowledge. We found a gradation of
increasing risk based on the number of arterial beds involved.
Despite the increased long-term risk associated with polyvascular disease, the use of guidelines-recommended therapies at
discharge was modest among all patients with NSTEMI (with
and without polyvascular disease), and patients with polyvascular disease were less likely to undergo early invasive therapy and revascularization. Given the high rate of mortality in
older patients with NSTEMI and polyvascular disease, future
studies targeting better use of secondary prevention strategies
and novel therapies are needed to help to reduce long-term
cardiovascular events in this vulnerable population.
Acknowledgments
We thank Amanda McMillan, MPH, MA, and Morgan deBlecourt
for their editorial contributions to this manuscript. Ms McMillan
and Ms deBlecourt did not receive compensation for their contributions apart from their employment at the institution where this study
was conducted. for her editorial contributions to this manuscript.
Ms McMillan did not receive compensation for her contributions
apart from her employment at the institution where this study was
conducted.
Sources of Funding
CRUSADE was funded by the Schering-Plough Corporation. A
Bristol-Myers Squibb/sanofi Pharmaceuticals partnership provided
additional funding support. Millennium Pharmaceuticals Inc also
funded this work. This work was supported in part by a grant from the
National Institute on Aging (R01 AG025312-01A1) to Dr Peterson,
principal investigator.
Disclosures
Dr Bhatt has received research grants from Amarin, AstraZeneca,
Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-aventis, and
The Medicines Company. Dr Wang has received research grants to the
Duke Clinical Research Institute from a Bristol-Myers Squibb/sanofi
Pharmaceuticals partnership, Schering-Plough (now Merck), The
Medicines Company, Canyon Pharmaceuticals, Heartscape, and an Eli
Lilly/Daiichi Sankyo partnership and has consulted for or received honoraria from Heartscape, Medco, and the American College of Cardiology
Foundation. Dr Patel has received research support from MAQUET
Cardiovascular LLC (formerly Boston Scientific Cardiac & Vascular);
Johnson & Johnson; the National Heart, Lung, and Blood Institute; and the
Agency for Healthcare Research and Quality and consults for Genzyme.
Dr Ohman has received research support from Daiichi Sankyo, Datascope,
and Eli Lilly & Company and consults for AstraZeneca; Boehringer
Ingelheim; Bristol-Myers Squibb; Gilead Sciences; Liposcience; Merck;
Pozen, Inc; sanofi-aventis; The Medicines Company; and WebMD. Dr
Peterson has received research support from Bristol-Myers Squibb, Eli
Lilly & Company, Johnson & Johnson, Merck & Co, sanofi-aventis, the
American Heart Association, the American College of Cardiology, and
the Society of Thoracic Surgeons and consults for Boehringer Ingelheim.
Dr Roe has received research funding from Eli Lilly, Roche, BristolMyers Squibb, the American College of Cardiology, and the American
Heart Association and has consulted for or received honoraria from
KAI Pharmaceuticals, Bristol-Myers Squibb, sanofi-aventis, Merck,
Orexigen, Helsinn Pharmaceuticals, AstraZeneca, and Regeneron. All
conflicts of interest for Drs Wang, Patel Ohman, Peterson, and Roe are
listed at www.dcri.org.
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Polyvascular Disease and Long-Term Cardiovascular Outcomes in Older Patients With
Non−ST-Segment−Elevation Myocardial Infarction
Sumeet Subherwal, Deepak L. Bhatt, Shuang Li, Tracy Y. Wang, Laine Thomas, Karen P.
Alexander, Manesh R. Patel, E. Magnus Ohman, W. Brian Gibler, Eric D. Peterson and
Matthew T. Roe
Circ Cardiovasc Qual Outcomes. 2012;5:541-549; originally published online June 19, 2012;
doi: 10.1161/CIRCOUTCOMES.111.964379
Circulation: Cardiovascular Quality and Outcomes is published by the American Heart Association, 7272
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Supplemental Material
Table. Discharge rates on warfarin among patients not discharged on clopidogrel
(n=9,106)
Discharge on Warfarin
CAD alone (n=6,930)
18.0%
CAD + PAD (n=989)
22.4%
CAD + CVD (n=941)
24.8%
CAD + PAD + CVD (n=246)
28.1%