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Original Contribution |

One-Year Cardiovascular Event Rates in Outpatients With Atherothrombosis FREE

Ph. Gabriel Steg, MD; Deepak L. Bhatt, MD; Peter W. F. Wilson, MD; Ralph D’Agostino, MD; E. Magnus Ohman, MD; Joachim Röther, MD; Chiau-Suong Liau, MD, PhD; Alan T. Hirsch, MD; Jean-Louis Mas, MD; Yasuo Ikeda, MD; Michael J. Pencina, PhD; Shinya Goto, MD; for the REACH Registry Investigators
[+] Author Affiliations

Author Affiliations: Département de Cardiologie, Hôpital Bichat-Claude Bernard, Paris, France (Dr Steg); Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio (Dr Bhatt); Cardiology Division, Emory University School of Medicine, Atlanta, Ga (Dr Wilson); Statistics and Consulting Unit, Department of Mathematics and Statistics, Boston University, Boston, Mass (Drs D’Agostino and Pencina); Division of Cardiology, Duke University, Durham, NC (Dr Ohman); Department of Neurology, Klinikum Minden, Minden, Germany (Dr Röther); Department of Internal Medicine, National Taiwan University Hospital and School of Medicine, Taipei, Taiwan (Dr Liau);Minneapolis Heart Institute Foundation and Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis (Dr Hirsch); Service de Neurologie, Centre Raymond Garcin, Hôpital Sainte-Anne, Paris, France (Dr Mas); Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan (Dr Ikeda); and Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan (Dr Goto).

More Author Information
JAMA. 2007;297(11):1197-1206. doi:10.1001/jama.297.11.1197.
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Published online

Context Few data document current cardiovascular (CV) event rates in stable patients with atherothrombosis in a community setting. Differential event rates for patients with documented coronary artery disease (CAD), cerebrovascular disease (CVD), or peripheral arterial disease (PAD) or those at risk of these diseases have not been previously evaluated in a single international cohort.

Objective To establish contemporary, international, 1-year CV event rates in outpatients with established arterial disease or with multiple risk factors for atherothrombosis.

Design, Setting, and Participants The Reduction of Atherothrombosis for Continued Health (REACH) Registry is an international, prospective cohort of 68 236 patients with either established atherosclerotic arterial disease (CAD, PAD, CVD; n = 55 814) or at least 3 risk factors for atherothrombosis (n = 12 422), who were enrolled from 5587 physician practices in 44 countries in 2003-2004.

Main Outcome Measures Rates of CV death, myocardial infarction (MI), and stroke.

Results As of July 2006, 1-year outcomes were available for 95.22% (n = 64 977) of participants. Cardiovascular death, MI, or stroke rates were 4.24% overall: 4.69% for those with established atherosclerotic arterial disease vs 2.15% for patients with multiple risk factors only. Among patients with established disease, CV death, MI, or stroke rates were 4.52% for patients with CAD, 6.47% for patients with CVD, and 5.35% for patients with PAD. The incidences of the end point of CV death, MI, or stroke or of hospitalization for atherothrombotic event(s) were 15.20% for CAD, 14.53% for CVD, and 21.14% for PAD patients with established disease. These event rates increased with the number of symptomatic arterial disease locations, ranging from 5.31% for patients with risk factors only to 12.58% for patients with 1, 21.14% for patients with 2, and 26.27% for patients with 3 symptomatic arterial disease locations (P<.001 for trend).

Conclusions In this large, contemporary, international study, outpatients with established atherosclerotic arterial disease, or at risk of atherothrombosis, experienced relatively high annual CV event rates. Multiple disease locations increased the 1-year risk of CV events.

Figures in this Article

Atherothrombosis (coronary artery disease [CAD], cerebrovascular disease [CVD], and peripheral arterial disease [PAD]) is associated with the main causes of mortality on a worldwide scale. Recent US data have confirmed that despite a decrease in age-standardized national death rates, the absolute number of deaths from these conditions continues to increase,1 and prevalence is sharply increasing in other parts of the world. Thus, atherothrombotic diseases are, and are projected still to be, the leading cause of death worldwide by 2020.2

Thus far, most of the information available on atherothrombosis risk has been derived from single regional locales (such as studies conducted in Europe or North America), often confined to a single subtype of patient (patients with CAD, previous stroke patients without PAD), and generally limited to hospitalized patients (as opposed to outpatients or individuals in primary care) or to patients in clinical trials (as opposed to patients in the community).

The REACH (Reduction of Atherothrombosis for Continued Health) Registry has been established to circumvent these limitations by recruiting and following up a large cohort of outpatients with a history of, or who are at high risk of developing, atherothrombosis. The REACH Registry aims to study contemporary outpatient populations from various regions of the world to describe the demographic characteristics and management as well as to determine the risk of cardiovascular (CV) events in the global population and in each clinical subgroup. Additional aims were to assess the risk related to the overlap between the subgroups within the various symptomatic locations of atherothrombosis, compare outcomes within different patient profiles, and define predictors of risk for subsequent CV events.

This article describes the characteristics and outcomes of patients for whom 1-year follow-up data were available and reports the association between multiple symptomatic locations of atherothrombosis (ie, polyvascular disease) and CV event rates.

The design, including the strategy for selecting physicians, collecting follow-up data, and ensuring data quality,3 and the baseline description of the REACH Registry4 have been published. Briefly, consecutive outpatients aged at least 45 years with established CAD, CVD, or PAD or patients with at least 3 atherothrombotic risk factors (multiple risk factors only) were enrolled by their physician over an initial 7-month recruitment period. The patients were from 5587 physician practices in 44 countries and were enrolled between December 2003 and June 2004. Due to regulatory requirements in Japan, enrollment in that country was delayed and occurred between August and December 2004.

The risk factors used for enrollment consisted of treated diabetes mellitus, diabetic nephropathy, ankle brachial index of less than 0.9, asymptomatic carotid stenosis of 70% or higher, carotid intima-media thickness more than 2 times adjacent sites, systolic blood pressure of at least 150 mm Hg despite therapy for at least 3 months, hypercholesterolemia treated with medication, current frequent smoking (≥15 cigarettes per day), and age 65 years or older (men) or 70 years or older (women). Patients already in a clinical trial or those who might have difficulty returning for a follow-up visit were excluded from enrollment. Patients with ongoing events were not enrolled and hospitalized patients were specifically excluded.

To ensure uniformity of the REACH Registry population, a site selection strategy was implemented at the national level, accounting for patient and physician profiles, type of health care environment, and medical practice, using the best available epidemiological data regarding the prevalence of atherothrombotic events and risk factors for the geographic distribution (urban vs suburban or local) and the types of physicians responsible for their management in each country. This protocol was submitted to the institutional review boards in each country according to local requirements and signed informed consent was required for all patients.

Data were collected centrally via use of a standardized international case report form, completed at the study visit. Body mass index (BMI) was defined as weight in kilograms divided by height in meters squared. Patients were considered to be overweight if their BMI ranged from 25 to 29 or obese if it were 30 or higher. Patients were also classified as obese if their waist circumference was more than 40 in (>102 cm) in men or more than 35 in (>88 cm) in women. Current smoking was defined as at least 5 cigarettes per day on average within the last month before enrollment; former smoking was defined as stopping more than a month before enrollment. Polyvascular disease was defined as coexistent established, clinically recognized arterial disease in 2 or 3 arterial territories (coronary, cerebral, lower extremity, or all 3).

Follow-up

At 12 months (plus or minus 3 months) after enrollment, data were collected from participating physicians regarding patients' clinical outcomes, vascular endovascular procedures, employment status, weight, and current smoking status, as well as whether patients were taking medications regularly since baseline for long-term disease. The current report is based on a database lock of July 21, 2006, for analysis of the 1-year follow-up. Events were not adjudicated; however, reports of ischemic stroke and transient ischemic attack had to be sourced from a neurologist or hospital to ensure a reliable diagnosis.

Cardiovascular death included fatal stroke, fatal myocardial infarction (MI), and other cardiovascular death. Other cardiovascular death included other death of cardiac origin; pulmonary embolism; any sudden death, including unobserved and unexpected death (eg, while sleeping) unless proven otherwise by autopsy; death following a vascular operation, vascular procedure, or amputation (except for trauma or malignancy); death attributed to heart failure; death following a visceral or limb infarction; and any other death that could not be definitely attributed to a nonvascular cause or hemorrhage. Any MI or stroke followed by death, whatever the cause, in the subsequent 28 days was considered as a fatal MI or fatal stroke.

This report was prepared in compliance with the STROBE checklist (version 3, accessible at http://www.strobe-statement.org).5

Statistical Analysis

Continuous variables are expressed as mean (SD). Categorical variables are expressed as frequencies and percentages. Event rates are reported as annualized event rates. All event rates are reported after adjustment for age and sex. This adjustment was accomplished through the corrected group prognosis method in the Cox proportional hazards model previously described.6 Only patients with complete outcome and covariate information for a given end point were included in calculating the rates for that end point. Three additional sets of analyses—which adjusted incrementally for age and sex, on risk factors, ethnicity/race, and BMI—provided very similar results.

Cumulative incidence curves were constructed for selected end points (nonfatal stroke; CV death; nonfatal MI; and CV death, MI, or stroke) using the Kaplan-Meier approach. The differences in incidence rates for selected end points (nonfatal stroke; CV death; nonfatal MI; CV death, MI, or stroke; and CV death, MI, stroke, or hospitalization) according to the number of atherothrombosis disease locations were tested using the test for trend in the Cox proportional hazards model. Statistical analysis was performed using SAS v8 software (SAS Institute Inc, Cary, NC).

Of the 68 375 patients enrolled in the REACH Registry, 68 236 entered the follow-up phase, with 139 (0.20%) patients withdrawing consent early. As of the database lock on July 21, 2006, 1-year follow-up was available for 64 977 (95.22%) of the patients who had entered the follow-up stage. Of those who withdrew, 2338 patients (3.43%) did so because of missed site visits and 910 (1.33%) because their enrolling physicians had withdrawn from the registry. Among the reasons for physician withdrawal were because their clinical sites had been destroyed by the 2004 tsunami in Asia or by Hurricane Katrina in the southern United States; because these physicians had died, retired, or decided to withdraw from the registry; or because their patients had withdrawn consent late (n = 11). Comparison of baseline demographics of patients for whom 1-year follow-up data were and were not available were similar in age, risk factors for atherosclerosis, previous history of CV disease, and use of medications (Table 1 and Table 2).

Table Graphic Jump LocationTable 1. Baseline Characteristics of Patients in 1-Year Follow-up Analysis by Geographic Distribution
Table Graphic Jump LocationTable 2. Baseline Medication and Physician Profile in 1-Year Follow-up Analysis by Geographic Distribution

The registry patients with 1-year follow-up were a mean (SD) age of 68.6 (10.1) years and were predominantly male (63.77%). The majority were either overweight or obese, were former or current smokers, and had a history of CAD (Table 1). Overall, 36.55% of patients were enrolled and followed up by family and general practitioners. The percentages of the remaining specialties are listed in Table 2 and detailed baseline characteristics of patients in the various geographic regions are shown in Table 1.

All-cause mortality was 2.58% overall at 1 year, with 2.81% of patients having established arterial disease compared with 1.51% of patients having multiple risk factors only (with ≥3 risk factors; Table 3). A total of 63.95% of those deaths were from CV causes. The overall combined CV death, MI, or stroke rate at 1 year was 4.24% (95% confidence interval [CI], 3.97%-4.51%), ranging from 2.15% (95% CI, 1.84%-2.46%) of patients with multiple risk factors only to 6.47% (95% CI, 5.96%-6.97%) of patients enrolled with CVD. Cardiovascular event rates for the total population, for each of the CAD, CVD, and PAD subsets, and for those with only multiple risk factors are shown in Table 3. Kaplan-Meier event curves as a function of time from enrollment for the triple end point of CV death, MI, or stroke and each of its components are shown in Figure 1 and demonstrate linearity.

Table Graphic Jump LocationTable 3. One-Year CV Event Rates for the Total Population and Main Subsets, Adjusted for Sex and Age*
Figure 1. Event Curves for CV Death, Nonfatal Myocardial Infarction, and Stroke From Enrollment to 1 Year
Graphic Jump Location

CV indicates cardiovascular; MI, myocardial infarction.

Event rates were consistently and markedly lower for patients with multiple risk factors only than for patients with established arterial disease. Patients with PAD had the highest CV mortality; CAD patients had the highest nonfatal MI rate, and the highest nonfatal stroke rate was seen among patients with CVD. The end points of CV death/MI/stroke or hospitalization for atherothrombotic event(s) were 12.81% (95% CI, 12.38%-13.23%) in the total patient population, 14.41% (95% CI, 13.93%-14.89%) in the population with established arterial disease, and 5.31% (95% CI, 4.86%-5.75%) in the population with multiple risk factors only. In the overall stable population with established arterial disease, approximately 1 in 7 patients had a major event (CV death, MI, and stroke) or was hospitalized for a CV event or revascularization procedure within a year of enrollment.

Data for other CV outcome events leading to hospitalization for such reasons as unstable angina (overall yearly rate, 4.26%) and congestive heart failure leading to hospitalization (which occurred in 3.42% of the overall population and in 3.77% of symptomatic patients) are shown in Table 3. Bleeding leading to hospitalization or transfusion occurred in 0.91% of the patients with established disease vs 0.55% of the patients with multiple risk factors only. The CV revascularization rate was approximately 5% for patients with CAD, predominantly via percutaneous coronary intervention in three quarters of those cases (Table 3). More than 1% of patients with CVD underwent surgery or angioplasty (with or without stenting) of the carotid artery, and more than 10% of patients with PAD underwent a lower-extremity revascularization procedure or an amputation, with a yearly lower-limb amputation rate of 1.63%. Notably, because of the overlap between groups, significant proportions of the CVD and PAD populations, 1.52% and 2.38%, respectively, also underwent coronary angioplasty.

There is a substantial overlap between the various locations of the atherosclerotic disease, such that patients with multiple arterial beds affected are counted in several groups (eg, a PAD patient with CAD is counted in the PAD group and in the CAD group). To further explore the relative risk of an acute ischemic event in an arterial bed that was not included as a qualifying condition (hereafter called the “cross-risk”), event rates are also reported as observed for predefined cohorts with either a single symptomatic arterial bed or multiple arterial beds (polyvascular disease; Table 4). Overall major CV event rates were approximately doubled in patients with polyvascular disease compared with patients with a single symptomatic arterial bed (Table 4). In an analysis of event rates as a function of the number of symptomatic arterial beds affected (Figure 2), counting patients with multiple risk factors only as 0 symptomatic beds, event rates increased in stepwise fashion with the number of symptomatic vascular beds, with the end point of CV death, MI, stroke, or hospitalization for a CV event ranging from 5.31% of patients with risk factors only to 12.58% with 1, 21.14% with 2, and 26.27% with 3 disease locations (P<.001 for trend).

Table Graphic Jump LocationTable 4. One-Year CV Outcomes Among Patients With Established Atherosclerotic Disease as a Function of Single Arterial or Polyvascular Diseases, Adjusted for Sex and Age*
Figure 2. One-Year CV Event Rates as a Function of Number of Symptomatic Disease Locations
Graphic Jump Location

All P values <.001. CV indicates cardiovascular; MI, myocardial infarction. Patients with at least 3 factors but no symptoms are counted as 0, even in the presence of asymptomatic carotid plaque or reduced ankle brachial index. Error bars represent 95% confidence intervals.

Major CV end points were also examined by geographic region (Table 5). Although the adjusted rates reported show overall consistency across geographic regions, with extremes of CV death rates ranging from 0.74% in Japan to 2.90% in Eastern Europe, there are some differences. Japan has the lowest rates of CV death and of nonfatal MI but higher rates of nonfatal stroke compared with North America, Western Europe, and Australia. The observed combined rates of CV death, MI, or stroke ranged from 3.13% in Australia to 7.62% in Eastern Europe. Patients from Japan experienced low rates for all end points, which were lower than those of other Asian countries. In all geographic regions, the rate of the triple end point of CV death, MI, or stroke exceeded the anticipated 3% event rate (Table 5).

Table Graphic Jump LocationTable 5. Geographic Variation of 1-Year CV End Points in the REACH Registry, Adjusted for Sex and Age*

These CV ischemic events were associated with changes in the employment of participating patients. Among 14 406 patients for whom part- or full-time employment had been documented at baseline (Table 1), 50.34% of those who experienced an event were no longer working at 1 year vs 29.79% of those without an event.

In this large, international study of a stable outpatient population with established atherothrombosis or at high risk of disease and receiving contemporary risk-reduction therapies, 1-year event rates are high and accrued almost linearly over time. This sustained event rate, observed in each region internationally, contrasts with the early steep increase in event rates followed by a plateau that is routinely observed in patients discharged from the hospital after acute events.

The 1-year hard event rates (CV death, MI, or stroke) increased markedly with the number of symptomatic arterial disease locations, ranging from 2.2% (in patients with risk factors only) to 9.2% (in patients with symptomatic disease in all 3 locations). Although this finding has been previously reported,7 the additive risk is well defined in this data set, as well as the specific risk of each symptomatic arterial location, alone and in combination. The totality of risk appeared defined not only by arterial bed initially affected but also by the extent of disease (the overlap between symptomatic locations). The current report may in fact underestimate the impact of polyvascular disease because the database only addresses diagnosed symptomatic polyvascular disease.

Patients with PAD are usually regarded as a group that is at particularly high risk of proximate cardiac ischemic events, yet PAD is commonly both underdiagnosed and undertreated.810 The REACH Registry findings support these concepts, with PAD patients experiencing the highest rates of CV death and major CV events due to an atherothrombotic event. Many clinically relevant morbid limb ischemic events are known to be common and relevant for individuals with PAD (such as critical limb ischemia, abdominal aortic aneurysm rupture, or peripheral embolism) but were not captured individually in the REACH Registry. Thus, these data potentially underestimate the apparent clinical effect of PAD event rates. Interestingly, these higher event rates may be driven by a larger proportion of patients with PAD (approximately 60%) having polyvascular disease than the CAD cohorts (25%) or CVD cohorts (40%).

When focusing on patients with disease of a single arterial bed, patients with PAD alone were observed to experience lower CV death and CV death, MI, or stroke rates than patients with CAD or CVD. The event rates in patients with PAD alone were lower than those for PAD in combination with any other arterial disease location. PAD patients also required a large number of lower-extremity revascularization procedures: more than 10% underwent peripheral procedures after a year, with a 1.6% annual lower-limb amputation rate. Overall, these findings support the need for increased awareness among physicians and patients of the amount of cross-risk that is related to overlap between the various locations of atherothrombosis11,12 and the value of actively seeking out the presence of multicirculation atherosclerotic arterial disease if individual risk is to be more precisely assessed.8,1315

Important advances have been made in the demonstration of the benefits of aggressive risk reduction using lifestyle and pharmacological interventions for preventing initial and recurrent CV events in patients at high risk of, or with, established atherothrombosis.16,17 Evidence stems mostly from large-scale clinical trials, which have provided the framework for recommendations regarding prevention. Yet there is evidence that in primary and secondary prevention—even in affluent geographic environments, such as Western Europe and North America—there is underuse of evidence-based preventive therapies across and among patients with various arterial beds affected by atherothrombosis.4 Although there were some regional variations in risk factors, ethnicity, and BMI, the prevalence of risk factors, including overweight or obesity, in the REACH population was remarkably high. To provide actual event rates, we computed event rates after adjusting for age and sex but did not adjust for risk factors, which may remove variables that are presumably in the causal pathway for the events. Likewise, we chose not to adjust for BMI or ethnicity. Interestingly, in 3 additional sets of analyses, with incremental adjustments on risk factors, BMI, and ethnicity, such adjustment did not substantially affect most of the point estimates for event rates.

Although only a minority of patients in the REACH Registry were at target goals for blood pressure, glycemic control, cholesterol levels, body weight, and nonsmoking status, the overall rate of use of the main pharmacologic interventions recommended for secondary prevention17 was relatively high. Approximately three quarters of patients in this registry received antiplatelet therapy, a similar proportion received either an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy and approximately the same proportion received lipid-lowering therapy. In addition, approximately half of the patients were receiving β-blocker therapy. Yet, despite receiving contemporary evidence-based preventive drug therapy, these stable outpatients with established arterial disease and those with multiple risk factors for atherothrombosis both experienced high CV event rates, with a 4.7% yearly rate of hard events in the former group and 2.2% in the latter group. During the 1-year follow-up period, approximately 1 in 7 patients with established arterial disease experienced either a hard CV event or required hospitalization for an atherothrombotic event, with the associated health economic implications.

Patients with established arterial disease experienced 2 to 3 times higher event rates than patients with multiple risk factors only. Although there appears to be a continuum of risk among individuals,16 the distinction between primary and secondary prevention remains valid from the standpoint of populations. This has important implications for designing large-scale preventive intervention trials.

The amount of cross-risk between arterial beds in patients with established disease has already been demonstrated in prior investigations,18 with a high risk of recurrence of the baseline event18 and of other manifestations of atherothrombosis.13,1923 The REACH data confirm that for patients with previous stroke, the risk of recurrent stroke exceeds the combined risks of MI and CV death. In addition, these data are consistent with findings from the Oxford Vascular Study, which have outlined the high rates of vascular events outside the coronary territory in a population-based study.24 In the REACH Registry, among patients with established disease or at risk of disease, there were at least as many nonfatal strokes (excluding transient ischemic attacks) as nonfatal MIs at follow-up.

The clinical burden of atherothrombosis is compounded because in addition to the hard events of CV death, MI, or stroke, patients with established atherothrombosis required a large number of revascularization interventions (approximately 5% coronary artery bypass graft surgery or percutaneous coronary intervention in CAD patients, 10% peripheral interventions in PAD patients, 1% carotid stenting or surgery in CVD patients), bleeding that leads to hospitalization or transfusion occurred in 0.9% of patients, and hospitalization due to congestive heart failure was required in 3.4% of patients. The socioeconomic effect of this disease burden is reflected in the fact that approximately 50% of the patients who were employed at baseline but who experienced an ischemic event during follow-up were not working at the 1-year follow up (twice the rate of patients without events).

The REACH Registry provides high-quality data (with a large sample size and with systematic audits and quality checks) with high follow-up rates and from diverse patient types and environments. These data complement other large-scale global data sets designed to explore the epidemiology25,26 or acute management of patients with atherothrombosis.2734 Despite the size, scope, and quality of the REACH data set, this analysis has several limitations. The external validity of the findings may be limited, as is often the case in non–population-based registries. It is possible that the mere acceptance of participation in the registry might result in selection of physicians and patients who are more adherent to guidelines and prevention than in the general population. However, this would likely result in underestimation of the degree of undertreatment and of the event rates.4 In addition, the event rates observed in the multiple risk factor population are only applicable to similar patient populations but should probably not be extrapolated to the wider primary prevention setting.

Follow-up rates were high, particularly for a registry of this scope and size. However, approximately 5.0% of the patients missed visits and, thus, we cannot actually exclude a small margin of error in the estimation of event rates. However, the clinical characteristics of patients with and without follow-up appear quite similar and suggest no systematic bias. The findings in the REACH Registry complement a previous analysis35 of several regional cohort studies that highlight the consistently high incidence of stroke throughout the world. The lower CV event rates in certain regions of the world, such as Japan, are important areas for future research.

The high event rates observed in this large, stable, contemporary outpatient cohort of patients with established atherosclerotic arterial disease or with multiple atherothrombotic risk factors indicate that continued efforts are needed to improve secondary prevention and clinical outcomes. Initiatives to improve adherence to evidence-based guidelines36 and care are an important tool in this respect. In addition, the strong association of asymptomatic and symptomatic multiple locations of atherothrombosis with event rates suggests that atherothrombosis should be addressed as a global arterial disease in patients.

Corresponding Author: Ph. Gabriel Steg, MD, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France (gabriel.steg@bch.aphp.fr).

Author Contributions: Dr Steg had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Steg, Bhatt, Wilson, Ohman, Röther, Hirsch.

Acquisition of data: Steg, Liau, Ikeda, Goto.

Analysis and interpretation of data: Steg, Bhatt, Wilson, D’Agostino, Hirsch, Mas, Ikeda, Pencina, Goto.

Drafting of the manuscript: Steg, Bhatt, D’Agostino, Hirsch, Goto.

Critical revision of the manuscript for important intellectual content: Steg, Bhatt, Wilson, D’Agostino, Ohman, Röther, Liau, Hirsch, Mas, Ikeda, Pencina, Goto.

Statistical analysis: Bhatt, Wilson, D’Agostino, Pencina.

Obtained funding: Steg, Goto.

Administrative, technical, or material support: Steg, Röther, Goto.

Study supervision: Steg, Bhatt, Wilson, Ohman, Röther, Hirsch, Mas.

REACH Registry Executive Committee: Deepak L. Bhatt, MD, Cleveland Clinic, Cleveland, Ohio (cochair); Ph. Gabriel Steg, MD, Hôpital Bichat-Claude Bernard, Paris, France (cochair); E. Magnus Ohman, MD, Duke University Medical Center, Durham, NC; Joachim Röther, MD, Klinikum Minden, Minden, Germany; Peter W. F. Wilson, MD, Medical University of South Carolina, Charleston.

REACH Registry Publication Committee: Deepak L. Bhatt, MD, Cleveland Clinic, Cleveland, Ohio (cochair); Ph. Gabriel Steg, MD, Hôpital Bichat-Claude Bernard, Paris, France (cochair); Shinya Goto, MD, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Alan T. Hirsch, MD, Minneapolis Heart Institute Foundation and Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis; Chiau-Suong Liau, MD, PhD, Taiwan University Hospital and College of Medicine, Taipei; Jean-Louis Mas, MD, Centre Raymond Garcin, Paris, France; E. Magnus Ohman, MD, Duke University Medical Center, Durham, NC; Joachim Röther, MD, Klinikum Minden, Minden, Germany; Peter W. F. Wilson, MD, Medical University of South Carolina, Charleston.

National Coordinators:Australia: Christopher Reid, Victoria. Austria: Franz Aichner, Linz; Thomas Wascher, Graz. Belgium: Patrice Laloux, Mont-Godinne. Brazil: Denilson Campos de Albuquerque, Rio de Janeiro. Bulgaria: Julia Djorgova, Sofia. Canada: Eric A. Cohen, Toronto, Ontario. Chile: Ramon Corbalan, Santiago. China: Chuanzhen LV, Frederiksberg. Finland: Ilkka Tierala, Helsinki. France: Jean-Louis Mas, Patrice Cacoub and Gilles Montalescot, Paris. Germany: Klaus Parhofer, Munich; Uwe Zeymer, Ludwigshafen; Joachim Röther, Minden. Greece: Moses Elisaf, Ioannina. Interlatina (Guatemala): Romulo Lopez, Guatemala City. Hong Kong: Juliana Chan, Shatin. Hungary: György Pfliegler, Debrecen. Indonesia: Bambang Sutrisna, Jakarta. Israel: Avi Porath, Beer Sheva. Japan: Yasuo Ikeda, Tokyo. Lebanon: Ismail Khalil, Beirut. Lithuania: Ruta Babarskiene, Kaunas. Malaysia: Robaayah Zambahari, Kuala Lumpur. Mexico: Efrain Gaxiola, Jalisco. the Netherlands: Don Poldermans, Rotterdam. Philippines: M. Teresa B. Abola, Quezon City. Portugal: Victor Gil, Amadora. Romania: Constantin Popa, Bucharest. Russia: Yuri Belenkov and Elizaveta Panchenko, Moscow. Saudi Arabia: Hassan Chamsi-Pasha, Jeddah. Singapore: Yeo Tiong Cheng, Singapore. South Korea: Oh Dong-Joo, Seoul. Spain: Carmen Suarez, Madrid. Switzerland: Iris Baumgartner, Bern. Taiwan: Chiau-Suong Liau, Taipei. Thailand: Piyamitr Sritara, Bangkok. United Arab Emirates: Wael Mahameed, Abu Dhabi. United Kingdom: Jonathan Morrell, Hastings. Ukraine: Vira Tseluyko, Kharkov. United States: Mark Alberts, Chicago, Ill; Robert M. Califf, Durham, NC; Christopher P. Cannon, Boston, Mass; Kim Eagle, Ann Arbor, Mich; Alan T. Hirsch, Minneapolis, Minn.

The List of REACH investigators is accessible online at http://www.reachregistry.org.

Financial Disclosures: Dr Bhatt reports that he has received honoraria for consulting on scientific advisory boards from AstraZeneca, Bristol-Myers Squibb, Centocor, Eisai, Eli Lilly, GlaxoSmithKline, Millennium, Otsuka, Paringenix, PDL, Sanofi-Aventis, Schering Plough, The Medicines Company; honoraria for lectures from Bristol-Myers Squibb, Sanofi-Aventis, and The Medicines Company; and provided expert testimony regarding clopidogrel (the compensation was donated to a nonprofit organization). Dr Röther reports that he has received honoraria from Bristol-Myers Squibb and Sanofi-Aventis. Dr Steg reports that he has received honoraria from Bristol-Myers Squibb and Sanofi-Aventis and has received research grants from Sanofi-Aventis. Dr Steg reports having served as a member of the speakers' bureau for Boehringer Ingelheim, Servier, GlaxoSmithKline, Merck, Sharp & Dohme, and Nycomed and also on a consultant ad board for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Sharp & Dohme, Sanofi-Aventis, Servier, and Takeda. Dr Ohman reports that he has received research grants from Berlex, Sanofi-Aventis, Schering-Plough, Eli Lilly, Bristol-Myers Squibb, and Millennium. Dr Ohman reports that he has stock ownership in Medtronic, Savacor, and Response Biomedical and is a consultant for Invoise, Response Biomedical, Savacor, and Liposcience. Dr Hirsch reports that he has received research grants from Bristol-Myers Squibb and Sanofi-Aventis; honoraria from Sanofi-Aventis; and speaker's bureau fees for Sanofi-Aventis. Dr Wilson reports that he has received a grant from Sanofi-Aventis. None of the other authors reported disclosures.

Funding/Support: The REACH Registry is sponsored by Sanofi-Aventis, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan), who assisted with the design and conduct of the study and data collection.

Role of the Sponsor: Data analysis and interpretation, as well as preparation, review, and approval of the manuscript, were done independently by academic authors who are not governed by the funding sponsors and under the control of an academic publications committee. The funding sponsors have the opportunity to review manuscript submissions but do not have authority to change any aspect of a manuscript.

Statistical Analysis: The statistical analysis for this study was performed under the supervision of Drs D’Agostino and Pencina from the Statistics and Consulting Unit, Department of Mathematics and Statistics, Boston University, Boston, Mass.

Acknowledgment: We thank Veronique Daclin, MD, and Luc Sagnard, MD, of Sanofi-Aventis, and Brian Gavin, PhD, of Bristol-Myers Squibb, for their support of the REACH Registry, as part of their regular duties.

A Complete List of the REACH Registry Investigators appears in JAMA (2006;295:180-189).

Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, 1970-2002.  JAMA. 2005;294:1255-1259
PubMed   |  Link to Article
Murray CJL, Lopez LD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study.  Lancet. 1997;349:1498-1504
PubMed   |  Link to Article
Ohman EM, Bhatt DL, Steg PG.  et al.  The Reduction of Atherothrombosis for Continued Health (REACH) Registry: an international, prospective, observational investigation in subjects at risk for atherothrombotic events-study design.  Am Heart J. 2006;151:786.e1-786.e10
PubMed   |  Link to Article
Bhatt DL, Steg PG, Ohman EM.  et al.  International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis.  JAMA. 2006;295:180-189
PubMed   |  Link to Article
Davidoff F, Batalden P. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statementhttp://www.strobe-statement.org. Accessed June 26, 2006
Chang IM, Gelman R, Pagano M. Corrected group prognostic curves and summary statistics.  J Chronic Dis. 1982;35:669-674
PubMed   |  Link to Article
Hirsch AT, Criqui MH, Treat-Jacobson D.  et al.  Peripheral arterial disease detection, awareness, and treatment in primary care.  JAMA. 2001;286:1317-1324
PubMed   |  Link to Article
Hirsch AT, Haskal ZJ, Hertzer NR.  et al.  ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic).  Circulation. 2006;113:e463-e654
PubMed   |  Link to Article
Belch JJ, Topol EJ, Agnelli G.  et al.  Critical issues in peripheral arterial disease detection and management: a call to action.  Arch Intern Med. 2003;163:884-892
PubMed   |  Link to Article
Diehm C, Lange S, Darius H.  et al.  Association of low ankle brachial index with high mortality in primary care.  Eur Heart J. 2006;27:1743-1749
PubMed   |  Link to Article
Creager MA, Jones DW, Easton JD.  et al.  Atherosclerotic Vascular Disease Conference: writing group V: medical decision making and therapy.  Circulation. 2004;109:2634-2642
PubMed   |  Link to Article
Hirsch AT, Gloviczki P, Drooz A.  et al.  Special communication: mandate for creation of a national peripheral arterial disease public awareness program: an opportunity to improve cardiovascular health.  Angiology. 2004;55:233-242
PubMed   |  Link to Article
Adams RJ, Chimowitz MI, Alpert JS.  et al.  American Heart Association/American Stroke Association. Coronary risk evaluation in patients with transient ischemic attack and ischemic stroke: a scientific statement for healthcare professionals from the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke Association.  Stroke. 2003;34:2310-2322
PubMed   |  Link to Article
Sacco RL, Adams R, Albers G.  et al.  Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline.  Circulation. 2006;113:e409-e449
PubMed
Wilterdink JL, Furie KL, Easton JD. Cardiac evaluation of stroke patients.  Neurology. 1998;51:(suppl 3)  S23-S26
PubMed   |  Link to Article
De Backer G, Ambrosioni E, Borch-Johnsen K.  et al.  European guidelines on cardiovascular disease prevention in clinical practice.  Eur Heart J. 2003;24:1601-1610
PubMed   |  Link to Article
Smith SC Jr, Allen J, Blair SN.  et al.  AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute.  Circulation. 2006;113:2363-2372
PubMed   |  Link to Article
Arima H, Tzourio C, Butcher K.  et al.  Prior events predict cerebrovascular and coronary outcomes in the PROGRESS trial.  Stroke. 2006;37:1497-1502
PubMed   |  Link to Article
Vickrey BG, Rector TS, Wickstrom SL.  et al.  Occurrence of secondary ischemic events among persons with atherosclerotic vascular disease.  Stroke. 2002;33:901-906
PubMed   |  Link to Article
Brown DL, Lisabeth LD, Roychoudhury C.  et al.  Recurrent stroke risk is higher than cardiac event risk after initial stroke/transient ischemic attack.  Stroke. 2005;36:1285-1287
PubMed   |  Link to Article
Budaj A, Flasinska K, Gore JM.  et al.  Magnitude of and risk factors for in-hospital and postdischarge stroke in patients with acute coronary syndromes: findings from a Global Registry of Acute Coronary Events.  Circulation. 2005;111:3242-3247
PubMed   |  Link to Article
Touzé E, Varenne O, Chatellier G.  et al.  Risk of myocardial infarction and vascular death after transient ischemic attack and ischemic stroke: a systematic review and meta-analysis.  Stroke. 2005;36:2748-2755
PubMed   |  Link to Article
Witt BJ, Brown RD Jr, Jacobsen SJ.  et al.  A community-based study of stroke incidence after myocardial infarction.  Ann Intern Med. 2005;143:785-792
PubMed   |  Link to Article
Rothwell PM, Coull A, Silver L.  et al.  Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study).  Lancet. 2005;366:1773-1783
PubMed   |  Link to Article
Yusuf S, Hawken S, Ounpuu S.  et al.  Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.  Lancet. 2004;364:937-952
PubMed   |  Link to Article
 Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA Project). http://www.ktl.fi/monica. Accessed June 26, 2006
Bhatt DL, Roe MT, Peterson ED.  et al.  CRUSADE Investigators. Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative.  JAMA. 2004;292:2096-2104
PubMed   |  Link to Article
The GRACE Investigators.  Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes.  Am Heart J. 2001;141:190-199
PubMed   |  Link to Article
Steg PG, Goldberg RJ, Gore JM.  et al.  Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE).  Am J Cardiol. 2002;90:358-363
PubMed   |  Link to Article
Fox KA, Goodman SG, Klein W.  et al.  Management of acute coronary syndromes: variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE).  Eur Heart J. 2002;23:1177-1189
PubMed   |  Link to Article
Maynard C, Weaver WD, Lambrew C.  et al.  Factors influencing the time to administration of thrombolytic therapy with recombinant tissue plasminogen activator (data from the National Registry of Myocardial Infarction): participants in the National Registry of Myocardial Infarction.  Am J Cardiol. 1995;76:548-552
PubMed   |  Link to Article
Barron HV, Bowlby LJ, Breen T.  et al.  Use of reperfusion therapy for acute myocardial infarction in the United States: data from the National Registry of Myocardial Infarction 2.  Circulation. 1998;97:1150-1156
PubMed   |  Link to Article
Hasdai D, Behar S, Wallentin L.  et al.  A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS).  Eur Heart J. 2002;23:1190-1201
PubMed   |  Link to Article
Sacco RL, Anand K, Lee HS.  et al.  Homocysteine and the risk of ischemic stroke in a triethnic cohort: the Northern Manhattan Study.  Stroke. 2004;35:2263-2269
PubMed   |  Link to Article
Menotti A, Jacobs DR Jr, Blackburn H.  et al.  Twenty-five-year prediction of stroke deaths in the seven countries study: the role of blood pressure and its changes.  Stroke. 1996;27:381-387
PubMed   |  Link to Article
Mehta RH, Montoye CK, Gallogly M.  et al.  Improving quality of care for acute myocardial infarction: the Guidelines Applied in Practice (GAP) Initiative.  JAMA. 2002;287:1269-1276
PubMed   |  Link to Article

Figures

Figure 1. Event Curves for CV Death, Nonfatal Myocardial Infarction, and Stroke From Enrollment to 1 Year
Graphic Jump Location

CV indicates cardiovascular; MI, myocardial infarction.

Figure 2. One-Year CV Event Rates as a Function of Number of Symptomatic Disease Locations
Graphic Jump Location

All P values <.001. CV indicates cardiovascular; MI, myocardial infarction. Patients with at least 3 factors but no symptoms are counted as 0, even in the presence of asymptomatic carotid plaque or reduced ankle brachial index. Error bars represent 95% confidence intervals.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of Patients in 1-Year Follow-up Analysis by Geographic Distribution
Table Graphic Jump LocationTable 2. Baseline Medication and Physician Profile in 1-Year Follow-up Analysis by Geographic Distribution
Table Graphic Jump LocationTable 3. One-Year CV Event Rates for the Total Population and Main Subsets, Adjusted for Sex and Age*
Table Graphic Jump LocationTable 4. One-Year CV Outcomes Among Patients With Established Atherosclerotic Disease as a Function of Single Arterial or Polyvascular Diseases, Adjusted for Sex and Age*
Table Graphic Jump LocationTable 5. Geographic Variation of 1-Year CV End Points in the REACH Registry, Adjusted for Sex and Age*

References

Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, 1970-2002.  JAMA. 2005;294:1255-1259
PubMed   |  Link to Article
Murray CJL, Lopez LD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study.  Lancet. 1997;349:1498-1504
PubMed   |  Link to Article
Ohman EM, Bhatt DL, Steg PG.  et al.  The Reduction of Atherothrombosis for Continued Health (REACH) Registry: an international, prospective, observational investigation in subjects at risk for atherothrombotic events-study design.  Am Heart J. 2006;151:786.e1-786.e10
PubMed   |  Link to Article
Bhatt DL, Steg PG, Ohman EM.  et al.  International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis.  JAMA. 2006;295:180-189
PubMed   |  Link to Article
Davidoff F, Batalden P. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statementhttp://www.strobe-statement.org. Accessed June 26, 2006
Chang IM, Gelman R, Pagano M. Corrected group prognostic curves and summary statistics.  J Chronic Dis. 1982;35:669-674
PubMed   |  Link to Article
Hirsch AT, Criqui MH, Treat-Jacobson D.  et al.  Peripheral arterial disease detection, awareness, and treatment in primary care.  JAMA. 2001;286:1317-1324
PubMed   |  Link to Article
Hirsch AT, Haskal ZJ, Hertzer NR.  et al.  ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic).  Circulation. 2006;113:e463-e654
PubMed   |  Link to Article
Belch JJ, Topol EJ, Agnelli G.  et al.  Critical issues in peripheral arterial disease detection and management: a call to action.  Arch Intern Med. 2003;163:884-892
PubMed   |  Link to Article
Diehm C, Lange S, Darius H.  et al.  Association of low ankle brachial index with high mortality in primary care.  Eur Heart J. 2006;27:1743-1749
PubMed   |  Link to Article
Creager MA, Jones DW, Easton JD.  et al.  Atherosclerotic Vascular Disease Conference: writing group V: medical decision making and therapy.  Circulation. 2004;109:2634-2642
PubMed   |  Link to Article
Hirsch AT, Gloviczki P, Drooz A.  et al.  Special communication: mandate for creation of a national peripheral arterial disease public awareness program: an opportunity to improve cardiovascular health.  Angiology. 2004;55:233-242
PubMed   |  Link to Article
Adams RJ, Chimowitz MI, Alpert JS.  et al.  American Heart Association/American Stroke Association. Coronary risk evaluation in patients with transient ischemic attack and ischemic stroke: a scientific statement for healthcare professionals from the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke Association.  Stroke. 2003;34:2310-2322
PubMed   |  Link to Article
Sacco RL, Adams R, Albers G.  et al.  Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline.  Circulation. 2006;113:e409-e449
PubMed
Wilterdink JL, Furie KL, Easton JD. Cardiac evaluation of stroke patients.  Neurology. 1998;51:(suppl 3)  S23-S26
PubMed   |  Link to Article
De Backer G, Ambrosioni E, Borch-Johnsen K.  et al.  European guidelines on cardiovascular disease prevention in clinical practice.  Eur Heart J. 2003;24:1601-1610
PubMed   |  Link to Article
Smith SC Jr, Allen J, Blair SN.  et al.  AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute.  Circulation. 2006;113:2363-2372
PubMed   |  Link to Article
Arima H, Tzourio C, Butcher K.  et al.  Prior events predict cerebrovascular and coronary outcomes in the PROGRESS trial.  Stroke. 2006;37:1497-1502
PubMed   |  Link to Article
Vickrey BG, Rector TS, Wickstrom SL.  et al.  Occurrence of secondary ischemic events among persons with atherosclerotic vascular disease.  Stroke. 2002;33:901-906
PubMed   |  Link to Article
Brown DL, Lisabeth LD, Roychoudhury C.  et al.  Recurrent stroke risk is higher than cardiac event risk after initial stroke/transient ischemic attack.  Stroke. 2005;36:1285-1287
PubMed   |  Link to Article
Budaj A, Flasinska K, Gore JM.  et al.  Magnitude of and risk factors for in-hospital and postdischarge stroke in patients with acute coronary syndromes: findings from a Global Registry of Acute Coronary Events.  Circulation. 2005;111:3242-3247
PubMed   |  Link to Article
Touzé E, Varenne O, Chatellier G.  et al.  Risk of myocardial infarction and vascular death after transient ischemic attack and ischemic stroke: a systematic review and meta-analysis.  Stroke. 2005;36:2748-2755
PubMed   |  Link to Article
Witt BJ, Brown RD Jr, Jacobsen SJ.  et al.  A community-based study of stroke incidence after myocardial infarction.  Ann Intern Med. 2005;143:785-792
PubMed   |  Link to Article
Rothwell PM, Coull A, Silver L.  et al.  Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study).  Lancet. 2005;366:1773-1783
PubMed   |  Link to Article
Yusuf S, Hawken S, Ounpuu S.  et al.  Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.  Lancet. 2004;364:937-952
PubMed   |  Link to Article
 Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA Project). http://www.ktl.fi/monica. Accessed June 26, 2006
Bhatt DL, Roe MT, Peterson ED.  et al.  CRUSADE Investigators. Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative.  JAMA. 2004;292:2096-2104
PubMed   |  Link to Article
The GRACE Investigators.  Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes.  Am Heart J. 2001;141:190-199
PubMed   |  Link to Article
Steg PG, Goldberg RJ, Gore JM.  et al.  Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE).  Am J Cardiol. 2002;90:358-363
PubMed   |  Link to Article
Fox KA, Goodman SG, Klein W.  et al.  Management of acute coronary syndromes: variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE).  Eur Heart J. 2002;23:1177-1189
PubMed   |  Link to Article
Maynard C, Weaver WD, Lambrew C.  et al.  Factors influencing the time to administration of thrombolytic therapy with recombinant tissue plasminogen activator (data from the National Registry of Myocardial Infarction): participants in the National Registry of Myocardial Infarction.  Am J Cardiol. 1995;76:548-552
PubMed   |  Link to Article
Barron HV, Bowlby LJ, Breen T.  et al.  Use of reperfusion therapy for acute myocardial infarction in the United States: data from the National Registry of Myocardial Infarction 2.  Circulation. 1998;97:1150-1156
PubMed   |  Link to Article
Hasdai D, Behar S, Wallentin L.  et al.  A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS).  Eur Heart J. 2002;23:1190-1201
PubMed   |  Link to Article
Sacco RL, Anand K, Lee HS.  et al.  Homocysteine and the risk of ischemic stroke in a triethnic cohort: the Northern Manhattan Study.  Stroke. 2004;35:2263-2269
PubMed   |  Link to Article
Menotti A, Jacobs DR Jr, Blackburn H.  et al.  Twenty-five-year prediction of stroke deaths in the seven countries study: the role of blood pressure and its changes.  Stroke. 1996;27:381-387
PubMed   |  Link to Article
Mehta RH, Montoye CK, Gallogly M.  et al.  Improving quality of care for acute myocardial infarction: the Guidelines Applied in Practice (GAP) Initiative.  JAMA. 2002;287:1269-1276
PubMed   |  Link to Article

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