The objective of this study was to determine cardiovascular event rates in diabetic patients and nondiabetic subjects from the REACH Registry with established coronary artery disease, cerebrovascular disease, peripheral arterial disease, or multiple risk factors for atherothrombosis. REACH is an international, prospective, and contemporaneous cohort of patients with ≥3 atherothrombotic risk factors only or established atherothrombotic disease, of which 30,043 have diabetes. The main outcomes after 1-year follow-up were cardiovascular death, myocardial infarction, stroke, major adverse cardiovascular events (MACEs; cardiovascular death, myocardial infarction, or stroke), and MACEs/hospitalization. The MACE rate at 1 year was positively related to the number of atherothrombotic anatomic sites in diabetic patients and nondiabetic subjects, and the rate was higher in those with (3.8%) than without (3.0%, p <0.001) diabetes. Diabetic patients with risk factors only had a lower MACE rate than nondiabetic subjects or diabetic patients with established atherothrombotic disease (2.2% vs 4.0% or 6.0%, respectively, p <0.001 for the 2 comparisons). These differences persisted after adjusting for gender and age. In conclusion, diabetic patients in the REACH Registry have an increased risk of cardiovascular events compared to nondiabetic subjects related to the number of atherothrombotic sites. Although increasing risk, diabetes may not be truly equivalent to previous atherothrombotic events on new cardiovascular event rates.
Diabetic patients are at high risk of cardiovascular events. After reports that type 2 diabetic patients without a history of myocardial infarction have the same risk of coronary artery disease (CAD) as nondiabetic subjects with a history of myocardial infarction, the National Cholesterol Education Program has stated that diabetes is considered a coronary heart disease risk equivalent. Although there is no doubt that there is an increased risk of CAD events in diabetic patients, there is still some uncertainty as to whether the cardiovascular risk conferred by diabetes is truly equivalent to that of a previous myocardial infarction. Different studies have produced conflicting results, and the discrepancies may relate to the relatively small number of patients studied, the inclusion of diabetic women (considered at a higher risk than men), the age and duration of diabetes (not considered in most of these studies), geographic variations, and additional risk factors such as proteinuria or metabolic syndrome, which have a strong impact on outcomes. Also, most studies antedate the widespread adoption of statins and the updated European and American guidelines for the treatment of diabetes and cardiovascular diseases. The REduction of Atherothrombosis for Continued Health (REACH) Registry provides a large, robust, international, and contemporary sample of outpatients with risk factors only (RFOs) or with established atherothrombotic disease (EAD) and provides an opportunity to examine the relative risks of cardiovascular events related to diabetes and to previous CAD.
Methods
Full details of the rationale and design of the REACH Registry have been published. REACH is a prospective observational registry designed to provide up to 48 months of clinical follow-up in >68,000 outpatients enrolled from approximately 5,000 sites in 44 countries from 2003 to 2004. Patients were ≥45 years of age and had ≥1 of the following criteria (EAD): previous atherothrombotic site, documented CAD (angina pectoris, myocardial infarction, or angioplasty/stent/bypass), cerebrovascular disease (ischemic stroke or transient ischemic attack), peripheral arterial disease (PAD; historical or current intermittent claudication associated with an ankle–brachial index <0.9), or ≥3 predefined atherothrombotic risk factors (RFO). Patients were evaluated at baseline and annually for up to 48 months after baseline evaluation. The study design was approved by the institutional review board in each participating country and all patients provided signed, informed consent.
Risk factors collected at baseline consisted of treated diabetes mellitus (any type), diabetic nephropathy, ankle–brachial index <0.9, known presence of ≥1 carotid plaque, asymptomatic carotid stenosis ≥70%, carotid intima media thickness ≥2 times that of adjacent sites, systolic blood pressure ≥150 mm Hg despite therapy for ≥3 months, hypercholesterolemia treated with medication, current smoking ≥15 cigarettes per day, and men ≥65 years old or women ≥70 years old. Fasting blood glucose levels were obtained at baseline, whereas hemoglobin A 1c tests were not performed in the REACH Registry due to variability between assays used worldwide. Polyvascular disease was defined as coexistent established if clinically recognized arterial disease was present in 2 or 3 arterial sites (e.g., coronary, cerebral, lower extremity).
The selection of physicians for the REACH Registry was carefully determined to reflect the medical practice in each country. Patients were recruited primarily by family practitioners and general practitioners. Data were collected using a standardized international case-report form.
At 1 year, clinical, biochemical, treatment, and outcome data were collected. Events were not adjudicated; however, reports of ischemic stroke and transient ischemic attack were sourced from a neurologist or hospital to ensure a reliable diagnosis. Cardiovascular death included fatal stroke, fatal myocardial infarction, other death of cardiac origin, pulmonary embolism, any sudden death, death after a vascular operation, vascular procedure, or amputation (except for trauma or malignancy), death attributed to heart failure, death after a visceral or limb infarction, and any other death that could not be definitely attributed to a nonvascular cause or hemorrhage. Any myocardial infarction or stroke followed by death, whatever the cause, in the subsequent 28 days was considered a fatal myocardial infarction or fatal stroke.
Continuous variables are expressed as mean ± SD and categorical variables as frequency and percentage. Adjustment for age and gender was made using a multiple logistic model giving the least squares mean of the logit for each percentage. Comparisons between categorical variables were performed using Pearson chi-square test. The t test was used to compare continuous variables. Multivariable-adjusted proportional hazard ratio modeling was carried out for each cardiovascular event to test the difference between diabetic patients and nondiabetic subjects. Statistical analysis was performed using SAS 9.1.3 (SAS Institute, Cary, North Carolina).
Results
A total of 69,055 patients were enrolled. Baseline data were available for 68,236 patients, including 30,043 diabetic patients (44%). Most patients with diabetes (70%) were recruited in North America and Western Europe. The 1-year follow-up rate was 95% (64,977 patients, which included 28,507 with diabetes) and was similar for diabetic and nondiabetic patients. Baseline demographics are listed in Table 1 .
| Variable | Diabetic Patients | Nondiabetic Subjects |
|---|---|---|
| (n = 28,507) | (n = 36,470) | |
| Characteristics | ||
| Age (years) | 68 ± 9.6 | 69 ± 11 |
| Women | 39% ⁎ | 34% |
| Region | ||
| North America | 46% ⁎ | 35% |
| Western Europe | 24% | 29% |
| Eastern Europe | 5.4% | 11% |
| Asia | 9.4% | 8.2% |
| Japan | 8.1% | 7.5% |
| Australia | 3.0% | 5.4% |
| Latin America | 2.8% | 2.8% |
| Middle East | 1.5% | 1.1% |
| Atherothrombotic risk factors | ||
| Body mass index (kg/m 2 ) | ||
| Men | 29 ± 5.6 ⁎ | 27 ± 4.5 |
| Women | 30 ± 6.9 ⁎ | 27 ± 5.6 |
| Waist circumference (cm) | ||
| Men | 102 ± 16 ⁎ | 98 ± 14 |
| Women | 99 ± 18 ⁎ | 91 ± 16 |
| Smoking ≥5 cigarettes/day | 14% ⁎ | 16% |
| Hypertension | 88% ⁎ | 77% |
| Blood pressure (mm Hg) | ||
| Systolic | 139 ± 19 | 137 ± 19 |
| Diastolic | 78 ± 11 | 78 ± 11 |
| Fasting blood glucose (mg/dl) | 146 ± 54 ⁎ | 98 ± 17 |
| Total cholesterol (mg/dl) | 191 ± 49 | 195 ± 45 |
| Triglycerides (mg/dl) | 175 ± 107 ⁎ | 149 ± 85 |
| Microalbuminuria/proteinuria (mg/L) † | 111 ± 329 ⁎ | 38.5 ± 171 |
| Treatments | ||
| Lipid-lowering drugs | 78% | 73% |
| Statins | 71% | 68% |
| Other | 14% | 10% |
| Antihypertensive agents | 93% | 90% |
| Angiotensin-converting enzyme inhibitors | 50% | 41% |
| Angiotensin II receptor blockers | 28% | 19% |
| Calcium channel inhibitors | 37% | 32% |
| β blockers | 44% | 50% |
| Diuretics | 47% | 35% |
| Other | 12% | 7.8% |
| Antiplatelet agents | 74% | 82% |
| Acetylsalicylic acid | 64% | 70% |
| Other | 22% | 27% |
| Patients achieving National Cholesterol Education Program risk factor goals ‡ | ||
| Blood pressure <140/90 mm Hg | 48% | 52% |
| Fasting blood glucose <126 mg/dl | 41% | 95% |
| Total cholesterol <200 mg/dl | 59% | 63% |
| Triglycerides <150 mg/dl | 50% | 61% |
⁎ p <0.0001 for each comparison.
† Only 8,022 diabetic patients and 1,999 nondiabetic subjects evaluated.
At baseline, there were more diabetic than nondiabetic patients in the group with atherothrombotic RFOs (74% of 12,416 patients with RFOs had diabetes). There were more nondiabetic subjects than diabetic patients in the following groups: CAD alone (64% of 30,410 nondiabetic subjects), cerebrovascular disease alone (66% of 11,354 patients), or PAD alone (62% of 3,210 patients). This difference was less apparent in patients with polyvascular disease: 59% of 5,719 patients with CAD/cerebrovascular disease, 53% of 3,197 patients with CAD/PAD, 56% of 794 patients with cerebrovascular disease/PAD, and 49% of 1,120 patients with CAD/cerebrovascular disease /PAD did not have diabetes.
The most commonly prescribed treatments for diabetes were sulfonylureas (45%) and biguanides (42%), followed by insulin (27%), glitazones (18%), and other drugs (11%). Fasting blood glucose was reported to be <126 mg/dl in 40% of diabetic patients. Overall, patients were receiving preventive treatments in line with current guidelines for patients with high cardiovascular risk, with no difference between groups ( Table 1 ).
One-year cardiovascular event rates were high, with 13% of patients having a major event. After adjustment for age, gender, hypertension, smoking, and cholesterol, 1-year cardiovascular event rates were higher in diabetic than in nondiabetic subjects ( Table 2 ). Risk of cardiovascular death (hazard ratio 1.45, 95% confidence interval [CI] 1.28 to 1.64, p <0.001), nonfatal myocardial infarction (hazard ratio 1.41, 95% CI 1.22 to 1.63, p <0.001), nonfatal stroke (hazard ratio 1.15, 95% CI 1.02 to 1.30, p = 0.03), and major adverse cardiovascular events (MACEs), including cardiovascular death, myocardial infarction, and stroke (hazard ratio 1.28, 95% CI 1.19 to 1.38, p <0.001) were increased. Incidence rates of all cardiovascular events were approximately 40% higher in diabetic patients. For diabetic patients with RFOs, the risk was significantly higher for nonfatal myocardial infarction (hazard ratio 2.20, 95% CI 1.19 to 4.08, p = 0.012) and MACEs (hazard ratio 1.52, 95% CI 1.11 to 2.08, p = 0.0095). For patients with EAD, rate of cardiovascular death increased with the number of diseased arterial sites and was higher in diabetic patients ( Figure 1 , Table 2 ). The highest rate of cardiovascular death was observed in patients with PAD and was higher in diabetic compared to nondiabetic patients ( Table 2 ). Overall, combined cardiovascular event rates were similar in patients with previous PAD and previous CAD ( Table 2 ). With the exception of cardiovascular death, a significant decrease in all event rates was observed according to the number of controlled risk factors in diabetic patients (p for trend <0.001) and nondiabetic patients (p for trend <0.01). Compared to patients with no controlled risk factors, when 3 of them were at or under the goals, rates of MACE were decreased 22% for diabetic and 29% for nondiabetic patients.
| Variable | Diabetic versus Nondiabetic (%) | ||||
|---|---|---|---|---|---|
| Cardiovascular Death | Nonfatal Myocardial Infarction | Nonfatal Stroke | MACE | MACE/Hospitalization | |
| All patients (n = 28,507 vs 36,470) | 1.9 versus 1.2 ⁎ | 1.3 versus 1.0 ⁎ | 1.7 versus 1.4 ⁎ | 3.8 versus 3.0 ⁎ | 12.0 versus 13.0 ⁎ |
| Patients with ≥3 risk factors only (n = 9,275 vs 3,141) | 0.7 versus 0.5 | 0.9 versus 0.3 † | 0.8 versus 0.7 | 2.2 versus 1.6 ‡ | 5.1 versus 5.3 |
| Patients with established atherothrombotic disease | |||||
| Patients with any site(s) (n = 19,232 vs 33,329) | 2.6 versus 1.5 ⁎ | 1.5 versus 1.0 ⁎ | 2.2 versus 1.6 ⁎ | 6.0 versus 4.0 ⁎ | 17 versus 13 ⁎ |
| Patients with 1 site (n = 16,003 vs 28,971) | 1.8 versus 1.1 ⁎ | 1.4 versus 1.0 ⁎ | 1.8 versus 1.3 ⁎ | 4.8 versus 3.3 ⁎ | 14 versus 12 ⁎ |
| Patients with 2 sites (n = 4,198 vs 5,511) | 3.0 versus 2.0 ⁎ | 2.1 versus 1.1 ⁎ | 3.0 versus 2.7 | 7.7 versus 5.5 ⁎ | 24 versus 19 ⁎ |
| Patients with 3 sites (n = 567 vs 553) | 4.6 versus 3.2 ⁎ | 2.5 versus 1.4 ⁎ | 4.6 versus 4.2 | 11 versus 7.1 ⁎ | 30 versus 24 ⁎ |
| Patients with a specific site | |||||
| Patients with coronary artery disease (n = 10,983 vs 19,427) | 2.3 versus 1.4 ⁎ | 1.8 versus 1.2 ⁎ | 1.6 versus 1.2 ⁎ | 4.6 versus 3.2 ⁎ | 18 versus 14 ⁎ |
| Patients with cerebrovascular disease (n = 3,809 vs 7,545) | 2.1 versus 1.4 | 1.5 versus 0.6 ⁎ | 4.2 versus 2.9 ⁎ | 6.4 versus 4.2 ⁎ | 17.0 versus 13 ⁎ |
| Patients with peripheral arterial disease (n = 1,211 vs 1,999) | 3.1 versus 1.7 ⁎ | 1.7 versus 1.0 | 1.7 versus 1.5 | 5.0 versus 3.5 ⁎ | 24 versus 20 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
