Objectives To examine the impact of cardiovascular risk factor control on 3-year cardiovascular event rates in patients with stable symptomatic atherothrombotic disease in Europe.
Methods The REduction of Atherothrombosis for Continued Health (REACH) Registry recruited patients aged ≥45 years with established atherothrombotic disease or three or more risk factors, of whom 20 588 symptomatic patients from 18 European countries were analysed in this study at baseline and 12, 24 and 36 months. ‘Good control’ of cardiovascular risk factors was defined as three to five risk factors at target values of international guideline recommendations (systolic blood pressure <140 mm Hg, diastolic blood pressure <90 mm Hg, fasting glycaemia <110 mg/dl, total cholesterol <200 mg/dl, non-smoking). Independent predictors of ‘good control’ of major risk factors were assessed by multivariate analysis.
Results Among symptomatic patients in the REACH Registry Europe (mean age 67 years, 70.6% male), 59.4% had good control of risk factors at baseline. Good risk factor control was associated with lower cardiovascular death/non-fatal stroke/non-fatal myocardial infarction (OR 0.76; 95% CI 0.69 to 0.83) and mortality (OR 0.89; 95% CI 0.79 to 0.99) at 36 months, compared with poor control. Independent predictors of good control of risk factors included residence in western versus eastern Europe (OR 1.29), high level of education (OR 1.16), established coronary artery disease (OR 1.18), treatment with one or more antithrombotic (OR 1.59) and one or more lipid-lowering agent (OR 1.16).
Conclusions In REACH, less than 60% of patients with stable atherothrombotic disease had good control of the five major cardiovascular risk factors. Improved risk factor control is associated with a positive impact on 3-year cardiovascular event rates and mortality.
- atherothrombotic disease
- cardiovascular events
- cohort study
- primary care
- REACH Registry
- risk factor control
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- atherothrombotic disease
- cardiovascular events
- cohort study
- primary care
- REACH Registry
- risk factor control
Atherothrombosis is a leading cause of morbidity and mortality.1 2 The frequent coexistence of atherothrombotic disease in different vascular beds, ie, coronary artery disease (CAD), cerebrovascular disease (CVD) or peripheral artery disease (PAD), is well established.3–5
The benefits of aggressive risk-reduction using lifestyle and pharmacological interventions to prevent recurrent cardiovascular events in patients with established atherothrombosis are well known.3 6 However, baseline data from the REduction of Atherothrombosis for Continued Health (REACH) Registry and follow-up data in different subgroups have shown that there is a substantial gap between guideline recommendations and actual clinical practice in the care of these patients. Indeed, classic cardiovascular risk factors are largely undertreated and undercontrolled. This is particularly the case for patients with PAD or polyvascular disease.7 8 To date, the impact of risk-reduction interventions on fatal and non-fatal ischaemic events in outpatients with atherothrombotic syndrome have only been assessed from retrospective surveys in populations of limited size.9 10 The REACH Registry was initiated to evaluate outpatients who would represent the entire spectrum of atherothrombotic clinical syndromes, from the most geographically and ethnically diverse population yet surveyed.
The REACH Registry provided a unique opportunity to analyse a global atherothrombotic population across Europe. This study of patients enrolled in the REACH Registry in Europe aimed to investigate the level of cardiovascular risk factor control, and a series of predictors of risk factor control in patients with stable atherothrombotic disease. We also examined the differences in risk factor management intensity in patients with CAD, CVD, PAD or polyvascular disease, as well as the impact of adherence to guidelines for the control of major cardiovascular risk factors in the REACH Registry Europe.
Full details of the rationale and design,11 baseline,7 1-year2 and 3-year12 data of the REACH Registry have been published previously. In brief, REACH is an international, prospective, observational registry providing up to 48 months of clinical follow-up of over 68 000 outpatients from more than 5000 sites in 44 countries.7 The 18 countries within Europe were considered in this analysis (figure 1). Consecutive eligible outpatients aged 45 years or over with established CAD, CVD or PAD, or with three or more atherothrombotic risk factors were enrolled worldwide over an initial 7-month recruitment period (December 2003–June 2004).
For the present study, we analysed data from patients with established atherothrombotic disease (PAD, CAD or CVD), documented by medical records at baseline. CAD was defined as one or more of stable angina with documented CAD, history of unstable angina with documented CAD, history of percutaneous coronary intervention or coronary artery bypass graft surgery, or previous myocardial infarction (MI). Documented CVD consisted of a hospital or neurologist report with the diagnosis of transient ischaemic attack (TIA) or ischaemic stroke. Documented PAD consisted of one or both criteria current intermittent claudication with an ankle–brachial index (ABI) of less than 0.9 and/or a history of intermittent claudication together with a previous lower extremity procedure, such as limb arterial angioplasty, stenting, atherectomy, peripheral arterial bypass graft, other vascular intervention, or amputation. Polyvascular disease was defined as coexistent symptomatic (clinically recognised) arterial disease in two or three territories (coronary, cerebral, and/or peripheral) within each patient.
Patients already in a clinical trial, hospitalised patients, or those who might have difficulty returning for a follow-up visit were excluded from enrolment. The protocol was submitted to the institutional review board in each country according to local requirements, and signed, informed consent was obtained for all patients. Family practitioners and general practitioners, as well as other office-based specialists in areas such as internal medicine, cardiology, neurology, vascular disease, general surgery, endocrinology and other fields recruited 15 or more patients into the study. Data were collected centrally using a standardised international case report form that was completed at the study visit. Baseline seated systolic blood pressure (SBP) and diastolic blood pressure (DBP), and available fasting glucose and cholesterol levels were obtained. Current smoking was defined as five or more cigarettes/day on average within the last month before study entry; former smoking was defined as five or more cigarettes/day on average more than 1 month before study entry.
Definition of risk factor control
Risk factors were included if documented in the subject's medical record or if the subject was receiving risk factor treatment at the time of study enrolment. Evidence of a risk factor was evaluated at baseline. We categorised each risk factor as ‘controlled’ if they were at the target goal of the international guideline recommendations,12–14 including SBP less than 140 mm Hg, DBP less than 90 mm Hg, glycaemia less than 110 mg/dl, total cholesterol less than 200 mg/dl, or non-smoking. We predefined a discriminating boundary between ‘good’ and ‘poor’ risk factor control by the median distribution, in which a definition of ‘good control’ was defined as three to five risk factors at target values (12 236 patients) and ‘poor control’ was defined when zero to two risk factors were at target (8340 patients). Independent predictors of ‘good control’ of major cardiovascular risk factors were assessed by multivariate analysis.
At 12±3 months, 24±3 months and 36±3 months from enrolment, data were collected regarding clinical outcomes, vascular procedures, employment status and current smoking status, as well as chronic medications taken regularly since baseline. Events were not adjudicated; however, reports of ischaemic stroke and TIA had to be sourced from a neurologist or hospital to ensure a reliable diagnosis. The current report is based on a database lock of 15 December 2005 for analysis of baseline data, and 16 May 2006, 15 June 2007 and 15 April 2008 for the 1-year, 2-year and 3-year follow-up data.
Continuous variables are expressed as mean (SD). Categorical variables are expressed as frequencies and percentages. Comparisons between categorical variables were performed using the Pearson χ2 test and continuous variables were compared using the Mann–Whitney–Wilcoxon test. Logistic regression models were built to determine the predictors of a good control of major risk factors, adjusting for all variables mentioned in the related results section. Statistical significance was considered as a two-tailed probability of less than 0.05. Statistical analysis was performed using SAS software version 8.
Among the 68 236 patients enrolled in the REACH Registry, 20 588 symptomatic patients were in the Europe area of the Registry. Their mean age was 67.0±9.8 years, and 40.7% were aged 70 years or older, while 70.6% were men (table 1). Among these patients were 70.6% (14 508) with CAD, 34.2% (6995) with CVD and 20.8% (4286) with PAD. Overall, 22.7% (4668) of patients had polyvascular disease. The fraction of patients enrolled varied geographically within Europe (figure 1).
Risk factor control and cardiovascular events
One-year, 2-year and 3-year follow-up data were available for 19 749, 19 117 and 15 783 patients, respectively. Mortality rates increased gradually from baseline to the 3-year follow-up (month 12, 2.7%; month 24, 5.1%; month 36, 10.1%). At month 36, mortality was significantly lower in patients with a good control of risk factors, compared with patients with poor control of risk factors (9.7% vs 10.8%; p<0.05; table 2).
The rates of non-fatal major cardiovascular events also increased between months 12, 24 and 36 in the total group, including non-fatal MI (1.2%, 2.0% and 3.6%, respectively), non-fatal stroke (2.0%, 3.3% and 6.1%), PAD worsening (5.0%, 7.7% and 12.9%) and hospitalisation (15.2%, 20.6% and 31.9%). However, patients with a good control of major risk factors showed lower rates of all non-fatal major cardiovascular events at months 12, 24 and 36 compared with those with poor control of major risk factors (table 2).
The rates of major cardiovascular events at the 36-month follow-up, including fatal and non-fatal events, was higher in the 3718 patients with polyvascular disease compared with the 12 059 patients with a single territory atherothrombotic disease (figure 2). In single territory disease patients, the rates of total mortality and cardiovascular death were significantly lower in patients with a good control of risk factors compared with those with poor control (both p<0.05). This difference did not reach significance in polyvascular disease patients. However, polyvascular disease patients with a good control of risk factors had lower rates of non-fatal MI (4.1% vs 6.6%; p<0.01), non-fatal stroke (9.1% vs 12.5%; p<0.01), and the cardiovascular event-composite index (MI/stroke/cardiovascular death/hospitalisation) (46.9% vs 55.5%; p<0.0001), compared with poor control patients. The same favourable impact of a good control of risk factors on non-fatal cardiovascular event rates was found to a lower extent in patients with a single territory disease (except for non-fatal MI). In a more detailed analysis of non-fatal events in each of the three arterial territories (for CAD, unstable angina or coronary revascularisation; for CVD, TIA or carotid revascularisation; and for PAD, worsening of claudication, revascularisation or amputation), a good control of risk factors was associated with lower event rates (figure 2).
Factors associated with risk factor control
Patients with a good control of major risk factors were older (by 0.5 years) and more frequently male, compared with patients with a poor control of major risk factors (table 1). More patients from western Europe than from eastern Europe had a good control of major risk factors (χ2 83.98, df 1; p<0.0001). Compared with ‘poor control’ patients, patients with a good control of major risk factors were less frequently of Caucasian origin (71.7% vs 74.9%; p<0.0001) and had a higher level of formal education, as shown by the higher rate of studies at university (15.3% vs 13.6%; p<0.001). Furthermore, patients with a good control of major risk factors had a higher prevalence of documented CAD but a lower prevalence of documented CVD, PAD and polyvascular disease compared with those without a good control of major risk factors (table 1). In their past medical history, patients with a good control of major risk factors less frequently had diabetes (23.1% vs 35.2%; p<0.0001) and hypertension (72.9% vs 85.9%; p<0.0001) compared with those without a good control of major risk factors.
The physician profile was associated with an impact on the control of risk factors, as patients showed higher rates of good control when they were followed by general practitioners or cardiologists, whereas they had lower rates of good control with vascular medicine physicians, surgeons or neurologists. Patients with a good control of major risk factors more frequently received an antithrombotic agent (95.4% vs 92.1%; p<0.0001) and a lipid-lowering agent (74.9% vs 66.8%; p<0.0001), whereas they less frequently received antidiabetic agents (diabetic patients only, 85.0% vs 88.9%; p<0.0001; figure 3).
Independent predictors of risk factor control
Predictors of a good control of major risk factors were defined by multivariate analysis, which demonstrated an independent association of good control with older age (OR 1.01; 95% CI 1.00 to 1.01; p<0.0003); residence in western Europe (1.29; 1.20 to 1.40; p<0.0001); a high level of formal education (1.16; 1.06 to 1.27; p<0.0014), CAD (1.18; 1.09 to 1.28; p<0.0001); treatment with at least one antithrombotic agent (1.59; 1.40 to 1.80; p<0.0001) and treatment with at least one lipid-lowering agent (1.16; 1.08 to 1.24; p<0.0001; table 3).
In contrast, female gender; the presence of CVD, PAD or polyvascular disease; follow-up by a vascular surgeon, vascular medicine physician or a neurologist and antidiabetic agent use were negative predictors of good control of cardiovascular risk factors.
In this recent large European registry experience, less than 60% of patients with stable atherothrombotic disease had good control of the five major cardiovascular risk factors. Optimal cardiovascular risk factor control was associated with reduced mortality at 3 years, and a positive impact on 1-year, 2-year and 3-year cardiovascular event rates, ie, fewer non-fatal cardiovascular events in polyvascular patients and both fatal and non-fatal events in patients with single territory atherothrombotic disease. Independent predictors of good control of cardiovascular risk factors were older age, residence in western Europe, high level of education, the presence of CAD, and established treatment with an antithrombotic or lipid-lowering agent.
Several previous studies have documented undertreatment of major cardiovascular risk factors in patients with atherothrombotic disease.13–16 There are several potential reasons to account for this undertreatment, particularly in patients with CVD, PAD or polyvascular disease. One is the low perception of risk associated with PAD compared with that associated with CAD or CVD. A US national survey reported a lack of physician knowledge and attitudes regarding the importance of atherothrombotic risk factor treatment in PAD patients.17 Moreover, the German getABI study identified high rates of PAD that would have gone undiagnosed without ABI measurement.18 Insufficient awareness among PAD patients of the risks of cardiovascular events and the importance of risk factor treatment influence low rates of risk factor control.19 In addition, patient-targeted healthcare campaigns have rarely provided information to individuals with PAD or CVD. Therefore, patient factors may also influence the intensity of risk factor reduction.19
As described previously in the REACH 1-year analysis,2 PAD confers a high cardiovascular risk, and the likelihood of patients with PAD experiencing future cardiovascular events is comparable or higher than in patients with CAD.2 4 20 21 Despite this, in the prise en charge de l'ArTériopaThie obliTérante des membres inférieurS (ATTEST) and PARTNERS studies, cardiovascular tests were performed less often in this group. In addition, patients with CVD or PAD were treated with risk factor-modifying therapies and antiplatelet drugs less frequently.15 22 Three classes of drugs—ACE inhibitors, statins and antiplatelet agents—have a large evidence base that demonstrates the benefit of these treatments in patients with atherothrombosis.4 20 21 However, in the REACH Registry, CVD and PAD patients were less likely to receive a lipid-lowering or an antithrombotic agent. In contrast, the use of claudication medications were more commonly used in PAD patients in this registry, suggesting that symptom relief is a therapeutic goal.
Although the use of evidence-based medicine improves outcomes after acute events in atherothrombotic patients, patients often discontinue prescribed therapies after discharge. A major issue is the high discontinuation rates (20–40%) of recommended medications by atherothrombotic patients soon after discharge.23 In a recent study, acute coronary syndrome patients without previous vascular disease had higher inhospital mortality compared with those with previous atherosclerosis, yet were paradoxically less likely to receive specific evidence-based acute coronary syndrome treatments, which can form the basis for targeted intervention.24 Interestingly, our study identified lower rates of good control when patients were enrolled by vascular medicine physicians, surgeons or neurologists. This might reflect an influence of the delegation of risk factor control to general practitioners.
In the present study, the progression of atherothrombotic disease was less frequent in patients with a good control of risk factors, as shown by lower rates of non-fatal events (for CAD patients, unstable angina, or coronary revascularisation; for PAD patients, worsening of claudication, revascularisation, or lower limb amputation; and for CVD patients, TIA or carotid revascularisation). The latter patients are at high risk of recurrent stroke and other atherothrombotic events. The prevalence of risk factors, comorbidities, use of secondary prevention therapies and adherence to guidelines all influence the recurrent event rate.25–27 Poor risk profiles put CVD patients at high risk of future atherothrombotic events. Similar results have been published in patients with polyvascular disease.5 28 Undertreatment is common worldwide and adherence to guidelines needs to be enforced. Our findings should help physicians and healthcare workers of atherothrombotic patients to reinforce the message of the major importance of tight control of risk factors.
The strength of this registry is that it is a large, prospective, international, multicentre, multiethnic cohort, inclusive of patients with distinct atherothrombotic syndromes. Moreover, it includes patients recruited from primary care and other office practices, helping to ensure that its conclusions can be extrapolated to the wider population. A very high percentage (93–96%) of patients contributed to the data analysed at 1 year and 2 years of follow-up, and a good percentage (77%) contributed to the 3-year follow-up.
This study's limitations include some of the characterisations of patient demographics that were used in order to accommodate the large sample size. For example, we defined cardiovascular risk factors as ‘controlled’ if they were at the target of the international guideline recommendations, regardless of whether patients received a specific risk factor treatment or not. We are not able to discern definitively how many patients were exposed to each risk factor beyond self-report, nor for how long each cardiovascular risk factor was present before entry into the REACH Registry. Individuals with unstable atherothrombotic disease at baseline were excluded. Despite the large sample size, these findings might not be extrapolated to patients with atherothrombotic disease who are identified from other settings. Furthermore, patients enrolled in the REACH Registry had established PAD, and the proportion of patients with symptomatic manifestations of PAD is higher compared with many epidemiological studies that detected PAD by ABI measurement.24 As a result, good risk factor control and treatment may be overestimated in the REACH Registry, even if patients are not reaching targets for risk factor control and following guideline therapies.
In this recent registry, less than 60% of European patients with stable atherothrombotic disease had a good control of the five major cardiovascular risk factors. Improved cardiovascular risk factor control is associated with a positive impact on 1-year, 2-year and 3-year major cardiovascular event rates. The identified treatment disparities should provide impetus for more directed physician and patient education, and serve to stimulate healthcare professionals globally to adhere to guidelines that designate therapeutic targets for patients with atherothrombotic disease.
The authors would like to thank Deborah Burrage, PhD, for her assistance with coordinating revisions and providing editorial help in preparing this manuscript including editing, checking content and language, formatting, referencing and preparing tables and figures, and Tobias Limbourg for his support with statistical analyses. The Institut für Herzinfarktforschung Ludwigshafen verified all statistical analyses.
REACH Registry Global Publication Committee
Mark Alberts, MD, NorthWestern University Medical School, Chicago, IL, USA; Deepak L. Bhatt, MD, VA Boston Healthcare System, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (chair); Ralph D'Agostino, PhD, Boston University, Boston, MA, USA; Kim Eagle, MD, University of Michigan, Ann Arbor, MI, USA; Shinya Goto, MD, PhD, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Alan T. Hirsch, MD, University of Minnesota School of Public Health and Minneapolis Heart Institute Foundation, Minneapolis, MN, USA; Chiau-Suong Liau, MD, PhD, Taiwan University Hospital and College of Medicine, Taipei, Taiwan, China; Jean-Louis Mas, MD, Centre Raymond Garcin, Paris, France; E. Magnus Ohman, MD, Duke University Medical Center, Durham, NC, USA; Joachim Röther, MD, Klinikum Minden, Minden, Germany; Sidney C. Smith, MD, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; P. Gabriel Steg, MD, Hôpital Bichat-Claude Bernard, Paris, France (chair); Peter W.F. Wilson, MD, Emory University School of Medicine, Atlanta, GA, USA.
The national coordinators of the REACH Registry in Europe are: lkka Tierala, Helsinki University Hospital, Helsinki Finland; Franz Aichner, Landesnervenklinik Wagner Jauregg, Linz, Austria; Thomas Wascher, Universitat Klinikum fur Innere Medizin, Graz, Austria; Patrice Laloux, Cliniques Universitaires UCL, Mont-Godinne, Belgium; Julia Jorgova, University Hospital St Ekaterina, Sofia, Bulgaria; Per Hildebrandt, H:S Frederiksberg Hospital, Frederiksberg, Denmark; Jean-Louis Mas, Hopital Saint-Anne, Paris, France; Patrice Cacoub, Groupe Hopitalier Universitaire Pitié Salpêtrière, Paris, France; Gilles Montalescot, Groupe Hopitalier Universitaire Pitié Salpêtrière, Paris, France; Klaus G. Parhofer, Universittätsklinikum München, München, Germany; Joachim Röther, Klinikum Minden, Minden, Germany; Uwe Zeymer, Institut für Herzinfarktforschung Ludwigshafen, Ludwigshafen, Germany; Moses Elisaf, University of Ioannina, Ioannina, Greece; Gyögy Pfliegler, University of Debrecen Medical and Health Science Center, Debrecen, Hungary; Marija Ruta Babarskiene, University Hospital, Kaunas, Lithuania; Don Poldermans, Erasmus Medisch Centrum, Rotterdam, The Netherlands; Victor Gil, Hospital de Santa Cruz, Carnaxide, Portugal; Constantin Popa, Institutul de Boli Cerebro-Vasculare, Bucharest, Romania; Yuri Belenkov, Cardiology Research Complex, Moscow, Russia; Elizaveta Panchenko Pavlovna, Cardiology Research Complex, Moscow, Russia; Carmen Suárez, Hospital de la Princesa, Madrid, Spain; Iris Baumgartner, Inselspital University Hospital, Bern, Switzerland; Franz Eberli, Stadtspital Triemli, Zurich, Switzerland; Patrik Michel, Centre Hospitalier Universitaire de Lausanne (CHUV), Lausanne, Switzerland; Jonathan Morrell, The Conquest Hospital, Hastings, UK; Vira Tseluyko, Kharkov, Ukraine.
The REACH Registry is endorsed by the World Heart Federation. A complete list of REACH investigators is accessible online at http://www.reachregistry.org. The REACH Registry enforces a no ghost-writing policy.
↵* A complete list of REACH Registry Investigators appears in the appendix.
Funding The REACH Registry is sponsored by Sanofi-Aventis (Paris, France), Bristol-Myers Squibb (Princeton, New Jersey, USA) and the Waksman Foundation (Tokyo, Japan). The sponsors provide logistical support. All manuscripts in the REACH Registry are led by independent authors who are not governed by the funding sponsors and are reviewed by an academic publication committee before submission. The funding sponsors have the opportunity to review manuscript submissions but do not have authority to change any aspect of a manuscript.
Competing interests PPC has received research grants from Sanofi-Aventis, Schering Plough, Servier and Roche; honoraria from Sanofi-Aventis, Schering Plough, Servier, Roche, AstraZeneca and Bristol-Myers Squibb. UZ has received research grants and speaker honoraria from Bristol-Myers-Squibb and Sanofi Aventis. JR has received honoraria and consulting fees from Sanofi-Aventis, Bristol-Myers Squibb, Lundbeck and Boehringer Ingelheim. DLB has received research grants (to the institution) from: AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis and The Medicines Company; has served as a consultant (honoraria waived or donated for past three years) for Arena, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola, Sanofi-Aventis, Schering Plough, Scios, Takeda, The Medicines Company and Vertex. PGS has received a research grant from Sanofi-Aventis (1999 to 2008); is on the speaker's bureau for Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Menarini, Medtronic, Nycomed, Pierre Fabre, Sanofi-Aventis, Servier and The Medicines Company; is on the consulting/advisory boards for Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Endotis, GlaxoSmithKline, Medtronic, MSD, Nycomed, Sanofi-Aventis, Servier and The Medicines Company and is a stockholder for Aterovax. TL, IB and DP: No interests declared.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the Paris University.
Provenance and peer review Not commissioned; externally peer reviewed.
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