Adv Ther (2014) 31:891–903 DOI 10.1007/s12325-014-0138-4
ORIGINAL RESEARCH
Thromboembolic Events Among Patients with Hepatitis C Virus Infection and Cirrhosis: A Matched-Cohort Study Cheryl Enger • Ulla M. Forssen • Dimitri Bennett • Dickens Theodore
•
Sumitra Shantakumar Andrew McAfee •
To view enhanced content go to www.advancesintherapy.com Received: May 21, 2014 / Published online: July 22, 2014 Ó Springer Healthcare 2014
ABSTRACT
thromboembolic
Introduction: Portal
a
cirrhosis and hepatitis C virus (HCV) infection and matched comparators.
known risk among patients with cirrhosis, but
Methods: Patients diagnosed with HCV or
the incidence of other thromboembolic events among patients with liver disease is
cirrhosis of various etiologies were identified from a large medical claims database and
inadequately delineated. This study examined the incidence of venous and arterial
matched by age and sex to comparator cohorts. New-onset diagnoses of venous and
vein
thrombosis
is
arterial Deceased: A. McAfee
events
in
thromboembolic
patients
events
Poisson regression baseline factors.
C. Enger Optum, 315 E. Eisenhower Parkway, Suite 305, Ann Arbor, MI 48108, USA
S. Shantakumar WorldWide Epidemiology, Research and Development, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
Present Address: U. M. Forssen CSL Behring, 1020 1st Ave, King of Prussia PA 19406, USA D. Theodore S. Shantakumar Clinical Development, Research and Development, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
were
determined. The incidence rate of each event was calculated and rate ratios computed using
Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0138-4) contains supplementary material, which is available to authorized users.
U. M. Forssen D. Bennett (&) WorldWide Epidemiology, Research and Development, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426, USA e-mail:
[email protected] with
models,
adjusting
A. McAfee Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
for
Adv Ther (2014) 31:891–903
892
Results: The study included 22,733 HCV-
that accumulates over time. Hepatitis C virus
infected patients and 68,198 comparators, and 15,158 cirrhosis patients and 45,473
(HCV), an RNA virus in the Flaviviridae family,
comparators. The incidence of any thromboembolic event was 233.4 events per 10,000 person-years for the HCV cohort and 138.5 per 10,000 person-years for the comparators; the adjusted incidence rate ratio for any thromboembolic event was 1.62 (95% confidence interval [CI]: 1.48–1.77). For the cirrhosis patients and comparators, the crude rates of any thromboembolic event were 561.1 and 249.7 per 10,000 person-years, respectively. The adjusted incidence rate ratio was 2.28 (95% CI: 2.11–2.47). Arterial events, especially unstable angina and transient ischemic attack, were the most frequent events seen in both the HCV and cirrhosis cohorts, but venous events, especially portal vein thrombosis, showed a more pronounced elevation in patients with liver disease. Conclusions: Patients with HCV and cirrhosis of various etiologies are at increased risk of several types of thromboembolic events. Physicians should consider this increased risk
has recently replaced alcohol abuse as the most common cause of cirrhosis in the US, responsible for over 1 in 4 cases (26% HCVrelated vs 21% alcohol abuse-related) [3]. Patients with liver disease may experience both bleeding complications and thrombotic episodes. Bleeding, the most common clinical manifestation, results from reduced platelet count, insufficient production of clotting factors,
a
reduced
production
of
thrombopoietin in the liver and a loss of functional platelets due to congestive splenomegaly [4, 5]. Conversely, hypercoagulative events also occur with endstage liver disease. Portal vein thrombosis (PVT) is the most commonly reported hypercoagulative event in patients with cirrhosis, occurring in 9–20% of patients, with rates increasing with liver disease severity [6, 7]. Sluggish blood flow and external compression may predispose the portal vein to be at the highest risk for thromboembolic events [8]. However, the systemic release of
when managing patients with liver disease.
inflammatory mediators and a dysregulation in the clotting cascade mean that other systems
Keywords: Arterial
outside the portal vein are also vulnerable. Indeed, in observational hospital studies,
and
venous
events;
Cirrhosis; Hepatitis C; Incidence rate; Liver diseases; Thromboembolic events
thromboembolic complications associated with
INTRODUCTION
peripheral extremities, and in extracorporeal circulation devices [5]. Population-based
In the United States (US) alone, about 27,000 people die each year from cirrhosis [1, 2].
research
cirrhosis have been documented throughout the mesenteric and pulmonary systems, the
investigating
the
risk
of
Cirrhosis refers to any progressive disease or
thromboembolic events in patients with liver cirrhosis has obtained inconsistent results,
chronic trauma to the liver that leads to diffuse damage of glandular tissue, development of scar
ranging from statistically significant decreases in risk to significant increases in risk relative to a
tissue, and eventual global loss of function. The cause of cirrhosis may be any mechanical,
comparator group, although the selection of
infectious, metabolic, or environmental insult
comparator groups has often been problematic [9–16].
Adv Ther (2014) 31:891–903
893
If the risk of thromboembolic events is
1, 2000 and September 30, 2006 were eligible for
elevated among patients with liver disease,
inclusion in the HCV or cirrhosis cohort,
physicians may want to consider this increased risk when managing their patients. The present
respectively. Patients diagnosed with both HCV infection and cirrhosis were included in
study was conducted to estimate the incidence and prevalence of thromboembolic events in
both cohorts. The index date for each patient was defined as the date of the first claims
two cohorts, patients with HCV infection and
diagnosis for HCV infection or cirrhosis.
patients with cirrhosis of various etiologies, and to find the relative risk of these events
Eligible patients had to be at least 18 years of age and continuously enrolled in the health
compared with matched cohorts without HCV infection or cirrhosis.
plan for at least 12 months prior to the index date (baseline period).
METHODS
population of patients identified from the same database. The comparison group for the HCV
Data Source
cohort consisted of patients without HCV infection or cirrhosis or immune
The comparator groups were drawn from a
Data for this study were obtained from the Optum research database (ORD), which contains eligibility and medical claims data from a large US health insurance plan. The individuals covered by this health plan are from geographically diverse regions across the US. The plan provides fully insured coverage for physician, hospital, and prescription drug services. The database contains medical and pharmacy data for *30 million current and past health-plan enrollees beginning from January 1994. The total enrollment for 2006 was over 12 million members from health plans located in the northeast, southeast, midwest, and western US. The data used for the present study were anonymized,
as
required
by
the
Health
Insurance Portability and Accountability Act (HIPAA).
thrombocytopenia
(ITP);
the
comparison
group for the cirrhosis cohort consisted of patients without cirrhosis or HCV infection or ITP; the ITP exclusion was made because the present analysis was conducted as part of a larger study examining ITP. Patients for the comparator cohorts were randomly selected, frequency matched at a ratio of 3:1 on age group, gender, and calendar quarter to each of the disease cohorts. Age and enrollment inclusion criteria were the same for the comparators as for the disease cohorts. Outcome Definitions Patients were followed for study outcomes from the index date through the earliest of either: disenrollment from the health plan, death, or December 31, 2006. The outcomes of interest were venous thromboembolic events, which
Cohort Definition
included deep vein pulmonary embolism,
Patients with an ICD-9-CM diagnosis code of
thromboembolic events, including myocardial infarction (MI), unstable angina (UA), ischemic
HCV (070.44, 070.54, 070.7, 070.70, or 070.71) or cirrhosis (571.29, 571.69, or 575.59) recorded in the ORD anytime between January
thrombosis and PVT;
(DVT), arterial
stroke, and transient ischemic attack (TIA); and ‘‘other thromboembolic events’’. Each of these
Adv Ther (2014) 31:891–903
894
events was identified through the ICD-9-CM
new event divided by the sum of the person-
codes listed in Additional File 1 in the electronic
time contributed by each patient in that cohort.
supplementary material. All patients meeting one of these outcome
Person-time for patients with an event was truncated as of the date of the first event of
definitions during the 12-month baseline period were considered to have prevalent
that type, but follow-up continued for potential events of a different type. The incidence rates
disease.
and 95%
For
quantifying
incidence,
only
confidence intervals (CIs) were
patients without evidence of the event at baseline were included; the events experienced
reported as events per 10,000 person-years and were calculated for any thromboembolic event,
along with the date of first occurrence of each event during the follow-up period were noted.
any venous event, any arterial event, and individually for each of the specific thromboembolic events.
Definition of Covariates
Poisson regression models provided incidence rate ratios and 95% CIs for the HCV
Demographic characteristics included age on the index date, sex, race/ethnicity (available
and cirrhosis cohorts relative to their respective comparison cohorts. Age group and gender
only for patients who were enrolled in the health plan as of November 2005), and
were
included
in
all
models
as
priori
geographic region. Medical and treatment
covariates. The remaining covariates (history of hypertension, past and recent use of systemic
history examined from the time period of within 1 year prior to the index date (i.e., the
corticosteroids, and past and recent use of interferon treatment) were selected if P\0.10
12-month baseline period) included hypertension and past or recent use of
in the univariate analysis. Because of the substantial overlap between the two disease
systemic corticosteroids (i.e., oral, injectable, or intravenous forms) or interferon alpha. For
cohorts and the possibility that the risk of
drug exposure, past use was defined as any use
thromboembolic events in the cirrhotic patients was driving findings in the HCV
between 45 and 365 days prior to the index date; recent use was use on or within 44 days
cohort, these analyses were repeated in the subset of the HCV cohort without cirrhosis and
prior to the index date.
in their matched comparators. The analysis in
Analysis
this article is based on previously conducted studies and does not involve any new studies of
All analyses were conducted in SAS version 9.2
human or animal subjects performed by any of the authors.
(SAS Institute Inc., Cary, NC, USA). The prevalence of thromboembolic events during
RESULTS
the 12-month baseline period was calculated as the number of patients with an event out of the
A total of 22,733 patients with HCV infection
total cohort, with separate estimates obtained for the HCV, cirrhosis, and comparator cohorts. The incidence of thromboembolic events during the follow-up period for each cohort was computed as the number of patients with a
were included and matched to 68,198 comparator subjects. The cirrhosis cohort included 15,158 patients and its comparison cohort included 45,473 patients. There were 2,712 patients in both the HCV and cirrhosis
Adv Ther (2014) 31:891–903
895
Table 1 Demographics and clinical characteristics Hepatitis C cohort (N 5 22,733)
Hepatitis C comparators (N 5 68,198)
Cirrhosis cohort (N 5 15,158)
Cirrhosis comparators (N 5 45,473)
n
%
n
%
n
%
n
%
8,542
37.6
25,625
37.6
6,056
40.0
18,168
40.0
14,191
62.4
42,573
62.4
9,102
60.0
27,305
60.0
Demographic characteristics Gender Female Male Age, years (mean, SD)
49.0
9.7
49.0
9.8
56.5
12.7
56.3
12.8
Age group 18–39
2,816
12.4
8,453
12.4
1,114
7.3
3,378
7.4
40–49
9,434
41.5
28,386
41.6
3,414
22.5
10,422
22.9
50–59
8,084
35.6
24,189
35.5
4,956
32.7
14,715
32.4
60–69
1,590
7.0
4,773
7.0
3,087
20.4
9,219
20.3
70–79
630
2.8
1,881
2.8
1,878
12.4
5,622
12.4
80?
179
0.8
516
0.8
709
4.7
2,117
4.7
10,167
44.7
27,339
40.1
7,886
52.0
18,660
41.0
1,193
5.2
2,443
3.6
423
2.8
1,731
3.8
953
4.2
2,132
3.1
603
4.0
1,225
2.7
9,983
43.9
35,081
51.4
6,043
39.9
23,214
51.1
Past use
1,545
6.8
11
\0.1
584
3.9
10
\0.1
Recent use
1,129
5.0
4
\0.1
316
2.1
3
\0.1
Past use
4,405
19.4
9,539
14.0
3,147
20.8
6,683
14.7
Recent use
1,084
4.8
1,614
2.4
926
6.1
1,241
2.7
4,708
20.7
9,208
13.5
4,697
31.0
9,106
20.0
814
3.6
1,089
1.6
1,109
7.3
1,247
2.7
Race/ethnicity No race data available African American Hispanic White Treatment history Interferon
Systemic corticosteroids
Medical characteristics History of hypertension History of any thromboembolic event SD Standard deviation
Adv Ther (2014) 31:891–903
896
Fig. 1 Percentage of patients experiencing thromboembolic events in the hepatitis C virus (HCV) and cirrhosis cohorts and their matched comparators (follow-up period)
cohorts, equivalent to 11.9% of the HCV patients and 17.9% of the cirrhosis patients;
cirrhosis cohort at 7.3%, followed by the HCV cohort at 3.6% (Table 1). Both of the disease
these patients and their matched comparators were included in both sets of analyses.
cohorts had a markedly higher prevalence at baseline of any thromboembolic event
More than half of each cohort was male
compared with their comparators. The types of
(Table 1). The mean age of the HCV-infected patients and their matched comparators was
events most commonly seen were UA and the category of ‘‘other thromboembolic events’’.
49 years, whereas the mean age of the cirrhosis patients and their comparators was 56 years.
During the follow-up period the proportion of patients with any thromboembolic event was
Information on race/ethnicity was available for
more than 50% higher in the disease cohorts than
just over half the patients, the majority of whom were white. Interferon treatment was
in the comparison cohorts (Fig. 1). Overall, the incidence of any thromboembolic event among
confined almost exclusively to the HCV and cirrhosis cohorts (hereafter referred to
patients with HCV infection was 233.4 (95% CI: 218.0–249.7) events per 10,000 person-years. In
collectively as the disease cohorts). In contrast,
the HCV comparator cohort, the corresponding
systemic corticosteroid use was more frequent in both of the disease cohorts but still relatively
rate was 138.5 (95% CI: 132.0–145.1) per 10,000 person-years (Table 2). After adjusting for
common (up to 14–15% for prior-year use) in the comparator groups. Hypertension was more
baseline characteristics the incidence rate ratio (IRR) between the HCV and comparator cohorts
prevalent in the disease cohorts than in the
was
comparator cohorts, as well as more prevalent among the cirrhotic compared with the HCV
thromboembolic event. Adjusted rate ratios also showed significant elevations in the HCV cohort
patients. The 12-month baseline prevalence of any
for UA, ischemic stroke, TIA, PVT, and the category of ‘‘other thromboembolic events’’. All
thromboembolic event was highest in the
these rates, except for ischemic stroke, remained
1.62
(95%
CI:
1.48–1.77)
for
any
Adv Ther (2014) 31:891–903
897
Table 2 Incidence rates and incidence rate ratios for thromboembolic events in the hepatitis C virus (HCV) and comparator cohorts Event
Incidence rate: HCV cohort
Incidence rate: comparator cohort
Crude IRR (95% CI)
Adjusted IRR (95% CI)
Adjusted IRR (95% CI) for non-cirrhotic HCV patientsa
Any TE 233.4 (218.0–249.7) 138.5 (132.0–145.1)
1.69 (1.55–1.84)
1.62 (1.48–1.77)b
1.44 (1.31–1.58)b
Venous TE
21.2 (16.9–26.2)
9.4 (7.9–11.2)
2.25 (1.69–2.98)
2.08 (1.56–2.77)c
1.49 (1.06–2.10)c
Arterial TE
134.3 (122.8–146.6)
97.3 (92.0–102.9)
1.38 (1.24–1.53)
1.36 (1.22–1.51)d
1.30 (1.15–1.46)d
DVT
9.5 (6.8–13.0)
6.2 (4.9–7.7)
1.31 (0.86–1.99)
1.22 (0.80–1.86)e
1.25 (0.80–1.97)e
PE
5.6 (3.5–8.3)
4.4 (3.4–5.7)
1.19 (0.71–2.01)
1.02 (0.60–1.73)b
1.02 (0.59–1.76)b
MI
25.3 (20.5–30.7)
24.9 (22.2–27.7)
1.00 (0.78–1.27)
0.94 (0.73–1.20)b
0.96 (0.74–1.24)b
UA
69.5 (61.4–78.4)
51.9 (48.0–56.0)
1.30 (1.12–1.51)
1.22 (1.05–1.42)b
1.25 (1.06–1.47)b
IS
13.2 (9.9–17.3)
7.9 (6.5–9.6)
1.83 (1.29–2.62)
1.76 (1.23–2.52)c
1.33 (0.90–1.99)c
TIA
48.4 (41.7–55.8)
30.7 (27.8–33.9)
1.65 (1.37–1.98)
1.57 (1.30–1.89)c
1.43 (1.17–1.75)c
PVT
7.4 (5.0–10.5)
0.5 (0.2–1.0)
Other TE
101.3 (91.4–111.9)
45.1 (41.5–48.9)
14.71 (6.05–35.73) 15.18 (6.22–37.03)c 6.06 (2.04–18.01)c 2.27 (1.98–2.60)
2.13 (1.86–2.44)c
1.77 (1.52–2.06)c
IR Incidence rate per 10,000 person-years, IRR incidence rate ratio, CI confidence interval, TE thromboembolic event, DVT deep vein thrombosis, PE pulmonary embolism, MI myocardial infarction, UA unstable angina, IS ischemic stroke, TIA transient ischemic attack, PVT portal vein thrombosis a N = 20,021 HCV patients and 60,062 matched comparators b IRR adjusted for age, gender, hypertension, past and recent corticosteroid use c IRR adjusted for age, gender, hypertension, past corticosteroid use d IRR adjusted for age, gender, hypertension, past and recent corticosteroid use, past interferon treatment e IRR adjusted for age, gender, past and recent corticosteroid use significantly elevated when examined in the subset of HCV patients without cirrhosis and
the comparators were considerably higher than for the HCV comparator cohort. The overall
their matched comparators (Table 2). Overall, the
incidence rate of any thromboembolic event
rate of any venous thromboembolic event was approximately double, and of any arterial
among cirrhotic patients was 561.1 (95% CI: 529.0–594.8) events per 10,000 person-years,
thromboembolic event was more than 30% higher, in HCV patients than in their
with an adjusted IRR of 2.28 (95% CI: 2.11–2.47). The effect was more pronounced
comparators.
for venous than for arterial thromboembolic
Patients with cirrhosis showed a similar but even more marked pattern of higher rates of
events, as was also found in HCV patients. All of the events examined showed significant
events than their comparators (Table 3). With the higher average age of the cirrhosis group
elevations relative to comparators, ranging from a 50% increase for MI to an estimated
and their comparator cohort, rates even among
elevation of over 300-fold for PVT, although the
Adv Ther (2014) 31:891–903
898
Table 3 Incidence rates and incidence rate ratios for thromboembolic events in the cirrhosis cohort and comparator cohorts Event
Incidence rate: cirrhosis cohort
Incidence rate: comparator Crude IRR cohort (95% CI)
Any TE
561.1 (529.0–594.8)
249.7 (239.1–260.6)
2.24 (2.07–2.42)
2.28 (2.11–2.47)a
Venous TE
73.7 (63.1–85.6)
13.9 (11.6–16.5)
5.31 (4.21–6.71)
4.94 (3.89–6.26)b
Arterial TE
294.3 (271.8–318.2)
184.8 (175.8–194.1)
1.59 (1.45–1.75)
1.62 (1.47–1.78)c
DVT
18.6 (13.6–24.9)
9.1 (7.3–11.3)
2.09 (1.41–3.09)
1.95 (1.31–2.90)d
PE
15.0 (10.6–20.7)
5.9 (4.4–7.6)
2.73 (1.70–4.38)
2.51 (1.54–4.07)a
MI
68.9 (58.7–80.5)
46.2 (41.9–50.9)
1.48 (1.21–1.81)
1.49 (1.21–1.82)a
UA
135.6 (120.8–151.8)
87.2 (81.2–93.6)
1.61 (1.39–1.86)
1.56 (1.35–1.80)a
37.3 (30.0–46.0)
20.9 (18.0–24.1)
1.84 (1.38–2.44)
1.90 (1.42–2.53)b
TIA
107.5 (94.5–121.8)
65.0 (59.9–70.6)
1.65 (1.42–1.92)
1.67 (1.41–1.98)b
PVT
43.1 (35.2–52.4)
0.2 (0.0–0.7)
Other TE
247.3 (226.9–268.9)
74.6 (69.1–80.5)
IS
Adjusted IRR (95% CI)
365.03 (50.88–2,619.0) 375.54 (52.29–2,697.0)b 3.39 (3.00–3.84)
3.32 (2.93–3.76)b
IR Incidence rate per 10,000 person-years, IRR incidence rate ratio, CI confidence interval, TE thromboembolic event, DVT deep vein thrombosis, PE pulmonary embolism, MI myocardial infarction, UA unstable angina, IS ischemic stroke, TIA transient ischemic attack, PVT portal vein thrombosis a IRR adjusted for age, gender, hypertension, past and recent corticosteroid use b IRR adjusted for age, gender, hypertension, past corticosteroid use c IRR adjusted for age, gender, hypertension, past corticosteroid use, past interferon treatment d IRR adjusted for age, gender, past and recent corticosteroid use latter was based on a very low rate of events in
diagnoses as arterial occlusion or embolism and
the comparator group.
phlebitis and thrombophlebitis. Venous events showed a larger relative risk for each of the
DISCUSSION
disease cohorts relative to their comparators;
This retrospective observational study found an
this difference was largely driven by the marked increase in the rate of PVT. Across each of the
elevated risk of all types of thromboembolic events among patients with cirrhosis and of several types of thromboembolic events among
event types examined, cirrhotic patients showed greater elevations than patients with HCV infection. Although HCV patients without
patients with HCV infection compared with patients without HCV infection or cirrhosis. A
cirrhosis had a lower relative risk of thromboembolic events compared with the
preponderance of these events was arterial
two broader disease cohorts studied, the rate of most events in this subgroup remained
rather than venous, although many fell into the unclassified category of ‘‘other thromboembolic events’’, which included such
significantly elevated above the comparator cohort, suggesting that HCV infection alone,
Adv Ther (2014) 31:891–903
899
in the absence of cirrhosis, is also associated
risk of cardiovascular disease associated with
with an increased risk of thromboembolic
chronic HCV infection. For example, Alyan
events. In previous
the
et al. [18] compared the risk of coronary arterial disease (CAD) in HCV seropositive and
percentage of cirrhotic patients with venous thromboembolism ranged from 0.5% to 4.7%,
seronegative patients. HCV seropositivity was found to be an independent risk factor for
which is consistent with our estimate in the
severity of coronary atherosclerosis with an
present study of 1.1%; however, cirrhotics in these studies showed no elevated risk compared
adjusted odds ratio of 2.018 (95% CI 1.57–2.57). Using data from the Veterans
with patients without liver disease [9–12]. As these hospital-based studies used hospitalized
Affairs health services, investigators compared the risk factors and prevalence of CAD among
patients as comparators, and many medical
82,000 HCV-infected and 90,000 HCV-negative
conditions and surgical procedures increase the risk of venous thromboembolism, these
patients. The results indicated that HCVinfected patients had a 27% (adjusted hazard
studies were not comparing cirrhotic patients to a general population sample and hence may
ratio: 1.27, 95% CI 1.22–1.31) increased risk of CAD compared with HCV-negative patients
have underestimated the risk associated with
despite having significantly lower mean values
liver disease in our view. Population-based case– control studies have obtained estimates of the
of traditional markers of cardiovascular health (cholesterol, triglycerides, low density
risk of venous thromboembolism ranging from a significant decrease in risk associated with
lipoprotein, hyperlipidemia) [19]. Another prospective cohort study examined
serious liver disease to a significant, nearly twofold increase in risk among patients with
the risk of atherosclerosis among two groups: Group A consisted of patients with chronic HCV
cirrhosis and those with non-cirrhotic liver
with and without steatosis and Group B consisted
disease [14–16]. The increased risk with liver disease was found in the largest of the studies,
of age-, gender-, and location-matched healthy individuals without steatosis and patients with
in which cirrhosis was examined separately from other liver diseases rather than in a
non-alcoholic fatty liver disease (NAFLD) [20]. The study findings showed that HCV infection
combined liver disease group [16]. In terms of
may have a direct pro-atherogenic role, with HCV
arterial disease, cirrhotic patients were found in one study to have a lower prevalence of
RNA levels independently associated with carotid atherosclerosis, and a twofold increased
ischemic stroke and MI than matched noncirrhotic patients, but these were unadjusted
prevalence of atherosclerosis among steatosisfree patients with chronic HCV infection
results, and risk factors such as hypertension
compared with matched controls. The other
were far less common in the cirrhotic group [13].
important findings were that patients with HCV-related steatosis had a significantly higher
Published studies examining the link between HCV infection and cardiovascular
prevalence of atherosclerosis compared with NAFLD patients, and HCV-related steatosis was
diseases and arterial thromboembolic events
an independent risk factor for atherosclerosis
are limited and results However, most recently
are mixed [17]. there has been
[20]. Kakinami et al. [21] evaluated the risk of
growing evidence to suggest an increase in the
cardiovascular disease (CVD) in a Rochester
hospital-based
studies,
Adv Ther (2014) 31:891–903
900
cohort consisting of HIV, HCV, and HIV/HCV
patients was evaluated in a retrospective cohort
co-infected individuals and compared it with
study conducted in southern Italy among 123
the general population in the National Health and Nutrition Examination Survey (NHANES)
adults with stroke compared with 697 matched non-stroke controls [26]. In the Italian study,
database, a nationwide survey in the US. The investigators found that the risk of CVD was
HCV infection was found to be an independent risk factor for stroke (odds ratio 2.04, 95% CI:
elevated in the HCV and HIV/HCV groups but
1.69–2.46) and a secondary analysis showed
not in the HIV group when compared with the general population. Maruyama et al. [22]
that HCV patients had a higher prevalence of past ischemic heart disease. A hospital-based
observed that 87% of their patients with chronic HCV infection had myocardial injury
case–control study in Japan evaluated HCV infection as a risk factor for spontaneous
measured
intracerebral
using
thallium-201
myocardial
hemorrhage
(ICH);
HCV
scintigraphy. Analyses of a large cohort in southern Taiwan showed that HCV-infected
infection was significantly more frequent in 462 ICH patients (8.7%) compared with 462
individuals had a 1.76-fold increased risk of an ischemic electrocardiogram when compared
non-ICH controls (3.5%) [27]. Recent findings emphasize that HCV may have extra-hepatic
with non-HCV individuals [23]. One case–
manifestations
control study investigated whether HCV infection was a risk factor for MI among
monitoring for cardiovascular diseases patients with chronic HCV infection.
members of the US military; no significant difference in HCV prevalence was observed
The incidence of PVT found in the present study (\1%) was lower than previous reports of
between the 292 MI cases (7.6%) and 290 nonMI controls (9.8%) [24]. In a retrospective
9–20% in cirrhotic patients [6, 7]. This discrepancy likely stems from the use of claims
cohort
and
may
warrant
careful in
Health
data as opposed to active surveillance for the
Improvement Network of the United Kingdom, 4,809 HCV-infected adults were
outcome; PVT may be asymptomatic and go undetected without appropriate imaging
matched to 71,668 adults without HCV infection to evaluate the risk of MI associated
studies, for example, Doppler abdominal ultrasound. For thromboembolic events other
with HCV infection [17]. During a median
than PVT, event rates for the comparator groups
follow-up of 3.2 years, no statistically significant difference was observed in the
in the present study were similar to general population rates reported in other studies [28–
incidence rates of MI between HCV-infected and HCV-negative adults (1.02 vs 0.92 events
31], suggesting that the data on these events in claims are moderately complete.
study
conducted
in
the
per 1,000 person-years, respectively) and HCV
We
found
corticosteroid
use
to
be
infection was not associated with an increased risk of incident MI. Another population-based
significantly predictive for each of the thromboembolic events investigated. The
cohort study using data derived from NHANES found that HCV-infected patients (n = 173)
primary reason for including corticosteroid use among the covariates was that this study was
were more likely to have congestive heart
also designed to evaluate cataracts, for which
failure compared with non-HCV controls (n = 19,568), but not ischemic heart disease or
corticosteroid exposure is a major risk factor (data not included in this report). At least one
stroke [25]. The prevalence of HCV in stroke
prior study, however, has also identified oral
Adv Ther (2014) 31:891–903
901
corticosteroids as a risk factor for venous
examined only among those patients with no
thromboembolism [15].
history of the same thromboembolic event
The present study provides estimates of the incidence of several thromboembolic events in
during the baseline period, but they could have had a history of a different
patients with HCV and cirrhosis, as well as in matched comparator groups. However, this
thromboembolic event; which might have influenced the likelihood of the event being
study has several limitations that should be
identified.
considered when interpreting the results. The use of administrative claims data allows the formation of very large cohorts that are representative of a commercially insured
CONCLUSION
population; yet this study had relatively few
The findings of this study present a clear pattern of an increased risk of both venous and arterial
elderly patients compared with the overall population in the US, limiting the ability to
thromboembolic events among patients with HCV, and even more so with cirrhosis. Hence,
generalize findings to the elderly population. Also, the analyses were based on exposure to
despite
the
bleeding
that
is
most
often
pharmacy
associated with liver disease, the failed liver cannot be presumed to provide ‘‘auto-
dispensing records. No documentation of actual compliance with prescribed therapy was
anticoagulation’’ preventing thromboembolism [5]. These patients have an
available. Data on the use of drug samples or inhospital treatment were not available. The
elevated risk of thromboembolic events and
steroids
and
interferon
from
analyses were also based on outcomes determined from administrative claims. No attempt was made to verify the accuracy or completeness of the outcome diagnoses based on the claims. However, consistent definitions were used for all outcomes across the cohorts, so that calculation of the rate ratios relative to the comparison cohorts gave unbiased results.
physicians should consider this information when developing a treatment plan or management strategy. PVT is a well-known complication in patients with cirrhosis, but our data suggest that MI/UA/TIA occurs more frequently. More aggressive management of modifiable risk factors for thromboembolism, such as smoking and obesity, may be warranted to help reduce the risk of these complications.
Moreover, all events and liver diseases were coded based on claims diagnoses only, with no validation through external sources such as medical charts. Although the analyses were
ACKNOWLEDGMENTS
adjusted for confounding covariates that were
Sponsorship and article processing charges for
identified in the data, information on potential confounders such as smoking status and body
this study were funded by a contract between Optum, Ann Arbor, MI and GlaxoSmithKline
weight was not available. Another limitation to our study is that patients with liver disease may
(GSK), Collegeville, PA. The contract granted
have been followed more closely than the
Optum full control of the study conduct, reporting and interpretation, as well as the
typical comparator patients, allowing increased opportunity for detection of events.
final wording of any resulting manuscript. All named authors meet the ICMJE criteria for
Incident
authorship
thromboembolic
events
were
for
this
manuscript,
take
Adv Ther (2014) 31:891–903
902
responsibility for the integrity of the work as a whole, and have given final approval for the
3.
National Digestive Diseases Information Clearinghouse. http://digestive.niddk.nih.gov/.
version to be published. The authors wish to acknowledge Ms. Claire Chiang, M.S. at Optum
4.
Lisman T, Leebeek FW. Hemostatic alterations in liver disease: a review on pathophysiology, clinical consequences, and treatment. Dig Surg. 2007;24: 250–8.
5.
Northup PG, Sundaram V, Fallon MB, et al. Hypercoagulation and thrombophilia in liver disease. J Thromb Haemost. 2008;6:2–9.
6.
Peck-Radosavljevic M. Review article: coagulation disorders in chronic liver disease. Aliment Pharmacol Ther. 2007;26(Suppl 1):21–8.
7.
Amitrano L, Guardascione MA, Brancaccio V, et al. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol. 2004;40:736–41.
8.
Amitrano L, Guardascione MA, Ames PR. Coagulation abnormalities in cirrhotic patients with portal vein thrombosis. Clin Lab. 2007;53: 583–9.
9.
Senzolo M, Sartori MT, Lisman T. Should we give thromboprophylaxis to patients with liver cirrhosis and coagulopathy? HPB (Oxford). 2009;11:459–64.
(i3 Drug Safety at the time the work was performed) for her contribution to the data analysis. Medical writing assistance for this study, in the form of development of draft outline and draft manuscript, assembling of tables and figures and referencing, was provided by Dr. Beth Nordstrom, PhD at Evidera (formerly United BioSource Corporation) and funded by GlaxoSmithKline (Collegeville, PA). Conflict of interest. Cheryl Enger reports that this work was conducted under a contract between GlaxoSmithKline and Cheryl Enger’s institution,
Optum.
Ulla
Forssen
was
an
employee of GSK and a GSK shareholder, now works for CSL Behring. Dimitri Bennett is an employee of GSK and is a GSK shareholder. Sumitra Shantakumar is an employee of GSK and is a GSK shareholder. Dickens Theodore is an employee of GSK and is a GSK shareholder. Compliance
with ethics guidelines. The
analysis in this article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.
REFERENCES
10. Gulley D, Teal E, Suvannasankha A, Chalasani N, Liangpunsakul S. Deep vein thrombosis and pulmonary embolism in cirrhosis patients. Dig Dis Sci. 2008;53:3012–7. 11. Lesmana CR, Inggriani S, Cahyadinata L, Lesmana LA. Deep vein thrombosis in patients with advanced liver cirrhosis: a rare condition? Hepatol Int. 2010;4:433–8. 12. Northup PG, McMahon MM, Ruhl AP, et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol. 2006;101: 1524–8. 13. Berzigotti A, Bonfiglioli A, Muscari A, et al. Reduced prevalence of ischemic events and abnormal supraortic flow patterns in patients with liver cirrhosis. Liver Int. 2005;25:331–6.
1.
˜o AM, Heron MP, Murphy SL, Kochankek KD. Minin Deaths: final data for 2004. National vital statistics reports. Hyattsville: National Center for Health Statistics. 2007;55(19).
14. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case–control study. Arch Intern Med. 2000;160:809–15.
2.
Saadatmand F, Stinson FS, Grant BF, Dufour MC. Surveillance report #48: liver cirrhosis mortality in the United States, 1970–1995. Rockville: National Institute on Alcohol Abuse and Alcoholism, Division of Biometry and Epidemiology; 1998.
15. Huerta C, Johansson S, Wallander MA, Garcia Rodriguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med. 2007;167:935–43.
Adv Ther (2014) 31:891–903
16. Sogaard KK, Horvath-Puho E, Gronbaek H, Jepsen P, Vilstrup H, Sorensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case–control study. Am J Gastroenterol. 2009;104:96–101. 17. Forde KA, Haynes K, Troxel AB, et al. Risk of myocardial infarction associated with chronic hepatitis C virus infection: a population-based cohort study. J Viral Hepat. 2012;19:271–7. 18. Alyan O, Kacmaz F, Ozdemir O, et al. Hepatitis C infection is associated with increased coronary artery atherosclerosis defined by modified Reardon severity score system. Circ J. 2008;72:1960–5. 19. Butt AA, Xiaoqiang W, Budoff M, Leaf D, Kuller LH, Justice AC. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis. 2009;49: 225–32. 20. Adinolfi LE, Restivo L, Zampino R, et al. Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis. Atherosclerosis. 2012;221:496–502. 21. Kakinami L, Block RC, Adams MJ, Cohn SE, Maliakkal B, Fisher SG. Risk of cardiovascular disease in HIV, hepatitis C, or HIV/hepatitis C patients compared to the general population. Int J Clin Pract. 2013;67:6–13. 22. Maruyama S, Koda M, Oyake N, et al. Myocardial injury in patients with chronic hepatitis C infection. J Hepatol. 2013;58:11–5. 23. Lin MS, Guo SE, Chen MY, et al. The impact of hepatitis C infection on ischemic heart disease via ischemic electrocardiogram. Am J Med Sci. 2014; 347:478–84.
903
24. Arcari CM, Nelson KE, Netski DM, Nieto FJ, Gaydos CA. No association between hepatitis C virus seropositivity and acute myocardial infarction. Clin Infect Dis. 2006;43:e53–6. 25. Younossi ZM, Stepanova M, Nader F, Younossi Z, Elsheikh E. Associations of chronic hepatitis C with metabolic and cardiac outcomes. Aliment Pharmacol Ther. 2013;37:647–52. 26. Adinolfi LE, Restivo L, Guerrera B, et al. Chronic HCV infection is a risk factor of ischemic stroke. Atherosclerosis. 2013;231:22–6. 27. Karibe H, Niizuma H, Ohyama H, Shirane R, Yoshimoto T. Hepatitis C virus (HCV) infection as a risk factor for spontaneous intracerebral hemorrhage: hospital based case–control study. J Clin Neurosci. 2001;8:423–5. 28. Harmsen P, Wilhelmsen L, Jacobsson A. Stroke incidence and mortality rates 1987–2006 related to secular trends of cardiovascular risk factors in Gothenburg, Sweden. Stroke. 2009;40:2691–7. 29. Parikh NI, Gona P, Larson MG, et al. Long-term trends in myocardial infarction incidence and case fatality in the National Heart, Lung, and Blood Institute’s Framingham Heart study. Circulation. 2009;119:1203–10. 30. Wattanakit K, Cushman M. Chronic kidney disease and venous thromboembolism: epidemiology and mechanisms. Curr Opin Pulm Med. 2009;15: 408–12. 31. White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res. 2009;123(Suppl 4):S11–7.