Polyvascular disease, pulse pressure and mortality
The Ludwigshafen Risk and Cardiovascular Health (LURIC) study
Abstract
Summary:Background: Peripheral arterial disease (PAD), coronary artery disease (CAD) and carotid stenosis (CS) are robust predictors of mortality. The value of individual vascular beds in polyvascular disease (PVD) to predict mortality in patients with atherosclerotic burden is not clear. Therefore, we have examined the predictive value of PAD, CAD and CS in patients at intermediate to high risk of cardiovascular (CV) disease. Patients and methods: In our retrospective observational study we analyzed baseline data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, a monocentric cohort study of 3316 patients referred to coronary angiography. Results: As the number of atherosclerotic vascular beds increased, the hazard ratios (HRs) for both all-cause mortality and CV mortality significantly increased in a multivariate analysis after adjusting for age, sex, body mass index, diabetes mellitus and estimated glomerular filtration rate, with HRs of 1.36 (95%CI: 1.11–1.68), 2.56 (95%CI: 2.01–3.26), 2.84 (95%CI: 1.93–4.17) and 1.56 (95%CI: 1.19–2.06), 2.70 (95%CI: 1.97–3.72), 3.50 (95%CI: 2.19–5.62), respectively. The combination of PAD with either CAD or CS was associated with higher HRs for all-cause (HR 2.81 and 7.53, respectively) and CV (HRs 2.80 and 6.03, respectively) mortality compared with the combination of CAD and CS (HRs 1.94 and 2.43, respectively). The presence of PVD was associated with higher age, systolic blood pressure, pulse pressure (PP; a marker of vascular stiffness), former smoking and inversely with lower eGFR. Conclusions: We show that as the number of atherosclerotic vascular beds increases, all-cause and CV mortality rates increase in parallel. Simultaneous prevalence of PAD is associated with significantly higher all-cause and CV mortality rates compared with CS coexistence. Furthermore, increasing atherosclerotic load may contribute to vascular stiffness and impaired renal function.
Introduction
Cardiovascular diseases are the leading cause of global mortality a major contributor to disability. According to the Global Burden of Disease Study 2019, more than half a billion people are affected and the burden continues to increase globally [1].
In the presence of an atherothrombotic disease in the coronary, carotid or peripheral arteries, patients are at high risk of cardiovascular morbidity in the respective other vascular beds as well as cardiovascular mortality. Recent guidelines have addressed this ‘cross-risk’ and recognize a lack of evidence regarding the impact of co-prevalence of coronary artery disease (CAD), carotid stenosis (CS) and/or peripheral arterial disease (PAD) on patient outcome [1, 2]. Notably, for patients with atherosclerotic cardiovascular disease who experience recurrent vascular events within two years “not necessarily of the same type as the first event” results in the recommendation of very low target LDL values in the current European dyslipidaemia guidelines [3].
In this study, we analyzed the data of a large cohort of patients undergoing coronary angiography for suspected CAD. Specifically, we evaluated the long-term cardiovascular (CV) and all-cause mortality, depending on different combinations of atherosclerosis in one, two or all three vascular beds. We tested the hypothesis that patients with known atherosclerosis in two or three vascular beds may have a significantly shorter CV and overall survival than patients with only one affected vascular bed.
Patients and methods
Study cohort
The Ludwigshafen Risk and Cardiovascular Health (LURIC) study is a prospective monocentric hospital-based cohort study that recruited 3,316 patients of German ancestry living in the surroundings of the German cities of Ludwigshafen, Mannheim and Heidelberg, who underwent coronary angiography between July 1997 and January 2000. The Landesärztekammer Rheinland-Pfalz provided ethical approval for this study (LURIC, #837.255.97[1394]). Furthermore, the study was conducted according to the Declaration of Helsinki. All study participants provided written consent to participate. The main indications for coronary angiography were acute chest pain and positive non-invasive cardiac stress test [4].
The study exclusion criteria were other acute cardiac diseases, such as decompensated heart failure or decompensated valvular disease; acute non-cardiac diseases, such as infection or endocrine disease; any type of surgery within the previous 3 months; chronic polymorbid disease where non-cardiac disease predominates (i.e., chronic renal failure and hemodialysis, severe rheumatic arthritis, persistent incapacitation after accident/trauma); a history of malignant disease within the previous 5 years; and individuals incapable of understanding the purpose of the study [4]. After study entry, physical examinations, including vital signs and detailed blood tests, were performed.
Blood pressure was measured using an automated oscillometric device (Omron MX4, Omron Healthcare GmbH, Hamburg, Germany) while patients were in a supine position for at least 10 minutes. At intervals of 30 seconds, at least three consecutive measurements of systolic and diastolic blood pressure were taken. If measurements varied by >10 mmHg for systolic blood pressure, >5 mmHg for diastolic blood pressure, or >5 beats/minute for heart rate (except for in patients with atrial fibrillation), they were regarded as invalid and were thus repeated. Both valid and invalid measurements were recorded. Invalid measurements were immediately identified as such. Only stable measurements that matched the reproducibility criteria were entered into the database. One part of the questionnaire investigated whether blood pressure had been measured according to the protocol (supine position, 10 minutes at rest). Pulse pressure (PP) was calculated as difference between SBP–DBP. The study protocol and study procedures were reported in detail previously [4].
Laboratory measurements
Venous blood was drawn from study participants after an overnight fasting period under standardized conditions. Within 30 minutes after venipuncture, the remaining blood was centrifuged at 3,000 g for 10 minutes, immediately aliquoted, and frozen at −80°C until further analysis. A summary of analytic methods was reported previously [4].
Cholesterol and triglycerides were quantified with enzymatic reagents from WAKO (Neuss, Germany) on a WAKO30R analyzer. This assay has a lower limit of detection of 1 mg/dl for triglycerides. Lipoproteins were separated using a combined ultra-centrifugation-precipitation method (β-quantification) in all 3140 LURIC participants. Plasma was ultracentrifuged at a density of d=1.0063 kg/l (30.000 rpm for 18 h). VLDL in the supernatant were removed. In the remainder, LDL (and IDL) were precipitated with phosphotungstic acid/MgCl2. Centrifugation (10,000 rpm for 5 min) was the performed to separate precipitated LDL (and IDL) from HDL in the remainder. LDL triglycerides were calculated as the difference between triglycerides in the remainder before and after separation of LDL [5]. N-terminal pro-B-type natriuretic peptide (NT-proBNP) was measured by electrochemiluminescence using an Elecsys 2010 (Roche Diagnostics). Creatinine was measured using the CREA assay (Roche Diagnostics) and a Hitachi 717 analyzer. The estimated glomerular filtration rate (eGFR) was calculated using the MDRD formula.
Clinical definitions
In our paper, we use the term PAD synonymously to LEAD (lower extremity artery disease), since PAD is still used much more commonly in scientific literature.
Coronary artery disease (CAD) was defined according to the American Heart Association by visible luminal narrowing of 20% or more in at least one of 15 coronary segments [4]. Coronary 1-vessel disease, coronary 2-vessel disease, and coronary 3-vessel disease were defined as a stenosis of 20% or higher in one, two or three of the major coronary arteries LAD (left anterior descending artery), RCX (ramus circumflexus) and RCA (right coronary artery) [4]. In the LURIC study PAD was defined by a history of intermittent claudication, angiographic documentation of atherosclerotic luminal obstruction of the peripheral arteries, or a history of a peripheral arterial intervention for atherosclerotic disease (angioplasty or surgery). Systematic screening for asymptomatic PAD or CS was not performed, rather the data retrieved from the patient files and from the patient history. The atherosclerosis score ranging from 1 to 3 reflects the number of atherosclerotically affected vascular beds.
Follow up
Patients were followed up for a median of 9.9 years. Information on vital status was obtained for all participants from local registries. Death certificates, medical records from local hospitals, and autopsy data were reviewed independently by two experienced clinicians. Clinicians were blinded to patient characteristics and classified the causes of death in each case. In cases of disagreement or uncertainty concerning the coding of a specific cause of death, the final decision was made by a principal investigator (W.M.). For 21 participants the cause of death could not be determined and these were excluded for cause-specific mortality.
Statistical analysis
IBM SPSS® Statistics version 25.0 (SPSS Inc., IBM Corporation, NY, USA) and R version 4.1.2 were used for all analyses [6]. Continuous data are shown as the mean and standard deviation (SD) when normally distributed or as the median and 25th and 75th percentile for non-normally distributed variables. Statistical differences between groups and continuous variables were determined using analysis of variance. Non-normally distributed variables were log-transformed before entering analysis. The chi-square test was used for categorical variables. We used the Kaplan–Meier method to estimate survival regarding CV and all-cause mortality in patients with PAD, CAD, and CS using the R package ‘survminer’ version 0.4.9. Hazard ratios (HRs) were calculated by Cox proportional hazards regression. We performed multivariate analysis with adjustment for the cardiovascular risk factors age, sex, body mass index (BMI), diabetes mellitus, and eGFR. For four study participants, data on CS was not available, and for another nine study participants, data on eGFR was missing. These participants were excluded from the analysis, leaving a total of 3,303 participants. No adjustment for multiple hypothesis testing was applied. All tests were two-sided and a P value <0.05 was considered statistically significant.
The STROBE cohort reporting guidelines were followed [7].
Results
Of 3,303 participants, 705 patients (21.3%) had no atherosclerosis and 2199 patients (66.6%) had stenotic atherosclerosis in one vascular bed, thereof 2,572 (77.9% of the overall cohort) CAD, 159 (4.8%) CS and 318 (9.6%) PAD. Multisite artery disease was present in 399 patients (12.1%), thereof 347 patients (10.5% of the overall cohort) in two and 52 patients (1.6%) in three vascular beds. Patients with a higher atherosclerosis score were older, more often male, had lower LDL and HDL cholesterol concentrations, were more often diabetic and hypertensive, and had a lower eGFR (Table I). Furthermore, high-sensitivity C-reactive protein, as well as NT-pro BNP, increased with a higher atherosclerosis score, while the percentage of current smokers and the BMI were not different between groups (Table I). All three groups with atherosclerosis present had a high percentage of CAD ranging from 98.9% to 100%. When focusing on the severity of CAD, the percentage of multivessel CAD was higher in the higher atherosclerosis score groups (Table I). A comparison of the cardiovascular risk factors in the various vascular beds affected by atherosclerosis can be found in the appendix (Electronic supplementary material [ESM] 1).
During a median follow-up of 9.9 (range: 0.5–11.9) years 992 (30.0%) participants died, 617 (18.9%) from cardiovascular causes. Cardiovascular mortality included sudden cardiac death (n=257), fatal myocardial infarction (n=106), death due to congestive heart failure (n=148), death after intervention to treat CAD (n=26), fatal stroke (n=61%), and other causes of death due to CAD (n=19). As the number of atherosclerotic vascular beds increased, the HRs for both all-cause mortality and CV mortality significantly increased in a multivariate analysis after adjusting for the cardiovascular risk factors age, sex, BMI, diabetes mellitus, and eGFR, with HRs of 1.36, 2.56, 2.84 and 1.56, 2.70, 3.50, respectively (Table II).
In addition, when we examined different combinations of two affected atherosclerotic vascular beds, such combinations were associated with different mortality rates. Specifically, a combination of PAD with either CAD or CS was associated with higher HRs for all-cause (HR 2.81 and 7.53, respectively) and CV (HR 2.80 and 6.03, respectively) mortality, compared with the combination of CAD and CS (HR 1.94 and 2.43, respectively), although the PAD + CS patient group was very small (Table III). Overall, our data show that in patients with known CAD, coexisting PAD confers a higher all-cause and CV mortality risk than coexisting CS (Table III).
In line with this, a CAD subgroup analysis showed that a combination of 1-vessel, 2-vessel and 3-vessel CAD with coexisting PAD was always associated with a higher all-cause mortality rate compared with coexisting CS (Figures 1 and 2); however, we did not include subgroups smaller than 25 due to their small size and for reasons of clarity in these figures. However, the complete analysis with all groups can be found in the appendix (ESM 2).
Furthermore, higher age, male sex, presence of diabetes and lower eGFR were all significantly associated with higher all-cause and CV mortality (Figure 2). Along with a higher number of atherosclerotically affected vascular beds age, male sex, SBP, PP (Figure 3), CRP, diabetes, and rate of ex-smokers were increased, whereas HDL and LDL cholesterol and eGFR (Figure 4) were decreased (Table I).
Discussion
We found a high prevalence of PVD – defined as affection of two or three vascular beds – in the LURIC study i.e. 12% in the total cohort and 15% in the atherosclerosis group. Conclusive with our results, the CRUSADE study and the ALLIANCE project, which together included over 100,000 patients after prior myocardial infarction, both had a PVD prevalence of 13% [8, 9]. PVD was found in 10.6% of patients with acute coronary syndrome in the IMPROVE-It study, with a mean age of PVD patients of 68 years [10]. With an average age of the PVD patients of 66.0 years in the LURIC cohort, the proportion of patients with diabetes mellitus among patients with PVD was 54.4%, which is 10% higher when compared with the IMPROVE-It study.
In contrast to these studies, the AMERICA RCT systematically screened for asymptomatic multisite artery disease in patients with ACS or three-vessel coronary disease [11]. The rate of PVD was almost 22%, which is significantly higher compared with the present study. It must be assumed that studies whose PAD and CS diagnoses are based on anamnestic and record-based data underestimate the true prevalence.
Depending on the number of atherosclerotic vascular beds, adjusted HRs for all-cause and CV mortality increased from 1.36 to 2.84 and 1.56 to 3.50, respectively. This is in line with the results from the REACH studies, which demonstrated, based on 68,000 patients, that the frequency of CV events, such as myocardial infarction or stroke, increases with the number of affected vascular beds [12, 13]. In patients with prior myocardial infarction who were enrolled in the placebo arm of the PEGASUS trial, concomitant PAD was associated with a markedly elevated risk of all-cause death (HR 3.16), CV death, myocardial infarction, or stroke (HR 2.46), the latter of which remained significantly heightened after adjusting for a number of baseline clinical characteristics (HR 1.60) [14]. In the AtheroGene study, CV mortality in patients with CAD increased by a factor of almost 4 within 3 years if at least one other vascular region was affected [15]. The IMPROVE-IT trial replicated the finding that patients with ACS with coexisting PVD more frequently reached primary cardiac endpoints at 7 years compared with patients without PVD [10]. We were able to follow up our large cohort of patients undergoing coronary angiography for suspected CAD for 10 years and to demonstrate with a greater number of atherosclerotic vascular beds, all-cause and CV mortality were higher, which was consistent over time.
In addition, it seems to be important which vascular beds are affected individually or combined. Coexistence of PAD with either CAD or CS was associated with the highest all-cause and CV mortality rates, although the number of patients with PAD + CS was very small, which precluded any conclusions with regard to this subgroup. Nevertheless, when comparing patient groups with CAD and coexisting PAD or CS, a much more marked additive effect of PAD on CV and all-cause mortality was evident (Table III). The additive effect of PAD was also shown in a CAD subgroup analysis of 1-vessel CAD, 2-vessel CAD, and 3-vessel CAD for both all-cause and CV mortality (Figures 1, 2, 3 and 4).
In a sub-analysis of the PRODIGY study on secondary prevention after percutaneous coronary intervention, PAD was an independent risk factor (adjusted HR 1.75) for the composite of death, myocardial infarction, and cerebrovascular events [16]. Similar, the PEGASUS trial revealed higher rates of major adverse CV events (MACEs, defined as CV death, myocardial infarction, or stroke) in patients with PAD (adjusted HR 1.60), and more than 10-fold higher rates of major adverse limb events [14].
In a pooled analysis of eight randomized trials on percutaneous coronary interventions encompassing almost 20,000 patients, PAD was an independent predictor of all-cause mortality at 30 days, 6 months and 1 year [17]. The latter data are older, but data from the 1990 and 2010 Global Burden of Disease projects show that disability associated with PAD has increased significantly, as has mortality, and according to a recent report, this trend is continuing [18, 19].
Notably, even in asymptomatic populations screened for multisite artery disease, PVD is associated with higher mortality. Zhang et al. performed ankle–brachial index measurements and transcranial Doppler screening in a random sample of more than 5,000 participants aged ≥40 years and found an increase in MACE and mortality rates of 1.5-fold for single-vascular disease and 2-fold for PVD [20].
Finally, the central therapeutic goal in patients with PVD is the reduction of cardiovascular events. The AMERICA study, combining systematic detection of extra-coronary atherothrombotic disease and intensified treatment failed to improve outcome in high-risk CAD patients [11]. One reason may be that 87% of patients in the screening arm were already on dual antiplatelet therapy, beta blockers, and statins prior to randomization. In contrast, the ALLIANCE study noted only 41% of the ACS patients found to have PVD received all four guideline-recommended medications and under-treatment of PAD patients is also assumed in 2021 [9, 21].
In addition, pulse pressure rises with an increasing number of arteriosclerotically changed vascular beds. Furthermore, renal function i.e. eGFR is conversely decreasing with the number of vascular beds affected by atherosclerosis. Thus, increasing atherosclerotic load may contribute to vascular stiffness and impaired renal function. However, these effects may also be mediated by increasing age, a higher number of males and former smokers, and more diabetes in the patient groups with a higher number of vascular beds affected by atherosclerosis. In turn the lower level of LDL cholesterol with a higher number of vascular beds affected by atherosclerosis might be explained by more intense lipid-lowering treatment.
Limitations
We only took blood pressure measurements at the beginning of the study and did not perform additional measurements during follow-up. Interestingly, a merely anamnestic diagnosis of CS and PAD is associated with a significant increase in CV and all-cause mortality, as discussed above. However, a detailed assessment and/or grading of PAD and CS is lacking in the LURIC trial. Duplex sonographic testing for CS was not performed as a screening procedure in every subject, but rather as a diagnostic procedure in those with clinical symptoms, signs or events and similarly, screening for asymptomatic PAD was not performed in all subjects. Therefore, we cannot answer the question of whether higher grades of PAD or CS would also convey a higher mortality risk compared with lower grades of PAD or CS. In addition, we do not know how many patients with PAD or CS may not have been identified by our diagnostic approach, which mainly relied on patient histories and reports. As this analysis is a retrospective observational study that was primarily designed for the study of CAD patients, residual confounding and selection bias cannot be excluded. Since the present study was done in on average 66-year old Caucasian, mostly male patients at intermediate to high risk of CV disease undergoing coronary angiography, the results may not be generalizable to patient cohorts with other ethnicities and demographics, and to the general population.
On the other hand, the strength of this study lies in the large number of patients and the relatively long follow-up time of almost 10 years.
Conclusions
We were able to demonstrate a high rate of PVD in a large cohort of patients undergoing coronary angiography for suspected CAD. The greater the number of atherosclerotic vascular beds, the higher the rate of both all-cause and CV mortality during a follow-up period of approximately 10 years. Specifically, the combination with PAD but less so with CS was associated with an inferior outcome. Furthermore, we have found that pulse pressure as a marker of vascular stiffness is increasing with the number of atherosclerotic vascular beds.
Electronic supplementary material
The electronic supplementary material (ESM) is available with the online version of the article at https://doi.org/10.1024/0301-1526/a001011
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