Derivation and internal validation of an expanded cardiovascular risk prediction score for rheumatoid arthritis: a Consortium of Rheumatology Researchers of North America Registry Study.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of mortality in rheumatoid arthritis (RA), but CV risk prediction scores derived from the general population do not accurately predict CV risk in RA patients. The goal of these analyses was to develop and internally validate an expanded CV risk prediction score for RA. METHODS: Study participants were patients with RA and no known CVD from the Consortium of Rheumatology Researchers of North America registry. Two-thirds of the cohort were used to derive the CV risk prediction score, and one-third for internal validation. Traditional CV risk factors were included in the base Cox regression model, and RA-related variables were assessed in an expanded model predicting confirmed CV events. Fit and utility of the expanded model were evaluated. RESULTS: The study cohort included 23,605 RA patients with 437 CV events over a median followup of 2.2 years. The RA variables found to be significant in the regression models and included in the expanded risk model were disease activity (Clinical Disease Activity Index >10 versus ≤10), disability (modified Health Assessment Questionnaire disability index >0.5 versus ≤0.5), daily prednisone use (any versus none), and disease duration (≥10 years versus <10 years). The expanded model had good fit (Hosmer-Lemeshow goodness of fit P = 0.94) and a lower Akaike's information criterion than the base model. In the internal validation cohort, the c-statistic for model discrimination was significantly improved from the base model to the expanded model (from 0.7261 to 0.7609; P = 0.0104). The net reclassification index of CV risk in models using a 4-category CV risk prediction tool was 40% (95% confidence interval 37-44%). CONCLUSION: This newly developed, expanded risk score for CV outcomes in RA performs well and improves the classification of CV risk in comparison to a risk prediction score in which only traditional risk factors were included.

Disease activity in rheumatoid arthritis and the risk of cardiovascular events.

OBJECTIVE: Use of several immunomodulatory agents has been associated with reduced numbers of cardiovascular (CV) events in epidemiologic studies of rheumatoid arthritis (RA). However, it is unknown whether time-averaged disease activity in RA correlates with CV events. METHODS: We studied patients with RA whose cases were followed in a longitudinal US-based registry. Time-averaged disease activity was assessed during followup using the area under the curve of the Clinical Disease Activity Index (CDAI), a validated measure of RA disease activity. Age, sex, presence of diabetes mellitus, hypertension, or hyperlipidemia, body mass index, family history of myocardial infarction (MI), use of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs), presence of CV disease, and baseline use of an immunomodulator were assessed at baseline. Cox proportional hazards regression models were examined to determine the risk of a composite CV end point that included MI, stroke, and death from CV causes. RESULTS: A total of 24,989 patients who had been followed up for a median of 2.7 years were included in these analyses. During followup, we observed 534 confirmed CV end points, for an incidence rate of 7.8 per 1,000 person-years (95% confidence interval [95% CI] 6.7-8.9). In models adjusted for variables noted above, a 10-point reduction in the time-averaged CDAI was associated with a 21% reduction in CV risk (95% CI 13-29). These results were robust in subgroup analyses stratified by the presence of CV disease, use of corticosteroids, use of NSAIDs or selective cyclooxygenase 2 inhibitors, and change in RA treatment, as well as when restricted to events adjudicated as definite or probable. CONCLUSION: Our findings showed that reduced time-averaged disease activity in RA is associated with fewer CV events.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

New insights into the link between cardiovascular disease and depression.

INTRODUCTION: Although the association between depression and cardiovascular disease (CVD) is well documented, the underlying mechanisms for this relationship remain unclear. In this paper, we present three possible models which account for the comorbidity between depression and cardiovascular disease. MODELS: The first model outlines depression as a risk factor for CVD and the second model presents CVD as a risk factor for depression. The third model proposes a common underlying pathway related to the effects of chronic stress on the body in manifesting as depression or cardiovascular disease. CONCLUSIONS: If the proposed model holds true, it may be possible that an intervention initiated before overt manifestations of CVD or depression become apparent, may delay or prevent the onset of these serious clinical entities.

Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib.

BACKGROUND: Evidence suggests that both selective cyclooxygenase (COX)-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX-2 inhibitors and non-selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin. OBJECTIVE: To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. METHODS: The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX-2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low-dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non-fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF). RESULTS: In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib. CONCLUSIONS: These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non-aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis-generating study.

Early coronary angiography improves long-term survival in unstable angina.

BACKGROUND: The role of early coronary angiography in the evaluation of patients with unstable angina has been controversial. This study was designed to determine the effect of early coronary angiography on long-term survival in patients with unstable angina. METHODS: We reviewed the Olmsted County Acute Chest Pain Database, a population-based epidemiologic registry that includes all patients residing within Olmsted County who were seen for emergency department evaluation of acute chest pain from 1985 to 1992. Patients with symptoms consistent with myocardial ischemia qualifying as unstable angina were classified as undergoing early (

Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin.

There is a need for a rapid antithrombotic effect after the administration of antiplatelet drugs in the setting of acute coronary syndromes and percutaneous interventions. Clopidogrel, a new thienopyridine derivative, is an efficient antiplatelet agent. However, the standard regimen of clopidogrel (75 mg/d) requires 2 to 3 days before significant antithrombotic effects. Patients with stable arterial disease on chronic aspirin therapy (n=20) were treated with clopidogrel either with a front-loaded regimen, 300 mg the first day and 75 mg/d the next 7 days, or with a standard regimen, 75 mg/d for 8 days. Blood thrombogenicity was assessed by quantification of platelet-thrombus formation in an ex vivo perfusion chamber, by ADP-induced platelet aggregation, and by ADP-induced fibrinogen binding. At 2 hours, mean total thrombus area with the standard regimen was not significantly reduced. In contrast, at 2 hours, the mean total thrombus area with the front-loaded regimen was significantly decreased by 23.1+/-8.5% versus baseline (P<0.05). ADP-induced platelet aggregation (with 5 and 10 micromol/L) was also significantly (P<0.05) reduced with the front-loaded regimen at 2 hours, with the mean platelet aggregation being 82.2+/-4.4% and 81.8+/-4.5%, respectively, versus baseline. Similarly, flow cytometry demonstrated a significant decrease (P<0. 05) in the ADP-induced fibrinogen binding (with 0.12 and 0.6 micromol/L) at 2 hours in this front-loaded regimen group (36.1+/-2. 0% and 53.2+/-9.3%). With the standard regimen, platelet activity was not significantly reduced at 2 hours. Our data suggest that a front-loaded regimen of clopidogrel added to aspirin achieves a significant antithrombotic effect at 2 hours in patients with known atherosclerotic disease on chronic aspirin therapy. This provides a rationale for using front-loaded clopidogrel in combination with aspirin in percutaneous coronary interventions.

Management of coronary risk factors by registered nurses versus usual care in patients with unstable angina pectoris (a chest pain evaluation in the emergency room [CHEER] substudy).

This study examined whether nurses could manage coronary risk factors in patients with unstable angina more effectively than physicians practicing usual care. Three hundred twenty-six patients were randomized in the emergency room to a 6-month program of risk factor management by a registered nurse versus participation in usual care. The nurse intervention consisted of a 30-minute counseling visit at 6 to 10 days after the chest pain episode and a second 30-minute session 1 month later. Multiple risk factors were assessed and addressed: smoking, blood lipids, blood pressure, blood glucose, physical inactivity, weight, psychological stress, and social isolation. Compared with usual care, nurse intervention patients significantly reduced both triglycerides (-29 +/- 8 vs 5 +/- 6 mg/dl; p <0.0004) and weight (-0.9 +/- 3.3 vs +0.1 +/- 2.1 kg; p = 0.0071), and had corresponding improvements in self-reported diet compliance and exercise (+34 +/- 106 vs +9 +/- 98 minutes, p = 0.0491). No significant differences between groups were observed in terms of 6-month changes in total, high-density lipoprotein, or low-density lipoprotein cholesterol, blood pressure, fasting blood glucose, percent body fat or waist-hip ratio, or psychological distress scores. The 6-month rate of recurrent events (cardiac death, out-of-hospital cardiac arrest, myocardial infarction) and/or revascularizations (coronary artery bypass surgery or coronary angioplasty) was lower in the nurse intervention group (1% vs 9%; p = 0.002). We conclude that a nurse-delivered risk factor intervention program for patients with chest pain is feasible and more effective than usual care in terms of fostering lifestyle changes that may lower coronary risk.

Sex differences in evaluation and outcome of unstable angina.

CONTEXT: The existence of sex bias in the delivery of cardiac care is controversial, and little is known about the association between sex and delivery of care and outcomes at an early point in the diagnostic sequence, such as when patients present for the evaluation of chest pain. OBJECTIVE: To test the hypothesis that female sex is negatively associated with care delivered to and outcomes of persons diagnosed as having unstable angina. DESIGN: Inception population-based cohort study with an average of 6 years of follow-up. SETTING: Emergency departments (EDs) in Olmsted County, Minnesota. PATIENTS: A total of 2271 Olmsted County residents (1306 men and 965 women) who presented to the ED for the first time with symptoms meeting criteria for unstable angina between 1985 and 1992. MAIN OUTCOME MEASURES: Use of cardiac procedures within 90 days of ED visit, overall mortality, and cardiac events (cardiac death, nonfatal myocardial infarction, nonfatal cardiac arrest, and congestive heart failure), compared by sex and Agency for Health Care Policy and Research cardiovascular risk category (low, intermediate, or high). RESULTS: Women were older (P<.001), more likely to have a history of hypertension (P = .001), and less likely to present with typical angina (P = .004) than men. Men were more likely than women to undergo noninvasive cardiac tests (relative risk [RR], 1.27; 95% confidence interval [CI], 1.14-1.40) as well as invasive cardiac procedures (RR, 1.72; 95% CI, 1.51-1.97). After adjustment, male sex was associated with a 24% increase in the use of cardiac procedures. Survival of both men and women in the high and intermediate risk categories was significantly lower than expected per the general population (P<.001). Women had a worse outcome than men, but after multivariate adjustment, male sex was associated with a trend toward an increase in the risk of death (RR, 1.23; 95% CI, 0.99-1.54) and significantly associated with increased risk of cardiac events (RR, 1.21; 95% CI, 1.03-1.42). CONCLUSIONS: Our population-based data indicate that after an ED visit for symptoms of unstable angina, the use of cardiac procedures was lower in women, but after taking into account baseline characteristics, men experienced worse outcomes.

A clinical trial of a chest-pain observation unit for patients with unstable angina. Chest Pain Evaluation in the Emergency Room (CHEER) Investigators.

BACKGROUND: Nearly half of patients hospitalized with unstable angina eventually receive a non-cardiac-related diagnosis, yet 5 percent of patients with myocardial infarction are inappropriately discharged from the emergency department. We evaluated the safety, efficacy, and cost of admission to a chest-pain observation unit (CPU) located in the emergency department for such patients. METHODS: We performed a community-based, prospective, randomized trial of the safety, efficacy, and cost of admission to a CPU as compared with those of regular hospital admission for patients with unstable angina who were considered to be at intermediate risk for cardiovascular events in the short term. A total of 424 eligible patients were randomly assigned to routine hospital admission (a monitored bed under the care of the cardiology service) or admission to the CPU (where patients were cared for according to a strict protocol including aspirin, heparin, continuous ST-segment monitoring, determination of creatine kinase isoenzyme levels, six hours of observation, and a study of cardiac function). The CPU was managed by the emergency department staff. Patients whose test results were negative were discharged, and the others were hospitalized. Primary outcomes (nonfatal myocardial infarction, death, acute congestive heart failure, stroke, or out-of-hospital cardiac arrest) and use of resources were compared between the two groups. RESULTS: The 212 patients in the hospital-admission group had 15 primary events (13 myocardial infarctions and 2 cases of congestive heart failure), and the 212 patients in the CPU group had 7 events (5 myocardial infarctions, 1 death from cardiovascular causes, and 1 case of congestive heart failure). There was no significant difference in the rate of cardiac events between the two groups (odds ratio for the CPU group as compared with the hospital-admission group, 0.50; 95 percent confidence interval, 0.20 to 1.24). No primary events occurred among the 97 patients who were assigned to the CPU and discharged. Resource use during the first six months was greater among patients assigned to hospital admission than among those assigned to the CPU (P<0.01 by the rank-sum test). CONCLUSIONS: A CPU located in the emergency department can be a safe, effective, and cost-saving means of ensuring that patients with unstable angina who are considered to be at intermediate risk of cardiovascular events receive appropriate care.

Strengths and limitations of meta-analysis: larger studies may be more reliable.

Meta-analysis of randomized controlled trials combines information from independent studies that address a similar question to provide more reliable estimates of treatment effects. At the present time, the methodology and usefulness of meta-analysis is under scrutiny. In the first part of this paper, we summarize the limitations of meta-analysis and make suggestions for improvements. In the second part, we illustrate strengths and limitations using examples of meta-analyses and subsequent large trials that address the same question. We develop the hypothesis that the size of the meta-analysis may be a useful measure of reliability. Small meta-analyses (i.e., those with less than 200 outcome events) may only be useful for summarizing the available information and generating hypotheses for future research. The results of small meta-analyses should be regarded with caution, even if the p value shows extreme statistical significance. Larger meta-analyses (i.e., those with several hundred events) are likely to be more reliable and may be clinically useful. Well-conducted meta-analyses of large trials using individual patient data may provide the best estimates of treatment effects in the cohort overall and in clinically important subgroups.

Outcome of patients discharged from a coronary care unit with a diagnosis of "chest pain not yet diagnosed".

OBJECTIVE: To determine the outcome and 3-year mortality rate among patients discharged from a coronary care unit (CCU) with a diagnosis of "chest pain not yet diagnosed." DESIGN: Prospective observational cohort study. SETTING: CCU in a university teaching hospital. PATIENTS: All 158 eligible patients discharged from the CCU between August 1986 and December 1988. Of them, 27 refused to participate and 31 did not meet the inclusion criteria because of significant co-morbidity or transportation difficulties. INTERVENTIONS: Evaluation with maximal and thallium exercise stress testing and four major gastrointestinal (GI) investigations: 24-hour intraesophageal pH monitoring, upper GI endoscopy with biopsy, esophageal motility studies and an upper GI barium series. OUTCOME MEASURES: Results of investigations and incidence of recurrent chest pain, CCU readmission, coronary angiography, coronary artery bypass surgery, myocardial infarction and death at 6, 12, 24 and 36 months after the index visit. RESULTS: Of the patients enrolled in the study 79% (79/100) had a normal exercise thallium stress test result, 74% (68/92) had an abnormal result from the 24-hour pH monitoring, 87% (82/94) had abnormal endoscopic results, 90% (84/93) had abnormal manometric results, and 89% (83/93) had signs of reflux with the barium series. At 3 years 50 patients had recurrent chest pain and 3 underwent coronary artery bypass surgery. Three patients died over the 3 years, all of noncardiac causes. CONCLUSION: Many patients discharged from the CCU with a diagnosis of chest pain not yet diagnosed have a high incidence of esophageal disorders and a very low 3-year mortality rate. More research into the early and effective identification and management of patients with such a diagnosis is needed.

Influence of coronary heart disease on morbidity and mortality after lower extremity revascularization surgery: a population-based study in Olmsted County, Minnesota (1970-1987).

OBJECTIVES: The aim of this study was to evaluate the short- and long-term postoperative cardiac outcome of patients undergoing lower extremity revascularization surgery in a geographically defined patient group. BACKGROUND: Among patients with peripheral vascular disease, cardiac events have an important effect on long-term outcome after peripheral vascular surgery. However, long-term outcome is poorly documented. METHODS: We examined the entire community medical records of 173 residents of Olmsted County, Minnesota, who underwent peripheral artery bypass surgery between 1970 and 1987 and were followed up to January 1, 1991. Patients were allocated to subgroups of 60 patients with and 106 patients without overt coronary artery disease. RESULTS: There were no significant differences in perioperative death, myocardial infarction or stroke between subgroups at 30 days after operation. The 5- and 10-year Kaplan-Meier survival rate after operation was 77% and 51% in those without and 54% and 24% in those with overt coronary artery disease (p < 0.001), respectively. For both groups, survival was significantly poorer than that expected for an age- and gender-matched group. Patients undergoing aortoiliac surgery were more likely to be alive at 10 years than those undergoing femoropopliteal surgery (47% vs. 28%, p = 0.001). The 5-year cumulative incidence of cardiac events was greater in those with overt coronary artery disease (50% vs. 28%, p = 0.003). In multivariable analysis, age, coronary artery disease and diabetes were independent predictors of death. CONCLUSIONS: Coronary events are the most important cause of long-term morbidity and mortality after peripheral vascular surgery. Patients without overt coronary artery disease are at significant risk for long-term cardiac events.

Eosinophiluria in atheroembolic renal disease.

PURPOSE AND PATIENTS: Eosinophiluria has been reported in acute interstitial nephritis and other renal diseases, but its presence in atheroembolic renal disease (AERD) has not been previously established. AERD has been identified as a cause of acute and chronic renal failure, particularly in elderly patients with advanced atherosclerosis and in those patients who have undergone manipulation or intervention of the abdominal aorta, renal artery, or coronary artery. The definitive diagnosis is made by renal biopsy. However, many patients are too acutely ill to tolerate renal biopsy and, in recent years, peripheral eosinophilia, hypocomplementemia, and thrombocytopenia have been recognized in association with AERD. Previous studies have reported that AERD is associated with an inactive renal sediment and an absence of urine eosinophils. We reviewed our experience over a 4-year period with 24 patients with renal biopsy-proven AERD. RESULTS: Urine eosinophils were evaluated in nine patients to help determine the cause of their renal deterioration. Seven of these patients presented with evidence of vascular disease. Three patients had procedures involving manipulation of the abdominal aorta. Physical examination revealed findings of atheroembolism in three of nine patients. Overall, eight of nine patients had a positive Hansel's stain for eosinophiluria. Six of eight patients had more than 5% of their urinary white cell count as eosinophils. The reason for failure of previous studies to detect eosinophiluria in AERD is unclear but may have been related to the use of Wright's stain instead of Hansel's stain. CONCLUSION: In the evaluation of acute renal insufficiency, eosinophiluria may indicate AERD in addition to the other known causes for this finding.