Risk Factors and Outcomes for Atherothrombotic Disease in French Patients

Thrombosis Research 95 (1999) 163–176

REGULAR ARTICLE

Risk Factors and Outcomes for Atherothrombotic Disease in French Patients: The RIVAGE Study E. Mazoyer1, L. Drouet1, C. Soria1, J.C. Fruchard2, A. Pellerin3, J.C. Arcan3 and G. Tobelem1 Institut des Vaisseaux et du Sang, Service d’Angio-He´matologie Clinique et Biologique, Hoˆpital Lariboisie`re, Paris; 2Institut Pasteur, Lille; 3Sanofi, Paris, France.

1

(Received 27 March 1998 by S. Bellucci; revised/accepted 19 January 1999)

Abstract This prospective observational study was designed to delineate the course of atherosclerotic disease in a representative group of French patients receiving standard medical care and to look for clinical and laboratory factors predictive of recurrent cardiovascular events. The 2416 study patients (75.2% men and 24.8% women) had diagnoses of peripheral arterial disease (stage II or III), ischemic heart disease (stable angina or myocardial infarction), or cerebrovascular disease (transient ischemic attack or stroke); 2004 patients (82.9%) had only one of these diagnoses, and 412 (17.1%) had more than one. Among patients with a given stage of peripheral arterial disease, mean age was older in the women than in the men. Coronary disease and cerebrovascular disease were more severe in the men. During the 18-month follow-up, 408 cardiovascular events were recorded in 380 patients (15.7% of the overall study group). In patients who had a single clinical event at inclusion, subsequent clinical events usually occurred in the same vascuAbbreviations: Fg, plasma fibrinogen; FVII, factor VII; tPA, tissue plasminogen activator; Lp(a), lipoprotein(a); PAD, peripheral arterial disease; IHD, ischemic heart disease; MI, myocardial infarction; CVD, cerebrovascular disease; TIA, transient ischemic attack; LpA1, lipoprotein A1; TC, total cholesterol; CRP, C-reactive protein; PPP, platelet-poor plasma; BMI, body mass index. The members of the RIVAGE Core Data Handling Center are listed in Appendix 1. Corresponding author: E. Mazoyer, Service d’Angio-He´matologie Biologique, Hopital Lariboisie`re, 2 rue Ambroise Pare´, 75010, Paris, France. Tel: 133 (1) 49 95 64 11; Fax: 133 (1) 49 95 63 97; E-mail: ,[email protected]..

lar bed. The incidences of coronary and cerebral events were correlated with age and the incidence of peripheral events with smoking status. Fatal events were correlated with age but not with the baseline diagnosis, except for a weak relationship with peripheral arterial disease. In a subset of 411 patients who had laboratory tests, plasma fibrinogen level was the only independent predictor of recurrence for all cardiovascular events; this parameter was more closely correlated with fatal events than with all events.  1999 Elsevier Science Ltd. All rights reserved. Key Words: Atherothrombosis; Risk factor; Fibrinogen; Factor VII; Plasminogen activator inhibitor; Cardiovascular events

T

he incidence of cardiovascular events is lower in France than in the United Kingdom, the United States, and Canada [1]. Most available data were from British and North American hospital-based studies and from placebo groups in therapeutic trials. Few population-based studies of atherosclerosis have been published. In Europe, the only population-based study of patients with atherosclerotic ischemic disease in at least one of the three main vascular areas (the PLAT study) was done in a teaching hospital in Milan, Italy [2–4]. We planned the RIVAGE study (“RIsque VAsculaire Groupe d’Etude”, vascular risk study group) to evaluate recurrent vascular events in patients with symptomatic vascular ischemic disease in the heart, brain, and/or major peripheral arteries. These patients were receiving care

0049-3848/99 $–see front matter  1999 Elsevier Science Ltd. All rights reserved. PII S0049-3848(99)00045-6

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E. Mazoyer et al./Thrombosis Research 95 (1999) 163–176

from physicians representative of the overall physician population. The study also examined correlations between recurrence and clinical parameters over an 18-month period. Acute ischemic events in patients with chronic atherosclerotic disease are usually thrombotic events precipitated by local blood flow abnormalities about an arterial lesion and often triggered by rupture of an atheroma plaque. Coagulation and fibrinolytic factors in the bloodstream and at the site of the lesion contribute to the development, extension, and persistence of arterial thrombosis. Prospective studies of subjects without symptoms of atherosclerotic disease in the general population indicated that increased concentrations of hemostatic factors, such as plasma fibrinogen (Fg), factor VII (FVII), tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1), and lipoprotein(a) (Lp[a]), were independently associated with ischemic events [5–17]. Several studies of patients with a history of at least one clinical ischemic event found correlations between some of these factors and recurrence of events, but others did not [3,4,18–26]. We sought to determine whether coagulation, fibrinolysis, and lipid parameters predicted recurrence of cardiovascular events in a subset of the RIVAGE patient population.

hours of a cardiovascular event were considered primarily due to that event. The detailed report of each event was reviewed by the core data-handling center for final validation.

1.2. Clinical Inclusion Criteria Men and women younger than 75 years of age were eligible if they had atherothrombotic disease meeting at least one of the following criteria: (1) peripheral arterial disease (PAD) satisfying Leriche and Fontaine criteria for stage II or stage III; (2) ischemic heart disease (IHD) manifesting as stable angina or as a history of myocardial infarction (MI) with or without residual angina; (3) cerebrovascular disease (CVD) with a history of transient ischemic attacks (TIA; symptoms lasting less than 24 hours) or minor nondisabling ischemic stroke. At inclusion, patients had to be clinically stable, with no ischemic event during the previous 6 months. Patients with stage IV PAD, unstable angina, major disabling stroke, valvular heart disease, or cardiac thromboembolism were excluded. Additional exclusion criteria were uncontrolled arterial hypertension, uncontrolled diabetes mellitus, and severe hyperlipidemia.

1.3. Blood Sampling and Measurements

1. Patients and Methods 1.1. Study Design and Patient Inclusion We randomly selected 1000 names from the list of general practitioners, cardiologists, and angiologists licensed to practice in France. The study was coordinated by a principal investigator and a core data-handling center independent from the study physicians. Each study physician was asked to enroll up to 10 consecutive patients seen at their office. During the first study visit, physicians recorded baseline characteristics, disease history, known risk factors, and current treatment. Patients attended three follow-up study visits, at intervals of 6 months, during the 18-month study period. Management was at the discretion of each physician. At each follow-up visit, physicians reported the following to the core data-handling center: (1) occurrence of major or minor events; (2) therapeutic modifications; (3) reasons for failure to attend the follow-up visit. Deaths that occurred within 24

A subset of 411 patients (17%) selected based on residence within a reasonable distance from one of the 23 hospital-based laboratories that participated in the study (see Appendix 2) were included in an ancillary laboratory parameter study. Fasting blood samples (20 mL) were drawn between 8 a.m. and 10 a.m.. Blood was collected on 0.13 mM trisodium citrate (Becton Dickinson, Grenoble, France) (1:9 v/v) for Fg and FVII; on ice-cold 0.13 mM trisodium citrate, PGE1, and Theophyllin (Diatube; Stago, Asnie`res, France) (1:9 v/v) for PAI-1 (activity and antigen); and on ice-cold EDTA (Becton-Dickinson) for Lp(a), lipoprotein A1 (LpA1), total cholesterol (TC), triglycerides (TG), and C-reactive protein (CRP). Platelet-poor plasma (PPP) was separated by centrifugation (1500g at 48C for 15 minutes, twice for PAI-I and once for all other parameters) and stored in polypropylene tubes (0.5-mL aliquots). Tubes were transported frozen in dry ice. Samples for Fg, FVII, and PAI-1 determination were sent to the Central Hematol-

E. Mazoyer et al./Thrombosis Research 95 (1999) 163–176

ogy Laboratory of the Lariboisie`re Hospital in Paris, France, and those for other parameters to the Pasteur Institute in Lille, France. Fg was assayed using the von Clauss technique (Stago, France) on a Fibrin-Timer Automate (Behring Paris La-Defense, France), FVII (antigen), and PAI-1 (antigen) by using ELISAs (Stago, France), PAI-1 (activity) by using a chronometric method (Biopool Diamed, Paris, France), Lp(a) by using immunonephelometry (Beckman, Villepinte, France), LpA1 by using electroimmunodiffusion (Sebia, Issy les Moulineaux, France), TC by using enzymatic colorimetry (Boehringer, Meylan, France), TG by using GPO-PAP (Boehringer), and CRP by using a nephelometric latex assay (Behring).

1.4. Statistical Analysis All statistical tests were done using SAS software. Comparisons of study group characteristics were evaluated using the x2 test or Fisher’s exact test for qualitative variables and analysis of variance for continuous variables. Survival curves were compared using the log rank test. Associations between the events and either clinical characteristics or hemostatic parameters were investigated using multiple regression analysis or Cox’s model. Five groups of vascular events were examined in the main clinical study: all events, deaths, cerebrovascular events, coronary events, and peripheral events. Because the ancillary study included fewer patients and consequently fewer events, its data were analyzed using only two groups of events, namely, deaths and all events. All tests were two-tailed, with significance levels set at 5%.

2. Results 2.1. Adherence to the Protocol During the 16-month recruitment period, 2416 patients were enrolled (7.5 patients per physician). Thirty-eight patients (1.5%) were lost to followup (eighteen at 6 months, eleven at 12 months, and nine at 18 months), either because they changed to another physician or because they moved to another city; data were obtained showing that none of these patients died during the study period. The ancillary study included 411 patients enrolled by 96 physicians (4.2 patients per physician).

165

2.2. Description of the Study Group at Inclusion 2.2.1. Clinical characteristics As shown in Table 1, mean age was 6368.7 years, the male-to-female ratio was 3:1, and mean age was younger in the men than in the women (6268.7 years vs. 65.868.2 years, respectively). A single vascular territory was involved in 2004 patients (82.9%). Of the 1474 patients (61% of the overall study group) with IHD, 1139 (77%) were free of PAD and CVD. PAD affected 877 patients (36.3% of the overall study group), of whom 537 (61%) were free of IHD and CVD. CVD was diagnosed in 515 patients (21% of the overall study group) including 328 (63%) without IHD or PAD. Mean age was younger in monovascular patients than in polyvascular patients. The youngest mean age was in patients with PAD with or without involvement of other vascular beds. 2.2.2. Risk factors 2.2.2.1. Smoking status. A current history of smoking was noted in 17.9% of patients overall and was accompanied with PAD (with or without CVD and/or IHD) in 66.3% of cases. Among patients with involvement of a single vascular bed, 9.9% of IHD patients, 13.1% of CVD patients, and 35.9% of PAD patients were current smokers. Most smokers with PAD as the only vascular disease smoked more than 20 cigarettes per day. Among ex-smokers, 57.4% of PAD patients, 82.7% of IHD patients, and 73.6% of CVD patients stopped smoking before inclusion in the study. Furthermore, PAD ex-smokers differed from IHD and CVD ex-smokers in that they had stopped smoking more recently (55.7 months vs. 86.6 months and 90.8 months, respectively) and had smoked longer before stopping (27.8% vs. 19.9% and 11.7%, respectively, had smoked for more than 30 years). Only one third of the overall study population had never smoked, and most never-smokers had IHD and/or CVD. 2.2.2.2. Other risk factors. Other risk factors were recorded by the physician. A known history of diabetes mellitus (14.4%) was most frequent among patients with PAD (16.4%) and among those with polyvascular involvement (20%). Among diabetics, 11.7% of patients were on insulin. A history

1139 (47) 292 (25.6) 847 (74.4) 207 (18.2) 705 (61.9) 226 (19.8) 1 (0.1) 62.668.7 113 (9.9) 542 (47.6) 480 (42.1) 4 (0.4) 73.8612.1 168.367.5 2663.6

537 (22)

89 (16.6)1 448 (83.4)

118 (22) 327 (60.9) 92 (17.1) 0 61.469

193 (35.9) 259 (48.2) 82 (15.3) 3 (0.6) 71.4611.5 168.966.7 2563.6

IHD

43 (13.1) 120 (36.6) 159 (48.5) 6 (1.8) 71.4611 166.567.7 25.763.4

35 (10.7) 198 (60.4) 95 (29) 0 64.668.7

124 (37.8) 204 (62.2)

328 (13.6)

CVD

53 (23.6) 128 (56.9) 44 (19.6) 0 75.1612.1 169.267 26.263.9

23 (10.2) 145 (64.4) 57 (25.3) 0 64.767.8

38 (16.9) 187 (83.1)

225 (9.3)

PAD1IHD

18 (23.4) 40 (51.9) 19 (24.7) 0 70.6610.2 167.767.5 25.162.9

7 (9.1) 49 (63.6) 20 (26) 1 (1.3) 65.167.7

21 (27.3) 56 (72.7)

77 (3.2)

PAD1CVD

5 (6.9) 29 (40.3) 37 (51.4) 1 (1.4) 69.7611.9 165.367.5 25.563.6

2 (2.8) 34 (47.2) 36 (50) 0 69.666.8

30 (41.7) 42 (58.3)

72 (2.9)

IHD1CVD

7 (18.4) 24 (63.2) 7 (18.4) 0 72.9611 167.968.1 25.863.2

2 (5.3) 25 (65.8) 11 (28.9) 0 66.465.3

6 (15.8) 32 (84.2)

38 (1.5)

PVD

432 (17.9) 1142 (47.3) 828 (34.3) 14 (0.5) 72.8611.8 168.267.4 25.763.6

394 (16.3) 1483 (61.4) 537 (22.2) 2 (0.1) 6368.7

600 (24.8) 1816 (75.2)

2416 (100)

Total

For each baseline diagnosis, numbers of patients are shown with the distributions according to sex, mean stratified age and smoking status. Also shown are mean age, weight, and height, as well as mean BMI. 1 Percentages are in parentheses.

Distribution n (%) Sex (n) Female Male Age (n) <54 years 55–69 >70 years Nonspecified Age (years) Tobacco (n) Smoker Ex-Smoker Never Smoked Nonspecified Weight (kg) Height (cm) BMI (kg/m2)

PAD

Table 1. Clinical characteristics and risk factors in 2416 French patients with atherosclerosis

166 E. Mazoyer et al./Thrombosis Research 95 (1999) 163–176

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Table 2. Baseline diagnoses in 2416 French patients with atherosclerosis Patients Entry diagnostic PAD (M5723, F5153) Stage II Stage III IHD (M51108, F5368) Stable angina MI CVD (M5333, F5182) TIA Stroke

n (%)

Sex

n (%)

Sex ratio (M/F) %1

690 (78.8) M 571 (82.8) F 119 (17.2) 172 (19.6) M 140 (81.4) F 32 (18.6) 1122 (76.2) M F 743 (50.5) M F

797 325 628 115

(71.1) (28.9) (84.5) (15.4)

368 (71.5) M 224 (60.8) F 144 (39.1) 147 (28.5) M 109 (74.1) F 38 (25.8)

4.8 4.4

2.5 5.5

1.6 2.9

Mean duration of symptom (years) Recurrence2 (%)

79 78 19 21

6.1 5.1

72 88 57 31

6.4 6.1 5.9 4.5

67 79 33 21

4.2 3.5 4.1 5.3

Previous surgery3 (%)

6

M543.3 F515.7

7.7 13.1

6

M525.6 F511.5

17.7 27.8 16.6 13.1

6

M517.4 F511.7

All patients had a history of atherosclerotic disease at baseline. Main clinical manifestations were: stage II or stage III peripheral arterial disease, stable angina, MI, stroke, and TIA. 1 Percentage of all patients of the same sex. 2 Percentage of patients with a history of more than one cardiovascular event at baseline. 3 Percentage of patients with a history of vascular surgery at baseline.

of arterial hypertension was noted in 47% of the study group overall and in 63% of the patients with CVD; of the patients with a history of hypertension, 97.4% were on antihypertensive drugs. There was a history of hypercholesterolemia in half the study group overall and in a slightly larger proportion of IHD patients; 84.1% of patients with hypercholesterolemia were receiving cholesterol-lowering treatment.

2.2.3. Clinical diagnosis 2.2.3.1. Peripheral arterial disease. As shown in Table 2, the typical PAD patient was fairly young (61.469 years, 22% younger than 54 years) and male (male-to-female ratio, 5:1). Neither sex nor age influenced the likelihood of having stage II or III disease or of having involvement of one or both legs. Mean time since diagnosis was 5.8 years overall and was slightly longer when another vascular territory also was involved. The subgroup of PAD patients who had had peripheral artery surgery accounted for 38.5% of the total PAD group and was predominantly composed of younger males with involvement of several vascular territories. At inclusion, as compared with men, women with PAD were older (mean age, 66 years vs. 62

years in men), had a shorter time since clinical PAD diagnosis (5 years vs. 6 years in men), were only half as likely to have had peripheral artery surgery, and had a shorter time since peripheral artery surgery.

2.2.3.2. Ischemic heart disease. IHD patients were the largest group. The male-to-female ratio was 4:1. Half the IHD patients had isolated stable angina, whereas the other half had a history of MI; among the IHD patients with a history of MI, half had residual stable angina. Mean time since clinical symptom onset was 6.3 years. Men were more likely to have a history of MI (56.7%), and for women, stable angina (88.8%). Only 31% of the women had had a MI; in this subgroup, 61% of women had residual stable angina. Congestive heart failure was present in 10% of all IHD patients. Younger patients were more likely to have a history of MI than older patients, and women were twice as likely to have had a second MI as men. 2.2.3.3. Cerebrovascular disease. CVD patients were the smallest group. The male-to-female ratio was 2:1. A history of stroke was noted in 28.5% of cases and a history of TIA in 71.5%; in the TIA

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subgroup, 78% of patients had had one TIA and 12% more than one TIA. The time since the first event was identical in the TIA and stroke subgroups. Carotid artery surgery had been performed in 15.4% of all CVD patients; in this subgroup, the disease usually also affected another organ. Compared with men, women were more frequently included for TIA (79% of women with CVD); women with a history of TIA experienced their initial event at an older age and had a larger number of recurrences, whereas women with a history of stroke (21% of women with CVD) experienced their initial event earlier and had fewer recurrences.

2.2.4. Treatment The overwhelming majority of patients (99%) were on medications designed to improve their vascular disorder. The most commonly prescribed medications were antithrombotic and vasoactive drugs (57.7% and 59.6%, respectively). Antithrombotic treatment for secondary prevention was used in 55% of the patients with one site of involvement, 60% of those with two sites, and 89.5% of those with three sites. Other medications included lipidlowering agents (41% of all patients), antihypertensive agents (39%), and beta-blockers (28%).

3. Clinical Follow-up 3.1. Patients with Cardiovascular Events The 380 patients who experienced events during follow-up were more likely to have polyvascular disease (30.5%) and less likely to have isolated IHD (36.8%) than the patients without events (14.5% and 49%, respectively). Mean age, sex distribution, and smoking habits were similar in these two groups.

Among the major cardiovascular events, 58 were fatal and 143 nonfatal; among the 143 nonfatal major events, there were 20 cases of MI, 8 of unstable angina, 29 of stroke, 4 of PAD, and 82 of surgery. The 184 minor cardiovascular events were distributed as follows: TIA, n539; worsening of stable angina, n560; worsening of intermittent claudication, n524; elective vascular surgery or angioplasty, n546; and other cardiovascular events, n515. Recurrence rates varied according to the baseline diagnosis: 28.1% in patients with polyvascular disease, 15.8% in patients with PAD only, 12.3% in patients with IHD only, and 11.9% in patients with CVD only. During follow-up, events tended to occur in the same vascular territory already affected at study inclusion; thus, 78% of events among IHD patients were coronary, 72% among CVD patients were cerebrovascular, and 58% among PAD patients were in peripheral arteries.

3.3. Mortality Global mortality in the overall RIVAGE study group was 3.4% (n581) during the 18-month follow-up. As compared with the general population of same age and sex distribution, overall mortality in the RIVAGE study group was the same, but mortality related to MI or stroke was increased twofold. Of the 81 deaths, 72% were fatal cardiovascular events (20 sudden deaths, 13 strokerelated deaths, 18 MI-related deaths, and 7 deaths due to other cardiovascular events). Fatal events tended to occur in the same organ as the baseline diagnosis: the most common cause of death was MI in the IHD-only subgroup (12:21 deaths), stroke in the CVD-only subgroup (6:13), and MI in the PAD-only and polyvascular subgroups (9:18).

3.4. Risk Factors for Recurrent Cardiovascular Events

3.2. Description of Cardiovascular Events Of the 2416 patients, 15.7% experienced at least one cardiovascular event during the 18-month follow-up. Acute vascular events accounted for 13.7% and elective vascular surgery for 2% of all cardiovascular events. Of the 408 events recorded, 385 were clinical cardiovascular events (201 major and 184 minor), and 23 were nonvascular deaths.

3.4.1. Univariate analysis As shown in Table 3, coronary events (48% of all events) occurred in 7.7% of the overall study group and in 9.7% of the IHD-only subgroup. Coronary events were more common in patients aged 70 years or older. Coronary event rates were similar in males and females. Cerebrovascular events (22.3% of all cardiovascular events) occurred in 3.6% of

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Table 3. Distribution of the 380 patients with at least one cardiovascular event during the 18-month follow-up, by baseline diagnosis and by site of event Entry diagnosis IHD CVD PAD PVD Total

Population with Events Patients (n) 1139 328 537 412 2416

Coronary

Cerebral

110 4 18 54 186

15 30 10 32 87

(9.7) (1.2) (3.4) (13.1) (7.7)

(1.3) (9.1) (1.9) (7.8) (3.6)

Peripheral 9 3 49 25 86

(0.8) (0.9) (9.1) (6) (3.6)

Other 6 2 8 5 21

(0.5) (0.6) (1.4) (1.2) (0.8)

Total 140 39 85 116 380

(12.3) (11.9) (15.8) (28.2) (15.7)

Event-free population 999 (87.7) 289 (88.1) 452 (84.2) 296 (71.8) 2036 (84.3)

n, number of patients with at least one event. In parentheses, percentage calculated as: (n with variable/n of each sample)3100.

the study group overall and 9.1% of the CVD-only subgroup; they were correlated with sex and were more common in patients aged 70 years or older. Peripheral events occurred in 3.6% of the overall study group and in 9.1% of the PAD-only subgroup; they were unrelated to age but were twice as common in men than in women. Survival curve analysis demonstrated that the rates of occurrence of each type of cardiovascular event were correlated to the baseline diagnosis, suggesting that the disease in each vascular bed was relatively independent; also, the overall prognosis was worse in patients with polyvascular disease (Figure 1).

3.4.2. Multivariate analysis (Cox proportional hazards model) As shown in Table 4, sex, body mass index (BMI), size, weight, age, and smoking were included in the multiple regression analysis. However classic risk factors, such as diabetes (glycemia), hypercholesterolemia (total cholesterol), and hypertension, were not included in the multiple regression analysis because precise clinical and laboratory data were not recorded to describe these risk factors. Age and baseline diagnoses of IHD and PAD were independent predictors of coronary events. Smoking and a baseline diagnosis of PAD were independent predictors of peripheral events. Age and a baseline diagnosis of CVD were independent predictors of cerebrovascular events.

4. Ancillary Hemostasis Study 4.1. Baseline Characteristics of the Hemostasis Study Subgroup As compared with the overall study patients, the hemostasis study patients were more likely to have

IHD (54% vs. 45%) and to be ex-smokers (56.4% vs. 45.3%). Both differences were small but significant; no other significant differences were found.

4.2. Plasma Parameters As shown in Table 5, mean plasma Fg level was 3.7060.87 g/L, increased with age, and was higher in the PAD-only and polyvascular subgroups and lower in the CVD-only subgroup. In the overall study group, mean plasma Fg was not influenced by smoking habits; however, women who smoked had a higher mean Fg level (4.5961.10 g/L) than those who did not smoke (3.7660.97 g/L). Mean plasma FVII level was 101629% overall and was higher in the PAD and polyvascular subgroups. Mean FVII was higher in women and varied with the BMI but not with age or smoking habits. Mean PAI-1 activity was 13.4610.1 IU/mL, and mean PAI-1 antigen was 26.7626.1 ng/mL; neither parameter differed across baseline diagnoses, whereas both were positively correlated with BMI. PAI-1 activity but not PAI-1 antigen was higher in smokers. LpA1 (0.4260.13 g/L) was higher in older patients and in women. TG was correlated with BMI and smoking status. Lp(a) (0.2560.23 g/L), TC, and CRP were not correlated with any of the clinical study parameters.

4.3. Correlations among Plasma Levels Fg showed weak positive correlations with CRP (r50.12; p,0.05) and FVII (r50.17; p,0.05). FVII was correlated with PAI-1 (0.19; p,0.001), TG (0.32; p,0.001), and TC (0.25; p,0.001). PAI-1 activity and PAI-1 antigen were correlated with each other (0.82; p,0.001), but only PAI-1 activity was correlated with TG (r5 0.44; p,0.001).

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Fig. 1. Event-free survival curves. Kaplan-Meier survival curve based on all events in any vascular bed in atherosclerotic patients, by baseline diagnosis. Survival was determined during the 18-month followup period.

4.4. Plasma Levels and Clinical Outcomes

events overall (p,0.05) and fatal events overall (p,0.05).

4.4.1. Univariate analysis Plasma Fg levels were higher in patients with than without events: 3.97 g/L vs. 3.65 g/L, a difference of 0.32 g/L or 9%. When only fatal events were considered, the difference reached 30% (4.78 g/L vs. 3.69 g/L, 1.09 g/L). 4.4.2. Multivariate analysis (Cox proportional hazards model) After stepwise adjustments for sex, age, and baseline diagnosis, only the plasma Fg level had a significant predictive value, being associated with both

5. Discussion This observational study was designed to delineate the course of vascular disease in France with special attention to the incidence of cardiovascular events in patients with atherosclerosis. In an earlier study, PAD patients had a relative risk of 3.7 for coronary or cerebrovascular disease as compared with the same-age general population [27]. In the RIVAGE study PAD patients, the pro-

Table 4. Stepwise multiple regression analysis of the relationship between selected clinical parameters and the occurrence of vascular events Clinical characters Entry diagnosis IHD CVD PAD Age Smoking

Clinical events Coronary (n5157)

Cerebral (n572)

Peripheral (n572)

5.91 (3.48; 10.05) 5.73 (3.29; 9.99) 1.66 (1.16; 2.36) 1.02 (1.0; 1.04)

9.35 (14.62; 18.94) 1.06 (1.02; 1.09)

All (n5366) 1.79 1.73 1.91 1.02

(1.39; 2.30) (1.33; 2.25) (1.51; 2.41) (1.0; 1.03)

1.87 (1.15; 3.05)

Stepwise multiple regression analysis was used (Cox proportional hazards model) to identify clinical parameters predictive of vascular events. Five groups of events were defined, as described in Patients and Methods. The numbers shown are the relative risk and in parentheses the 95% confidence interval.

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Table 5. Plasma levels of hemostatic factors assayed among 411 atherosclerotic patients in the ancillary study Fg (g/L) Clinic IHD CVD PAD PVD Age <54 years 55–69 years >70 years Sex Male Female BMI ,24 24–27 .27 Smoking Smokers Ex-smokers Never-smokers

PAI-1 (act.) (UI/mL)

F VII (%)

PAI-1 (ag) (ng/mL)

3.6160.85 3.5861.08 3.8461.14 3.9260.87

*

99626 93.4623 104.2624 113631

**

14.1610.4 11.868.5 11.969.7 13.3610.1

ns

27.5627.3 21.4621.4 24.8624.5 29.5626.2

ns

3.4560.87 3.7460.97 3.8560.86

*

97622 102628 106.9629

ns

13.2610.1 13.6610.1 12.369.7

ns

26.6628 27.1625.2 26.1627.9

ns

3.6960.93 3.7860.97

ns

99.3626 110.4629

***

13.3610.1 13.4610

ns

26.9625.8 26.4627.5

ns

3.6961.07 3.6660.86 3.7960.90

ns

102.1627 97.7629 106.8628

*

10.568.4 12.669.6 16.9611.1

**

20.6623.7 25.3622.7 35.5630.2

**

3.8661.01 3.6460.95 3.7560.89

ns

ns

14.669.1 14.2610.4 11610.3

*

29.7623.9 28.3627.8 22.3623.2

ns

104629 101624.6 102626.8

Values are means6SD. p values under 0.05 were considered statistically significant; ns, not significant. * Significant at 5%. ** Significant at 1%. *** Significant at 1:1000.

portion of patients with PAD alone or in combination with disease in another vascular bed was similar to that in the PACK study [28]. However, the time since PAD symptom onset was not specified in the PACK study; it was 5.8 years in the RIVAGE study, consistent with the fact that PAD stage was II or III. However, the 5-year lag in PAD symptom onset in women as compared with men in the RIVAGE study was shorter than the 10-year lag in earlier studies [29,30]. The incidence of peripheral events was higher in our PAD patients than in previous studies in patients with stage I and II PAD [18] or stage II and III PAD [3]. The proportion of amputees was similar to that observed by others [27,28], although amputation was performed at a more advanced stage, reflecting a preference for elective preventive surgery for PAD in the RIVAGE study as compared with earlier studies (data not shown). Despite the higher risk of peripheral events, the fatal and nonfatal cardiovascular or cerebrovascular events in our PAD patients was similar to that in earlier studies [3,18,19,28,31]. The incidence of events in our IHD patients,

who had either stable angina pectoris or a history of MI, was similar to [3,26] or slightly higher than [20] that in other studies that included only angina pectoris patients. In our CVD patients, who had a history of TIA or stroke, the incidence of events was slightly lower than that reported in stroke patients only [32,33] and was similar to that in patients with a history of TIA [34]. These discrepancies may be ascribable to baseline differences in disease stage and in time since the last acute event. RIVAGE patients were included at least 6 months after the last event. The high proportion of cardiovascular events in our polyvascular patients suggests that the overall risk is the sum of the risks in each vascular bed involved with the disease. The subgroup with IHD, CVD, and PAD was the smallest subgroup and had a younger mean age than the subgroup of patients with IHD and CVD. This suggests that symptomatic PAD, when associated with IHD, CVD, or both, may be a marker of the disease severity rather than of disease duration. Analyses based on the outcome showed, in the RIVAGE population, that the localisation of the

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recurrent event depends on the initial localisation of the disease. Recurrent coronary events were more common in IHD group; recurrent cerebrovascular events were more common in CVD group. Baseline site of the arterial disease predicted recurrence at the same site. Similar findings were recently observed in the CAPRIE study, independently of the antiplatelet drug administrated [35]. The absence of excess overall mortality may be ascribable to the low incidence of noncardiovascular deaths and the high proportion of coronary patients, whose mortality was half that of patients with CVD or PAD. Mortality rates were similar in the CVD-only subgroup (the oldest subgroup at baseline) and the PAD-only subgroup (the youngest subgroup at baseline), indicating that patients with PAD only died at a younger age than those with CVD only. The high proportion of current or ex-smokers in the PAD-only subgroup as compared with the IHD-only and CVD-only subgroups is further evidence of the close association between smoking and PAD [36]. Moreover, smoking status was related not only to PAD but also to recurrence of a peripheral arterial event, especially among patients with a baseline diagnosis of PAD, suggesting that PAD indicated progressive arterial disease. In a subset of 411 patients, coagulation factors and lipid levels were studied to look for correlations with baseline diagnosis and with recurrence of ischemic events. Plasma Fg levels was decreased in IHD and increased in PAD and CVD in some studies [37] but not in others [3]. Fg elevation was correlated with the number of sites of arterial plaque in patients with asymptomatic atherosclerotic disease [38] and with the severity of symptomatic atherosclerotic disease at any site [20,36,39,40]. Fg levels differed between smokers and nonsmokers in the general population of healthy individuals [7,41,42]; similar differences were found in some [2,43] but not all [44] studies of atherosclerotic patients. The nonsignificant increase in plasma Fg in smokers compared with nonsmokers in the RIVAGE study may reflect not only the extent of the disease but also the high proportion of smokers in the study group. However, when studying only women with less advanced and less extensive disease, Fg was significantly higher in women who smoked than in those who did not smoke. Fg elevation has been reported to predict occur-

rence of cardiovascular events in the general population (reviewed in [12]). Fg elevation also predicted recurrent events in our study of patients with atherothrombotic disease in keeping with earlier findings in patients with PAD [18,19], CVD [22], and IHD [20,21]. Some studies, however, found either a nonsignificant trend towards higher Fg levels [3,24] or lower plasma Fg levels [3,25] in patients with cardiovascular events than without. These discrepancies cannot be explained by technical differences Fg assay methods, since these were all sensitive to Fg function; the von Clauss technique was used in most studies. Either human or bovine thrombin was used, and values were not corrected for hematocrit and anticoagulant volume. Fg is not only a hemostatic factor but also an acute phase reactant. Increased plasma Fg levels in atherosclerotic patients may reflect inflammation, and atherosclerosis can indeed be considered an inflammatory disease. The level of CRP, another acute phase reactant, was correlated with Fg increased and was not an independent predictor of cardiovascular events. In contrast, in the ECAT study [20], both CRP and Fg predicted coronary events in angina pectoris patients; however, Fg remained predictive after adjustment for CRP, whereas CRP was no longer predictive after adjustment for Fg. Thus, although inflammation as gauged by the CRP level influences the Fg level, Fg remains an independent predictor of vascular risk. Plasma FVII elevation in patients with PAD or polyvascular disease has been found in some studies [2] but not in others [44]. In several prospective population-based studies, FVIIc was predictive of fatal but not of nonfatal cardiovascular events. One of these studies found a significant correlation [45], whereas another found just a trend that barely reached statistical significance [15]. In some studies, FVII antigen was not predictive of [19,21] or was inversely correlated with [3] cardiovascular events. These discrepancies may be due to differences in assay methods, to the lability of factor VII, or to variations in sensitivity of the thromboplastin used for the assay. The factor VIIc assay used in the Northwick Park study [5], for example, was more sensitive to activated FVII (FVIIa) than other, more widely used FVIIc assays [46]. Moreover, concentrations of the two chains of activated FVII (FVIIa) may be more relevant to the risk

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of thrombosis than the single-chain nonactivated FVII measured by FVIIc assays. The two methods used to determine PAI-1 in our study produced widely variable values. However, the qualitative method seemed more sensitive. The absence of any correlations between PAI-1 levels and other parameters in our study is at variance with earlier reports of higher PAI-1 levels in current smokers and obese patients and of a positive correlation between PAI-1 and triglycerides [44,47]. An association between PAI-1 and cardiovascular disease has been reported among angina pectoris patients [4]. In our patients, neither PAI-1 activity nor PAI-1 antigen predicted the recurrence of cardiovascular events. In populations with [4,24] and without [10,14] cardiovascular disease, cardiovascular events have been found to correlate with decreased fibrinolytic activity, usually linked to increased PAI-1 levels. Interestingly, some studies found evidence that cardiovascular events were associated with an increase in the mass concentration of tPA rather than with increased PAI-1 activity [20,25,26]. The positive correlation reported between these two parameters [20] suggests that increased tPA concentrations may reflect an increase in the amount of circulating tPAPAI-1 complex and therefore an increase in PAI-1 activity. The RIVAGE study is the first French study of the course and risk of recurrent thrombosis in patients with atherosclerotic disease affecting at least one vascular bed. On the whole, RIVAGE study data are similar to those from patients in other countries of Western Europe. The “French paradox” mentioned in the introduction is ascribable to a lower incidence of first atherothrombotic events and a similar incidence of subsequent atherothrombotic events. Thus, once the disease has developed, its course is similar to that in other countries. The baseline disease site predicted recurrence at the same site, and the plasma Fg level predicted cardiovascular event recurrence at any site. The data suggest that plasma Fg elevation may be a marker for extensive atherothrombotic disease and acute event recurrence. This work received financial support and organizational assistance from the Cardiovascular Division of SANOFI, Paris, France. We are grateful to the 321 physicians who recruited and monitored the study patients and to the 23 hospital-based laboratories (Appendix 2) that participated in the ancillary study.

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Appendix 1. Core Data Handling Center Dr. Arcan JC (Sanofi, Paris), Prof. Boneu B (Toulouse), Prof. Bousser MG (Paris), Prof. Caen J (Paris), Prof. Fruchard JC (Lille), Prof. Kieffer E (Paris), Dr. Scarabin PY (Paris), Prof. Tobelem G (Paris), Prof. Vacheron A (Paris).

Appendix 2. Hospital-Based Laboratories that Participated in the RIVAGE Study Dr. Abgrall JF (Finistere), Prof. Alexandre P (Meurthe et Moselle), Dr. Bayle J (Alpes Maritime), Dr. Berthier AM (Ile et Vilaine), Prof. Boisseau M (Gironde), Prof. Boneu B (Haute Garo-

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nne), Dr. Bordessoule D (Haute Vienne), Dr. Borg JY (Seine Maritime), Prof. Cazenave JP (BasRhin), Prof. Dechavanne M (Rhone), Prof. Delobel J (Somme), Dr. Derlon A (Calvados), Dr. Fiks M (Loire Atlantique), Dr. Fressinaud E (Maine et

Loire), Prof. Goudemand J (Nord), Prof. Juhan I (Bouches du Rhone), Prof. Kolodie L (Isere), Prof. Leroy J (Indre et Loire), Dr. Lorenzini JL (Cote d’Or), Prof. Potron G (Marne), Ms. Reynaud J (Loire), Dr. Schved JF (Gard), Prof. Caen J (Seine).