Noncardiac vascular disease in rheumatoid arthritis: Increase in venous thromboembolic events?

Objective

To investigate the incidence of noncardiac vascular disease in a community‐based incidence cohort of patients with rheumatoid arthritis (RA) and compare it to that in the general population and to investigate trends in the incidence of noncardiac vascular disease in patients with RA.

Methods

A population‐based inception cohort of patients with incident RA between January 1, 1980 and December 31, 2007 in Olmsted County, Minnesota and a cohort of non‐RA subjects from the same population base was assembled and followed up until December 31, 2008. Venous thromboembolic, cerebrovascular, and peripheral arterial events were ascertained by medical record review.

Results

The study population included 813 patients with RA with a mean ± SD age of 55.9 ± 15.7 years (68% women) and an average length of followup of 9.6 ± 6.9 years. Compared to non‐RA subjects of similar age and sex, patients diagnosed as having RA between 1995 and 2007 had a higher incidence (%) of venous thromboembolism (cumulative incidence ± SE 6.7 ± 1.7 versus 2.8 ± 1.1, respectively; P = 0.005) but similar rates of cerebrovascular and peripheral arterial events. Among patients with RA, the incidence of venous thromboembolic, cerebrovascular, and peripheral arterial events was similar in the 1995–2007 time period compared to the 1980–1994 time period.

Conclusion

Our findings indicate that the incidence of venous thromboembolism is increased in patients with RA compared to non‐RA subjects. The incidence of cerebrovascular events and peripheral vascular disease events is similar in patients with RA compared to non‐RA subjects. Among patients with RA, the incidence of noncardiac vascular disease has remained stable in recent decades.

     

Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years

Objective: To investigate the trends in incidence of extra-articular rheumatoid arthritis (ExRA) in a well defined community based cohort of patients with rheumatoid arthritis (RA), and to examine possible predictors of ExRA occurrence. Methods: Using the resources of the Rochester Epidemiology Project, a retrospective medical record review was conducted of a cohort of 609 cases of RA in Olmsted County, MN, diagnosed during 1955–94. These cases had been previously classified using the ACR 1987 criteria for RA. Patients were followed up from 1955 to 2000 (median follow up 11.8 years; range 0.1–42.8), and incident ExRA manifestations were recorded according to predefined criteria. Time to first presentation of ExRA was compared in patients with RA by decade of diagnosis. Possible ExRA risk factors were identified in case record reviews. Results: ExRA occurred in 247 patients (40.6%). A subgroup of 78 patients (12.8%) had ExRA manifestations considered to be severe in a previous study from Malmö, Sweden. The incidence of severe ExRA did not change significantly over the decades (p=0.165). In a multivariate analysis the main predictors of severe ExRA were smoking at RA diagnosis (risk ratio (RR)=2.94; 95% confidence interval (95% CI) 1.68 to 5.13) and early disability (Steinbrocker class III-IV at diagnosis) (RR=2.45; 95% CI 1.51 to 4.00). The effect of smoking overwhelmed the weaker effect of rheumatoid factor seropositivity. Conclusion: There was no decrease in the incidence of extra-articular manifestations in patients with RA diagnosed up to 1995. Smoking and early disability are independent risk factors for extra-articular RA.     

Association between anticardiolipin antibodies and mortality in patients with peripheral arterial disease

PURPOSE: Anticardiolipin antibodies may be associated with recurrent thromboembolic events in patients with myocardial infarction or stroke. We sought to determine the prevalence of anticardiolipin antibodies in patients with peripheral arterial disease and their association with subsequent thromboembolic events and mortality. METHODS: We ascertained anticardiolipin antibodies using a standardized enzyme-linked immunosorbent assay (immunoglobulin G [IgG] anticardiolipin > or =15 GPL units or IgM anticardiolipin > or =15 MPL units) in 232 patients with peripheral arterial disease and 100 control subjects. Patients were observed to determine overall and cardiovascular mortality, and incident thromboembolic events. RESULTS: IgG anticardiolipin antibodies were significantly more common in the patients with peripheral arterial disease (36 of 232 [16%]) than in the controls (7 of 100 [7%], P = 0.03). During a median follow-up of 3.5 years, 3 of the 232 patients were lost to follow-up and 56 (24%) died. Overall mortality was significantly greater in the IgG anticardiolipin-positive patients (16 of 35 [46%]) compared with those who were IgG anticardiolipin-negative (40 of 194 [21%], P = 0.0003), largely due to an increase in cardiovascular mortality among the IgG anticardiolipin-positive patients. In a multivariate proportional hazards analysis, IgG anticardiolipin antibodies were an independent risk factor for overall mortality (hazard ratio [HR] = 2.1, 95% confidence interval [CI]: 1.2 to 4.0) and cardiovascular mortality (HR = 4.4, 95% CI: 1.6 to 12). CONCLUSIONS: IgG anticardiolipin antibodies are common in patients with peripheral arterial disease and are associated with an increased risk of overall and cardiovascular mortality.     

Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis

OBJECTIVE: To investigate the occurrence of extraarticular manifestations (ExRA) in a well defined community based cohort of patients with rheumatoid arthritis (RA), and to examine their effect on mortality. METHODS: Using the resources of the Rochester Epidemiology Project, a retrospective medical record review was conducted of a cohort of 424 cases of RA in Olmsted County, MN, USA, diagnosed during the period 1955-1985. These cases had been classified using the American College of Rheumatology 1987 criteria for RA. Patients were followed 1955-1998 (median followup 14.8 yrs; range 0.2-42.8 yrs), and incident ExRA manifestations were recorded according to predefined criteria. Data on comorbidities were extracted using the definitions of the Charlson comorbidity index. Survival was compared to the general population using Kaplan-Meier estimates. RESULTS: ExRA occurred in 169 patients, corresponding to an incidence rate of 3.67/100 person-yrs. Compared to the general population, survival among patients with RA was decreased. Survival among patients with ExRA was markedly decreased compared to the general population and to patients without ExRA (p < 0.001). A particularly poor prognosis was noted in a subgroup of 63 patients (incidence rate 1.04/100 person-yrs) who fulfilled predefined criteria for severe ExRA (i.e., vasculitis, pericarditis, pleuritis, and/or Felty's syndrome). For RA patients who did not fulfill these criteria, there was no significant increase of mortality (p = 0.09). In a multivariate model of mortality, including age, sex, and the presence of known comorbidities, the presence of one or more of these ExRA was the strongest predictor of mortality. CONCLUSION: In this first community based study of extraarticular manifestations in RA, virtually all the excess mortality occurred in a subgroup of patients with severe extraarticular disease, suggesting that extraarticular disease is the major predictor of mortality in patients with RA.     

Carotid intima-media thickness and the risk of new vascular events in patients with manifest atherosclerotic disease: the SMART study.

AIMS: Carotid intima-media thickness (CIMT) is an independent predictor of vascular events in the general population. Currently, little is known about the relationship between CIMT and new vascular events in patients with manifest arterial disease. We aimed to assess the strength of this relationship. METHODS AND RESULTS: The study was performed in the first consecutive 2374 patients with manifest arterial disease enrolled in the cohort study SMART (Second Manifestations of ARTerial disease), a cohort study among patients with manifest arterial disease or cardiovascular risk factors. Common CIMT was measured at baseline in both carotid arteries. Vascular events were vascular death, non-fatal myocardial infarction, or stroke, whichever occurred first. Adjusted for age and sex, an increase in common CIMT of 1 SD ( approximately 0.32 mm) was associated with the occurrence of vascular events [hazard ratio (HR) 1.18; 95% confidence interval (95% CI) 1.04-1.32]. Increasing CIMT was most strongly related to ischaemic stroke incidence (HR 1.35; 95% CI 1.16-1.59). Results were similar in the 2177 patients without large common carotid plaques (CIMT <2 mm at all measurements sites). The findings were similar after additional adjustment for risk factors of CIMT and vascular risk. CONCLUSION: Common CIMT is associated with the occurrence of new vascular events, mostly for ischaemic stroke, in patients with manifest arterial disease. This relation does not appear to depend on the presence of plaques.     

Patient, disease, and therapy-related factors that influence discontinuation of disease-modifying antirheumatic drugs: a population-based incidence cohort of patients with rheumatoid arthritis

OBJECTIVE: A major challenge in management of rheumatoid arthritis (RA) is prediction of longterm response to disease-modifying antirheumatic drug (DMARD) treatment. Our objective was to identify the predictors of DMARD discontinuation in an incidence cohort of patients with RA followed continuously from their incidence date. METHODS: Members of a population-based incidence cohort of Rochester, Minnesota, residents aged > or = 18 years diagnosed with RA (by 1987 American College of Rheumatology criteria) from January 1, 1955, to January 1, 1995, were followed longitudinally through their complete medical records until January 1, 2001. Detailed drug exposure data were collected on all DMARD and glucocorticoid regimens. Subjects were considered exposed to a DMARD if duration of use was > or = 30 days. Time to discontinuation of DMARD was estimated using survival analysis techniques. Andersen-Gill models with multiple events per patient were used to assess the influence of demographics, calendar time, comorbidities, disease characteristics [disease duration, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), joint counts, radiographic changes, nodules, RA complications], and therapy characteristics (DMARD use, singly or in combination, glucocorticoid use, first or subsequent regimen, effect of previous therapy) on time from DMARD initiation to discontinuation. RESULTS: The study population comprised 345 DMARD-treated patients (73% female) with mean age of 53.1 years and mean followup 15.4 years. Median time taking any DMARD was 16.0 months for the first, and 17.9 months for all regimens. Methotrexate (MTX) had the longest time to discontinuation, with a median of 30.3 months without folate, and 61.7 months with folate supplementation. Among the various disease characteristics examined, only higher ESR at DMARD initiation was significantly associated with a shorter time taking DMARD [hazard ratio (HR) 1.05 per 10 mm/h increase, 95% CI 1.02, 1.08]. In multivariable Andersen-Gill models considering all DMARD regimens, hydroxychloroquine use (HR 0.77, 95% CI 0.64, 0.92) and MTX use (HR with folate 0.39, 95% CI 0.30, 0.51; HR without folate 0.51, 95% CI 0.39, 0.67) were significantly associated with longer time to DMARD discontinuation, whereas prior MTX use (HR 1.96, 95% CI 1.57, 2.45) was associated with shorter time to DMARD discontinuation, after adjusting for age, sex, calendar year, Charlson comorbidity index, disease duration, and ESR at DMARD initiation. Disease duration was negatively associated with time to DMARD discontinuation; each 10 year increase in disease duration corresponded to a 14% decrease in the risk of discontinuation (HR 0.86, 95% CI 0.75, 0.98). CONCLUSION: Longer RA disease duration does not appear to increase the risk of DMARD discontinuation. However, high disease activity (as assessed by ESR) is associated with a higher likelihood of discontinuing DMARD. MTX failure may identify a subgroup of patients who are less likely to respond to other DMARD and therefore could be considered as candidates for biological therapies.     

Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study

OBJECTIVE: To examine the risk of clinical coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) compared with age- and sex-matched non-RA subjects, and to determine whether RA is a risk factor for CHD after accounting for traditional CHD risk factors. METHODS: We assembled a population-based incidence cohort of 603 Rochester, Minnesota residents ages >or=18 years who first fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA between January 1, 1955 and January 1, 1995, and 603 age- and sex-matched non-RA subjects. All subjects were followed up through their complete inpatient and outpatient medical records, beginning at age 18 years until death, migration, or January 1, 2001. Data were collected on CHD events and traditional CHD risk factors (diabetes mellitus, hypertension, dyslipidemia, body mass index, smoking) using established diagnostic criteria. CHD events included hospitalized myocardial infarction (MI), unrecognized MI, coronary revascularization procedures, angina pectoris, and sudden CHD deaths. Conditional logistic regression and Cox regression models were used to estimate the risk of CHD associated with RA, both prior to and following RA diagnosis, after adjusting for CHD risk factors. RESULTS: During the 2-year period immediately prior to fulfillment of the ACR criteria, RA patients were significantly more likely to have been hospitalized for acute MI (odds ratio [OR] 3.17, 95% confidence interval [95% CI] 1.16-8.68) or to have experienced unrecognized MIs (OR 5.86, 95% CI 1.29-26.64), and less likely to have a history of angina pectoris (OR 0.58, 95% CI 0.34-0.99) compared with non-RA subjects. After the RA incidence date, RA patients were twice as likely to experience unrecognized MIs (hazard ratio [HR] 2.13, 95% CI 1.13-4.03) and sudden deaths (HR 1.94, 95% CI 1.06-3.55) and less likely to undergo coronary artery bypass grafting (HR 0.36, 95% CI 0.16-0.80) compared with non-RA subjects. Adjustment for the CHD risk factors did not substantially change the risk estimates. CONCLUSION: Patients with RA have a significantly higher risk of CHD when compared with non-RA subjects. RA patients are less likely to report symptoms of angina and more likely to experience unrecognized MI and sudden cardiac death. The risk of CHD in RA patients precedes the ACR criteria-based diagnosis of RA, and the risk cannot be explained by an increased incidence of traditional CHD risk factors in RA patients.     

Cardiovascular death in rheumatoid arthritis: a population-based study

OBJECTIVE: To determine whether systemic inflammation confers any additional risk for cardiovascular death among patients with rheumatoid arthritis (RA), after adjusting for traditional cardiovascular risk factors and comorbidities. METHODS: Using the population-based data resources of the Rochester Epidemiology Project, we assembled an incidence cohort of all Rochester, Minnesota residents ages >or=18 years who first fulfilled the American College of Rheumatology 1987 criteria for RA between January 1, 1955 and January 1, 1995. All subjects were followed up longitudinally through their complete (inpatient, outpatient) medical records, beginning at age 18 years and continuing until death, migration, or January 1, 2001. Detailed information on the occurrence of various cardiovascular risk factors (personal history of coronary heart disease [CHD], congestive heart failure, smoking, hypertension, dyslipidemia, body mass index [BMI], diabetes mellitus, menopausal status) as well as indicators of systemic inflammation and RA disease severity (rheumatoid factor [RF] seropositivity, erythrocyte sedimentation rate [ESR], joint swelling, radiographic changes, RA nodules, RA complications, RA treatments, disease duration) and comorbidities were collected on all subjects. Causes of death were ascertained from death certificates and medical records. Cox regression models were used to estimate the independent predictors of cardiovascular death. RESULTS: This inception cohort comprised a total of 603 RA patients whose mean age was 58 years, of whom 73% were women. During a mean followup of 15 years, 354 patients died and cardiovascular disease was the primary cause of death in 176 patients. Personal history of CHD, smoking, hypertension, low BMI, and diabetes mellitus, as well as comorbidities, including peripheral vascular disease, cerebrovascular disease, chronic pulmonary disease, dementia, ulcers, malignancies, renal disease, liver disease, and history of alcoholism, were all significant risk factors for cardiovascular death (P < 0.01 for each). Multivariable Cox regression analyses, controlled for cardiovascular risk factors and comorbidities, revealed that the risk of cardiovascular death was significantly higher among RA patients with at least 3 ESR values of >or=60 mm/hour (hazard ratio [HR] 2.03, 95% confidence interval [95% CI] 1.45-2.83), RA vasculitis (HR 2.41, 95% CI 1.00-5.81), and RA lung disease (HR 2.32, 95% CI 1.11-4.84). CONCLUSION: These results indicate that markers of systemic inflammation confer a statistically significant additional risk for cardiovascular death among patients with RA, even after controlling for traditional cardiovascular risk factors and comorbidities.     

Self-rated health status as a risk factor for future vascular events and mortality in patients with symptomatic and asymptomatic atherosclerotic disease: the SMART study

Abstract. Grool AM, van der Graaf Y, Visseren FLJ, de Borst GJ, Algra A, Geerlings MI, on behalf of the SMART Study Group (University Medical Center Utrecht, Utrecht, The Netherlands). Self‐rated health status as a risk factor for future vascular events and mortality in patients with symptomatic and asymptomatic atherosclerotic disease: the SMART study. J Intern Med 2012; 272: 277–286. Objectives. Lower self‐rated health status has been associated with worse prognosis in patients with coronary artery disease (CAD). We investigated the influence of self‐rated physical and mental health status on the risk of future vascular events and mortality for various locations of symptomatic atherosclerotic disease and asymptomatic disease. Design. Patients with CAD (n = 2547), cerebrovascular disease (n = 1061), peripheral arterial disease (PAD; n = 648), abdominal aortic aneurysm (AAA; n = 272) and asymptomatic atherosclerotic disease (n = 1933) were followed for a median of 4 years for the occurrence of a new vascular event or death. Self‐rated health status was assessed with the Short Form‐36 physical and mental component summary scales. Cox regression models were used to estimate associations between health status and vascular events and death, adjusted for age, sex, vascular risk factors and intima–media thickness. Results. In the total population, lower self‐rated physical health status (per 10‐point decrease) increased the risk of vascular events [hazard ratio (HR) = 1.37, 95% confidence interval (CI) 1.24–1.52], and all‐cause (HR = 1.45, 95% CI 1.29–1.63) and vascular mortality (HR = 1.40, 95% CI 1.20–1.64). A 10‐point decrease in mental health status was associated with a modest increase in the risk of vascular events (HR = 1.19, 95% CI 1.08–1.32), and all‐cause (HR = 1.19, 95% CI 1.05–1.34) and vascular mortality (HR = 1.28, 95% CI 1.09–1.49). Risk estimates of physical and mental health status were highest in patients with asymptomatic atherosclerotic disease and lowest in those with PAD. Conclusions. Poorer self‐rated physical and mental health status increases the risk of vascular events and mortality in a broad population of patients with symptomatic and asymptomatic atherosclerotic disease.     

D-dimer and platelet aggregability are related to thrombotic events in patients with peripheral arterial occlusive disease.

AIMS: To evaluate the frequency of arterial thrombotic events in patients with peripheral arterial occlusive disease during 3-5 years of follow-up and to determine whether baseline levels of haemostatic factors were related to the risk of future thrombotic events. METHODS AND RESULTS: One hundred and twenty-three patients, mean age 56 years, with peripheral arterial occlusive disease and intermittent claudication were followed prospectively for an average of 4.2 years. Fibrinogen, prothrombin fragment 1+2, D-dimer, tissue plasminogen activator, plasminogen activator inhibitor type I antigen and activity, plasmin-alpha(2)-antiplasmin complex, beta thromboglobulin and ADP-induced platelet aggregation were measured at the recruitment. Thirty-eight new vascular events (15 fatal) were identified. Age- (and other clinical and laboratory variables) -adjusted relative risks (RR) of thrombotic events were significantly elevated (P<0.05) per higher value of D-dimer (RR: 14.1, 95% CI 1.7;115.8) and platelet aggregation was low (RR: 4.6, 95% CI 1.3;16.3). Diabetes mellitus, cerebrovascular disease, and continuing deterioration of intermittent claudication at the recruitment were also independently associated with risk of thrombotic events in the multiple regression model (RR: 5.2, 95% CI 1.5;17.5; RR: 8.6, 95% CI 2.7;27.4; RR: 2.6, 95% CI 1.2;5.7 respectively). CONCLUSION: Elevated level of D-dimer and low platelet aggregation are independent haemostatic predictors of thrombotic events in patients with peripheral arterial occlusive disease.     

Asymmetric dimethylarginine as an independent risk marker for mortality in ambulatory patients with peripheral arterial disease

Abstract. Böger RH, Endres HG, Schwedhelm E, Darius H, Atzler D, Lüneburg N, von Stritzky B, Maas R, Thiem U, Benndorf RA, Diehm C (Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg‐Eppendorf, Hamburg; Ruhr University Bochum; Vivantes Berlin‐Neukölln Medical Center, Berlin; Sanofi‐Aventis Pharma GmbH, Berlin; Institute of Clinical Pharmacology and Toxicology, University of Erlangen; Ruhr University Bochum, Herne; Klinikum Karlsbad‐Langensteinbach, Affiliated Teaching Hospital of the Ruprecht‐Karls‐University of Heidelberg, Germany) Asymmetric dimethylarginine as an independent risk marker for mortality in ambulatory patients with peripheral arterial disease. J Intern Med 2010; 269 : 349–361. Background. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis causing endothelial dysfunction, an early sign of atherogenesis. Symmetric dimethylarginine (SDMA) does not inhibit NO synthases. Peripheral arterial disease (PAD) is a systemic indication of atherosclerosis. Methods. We assessed the associations between both ADMA and SDMA blood levels and major cardiovascular and cerebrovascular events or death from any cause within a 5‐year follow‐up in the multicentre getABI trial. From a cohort of 6821 primary care patients, aged ≥65 years, all 1260 patients with prevalent PAD were compared with a random sample of 1187 non‐PAD controls. A total of 11 544 patient‐years were documented. Multivariate risks were calculated by Cox proportional hazard models, adjusting for PAD, renal dysfunction and other important cardiovascular risk factors. Results. We documented 390 deaths, 296 cardiovascular events and 98 cerebrovascular events. Increased ADMA levels in the 4th quartile were significantly associated with total mortality [hazard ratio (HR) 1.41; 95% CI 1.14–1.74] and with cardiovascular events (HR 1.32; 95% CI 1.03–1.69), but there was a nonsignificant association with cerebrovascular events (HR 1.50; 95% CI 0.98–2.29). Increased SDMA was only just significantly associated with mortality (HR 1.27; 95% CI 1.01–1.59). In PAD patients compared with non‐PAD controls, only mean SDMA concentration was considerably increased (0.52 μmol L^?1 vs. 0.48 μmol L^?1; P < 0.001) mainly because of a highly significant association with impaired renal function. Conclusion. These data suggest that ADMA but not SDMA is an independent risk marker for death from any cause or from cardiovascular events. The association between SDMA and mortality is in part explained by a close link between SDMA and renal function.     

The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years

OBJECTIVE: It is hypothesized that the systemic inflammation associated with rheumatoid arthritis (RA) promotes an increased risk of cardiovascular (CV) morbidity and mortality. We examined the risk and determinants of congestive heart failure (CHF) in patients with RA. METHODS: We assembled a population-based, retrospective incidence cohort from among all individuals living in Rochester, Minnesota, in whom RA (defined according to the American College of Rheumatology 1987 criteria) was first diagnosed between 1955 and 1995, and an age- and sex-matched non-RA cohort. After excluding patients in whom CHF occurred before the RA index date, all subjects were followed up until either death, incident CHF (defined according to the Framingham Heart Study criteria), migration from the county, or until January 1, 2001. Detailed information from the complete medical records (including all inpatient and outpatient care provided by all local providers) regarding RA, ischemic heart disease, and traditional CV risk factors was collected. Cox models were used to estimate the effect of RA on the development of CHF, adjusting for CV risk factors and/or ischemic heart disease. RESULTS: The study population included 575 patients with RA and 583 subjects without RA. The CHF incidence rates were 1.99 and 1.16 cases per 100 person-years in patients with RA and in non-RA subjects, respectively (rate ratio 1.7, 95% confidence interval [95% CI] 1.3-2.1). After 30 years of followup, the cumulative incidence of CHF was 34.0% in patients with RA and 25.2% in non-RA subjects (P< 0.001). RA conferred a significant excess risk of CHF (hazard ratio [HR] 1.87, 95% CI 1.47-2.39) after adjusting for demographics, ischemic heart disease, and CV risk factors. The risk was higher among patients with RA who were rheumatoid factor (RF) positive (HR 2.59, 95% CI 1.95-3.43) than among those who were RF negative (HR 1.28, 95% CI 0.93-1.78). CONCLUSION: Compared with persons without RA, patients with RA have twice the risk of developing CHF. This excess risk is not explained by traditional CV risk factors and/or clinical ischemic heart disease.     

Effect of metabolic syndrome or type II diabetes mellitus on the occurrence of recurrent vascular events in hypertensive patients

Patients with hypertension and manifest vascular disease are at high risk for recurrent cardiovascular diseases. It is unknown if the metabolic syndrome further increases the risk in these patients. This study aims to quantify the effect of metabolic syndrome and type II diabetes on cardiovascular events in hypertensive patients with vascular disease. A total of 2,196 hypertensive patients with vascular disease (cerebrovascular disease (34%), coronary heart disease (50%), peripheral arterial disease (28%), abdominal aortic aneurysm (13%)) from the Second Manifestations of Arterial Disease study were followed for up to 10 years (mean 3.9 years) for death, stroke and myocardial infarction. Age and sex adjusted hazard ratios (HR) were calculated for hypertensive patients with metabolic syndrome but without diabetes (n=775) and for hypertensive patients with type II diabetes (n=381), compared to merely hypertensive patients (n=1,040). Forty-nine percent had metabolic syndrome (NCEP ATPIII definition) and 17% had type II diabetes. Metabolic syndrome predicted vascular death (HR 1.41, 95% confidence interval (CI) 1.01-1.98), stroke (HR 1.36, 95% CI 0.85-2.16) and myocardial infarction (HR 1.40, 95% CI 0.97-2.01). Type II diabetes accounted for even higher risks of vascular end points (HR 1.41-1.64). The effect of metabolic syndrome on future events could not be explained by the presence of type II diabetes. Even in high-risk patients with hypertension and vascular disease, presence of metabolic syndrome or type II diabetes identifies patients at high risk for future cardiovascular events. Identifying metabolic syndrome patients may direct therapy focusing on treatment of insulin resistance by reducing weight and increasing physical activity.     

Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis

BACKGROUND: Rheumatoid arthritis is associated with increased cardiovascular mortality and morbidity. OBJECTIVE: To assess the effect of severe extra-articular rheumatoid arthritis (ExRA) manifestations on the risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis. METHODS: Patients with ExRA (n = 81) according to predefined criteria and controls (n = 184) without evidence of extra-articular disease were identified from a large research database of patients with rheumatoid arthritis. In a structured review of the medical records, the occurrence and the date of onset of clinically diagnosed CVD events were noted. Cox proportional hazards models were used to estimate the effect of ExRA on the risk of first ever CVD events after the diagnosis of rheumatoid arthritis. ExRA manifestations were modelled as time-dependent covariates, with adjustment for age, sex and smoking at the diagnosis of rheumatoid arthritis. Onset of erosive disease and rheumatoid factor seropositivity were entered as time-dependent variables. Patients were followed until onset of CVD, death or loss to follow-up. RESULTS: ExRA was associated with a significantly increased risk of first ever CVD events (p<0.001), and also with an increased risk of new-onset coronary artery disease, adjusted for age, sex and smoking (hazard ratio (HR): 3.16; 95% confidence interval (95% CI: 1.58 to 6.33). The association between ExRA and any first ever CVD event remained significant when controlling for age, sex, smoking, rheumatoid factor and erosive disease (HR: 3.25; 95% CI: 1.59 to 6.64). CONCLUSION: Severe ExRA manifestations are associated with an increased risk of CVD events in patients with rheumatoid arthritis. This association is not due to differences in age, sex, smoking, rheumatoid factor or erosive joint damage. It is suggested that systemic extra-articular disease is a major determinant of cardiovascular morbidity in rheumatoid arthritis.     

Different prognostic value of silent peripheral artery disease in type 2 diabetic and non-diabetic subjects with stable cardiovascular disease

ObjectiveABI is a good predictor of morbidity and motality in diabetic subjects with no known cardiovascular disease. However, its prognostic value in diabetic patients with prior coronary or cerebrovascular disease has not previously been evaluated.MethodsMulticenter, prospective study of 1 year of follow-up, in 1096 patients (73.6 years, 65% males, 45.4% with diabetes) with cardiovascular disease and without known peripheral arterial disease. The main outcome measure was the first occurrence of a major cardiovascular event (non-fatal acute coronary syndrome, non-fatal stroke, revascularization procedure, or cardiovascular death). Secondary endpoints included major cardiovascular events, cardiovascular death and death from any cause.ResultsPrevalence of an abnormal ABI (<0.9 or >1.4) was 38.2% in diabetic and 26.8% in non-diabetic subjects. There were 150 major cardiovascular events (38.3/1000 person-years in diabetics vs. 30.6/1000 person-years in non-diabetics subjects, p = 0.012) and 60 cardiovascular deaths (11.8/1000 person-years in diabetics vs. 10.7/1000 person-years in non-diabetics subjects, p = 0.156). Patients with abnormal ABI had a higher rate of vascular complications. There was a significant interaction between ABI and diabetes. In non-diabetic patients, an abnormal ABI was associated with an increase risk of the primary endpoint (HR 2.71; 95% CI 1.54–4.76), cardiovascular mortality (HR 4.62; 95% CI 1.47–14.52) and total mortality (HR 2.80; 95% CI 1.08–7.27). These associations were not observed in patients with diabetes.ConclusionIn patients with cardiovascular disease, ABI is a good predictor of risk of recurrent cardiovascular events and death, only in non-diabetic subjects.     

Cardiovascular death in rheumatoid arthritis: A population‐based study

Objective

To determine whether systemic inflammation confers any additional risk for cardiovascular death among patients with rheumatoid arthritis (RA), after adjusting for traditional cardiovascular risk factors and comorbidities.

Methods

Using the population‐based data resources of the Rochester Epidemiology Project, we assembled an incidence cohort of all Rochester, Minnesota residents ages ≥18 years who first fulfilled the American College of Rheumatology 1987 criteria for RA between January 1, 1955 and January 1, 1995. All subjects were followed up longitudinally through their complete (inpatient, outpatient) medical records, beginning at age 18 years and continuing until death, migration, or January 1, 2001. Detailed information on the occurrence of various cardiovascular risk factors (personal history of coronary heart disease [CHD], congestive heart failure, smoking, hypertension, dyslipidemia, body mass index [BMI], diabetes mellitus, menopausal status) as well as indicators of systemic inflammation and RA disease severity (rheumatoid factor [RF] seropositivity, erythrocyte sedimentation rate [ESR], joint swelling, radiographic changes, RA nodules, RA complications, RA treatments, disease duration) and comorbidities were collected on all subjects. Causes of death were ascertained from death certificates and medical records. Cox regression models were used to estimate the independent predictors of cardiovascular death.

Results

This inception cohort comprised a total of 603 RA patients whose mean age was 58 years, of whom 73% were women. During a mean followup of 15 years, 354 patients died and cardiovascular disease was the primary cause of death in 176 patients. Personal history of CHD, smoking, hypertension, low BMI, and diabetes mellitus, as well as comorbidities, including peripheral vascular disease, cerebrovascular disease, chronic pulmonary disease, dementia, ulcers, malignancies, renal disease, liver disease, and history of alcoholism, were all significant risk factors for cardiovascular death (P < 0.01 for each). Multivariable Cox regression analyses, controlled for cardiovascular risk factors and comorbidities, revealed that the risk of cardiovascular death was significantly higher among RA patients with at least 3 ESR values of ≥60 mm/hour (hazard ratio [HR] 2.03, 95% confidence interval [95% CI] 1.45–2.83), RA vasculitis (HR 2.41, 95% CI 1.00–5.81), and RA lung disease (HR 2.32, 95% CI 1.11–4.84).

Conclusion

These results indicate that markers of systemic inflammation confer a statistically significant additional risk for cardiovascular death among patients with RA, even after controlling for traditional cardiovascular risk factors and comorbidities.

     

Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: A population‐based cohort study

Objective

To examine the risk of clinical coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) compared with age‐ and sex‐matched non‐RA subjects, and to determine whether RA is a risk factor for CHD after accounting for traditional CHD risk factors.

Methods

We assembled a population‐based incidence cohort of 603 Rochester, Minnesota residents ages ≥18 years who first fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA between January 1, 1955 and January 1, 1995, and 603 age‐ and sex‐matched non‐RA subjects. All subjects were followed up through their complete inpatient and outpatient medical records, beginning at age 18 years until death, migration, or January 1, 2001. Data were collected on CHD events and traditional CHD risk factors (diabetes mellitus, hypertension, dyslipidemia, body mass index, smoking) using established diagnostic criteria. CHD events included hospitalized myocardial infarction (MI), unrecognized MI, coronary revascularization procedures, angina pectoris, and sudden CHD deaths. Conditional logistic regression and Cox regression models were used to estimate the risk of CHD associated with RA, both prior to and following RA diagnosis, after adjusting for CHD risk factors.

Results

During the 2‐year period immediately prior to fulfillment of the ACR criteria, RA patients were significantly more likely to have been hospitalized for acute MI (odds ratio [OR] 3.17, 95% confidence interval [95% CI] 1.16–8.68) or to have experienced unrecognized MIs (OR 5.86, 95% CI 1.29–26.64), and less likely to have a history of angina pectoris (OR 0.58, 95% CI 0.34–0.99) compared with non‐RA subjects. After the RA incidence date, RA patients were twice as likely to experience unrecognized MIs (hazard ratio [HR] 2.13, 95% CI 1.13–4.03) and sudden deaths (HR 1.94, 95% CI 1.06–3.55) and less likely to undergo coronary artery bypass grafting (HR 0.36, 95% CI 0.16–0.80) compared with non‐RA subjects. Adjustment for the CHD risk factors did not substantially change the risk estimates.

Conclusion

Patients with RA have a significantly higher risk of CHD when compared with non‐RA subjects. RA patients are less likely to report symptoms of angina and more likely to experience unrecognized MI and sudden cardiac death. The risk of CHD in RA patients precedes the ACR criteria–based diagnosis of RA, and the risk cannot be explained by an increased incidence of traditional CHD risk factors in RA patients.

     

White blood cell count and the incidence of ischemic stroke in coronary heart disease patients

PURPOSE: White blood cell (WBC) count is a marker of inflammation and has been associated with the development of cardiovascular disease. We investigated the relationship between WBC counts and the incidence of ischemic cerebrovascular disease in a large cohort of patients with pre-existing atherothrombotic disease and defined blood lipid boundaries. SUBJECTS AND METHODS: We followed up patients with documented coronary heart disease for 4.8 to 8.1 years. An extensive medical evaluation, conducted at baseline, included assessment of vascular risk factors and measures of blood lipids. Among 5435 patients with WBC counts, free of stroke, 295 developed an ischemic cerebrovascular disease (fatal and nonfatal). After review of available medical records, 186 of these cases had ischemic stroke or TIA. RESULTS: Higher WBC counts were associated with increased risk for ischemic cerebrovascular disease. Age-adjusted hazard ratio (HR) was 1.55 with 95% confidence interval (CI) 1.16-2.07, upper WBC tertile compared with the lowest. Adjusting for clinical covariates, WBC count remained an independent predictor for ischemic cerebrovascular disease (HR = 1.39; 95% CI 1.03-1.87, upper WBC tertile compared with the lowest). A similar trend appeared for the endpoint of ischemic stroke/transient ischemic attack (TIA). Further adjustment for plasma fibrinogen did not change the association materially (HR = 1.32; 95% CI 1.01-1.80; upper tertile of WBC compared with lowest). CONCLUSIONS: These findings support the role of WBC count as a simple inexpensive and readily available marker for risk stratification of ischemic cerebrovascular disease among patients with pre-existing atherothrombotic disease and defined blood lipid boundaries.     

The Impact of Atrial Fibrillation on Outcomes of Peripheral Arterial Disease: Analysis of Routinely Collected Primary Care Data

BackgroundThe combination of peripheral arterial disease and atrial fibrillation is linked with high risk of mortality and stroke. This study aims to investigate the impact of atrial fibrillation on patients with diagnosed peripheral arterial disease.MethodsThis is a retrospective study using The Health Improvement Network database, which contains prospectively collected data from participating primary care practices. Patients with a new diagnosis of peripheral arterial disease between January 8, 1995 and January 5, 2017 were identified in the database alongside relevant demographic information, clinical history, and medications. Every patient in the dataset with peripheral arterial disease and baseline atrial fibrillation (case) was matched to a patient without atrial fibrillation (control) with similar characteristics using propensity score matching. Cox-regression analysis was performed and hazard ratios (HR) calculated for the outcomes of death, stroke, ischemic heart disease, heart failure, and major amputation.ResultsPrevalence of atrial fibrillation in this cohort was 10.2%. All patients with peripheral arterial disease and atrial fibrillation (n = 5685) were matched with 5685 patients without atrial fibrillation but otherwise similar characteristics. After multivariate analysis, atrial fibrillation was independently associated with mortality (HR 1.18; 95% confidence interval [CI], 1.12-1.26; P < .01), cerebrovascular events (HR 1.35; 95% CI, 1.17-1.57; P < .01), and heart failure (HR 1.87; 95% CI, 1.62-2.15; P < .01), but not with ischemic heart disease or limb loss.ConclusionIn peripheral arterial disease patients, atrial fibrillation is a risk factor for mortality, stroke, and heart failure. This emphasizes the need for proactive surveillance and holistic management of these patients.