Content uploaded by Fredrik Sartipy
Author content
All content in this area was uploaded by Fredrik Sartipy on Apr 25, 2022
Content may be subject to copyright.
Content uploaded by Birgitta Sigvant
Author content
All content in this area was uploaded by Birgitta Sigvant on Jul 19, 2019
Content may be subject to copyright.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Cardiovascular long-term outcome and
prophylactic treatment patterns in peripheral
arterial disease in a population-based cohort
Fredrik Sartipy
1
*, Fredrik Lundin
2
, Eric Wahlberg
3
, and Birgitta Sigvant
4
1
Department of Clinical Science and Education, Section of Vascular Surgery, Karolinska Institutet at So¨dersjukhuset, Kirurgkliniken, Sjukhusbacken 10, 118 83 Stockholm, Sweden;
2
Centre of Clinical Research, County Council of Va¨ rmland, A
¨lvgatan 49, 652 30 Karlstad, Sweden;
3
Department of Medicine and Health, Linko¨ ping University, Linkoping
University Hospital, SE 581-53 Linko¨ ping, Sweden; and
4
Department of Surgical Sciences, Uppsala University, Uppsala, Dag Hammarskjo¨lds va¨g 38, 75185 Sweden
Received 19 May 2019; revised 8 July 2019; editorial decision 10 July 2019; accepted 12 July 2019
Aims This study evaluates 10-year follow-up data on associated comorbidity, mortality, and pharmacological treatment
patterns for men and women with different stages of peripheral arterial disease (PAD) in a population-based
setting.
........................................................................ ............. ............. ............. .................. ......................................................... .........
Methods
and results
This was a prospective observational population-based cohort study, based on physical examinations and question-
naires at baseline supplemented with national register data between 2005 and 2015. Subjects were placed in sub-
groups defined by ankle–brachial index levels and reported symptoms; asymptomatic PAD (APAD), intermittent
claudication (IC), severe limb ischaemia (SLI), or references (Ref). Cox proportional hazards regression models
were used for analysis with adjustments for sex and baseline age and comorbidity. The cohort consisted of 5080
subjects (45% males). At baseline, APAD, IC, and SLI were prevalent in 559 (11%), 320 (6.3%), and 78 (1.5%) sub-
jects, respectively. A significant increased risk for cardiovascular (CV) death, even when adjusted for age and base-
line morbidity, were noted in all PAD stages as compared with reference group with a small difference between
APAD and IC, an adjusted hazard ratio 1.80 (confidence interval 1.45–2.22) and 1.95 (1.50–2.53), respectively.
Only about 60% of PAD subjects received medical prophylactic treatment as recommended in guidelines.
........................................................................ ............. ............. ............. .................. ......................................................... .........
Conclusion Peripheral arterial disease subjects had significantly increased CV morbidity and mortality risks, especially males.
Asymptomatic PAD subjects confer similar risk for CV events as symptomatic patients. Our findings motivate
enhanced preventive efforts of all PAD stages, including in asymptomatic disease.
䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏䊏
Keywords Peripheral •Arterial •Disease •Cardiovascular •Mortality •Risk
Introduction
It is well-known that both symptomatic and asymptomatic patients
with peripheral arterial disease (PAD) face an increased risk for car-
diovascular (CV) events.
1,2
This risk can be decreased through
life-style modifications and prophylactic medication.
3,4
Over the last
decades, major improvements in this area have reduced death in
stroke- and cardiac disease,
5,6
while PAD mortality remains high.
7
For unknown reasons many symptomatic PAD patients, particularly
women, are not provided accurate prophylactic treatment.
8
The association between the evolution of PAD and its related
comorbidities is not yet elucidated covering all disease stages and
patients’ sex.
9–11
In a systematic review of major CV prevention trials,
18% of all studies presented data for PAD and only 27% of enrolled
patients were women.
12
For coronary heart disease and stroke, the
knowledge gap between men and women’s disease patterns has nar-
rowed the last decades. One reason may be that men are more
prone to present with typical clinical symptoms and events early in
life, whereas women’s problems occur later with more atypical pat-
terns.
13,14
Accordingly, epidemiology, risk factors and outcome for
women with PAD still needs to be addressed.
15
Peripheral arterial disease is present in about 20% of the elderly
population
16
and easily detected by ankle–brachial index (ABI)
* Corresponding author. Tel: þ46 70 251 7322, Fax: 0046086162438, Email: fredrik.sartipy@sll.se
Published on behalf of the European Society of Cardiology. All rights reserved. V
CThe Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
European Heart Journal - Quality of Care and Clinical Outcomes (2019) 0, 1–11 ORIGINAL ARTICLE
doi:10.1093/ehjqcco/qcz037
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
measurements. Improved knowledge of associations between PAD
and related comorbidity is essential for anticipation of risk, optimizing
treatment, and actions against PAD morbidity and mortality for men
and women.
The aim of this population-based, longitudinal study was to de-
scribe CV morbidity and mortality combined with medical treatment
patterns in a cohort of PAD subjects separated by different stage
groups and sex during an observation period of10 years.
Methods
Study design
This is a prospective observational population-based cohort study includ-
ing long-term follow-up. The cohort has previously been described.
17
Data on fatal and non-fatal CV events, such as myocardial infarction (MI),
andstrokeaswellastoPAD-associateddiseasessuchashypertension,
diabetes, chronic renal insufficiency, and cancer were collected during the
observation period. The study population was classified into three PAD
stages and a reference group at baseline. Analyses were performed sepa-
rated by sex when possible.
At baseline physical examinations were performed and questionnaires
administered, which was supplemented with national register data. For
follow-up, three Swedish national health registers were used; the
National Patient Register, the Prescribed Drug Register, and the Cause of
Death Register.
Study population
The cohort was assembled between 13 August 2004 and 13 January
2005. At that time 8000 men and women, aged 60–90years, were ran-
domly selected from the Swedish tax register and invited to participate.
The enrolled cohort had the same age and sex distribution as the general
population in this age group. Four different regions participated (Malmo¨,
Karlstad, A
¨lvkarleby, and Skelleftea˚), which each invited 2000 subjects, to
obtain representation from urban, industrial, rural, and agricultural dis-
tricts. Subjects accepting to participate signed an informed consent form.
The observation period ended on 31 December 2015 when individual
patient register data from the national registers covering 2004–15 was
retrieved, thus rendering an observation time of 10 years.
Data collection
All subjects were invited to participate by a letter, including three self-
administered questionnaires that assessed risk factors for PAD, such as
smoking habits, current pharmacological treatment, concomitant dis-
eases, and leg symptoms. The participants were invited to a primary
healthcare clinic where specially trained nurses performed bilateral ABI
measurements and assisted subjects in completion of the questionnaires
when necessary. The procedure has been described in detail
previously.
17
Information on concomitant diseases such as angina pectoris (ICD-10
codes: I20), MI (I21), heart failure (I50), diabetes mellitus (E10–14), stroke
(I60–69), renal insufficiency (N17–19), and hypertension (I10–15) were
obtained at inclusion by cross-linking the self-reported information with
data from the National Patient Register 2004–05.
Pharmacological treatment at inclusion was also collected as self-
reported information, completed with data from the Prescribed Drug
Register by 2004–05. Any antiplatelet or anticoagulation, antihyperten-
sive, statin, and diabetic therapy were recorded. Changes in medication
use during the observation period were recorded using register data.
Subjects who were diagnosed and considered at risk for critical limb is-
chaemia or had a brachial blood pressure above 180 mmHg were
referred to their general practitioner, but no other interventions were
made during the observation period.
Definition of peripheral arterial disease stage
groups
Subjects were placed in subgroups defined by ABI levels and reported
symptoms; Asymptomatic PAD (APAD), intermittent claudication (IC),
or severe limb ischaemia (SLI). Subjects with normal ABI and no qualifying
symptoms were classified as Reference group (Ref).
APAD: subjects with an ABI <0.9 without qualifying answers in the
questionnaire (i.e. no pain in the calf or thigh when walking).
IC: subjects with an ABI <0.9 and qualifying answers in the question-
naire (i.e. pain in calf or thigh when walking with relief at rest).
SLI: all subjects with an ankle blood pressure <_70 mm Hg.
Ref: subjects with an ABI >_0.9 and no symptomatic qualifying answers.
Severe limb ischaemia was used as a proxy for critical limb ischaemia,
17
which was difficult to assess in an epidemiological study of this kind relying
on questionnaire data.
Register data
In Sweden, healthcare is mainly organized by the government and regions
and is publicly funded. The government also keeps several mandatory
healthcare registers. All citizens have a unique personal registration num-
ber that makes it possible to followindividuals in the registers for scientif-
ic reasons and to cross-link data. This requires approval by an ethical
board and the register holder. In this study, the following three registers
were used;
The National Patient Register (NPR)
The National Patient Register (NPR) that includes alldiagnoses, recorded
and coded with the International Classification of Diseases 10th revision
(ICD-10), at Swedish hospitals covering all inpatient and outpatient care.
The NPR is updated yearly and covers >99% of all hospital discharges.
Cases with missing main diagnosis are around 1%. The NPR is regularly
checked for quality and validity.
18
The Cause of Death Register (CDR)
The Cause of Death Register (CDR) contains data of all deaths in
Sweden since 1961. The data collected include time of death, underlying,
and contributing causes of death. The use of CDR, in combination with
NPR, has previously been demonstrated to provide highly accurate data
in similar patient populations.
19
The Prescribed Drug Register (PDR)
The Prescribed Drug Register (PDR) includes data on all prescribed and
by pharmacy dispensed drugs. Drugs in the register are classified accord-
ing to Anatomical Therapeutic Chemical (ATC) classification system.
Definitions of outcome
All events were obtained from the NPR and CDR and are based on indi-
vidual data via personal registration number identification. Deaths were
defined as the primary cause of death according to the CDR. The disease
areas observed were either considered as CV (ICD-10 codes: I10–15,
I20–25, I50–51, I60–69, and I70–73), cancer (C00–D48), or as other
death than CV or cancer (any other ICD code) followed by contributing
risk factors such as the chronic conditions renal insufficiency (N17–19),
diabetes mellitus (E10–14), and hypertension (I10–15). The non-fatal CV
events were subclassified as either MI (I21) or stroke/transient ischaemic
2F. Sartipy et al.
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
attack (TIA; I60–69) since these were the two dominating CV events
groups, or as other non-fatal CV event. All non-fatal CV events were
counted each time when repeated events occurred, except from events
that re-occurred within 30 days to avoid counting multiple registrations
within the same care episode. The conditions that were defined as chron-
ic, for example hypertension, were counted only by the first event
recorded in the NPR or CDR register.
For assessment of pharmacological treatment, the PDR was used. In
this study, periods of expected therapeutic drug effect were monitored
for each. Drugs dispensed by pharmacies were recorded and used as a
proxy for treatment, and the following drug categories; platelet inhibitors
(ATC code B01AC), anticoagulation therapy (B01AA, B01AB, B01AE,
B01AF, and B01AX), statins (C10AA and C10B), antihypertensive treat-
ment (C02, C03, C07, C08, and C09) and antidiabetic drugs (A10), were
assessed. We defined the period with drug effect as the time starting
from the day of retrieval of the drug from pharmacy and ending when the
prescription expired. For warfarin (B01AA), the drug-effect period was
counted from 3 days after the date of drug retrieval and ending 3 days
after the ending date of the prescription, while it for statins (C10AA and
C10B) was counted from 2 weeks after the drug retrieval date and ending
5 days after expiration of the prescription, in order to more precisely
catch the expected periods of therapeutic drug effect.
Statistical analysis
Baseline characteristics are described with absolute and relative frequen-
cies for category variables and mean and standard deviations for continu-
ous variables. Mortality measures and chronic diseases (diabetes mellitus,
renal insufficiency, and hypertension) are described with absolute and
relative frequencies for number and proportion of afflicted subjects dur-
ing the follow-up period. For age-adjusted mortality direct standardiza-
tion based on 5-year age, intervals were used. CV events (all CV events,
non-fatal MI, and non-fatal stroke) are described as number of events dur-
ing follow-up, and as incidence (events per 1000 person-years). To illus-
trate and compare CV-, cancer, and other mortalities between baseline
groups, cumulative incidence functions was used.
20
To further investigate the differences in mortality, occurrence of CV
events and incidence of chronic diseases between baseline groups, Cox
proportional hazards regression models were used. In each regression
model, the proportional hazards assumption was examined. In the ana-
lysis of mortality, adjustments were made for sex, baseline age, and base-
line comorbidity (MI, stroke, other CV disease, cancer, renal insufficiency,
diabetes mellitus, and hypertension).
In the analysis of CV events repeated events Cox regression were
used, where the exit event was death or end of study, with last follow-up
date 31 December 2015. Adjustments were made for sex, baseline age,
and baseline comorbidities (MI, stroke, other CV disease, cancer, renal in-
sufficiency, diabetes mellitus, and hypertension).
Each analysis of incidence changes of chronic disease (diabetes mellitus,
hypertension, cancer, and renal insufficiency) was made in the population
not afflicted with the condition at baseline. Adjustment was made for sex,
baseline age, and other baseline comorbidities. For example, the analysis
of new cases of hypertension was made in the population without base-
line hypertension, and adjustments made for sex, age, and baseline
comorbidities but not hypertension. Venn diagrams with proportions in
percent, separated by sex, were used for illustrations of affected vascular
beds at baseline.
Drug use was described using drug prevalence plots, separated by
PAD stage at baseline. Similar plots were used for description of best
medical treatment among subjects with symptomatic PAD.
In all regression analyses, the proportional hazards assumption was
found adequate.
All statistical analyses were performed in Stata MP4 ver. 15.1
(StataCorp LLC, College Station, TX, USA) and all tests were two-sided.
Results
Cohort
The cohort consisted of 5080 subjects (45% males), with 5057 eli-
gible for analysis. The difference caused by missing ABI measurements
(23 subjects). At baseline, APAD, IC, and SLI were prevalent in 559
(11%), 320 (6.3%), and 78 (1.5%) subjects, respectively. The overall
PAD prevalence was higher among women and of the total number
of subjects with PAD 60% were female (Table 1). The mean age in
the total cohort and among all PAD subjects was 71.0 years (SD 7.9)
and 75.8 (8.0), respectively. Ages were similar between the sexes in
all the stage groups. Smoking prevalence at baseline in the reference
population was 51% (men 62% and women 42%), and 58% among
PAD subjects (75% and 46%). The occurrence of associated comor-
bidities increased by severity of PAD stage. For example, 7% in the
Ref population had a history of MI as compared to 13%, 28%, and
31% in APAD, IC, and SLI, respectively. Corresponding figures for
diabetes was 9%, 13%, 22%, and 24% (Table 1). Disease burden was
more pronounced among men. For example, having a history of MI,
diabetes, stroke, and renal failure was close to twice as common in
men than in women (Table 1). Figure 1shows the distribution of dif-
ferent CV manifestations among men and women at baseline. Men
were more often affected by MI and stroke, while PAD was more
common in women.
Pharmacological treatment patterns
Dispensed drugs increased in all groups during follow-up (Figure 2A–
D). For example, in the IC group, antihypertensive therapy increased
from 76% to 92%, statins from 25% to 71%, and antiplatelet therapy
from 53% to 72%. Best medical treatment as recommended by guide-
lines,
21,22
including a combination of platelet inhibition or anticoagula-
tion therapy, statins, and antihypertensive treatment when
hypertension was present, increased among IC subjects from 18% to
60% (Figure 3). One example of medication trends is that IC patients
were prescribed drugs for diabetes twice as often as in the Ref group,
and in all groups’ diabetes drug treatment increased over time with
approximately 10% (Figure 2A–D).
Overall mortality
During the observation time, 1704 (34%) subjects died, were of 36%
by CV diseases, 28% by cancer, and 36% by other causes dominated
by neurological, psychiatric, and respiratory diseases (Table 2). In
each stage group, the 10-year all-cause mortality was for Refs, APAD,
IC, and SLI 27%, 56%, 64%, and 76%, respectively. A significant
increased risk for CV death, even when adjusted for age and baseline
morbidity, were noted in all PAD stages as compared to references
with a small difference between APAD and IC, the latter with
adjusted hazard ratios (HRs) of 1.80 [confidence interval (CI) 1.45–
2.22] and 1.95 (1.50–2.53), respectively (Table 3). The 10-year
adjusted HR for cancer mortality was for APAD 1.14 (95% CI 0.84–
1.50) and IC 0.93 (95% CI 0.60–1.34). All-cause mortality was higher
among men 40.0% (age-standardized and 95% CI: 38.0–41.4) than in
women 28.9% (27.5–30.4). In the age-adjusted analysis, the HR for
CV long-term outcome in PAD 3
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
....................................................................................................................................................................................................................
Table 1 Baseline characteristics 2005
Baseline variables Sex All References Asymptomatic
PAD
Intermittent
claudication
Severe limb
ischaemia
All PAD
Group size, n(%) All 5080 (100.0) 4100 (100.0) 559 (100.0) 320 (100.0) 78 (100.0) 980 (100.0)
Men 2301 (45.3) 1908 (46.5) 211 (37.7) 154 (48.1) 22 (28.2) 393 (40.1)
Women 2779 (54.7) 2192 (53.5) 348 (62.3) 166 (51.9) 56 (71.8) 587 (59.9)
Age (years), mean (SD) All 71.0 (7.9) 69.8 (7.5) 75.6 (8.0) 75.7 (8.0) 77.9 (6.9) 75.8 (8.0)
Men 70.6 (7.8) 69.5 (7.4) 75.4 (8.0) 75.3 (8.2) 77.7 (5.5) 75.5 (8.0)
Women 71.3 (8.0) 70.1 (7.6) 75.8 (8.1) 76.0 (7.7) 78.0 (7.4) 76.0 (7.9)
Ankle–brachial index, mean (SD) All 0.99 (0.17) 1.05 (0.09) 0.78 (0.11) 0.72 (0.13) 0.39 (0.12) 0.73 (0.16)
Men 1.02 (0.17) 1.08 (0.10) 0.77 (0.10) 0.72 (0.12) 0.46 (0.13) 0.73 (0.13)
Women 0.97 (0.16) 1.03 (0.08) 0.78 (0.12) 0.73 (0.13) 0.36 (0.10) 0.72 (0.17)
Smoking habits, n(%)
No smoking All 2423 (47.7) 2008 (49.0) 253 (45.3) 125 (39.1) 24 (30.8) 415 (42.3)
Men 826 (35.9) 726 (38.1) 61 (28.9) 35 (22.7) 2 (9.1) 100 (25.4)
Women 1597 (57.5) 1282 (58.5) 192 (55.2) 90 (54.2) 22 (39.3) 315 (53.7)
Smoked <10 years All (12.7) 551 (13.4) 54 (9.7) 30 (9.4) 8 (10.3) 96 (9.8)
Men 310 (13.5) 269 (14.1) 24 (11.4) 15 (9.7) 2 (9.1) 41 (10.4)
Women 337 (12.1) 282 (12.9) 30 (8.6) 15 (9.0) 6 (10.7) 55 (9.4)
Smoked 10–30 years All 1050 (20.7) 877 (21.4) 94 (16.8) 54 (16.9) 21 (26.9) 173 (17.7)
Men 607 (26.4) 518 (27.1) 43 (20.4) 35 (22.7) 8 (36.4) 89 (22.6)
Women 443 (15.9) 359 (16.4) 51 (14.7) 19 (11.4) 13 (23.2) 84 (14.3)
Smoked >30 years All 960 (18.9) 664 (16.2) 158 (28.3) 111 (34.7) 25 (32.1) 296 (30.2)
Men 558 (24.3) 395 (20.7) 83 (39.3) 69 (44.8) 10 (45.5) 163 (41.5)
Women 402 (14.5) 269 (12.3) 75 (21.6) 42 (25.3) 15 (26.8) 133 (22.7)
Morbidity, n(%)
Angina pectoris All 727 (14.3) 490 (12.0) 93 (16.6) 105 (32.8) 35 (44.9) 237 (24.2)
Men 370 (16.1) 262 (13.7) 42 (19.9) 54 (35.1) 11 (50.0) 108 (27.5)
Women 357 (12.8) 228 (10.4) 51 (14.7) 51 (30.7) 24 (42.9) 129 (22.0)
Myocardial infarction All 481 (9.5) 293 (7.1) 73 (13.1) 90 (28.1) 24 (30.8) 188 (19.2)
Men 299 (13.0) 194 (10.2) 45 (21.3) 51 (33.1) 9 (40.9) 105 (26.7)
Women 182 (6.5) 99 (4.5) 28 (8.0) 39 (23.5) 15 (26.8) 83 (14.1)
Heart failure All 340 (6.7) 207 (5.0) 47 (8.4) 62 (19.4) 19 (24.4) 133 (13.6)
Men 172 (7.5) 115 (6.0) 16 (7.6) 33 (21.4) 7 (31.8) 57 (14.5)
Women 168 (6.0) 92 (4.2) 31 (8.9) 29 (17.5) 12 (21.4) 76 (12.9)
Diabetes mellitus All 529 (10.4) 363 (8.9) 75 (13.4) 70 (21.9) 19 (24.4) 166 (16.9)
Men 265 (11.5) 182 (9.5) 34 (16.1) 41 (26.6) 8 (36.4) 83 (21.1)
Women 264 (9.5) 181 (8.3) 41 (11.8) 29 (17.5) 11 (19.6) 83 (14.1)
Stroke All 395 (7.8) 248 (6.0) 79 (14.1) 52 (16.3) 14 (17.9) 147 (15.0)
Men 231 (10.0) 142 (7.4) 42 (19.9) 41 (26.6) 6 (27.3) 89 (22.6)
Women 164 (5.9) 106 (4.8) 37 (10.6) 11 (6.6) 8 (14.3) 58 (9.9)
Renal failure All 132 (2.6) 80 (2.0) 19 (3.4) 25 (7.8) 5 (6.4) 52 (5.3)
Men 78 (3.4) 49 (2.6) 8 (3.8) 18 (11.7) 2 (9.1) 29 (7.4)
Women 54 (1.9) 31 (1.4) 11 (3.2) 7 (4.2) 3 (5.4) 23 (3.9)
Hypertension All 1885 (37.1) 1420 (34.6) 239 (42.8) 179 (55.9) 37 (47.4) 465 (47.4)
Men 812 (35.3) 629 (33.0) 81 (38.4) 87 (56.5) 11 (50.0) 183 (46.6)
Women 1073 (38.6) 791 (36.1) 158 (45.4) 92 (55.4) 26 (46.4) 282 (48.0)
Therapy, n(%)
Thrombocytic inhibition All 1225 (24.1) 843 (20.6) 183 (32.7) 144 (45.0) 50 (64.1) 382 (39.0)
Men 651 (28.3) 475 (24.9) 87 (41.2) 76 (49.4) 13 (59.1) 176 (44.8)
Women 574 (20.7) 368 (16.8) 96 (27.6) 68 (41.0) 37 (66.1) 206 (35.1)
Anticoagulation All 197 (3.9) 131 (3.2) 35 (6.3) 24 (7.5) 6 (7.7) 66 (6.7)
Men 123 (5.3) 88 (4.6) 19 (9.0) 14 (9.1) 2 (9.1) 35 (8.9)
Women 74 (2.7) 43 (2.0) 16 (4.6) 10 (6.0) 4 (7.1) 31 (5.3)
Continued
4F. Sartipy et al.
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
CV death for men with IC was 2.09 (1.47–2.98), P< 0.0001 as com-
pared 1.68 (1.10–2.53), P= 0.009 for women. The incidence of fatal
MI was doubled for men compared to women, and the incidence of
stroke events increased from 25 events/1000 person-years for
women to 40 for men.
Figure 4illustrates the cumulative incidence for death by CV, can-
cer, and other mortality by PAD stage.
Overall morbidity
During the observation period, 1532 non-fatal strokes/TIAs occurred
and 647 non-fatal MIs. Fifty-fiveand 61% of these events, respectively,
occurred in men. Incidence rates for stroke/TIA and MI increased by
severity of PAD stage. In the Ref group, the incidence of stroke/TIA
was 27.3 events/1000 person-years and for MI 10.6. Corresponding
figures for the IC group were 67.9 and 38.7. Both absolute numbers
and incidences of CV events were higher for men than for women in
all PAD stages. For example, incidences of MI for men were 38.2
events/1000 person-years and in women 22.9.
Almost 40% (men: 42% and women: 38%) of the total cohort had
a diagnosis of cancer during Follow-up, as compared to 5% at base-
line, with similar prevalence between the PAD stage groups.
Adjusted HR for cancer among APAD and IC was similar, 0.85 (95%
CI 0.72–1.00) and 0.84 (95% CI 0.67–1.03), respectively (Table 3).
Diagnosis of diabetes mellitus in APAD patients increased from
13.4% at baseline to 22.5% at the end of follow-up, with a similar rise
for renal insufficiency at 3.4–10.2%. For IC subjects, diabetes
increased to 31.9% and renal insufficiency 11.3% during follow-up
(Table 2). Corresponding adjusted HR was for APAD 1.38 (95% CI
1.11–1.69) and 1.68 (95% CI 1.18–2.31) and for IC 1.69 (95% CI
1.30–2.16) and 1.38 (95% CI 0.88–2.04) (Table 3).
Discussion
Part of the rationale behind this 10-year follow-up study of a
population-based cohort was the assumption that the morbidity and
mortality are affected by changes in pharmacological treatment
....................................................................................................................................................................................................................
Table 1 Continued
Baseline variables Sex All References Asymptomatic
PAD
Intermittent
claudication
Severe limb
ischaemia
All PAD
Statin All 856 (16.9) 626 (15.3) 99 (17.7) 96 (30.0) 32 (41.0) 230 (23.5)
Men 431 (18.7) 322 (16.9) 44 (20.9) 55 (35.7) 9 (40.9) 109 (27.7)
Women 425 (15.3) 304 (13.9) 55 (15.8) 41 (24.7) 23 (41.1) 121 (20.6)
Antihypertensive All 2126 (41.9) 1536 (37.5) 303 (54.2) 220 (68.8) 57 (73.1) 590 (60.2)
Men 951 (41.3) 710 (37.2) 116 (55.0) 107 (69.5) 17 (77.3) 241 (61.3)
Women 1175 (42.3) 826 (37.7) 187 (53.7) 113 (68.1) 40 (71.4) 349 (59.5)
Diabetic All 369 (7.3) 241 (5.9) 55 (9.8) 56 (17.5) 15 (19.2) 128 (13.1)
Men 193 (8.4) 129 (6.8) 22 (10.4) 36 (23.4) 6 (27.3) 64 (16.3)
Women 176 (6.3) 112 (5.1) 33 (9.5) 20 (12.0) 9 (16.1) 64 (10.9)
Figure 1 Relationship of prevalence in percent (%) of all peripheral arterial disease and myocardial infarction, and stroke/transient ischaemic attack
(stroke) at baseline 2005 separated by sex.
CV long-term outcome in PAD 5
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.patterns. However, the findings revealed stable mortality rates for
the PAD population today as compared those presented three deca-
des ago.
23
Second, APAD subjects, even in a population-based set-
ting, have similar risks compared to subjects with symptomatic
disease. Third, PAD is less common among men than in females in
the same age group. Men also have more manifestations of CV dis-
ease in other vascular beds and face a higher risk for CV-related
death and events. Finally, only about 60% of PAD subjects received
the pharmacological prophylactic treatment recommended in
guidelines.
After adjustments for age, comorbidity, and sex, the risk was
doubled for CV death among IC and APAD subjects (HR 1.95 and
1.80) as compared to Refs. This is consistent with the literature,
which presents similar results.
9,24
However, these studies enrolled
patients referred to clinics and were not population-based. In a simi-
lar population-based observational study performed 10 years ago,
Lakshmanan et al.
25
presented an almost identical risk of CV death
(HR 2.00, 95% CI 1.52–2.64) for male IC patients, indicating little
Figure 2 Drug usage among (A) references, (B) asymptomatic peripheral arterial disease, (C) intermittent claudication, and (D) severe limb ischaemia.
Figure 3 Subjects within symptomatic subgroups receiving best
medical treatment according to guidelines for PAD by 2005–16.
6F. Sartipy et al.
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
progress over time for men. A much higher mortality risk for PAD
subjects was presented by Criqui et al.
23
when using a reference
population in which all subjects with any concomitant CV disease
was excluded.
Smoking is perhaps the strongest risk factor associated to PAD,
26,27
but particularly in Northern Europe widespread awareness of smoke-
related health problems has led to cessation during the latest decades,
28
and the number of smokers in the population is low. According to the
Public Health Agency of Sweden, between 2004 and 2016 daily smoking
in Sweden decreased by approximately one-third in the population aged
16–84 years. Only 8% of men and 11% of women smoked daily in 2016.
Diabetes, which is seen as the second strongest risk factor for
PAD, was twice as common in the IC group as in the reference
group. In Sweden, the prevalence of diabetes rose between 2007 and
2013 from 5.8% to 6.8%, but incidence remained constant at 4.4 per
1000 inhabitants (2013).
29
....................................................................................................................................................................................................................
Table 2 Cardiovascular and chronic comorbidity events between 2005 and 2015 by different peripheral arterial dis-
ease stage groups
Outcomes Sex Baseline
morbidity
All subjects References APAD IC SLI All PAD
Group size, n(%) Total 0 5057 (100.0) 4100 (100.0) 559 (100.0) 320 (100.0) 78 (100.0) 957 (100.0)
Men 0 2295 (45.4) 1908 (46.5) 211 (37.7) 154 (48.1) 22 (28.2) 387 (40.4)
Women 0 2762 (54.6) 2192 (53.5) 348 (62.3) 166 (51.9) 56 (71.8) 570 (59.6)
All-cause mortality, n(%) Total 0 1704 (33.7) 1125 (27.4) 314 (56.2) 206 (64.4) 59 (75.6) 579 (60.5)
Men 0 880 (38.3) 615 (32.2) 132 (62.6) 112 (72.7) 21 (95.5) 265 (68.5)
Women 0 824 (29.8) 510 (23.3) 182 (52.3) 94 (56.6) 38 (67.9) 314 (55.1)
Development of cardiovascular events
Cardiovascular mortality Total 0 611 (12.1) 353 (8.6) 132 (23.6) 96 (30.0) 30 (38.5) 258 (27.0)
Men 0 342 (14.9) 211 (11.1) 63 (29.9) 58 (37.7) 10 (45.5) 131 (33.9)
Women 0 269 (9.7) 142 (6.5) 69 (19.8) 38 (22.9) 20 (35.7) 127 (22.3)
All cardiovascular events Total 2494 (49.3) 10 407 (215.9) 7277 (179.2) 1418 (306.1) 1317 (541.7) 395 (768.5) 3130 (413.1)
Men 1154 (50.3) 5912 (280.0) 4374 (238.5) 648 (406.9) 763 (723.7) 127 (1001.2) 1538 (554.5)
Women 1340 (48.5) 4495 (166.0) 2903 (130.3) 770 (253.3) 554 (402.4) 268 (692.2) 1592 (331.4)
Non-fatal myocardial infarction Total 480 (9.5) 647 (13.4) 431 (10.6) 103 (22.2) 94 (38.7) 19 (37.0) 216 (28.5)
Men 299 (13.0) 397 (18.8) 291 (15.9) 48 (30.1) 53 (50.3) 5 (39.4) 106 (38.2)
Women 181 (6.6) 250 (9.2) 140 (6.3) 55 (18.1) 41 (29.8) 14 (36.2) 110 (22.9)
Non-fatal stroke/TIA Total 393 (7.8) 1532 (31.8) 1110 (27.3) 212 (45.8) 165 (67.9) 45 (87.5) 422 (55.7)
Men 231 (10.1) 844 (40.0) 610 (33.3) 121 (76.0) 100 (94.8) 13 (102.5) 234 (84.4)
Women 162 (5.9) 688 (25.4) 500 (22.4) 91 (29.9) 65 (47.2) 32 (82.7) 188 (39.1)
Development of chronic comorbidity events
Cancer Total 269 (5.3) 2033 (402.0) 1664 (405.9) 217 (388.2) 123 (384.4) 29 (371.8) 369 (385.6)
Men 138 (6.0) 976 (425.3) 814 (426.6) 84 (398.1) 67 (435.1) 11 (500.0) 162 (418.6)
Women 131 (4.7) 1057 (382.7) 850 (387.8) 133 (382.2) 56 (337.3) 18 (321.4) 207 (363.2)
Cancer mortality Total 0 475 (9.4) 382 (9.3) 61 (10.9) 28 (8.8) 4 (5.1) 93 (9.7)
Men 0 271 (11.8) 226 (11.8) 25 (11.8) 18 (11.7) 2 (9.1) 45 (11.6)
Women 0 204 (7.4) 156 (7.1) 36 (10.3) 10 (6.0) 2 (3.6) 48 (8.4)
Renal insufficiency Total 129 (2.6) 305 (60.3) 200 (48.8) 57 (102.0) 36 (112.5) 12 (153.8) 105 (109.7)
Men 77 (3.4) 189 (82.4) 136 (71.3) 28 (132.7) 22 (142.9) 3 (136.4) 53 (137.0)
Women 52 (1.9) 116 (42.0) 64 (29.2) 29 (83.3) 14 (84.3) 9 (160.7) 52 (91.2)
Diabetes mellitus Total 527 (10.4) 877 (173.4) 620 (151.2) 126 (225.4) 102 (318.8) 29 (371.8) 257 (268.5)
Men 265 (11.5) 443 (193.0) 331 (173.5) 47 (222.7) 56 (363.6) 9 (409.1) 112 (289.4)
Women 262 (9.5) 434 (157.1) 289 (131.8) 79 (227.0) 46 (277.1) 20 (357.1) 145 (254.4)
Hypertension Total 1875 (37.1) 2350 (464.7) 1836 (447.8) 278 (497.3) 193 (603.1) 43 (551.3) 514 (537.1)
Men 808 (35.2) 1082 (471.5) 882 (462.3) 101 (478.7) 88 (571.4) 11 (500.0) 200 (516.8)
Women 1067 (38.6) 1268 (459.1) 954 (435.2) 177 (508.6) 105 (632.5) 32 (571.4) 314 (550.9)
Other death than cardiovascular
or cancer
Total 0 618 (12.2) 390 (9.5) 121 (21.6) 82 (25.6) 25 (32.1) 228 (23.8)
Men 0 267 (11.6) 178 (9.3) 44 (20.9) 36 (23.4) 9 (40.9) 89 (23.0)
Women 0 351 (12.7) 212 (9.7) 77 (22.1) 46 (27.7) 16 (28.6) 139 (24.4)
Values are presented as number of events (and incidence in events/1000 person-years). The PAD stage groups are abbreviated as follows asymptomatic PAD (APAD), intermit-
tent claudication (IC), and severe limb ischaemia (SLI). All cardiovascular events are presented also with the two subgroups non-fatal myocardial infarction and non-fatal stroke/
TIA (shaded rows).
CV long-term outcome in PAD 7
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
....................................................................................................................................................................................................................
Table 3 Cardiovascular and chronic comorbidity event risk by hazard ratio (crude and adjusted by age and baseline
morbidity) divided by different peripheral arterial disease stage groups
Outcome Group Subjects (%) Events (inc) Crude HR
(95%CI)
P-value Adjusted HR
(95%CI)
P-value
All-cause mortality All 1704 (33.7) 1704 (35.4)
Ref 1125 (27.4) 1125 (27.7) 1 1
APAD 314 (56.2) 314 (67.8) 2.57 (2.27–2.92) <0.001 1.53 (1.34–1.75) <0.001
IC 206 (64.4) 206 (84.7) 3.32 (2.84–3.86) <0.001 1.63 (1.38–1.93) <0.001
SLI 59 (75.6) 59 (114.8) 4.68 (3.56–6.20) <0.001 2.41 (1.80–3.26) <0.001
Cardiovascular risk
Cardiovascular mortality All 611 (12.1) 611 (12.7)
Ref 353 (8.6) 353 (8.7) 1 1
APAD 132 (23.6) 132 (28.5) 3.43 (2.78–4.19) <0.001 1.80 (1.45–2.22) <0.001
IC 96 (30.0) 96 (39.5) 4.89 (3.84–6.07) <0.001 1.95 (1.50–2.53) <0.001
SLI 30 (38.5) 30 (58.4) 7.49 (4.99–10.68) <0.001 3.36 (2.22–4.89) <0.001
All cardiovascular events All 3061 (60.5) 10 407 (215.9)
Ref 2320 (56.6) 7277 (179.2) 1 1
APAD 395 (70.7) 1418 (306.1) 1.76 (1.62–1.91) <0.001 1.42 (1.30–1.56) <0.001
IC 279 (87.2) 1317 (541.7) 3.17 (2.89–3.49) <0.001 1.89 (1.71–2.10) <0.001
SLI 67 (85.9) 395 (768.5) 4.60 (3.86–5.55) <0.001 2.73 (2.29–3.32) <0.001
Non-fatal myocardial infarction All 469 (9.3) 647 (13.4)
Ref 320 (7.8) 431 (10.6) 1 1
APAD 73 (13.1) 103 (22.2) 2.12 (1.68–2.63) <0.001 1.57 (1.24–1.96) <0.001
IC 63 (19.7) 94 (38.7) 3.70 (2.89–4.65) <0.001 1.92 (1.47–2.47) <0.001
SLI 13 (16.7) 19 (37.0) 3.57 (2.01–5.52) <0.001 1.90 (1.04–2.99) 0.020
Non-fatal stroke/TIA All 738 (14.6) 1532 (31.8)
Ref 542 (13.2) 1110 (27.3) 1 1
APAD 107 (19.1) 212 (45.8) 1.71 (1.45–2.00) <0.001 1.23 (1.03–1.45) 0.019
IC 73 (22.8) 165 (67.9) 2.58 (2.15–3.07) <0.001 1.59 (1.30–1.93) <0.001
SLI 16 (20.5) 45 (87.5) 3.39 (2.39–4.69) <0.001 2.17 (1.54–2.95) <0.001
Chronic comorbidity event risk
Cancer All 2033 (40.2) 2033 (42.2)
Ref 1664 (40.6) 1664 (41.0) 1 1
APAD 217 (38.8) 217 (46.8) 0.90 (0.77–1.05) 0.204 0.85 (0.72–1.00) 0.052
IC 123 (38.4) 123 (50.6) 0.89 (0.72–1.08) 0.273 0.84 (0.67–1.03) 0.109
SLI 29 (37.2) 29 (56.4) 0.91 (0.56–1.35) 0.655 0.87 (0.53–1.32) 0.555
Cancer mortality All 475 (9.4) 475 (9.9)
Ref 382 (9.3) 382 (9.4) 1 1
APAD 61 (10.9) 61 (13.2) 1.45 (1.08–1.86) 0.008 1.14 (0.84–1.50) 0.376
IC 28 (8.8) 28 (11.5) 1.30 (0.82–1.84) 0.191 0.93 (0.60–1.34) 0.735
SLI 4 (5.1) 4 (7.8) 0.90 (0.20–1.98) 0.843 0.72 (0.15–1.61) 0.534
Renal insufficiency All 305 (6.0) 305 (6.3)
Ref 200 (4.9) 200 (4.9) 1 1
APAD 57 (10.2) 57 (12.3) 2.26 (1.64–2.99) <0.001 1.68 (1.18–2.31) 0.004
IC 36 (11.3) 36 (14.8) 2.33 (1.52–3.30) <0.001 1.38 (0.88–2.04) 0.139
SLI 12 (15.4) 12 (23.3) 3.51 (1.69–5.89) 0.001 2.25 (1.03–4.07) 0.025
Diabetes mellitus All 877 (17.3) 877 (18.2)
Ref 620 (15.1) 620 (15.3) 1 1
APAD 126 (22.5) 126 (27.2) 1.56 (1.26–1.90) <0.001 1.38 (1.11–1.69) 0.003
IC 102 (31.9) 102 (42.0) 2.26 (1.78–2.81) <0.001 1.69 (1.30–2.16) <0.001
SLI 29 (37.2) 29 (56.4) 2.64 (1.66–3.84) <0.001 2.02 (1.24–3.02) 0.004
Hypertension All 2350 (46.5) 2350 (48.8)
Ref 1836 (44.8) 1836 (45.2) 1 1
APAD 278 (49.7) 278 (60.0) 1.20 (1.05–1.36) 0.005 0.98 (0.85–1.12) 0.747
Continued
8F. Sartipy et al.
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Hypertension, without adequate blood pressure control, exposes
symptomatic PAD subjects for an increased risk for CV events, as re-
cently presented by Ya’qoub et al.
30
Achieving therapeutic blood
pressure goals are essential for vulnerable PAD subjects in risk reduc-
tion management.
31
Mortality rates related to MI have declined by almost 40% during
the last 10years in Sweden. Two-thirds of this is explained by more
intense risk factor management.
6
The persistent high CV event rates
for the PAD population may thus be explained by underuse of sec-
ondary preventive medication. A finding supporting this assumption
was that only 60% of the symptomatic PAD subjects used pharmaco-
logical treatment according to guidelines.
Asymptomatic PAD subjects faced similar risks as IC patients in
this study. Consequently, screening activities could be considered, es-
pecially since the condition is easily detected by ABI measurement.
Surprisingly, a large systemic review by Alahdab et al.,
32
did not find
support for screening for APAD. The reason given was that informa-
tion on benefits and cost-effectiveness of screening is limited. This
contradicts the results of Vaidya et al.,
33
who proposed that screening
of PAD and treatment with platelet inhibitors is a cost-effective strat-
egy, based on results of a cost-effectiveness model analysis. Both
European and American guidelines,
34,35
however, do not recom-
mend drug intervention in asymptomatic disease, particularly because
the role of statins is unclear in this population. Considering the high
risk observed, further studies regarding prophylactic strategies of the
large APAD population is needed. It is reasonable to believe that the
APAD group holds subjects with a wide range of arteriosclerotic bur-
den and risks, why further analysis of CV risks within this subgroup
could be particularly interesting. Persons with abnormal ABI who
never experience exertional leg symptoms might even be in a more
severe state than IC subjects due to low over all functional perform-
ance capacity.
36
Because men are affected by a more severe CV disease burden in
general and consequently heavier comorbidity when diagnosed hav-
ing PAD, presentation with PAD as primary and single diagnosis
seems to be a female-type expression of arteriosclerosis. Sole leg ar-
tery affliction was predominately a female CV disease pattern in this
study (Figure 1). However, this observation also depends on the fact
that men die off at earlier ages in other CV conditions and may partly
explain why women dominate in all observed PAD stage groups.
Appelman et al.
37
presented that CV risk factors affect men and
women differently and that smoking have a stronger impact on
females, which also has been shown by Sigvant et al.
38
within this co-
hort. Women might have specific risk factors. Examples of such are
gestational hypertension and polycystic ovarian syndrome, which
both increases the need of attention and detection of PAD in
....................................................................................................................................................................................................................
Table 3 Continued
Outcome Group Subjects (%) Events (inc) Crude HR
(95%CI)
P-value Adjusted HR
(95%CI)
P-value
IC 193 (60.3) 193 (79.4) 1.65 (1.40–1.94) <0.001 1.18 (0.98–1.41) 0.075
SLI 43 (55.1) 43 (83.7) 1.27 (0.89–1.76) 0.164 0.83 (0.56–1.18) 0.329
Other death than cardiovascular and cancer mortality All 618 (12.2) 618 (12.8)
Ref 390 (9.5) 390 (9.6) 1 1
APAD 121 (21.6) 121 (26.1) 2.91 (2.34–3.55) <0.001 1.56 (1.25–1.92) <0.001
IC 82 (25.6) 82 (33.7) 3.91 (3.03–4.91) <0.001 1.75 (1.33–2.31) <0.001
SLI 25 (32.1) 25 (48.6) 5.95 (3.74–8.90) <0.001 2.66 (1.60–4.25) <0.001
The PAD stage groups are abbreviated as follows asymptomatic peripheral arterial disease (APAD), intermittent claudication (IC), and severe limb ischaemia (SLI). All cardiovas-
cular events are presented also with the two subgroups non-fatal myocardial infarction and non-fatal stroke/TIA (shaded rows).
Figure 4 Cumulative incidence for death by cardiovascular, can-
cer, and other mortality by the peripheral arterial disease stage
group’s asymptomatic peripheral arterial disease, intermittent clau-
dication, severe limb ischaemia, and references.
CV long-term outcome in PAD 9
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
women. A study by Hiramoto et al.,
13
having APAD was strongly
associated with the risk for experiencing a future CV event in both
women and men, and in this study, women had a higher prevalence
of subclinical PAD and their risk for both cardiac and stroke mortality
were higher than in men.
Unexpectedly, cancer mortality decreased by worsening PAD
stage, possibly a consequence of competing risks.
39
The risk for mor-
tality by other causes than CV and cancer, including neurological, psy-
chiatric and respiratory diseases,
7
also increased significantly by PAD
stage severity. This can also possibly be explained by smoke-related
risk-associations.
Limitations
One major limitation in this study is that conditions and events diag-
nosed at a primary care unit not are covered by the NPR, which only
record hospital data. In this study, we also tried to analyse if drug
treatment affected the risk for mortality and morbidity. While it was
possible to record drug treatment, the indications behind new pre-
scriptions during the observation period, as well as new diagnoses
not requiring hospital care, was not covered in the registers.
Moreover, the sample size did probably not allow meaningful drug-ef-
fect analyses in the different PAD stage groups.
As in most cohort studies, non-participation is a possible limitation,
and it is likely that the oldest and most ill subjects were in majority
among non-participants rendering underrepresentation in the symp-
tomatic stage groups.
Conclusion
This study reveals that CV mortality for PAD subjects are unchanged
over the last three decades and that asymptomatic subjects have a
similar risk as symptomatic patients. PAD is more common in
women, but men face a higher risk for death and CV events.
Unfortunately, only about 60% of PAD subjects receive prophylactic
drugs according to guidelines. A further study of intervention strat-
egies in APAD is highly needed.
Ethical approval
The study was approved by the local ethics committees in Stockholm
(KI 03-538 and Dnr 2014/2070-32), Umea˚ University (Dnr 03-459),
Lunds University (832-0), Uppsala University (Dnr 03-564), and
O
¨rebro (Dnr 374-03). Informed consent was obtained from each
participant.
Acknowledgements
All of the authors are deeply grateful for the invaluable help with ini-
tial data collection from O. Rolandsson, MD and B. Andersson, MD.
Funding
The original study was supported by unrestricted grants from The
Swedish Heart-Lung Foundation, Va¨rmland’s County Research Council,
and Sanofi-Aventis
V
R
.
Conflict of interest: F.S. and B.S. report unrestricted grants from The
Swedish Heart-Lung Foundation, Va¨ rmland’s County Research Council,
and Sanofi-Aventis
V
R
during the conduct of the study. B.S. also reports un-
restricted grants from Astra Zeneca
V
R
. And all other authors have no con-
flict of interest to declare.
References
1. Hajibandeh S, Hajibandeh S, Shah S, Child E, Antoniou GA, Torella F. Prognostic
significance of ankle brachial pressure index: a systematic review and meta-ana-
lysis. Vascular 2017;25:208–224.
2. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res 2015;
116:1509–1526.
3. Feringa HH, van Waning VH, Bax JJ, Elhendy A, Boersma E, Schouten O et al.
Cardioprotective medication is associated with improved survival in patients
with peripheral arterial disease. J Am Coll Cardiol 2006;47:1182–1187.
4. Hackam DG. Cardiovascular risk prevention in peripheral artery disease. J Vasc
Surg 2005;41:1070–1073.
5. Herrington W, Lacey B, Sherliker P, Armitage J, Lewington S. Epidem iology of
atherosclerosis and the potential to reduce the global burden of atherothrom-
botic disease. Circ Res 2016;118:535–546.
6. Berg J, Bjorck L, Lappas G, O’Flaherty M, Capewell S, Rosengren A. Continuing
decrease in coronary heart disease mortality in Sweden. BMC Cardiovasc Disord
2014;14:9.
7. Sartipy F, Sigvant B, Lundin F, Wahlberg E. Ten year mortality in different periph-
eral arterial disease stages: a population based observational study on outcome.
Eur J Vasc Endovasc Surg 2018;55:529–536.
8. Sigvant B, Kragsterman B, Falkenberg M, Hasvold P, Johansson S, Thuresson M
et al. Contemporary cardiovascular risk and secondary preventive drug treat-
ment patterns in peripheral artery disease patients undergoing revascularization.
J Vasc Surg 2016;64:1009–1017.e3.
9. Caro J, Migliaccio-Walle K, Ishak KJ, Proskorovsky I. The morbidity and mortality
following a diagnosis of peripheral arterial disease: long-term follow-up of a large
database. BMC Cardiovasc Disord 2005;5:14.
10. Welten GM, Schouten O, Hoeks SE, Chonchol M, Vidakovic R, van Domburg
RT et al. Long-term prognosis of patients with peripheral arterial disease: a com-
parison in patients with coronary artery disease. J Am Coll Cardiol 2008;51:
1588–1596.
11. Brevetti G, Giugliano G, Oliva G, Lanero S, De Maio JI, Chiariello M. The impact
of comorbidity burden on the cardiovascular risk in the Peripheral Arteriopathy
and Cardiovascular Events study. QJM 2008;101:575–582.
12. Vyas MV, Mrkobrada M, Donner A, Hackam DG. Underrepresentation of per-
ipheral artery disease in modern cardiovascular trials: systematic review and
meta-analysis. Int J Cardiol 2013;168:4875–4876.
13. Hiramoto JS, Katz R, Ix JH, Wassel C, Rodondi N, Windham BG et al. Sex differ-
ences in the prevalence and clinical outcomes of subclinical peripheral artery dis-
ease in the Health, Aging, and Body Composition (Health ABC) study. Vascular
2014;22:142–148.
14. Parvand M, Rayner-Hartley E, Sedlak T. Recent developments in sex-related dif-
ferences in presentation, prognosis, and management of coronary artery disease.
Can J Cardiol 2018;34:390–399.
15. Hirsch AT, Allison MA, Gomes AS, Corriere MA, Duval S, Ershow AG et al.A
call to action: women and peripheral artery disease: a scientific statement from
the American Heart Association. Circulation 2012;125:1449–1472.
16. Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin
JW et al. Peripheral arterial disease detection, awareness, and treatment in pri-
mary care. JAMA 2001;286:1317–1324.
17. Sigvant B, Wiberg-Hedman K, Bergqvist D, Rolandsson O, Andersson B, Persson
Eet al. A population-based study of peripheral arterial disease prevalence with
special focus on critical limb ischemia and sex differences. J Vasc Surg 2007;45:
1185–1191.
18. Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C et al.
External review and validation of the Swedish national inpatient register. BMC
Public Health 2011;11:450.
19. Johansson LA, Westerling R. Comparing Swedish hospital discharge records with
death certificates: implications for mortality statistics. Int J Epidemiol 2000;29:
495–502.
20. Coviello V, Boggess M. Cumulative incidence estimation in the presence of com-
peting risks. Stata J 2004;4:103–112.
21. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL et al.
ACC/AHA 2005 Practice Guidelines for the management of patients with per-
ipheral arterial disease (lower extremity, renal, mesenteric, and abdominal aor-
tic): a collaborative report from the American Association for Vascular Surgery/
Society for Vascular Surgery, Society for Cardiovascular Angiography and
Interventions, Society for Vascular Medicine and Biology, Society of
10 F. Sartipy et al.
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines
(Writing Committee to Develop Guidelines for the Management of Patients
With Peripheral Arterial Disease): endorsed by the American Association of
Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood
Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus;
and Vascular Disease Foundation. Circulation 2006;113:e463–e654.
22. Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T et al.
2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial
Diseases, in collaboration with the European Society for Vascular Surgery
(ESVS): Document covering atherosclerotic disease of extracranial carotid and
vertebral, mesenteric, renal, upper and lower extremity arteries. Endorsed by:
the European Stroke Organization (ESO) The Task Force for the Diagnosis and
Treatment of Peripheral Arterial Diseases of the European Society of Cardiology
(ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J
2018;39:763–816.
23. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ et al.
Mortality over a period of 10 years in patients with peripheral arterial disease.
N Engl J Med 1992;326:381–386.
24. Malyar N, Furstenberg T, Wellmann J, Meyborg M, Luders F, Gebauer K et al.
Recent trends in morbidity and in-hospital outcomes of in-patients with periph-
eral arterial disease: a nationwide population-based analysis. Eur Heart J 2013;34:
2706–2714.
25. Lakshmanan R, Hyde Z, Jamrozik K, Hankey GJ, Norman PE. Population-based
observational study of claudication in older men: the Health in Men Study. Med J
Aust 2010;192:641–645.
26. Criqui MH, Denenberg JO, Langer RD, Fronek A. The epidemiology of periph-
eral arterial disease: importance of identifying the population at risk. Vasc Med
1997;2:221–226.
27. Fowkes FG, Housley E, Riemersma RA, Macintyre CC, Cawood EH, Prescott RJ
et al. Smoking, lipids, glucose intolerance, and blood pressure as risk factors for
peripheral atherosclerosis compared with ischemic heart disease in the
Edinburgh Artery Study. Am J Epidemiol 1992;135:331–340.
28. Pesce G, Marcon A, Calciano L, Perret JL, Abramson MJ, Bono R et al. Time and
age trends in smoking cessation in Europe. PLoS One 2019;14:e0211976.
29. Andersson T, Ahlbom A, Carlsson S. Diabetes prevalence in Sweden at present
and projections for year 2050. PLoS One 2015;10:e0143084.
30. Ya’qoub L, Peri-Okonny P, Wang J, Patel KK, Stone N, Smolderen K. Blood pres-
sure management in patients with symptomatic peripheral artery disease: insights
from the PORTRAIT registry. Eur Heart J Qual Care Clin Outcomes 2019;5:79–81.
31. Vrsalovic M. Blood pressure goals in hypertensive patients with peripheral arter-
ial disease. Eur Heart J Qual Care Clin Outcomes 2019;5:183.
32. Alahdab F, Wang AT, Elraiyah TA, Malgor RD, Rizvi AZ, Lane MA et al. A sys-
tematic review for the screening for peripheral arterial disease in asymptomatic
patients. J Vasc Surg 2015;61(3 Suppl):42S–53S.
33. Vaidya A, Joore MA, Ten Cate-Hoek AJ, Ten Cate H, Severens JL. Screen or not
to screen for peripheral arterial disease: guidance from a decision model. BMC
Public Health 2014;14:89.
34. Society for Vascular Surgery Lower Extremity Guidelines Writing Group, Conte
MS, Pomposelli FB, Clair DG, Geraghty PJ et al. Society for Vascular Surgery
practice guidelines for atherosclerotic occlusive disease of the lower extremities:
management of asymptomatic disease and claudication. J Vasc Surg 2015;
61(3 Suppl):2S–41S.
35. Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T et al.
Editor’s Choice—2017 ESC Guidelines on the diagnosis and treatment of periph-
eral arterial diseases, in collaboration with the European Society for Vascular
Surgery (ESVS). Eur J Vasc Endovasc Surg 2018;55:305–368.
36. McDermott MM, Guralnik JM, Ferrucci L, Tian L, Liu K, Liao Y et al.
Asymptomatic peripheral arterial disease is associated with more adverse lower
extremity characteristics than intermittent claudication. Circulation 2008;117:
2484–2491.
37. Appelman Y, van Rijn BB, Ten Haaf ME, Boersma E, Peters SA. Sex differences in
cardiovascular risk factors and disease prevention. Atherosclerosis 2015;241:
211–218.
38. Sigvant B, Wiberg-Hedman K, Bergqvist D, Rolandsson O, Wahlberg E. Risk fac-
tor profiles and use of cardiovascular drug prevention in women and men with
peripheral arterial disease. Eur J Cardiovasc Prev Rehabil 2009;16:39–46.
39. Satagopan JM, Ben-Porat L, Berwick M, Robson M, Kutler D, Auerbach AD. A
note on competing risks in survival data analysis. Br J Cancer 2004;91:1229–1235.
CV long-term outcome in PAD 11
Downloaded from https://academic.oup.com/ehjqcco/advance-article-abstract/doi/10.1093/ehjqcco/qcz037/5532223 by Stockholms lans landsting user on 06 August 2019
