Composite Cardiovascular Disease Events Research Articles

Abstract 16746: Cardiovascular Disease Outcomes After Breast Cancer in Postmenopausal Women: Results From the Women’s Health Initiative

Introduction: A growing population of older breast cancer (BC) survivors may be at risk of cardiovascular disease (CVD). Pre-existing CVD risk factors may impact on subsequent development of CVD after BC among postmenopausal women. Objectives: (1) To describe baseline CVD risk factors among postmenopausal women with and without BC prior to diagnosis of BC; and (2) To examine independent associations of BC with individual and composite CVD events (i.e., the first occurrence of coronary heart disease [CHD], angina, coronary revascularization, congestive heart failure, peripheral arterial disease, and stroke) and mortality outcomes (i.e., all-cause, CVD, and CHD death) after BC adjusting for baseline characteristics and CVD risk factors. Methods: This prospective cohort study included 101,916 women in the Women’s Health Initiative (WHI) (including 4,340 women with invasive BC) aged 50-79 years without CVD at baseline (1993-1998) through December 2010. Over a period of 10 years after BC, CVD morbidity and mortality outcomes were identified and age-adjusted rates per 1,000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) from Cox models were determined for women who did and did not develop BC. Results: Regardless of BC status, baseline CVD risk factors prior to BC, such as smoking, hypertension, diabetes and hypercholesterolemia, were strong predictors of CVD outcomes in postmenopausal women. Multivariable Cox models revealed that women who developed BC (n = 4,340) had a similar risk of composite CVD (HR = 0.91, 95% CI, 0.82-1.02), but a higher risk of CHD (HR=1.33, 95% CI, 1.12-1.58), compared with women without BC (n = 97,576). Women aged 70-79 and on hormonal therapy at the WHI entry with localized BC during follow-up period had the highest CHD death rate. The results were similar after excluding women with baseline cancer at the WHI study entry. Conclusions: These results emphasize the great need for identification and timely management of pre-existing CVD risk factors for postmenopausal women with BC. CVD accounts for almost as many deaths as BC among women with localized disease, indicating that improved effort to prevent and treat CVD risk factors could improve survival of postmenopausal BC survivors.

Subcutaneous nodules are associated with cardiovascular events in patients with rheumatoid arthritis: results from a large US registry.

Subcutaneous nodules are the most common conspicuous extra-articular manifestation of rheumatoid arthritis (RA). Cardiovascular disease (CVD) is the leading cause of death in patients with RA. The objective of this study is to examine the possibility of a relationship between subcutaneous nodules and "first ever" cardiovascular disease event, i.e., myocardial infarction (MI), stroke, or cardiovascular death in a large registry-cohort of patients with RA. Patient information was collected from the CORRONA registry from October 2001 to September 2011. A total of 26,042 patients with RA were studied for the presence or absence of subcutaneous nodules. Cox proportional hazards regression models were constructed to estimate the hazard ratios (HR) for CVD events in relation to subcutaneous nodules at baseline. Three statistical models were used to examine the association between subcutaneous nodules and CVD: Model A adjusted for age and sex associated risk, model B adjusted for traditional CV risk factors, and model C adjusted for factors in models A and B plus underlying RA-specific measures. The definition of primary exposure was "subcutaneous nodules at baseline." A total of 3908 patients had subcutaneous nodules at baseline. Of the 566 total composite CVD events, 138 occurred in the group that had SCN at baseline. Incidence rate-ratio values (patients with subcutaneous nodules at baseline vs. no subcutaneous nodules at baseline) for composite CVD events, MI, stroke, and cardiovascular death were 1.55, 1.65, 1.37, and 1.68, respectively. Adjusted HR values (95% CI) for composite CVD events based on "subcutaneous nodules-status at baseline" (primary exposure) were as follows: 1.35 (1.11-1.63) for model A, 1.25 (1.03-1.52) for model B, and 1.03 (0.831-1.277) for model C. Subcutaneous nodules were associated with increased CVD events in RA. This association persisted after adjusting for age, sex, and traditional CV risk factors.

Association of cardiovascular health screening with mortality, clinical outcomes, and health care cost: A nationwide cohort study

ObjectiveTo determine whether a cardiovascular disease (CVD) health screening program is associated with CVD-related health conditions, incidence of cardiovascular events, mortality, healthcare utilization, and costs. MethodsCohort study of a 3% random sample of all Korea National Health Insurance members 40years of age or older and free of CVD or CVD-related health conditions was conducted. A total 443,337 study participants were followed-up from January 1, 2005 through December 31, 2010. ResultsIn primary analysis, the hazard ratios for CVD mortality, all-cause mortality, incident composite CVD events, myocardial infarction, cerebral infarction, and cerebral hemorrhage comparing participants who attended a screening exam during 2003–2004 compared to those who did not were 0.58 (95% CI: 0.53–0.63), 0.62 (95% CI: 0.60–0.64), 0.82 (95% CI: 0.78–0.85), 0.84 (95% CI: 0.75–0.93), 0.84 (95% CI: 0.79–0.89), and 0.73 (95% CI: 0.67–0.80), respectively. Screening attenders had higher rates of newly diagnosed hypertension, diabetes mellitus, and dyslipidemia, lower inpatient days of stay and cost, and lower outpatient cost compared to non-attenders. ConclusionsParticipation in CVD health screening was associated with lower rates of CVD, all-cause mortality, and CVD events, higher detection of CVD-related health conditions, and lower healthcare utilization and costs.

Walking Disability Raises Risk of CVD, Diabetes Problems

Walking Disability Raises Risk of CVD, Diabetes Problems

Risk factors for cardiovascular disease across the spectrum of older age: The Cardiovascular Health Study

Objective: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age. Methods: Participants (n = 4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65–74, 75–84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP). Results: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65–74, 75–84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65–74, 75–84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45). Conclusions: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.

Variation in prescribing of lipid-lowering medication in primary care is associated with incidence of cardiovascular disease and all-cause mortality in people with screen-detected diabetes: findings from the ADDITION-Denmark trial.

AimsTo examine variation between general practices in the prescription of lipid-lowering treatment to people with screen-detected Type 2 diabetes, and associations with practice and participant characteristics and risk of cardiovascular events and all-cause mortality.MethodsObservational cohort analysis of data from 1533 people with screen-detected Type 2 diabetes aged 40–69 years from the ADDITION-Denmark study. One hundred and seventy-four general practices were cluster randomized to receive: (1) routine diabetes care according to national guidelines (623 individuals), or (2) intensive multifactorial target-driven management (910 individuals). Multivariable logistic regression was used to quantify the association between the proportion of individuals in each practice who redeemed prescriptions for lipid-lowering medication in the two years following diabetes diagnosis and a composite cardiovascular disease (CVD) outcome, adjusting for age, sex, prevalent chronic disease, baseline CVD risk factors, smoking and lipid-lowering medication, and follow-up time.ResultsThe proportion of individuals treated with lipid-lowering medication varied widely between practices (0–100%). There were 118 CVD events over 9431 person-years of follow-up. For the whole trial cohort, the risk of CVD was significantly higher in practices in the lowest compared with the highest quartile for prescribing lipid-lowering medication [adjusted odds ratio (OR) 3.4, 95% confidence interval (CI) 1.6–7.3]. Similar trends were found for all-cause mortality.ConclusionsMore frequent prescription of lipid-lowering treatment was associated with a lower incidence of CVD and all-cause mortality. Improved understanding of factors underlying practice variation in prescribing may enable more frequent use of lipid-lowering treatment. The results highlight the benefits of intensive treatment of people with screen-detected diabetes (Clinical Trials Registry No; NCT 00237549).What's new Despite the well-established cardioprotective benefits of lipid-lowering treatment in Type 2 diabetes, evidence suggests large variations in statin use in primary care. Variation may be particularly high among people with screen-detected diabetes because general practitioners (GPs) might be reluctant to prescribe cardioprotective drugs for asymptomatic patients. There was wide variation in the prescription of lipid-lowering treatment among people with screen-detected diabetes in Danish primary care; more frequent prescription of lipid-lowering treatment was associated with a lower incidence of cardiovascular disease and all-cause mortality. More work is needed to improve understanding of the factors underlying practice variation in prescribing in order to encourage GPs to offer lipid-lowering treatment to this high-risk group.

Abstract P188: Urinary Sodium and Potassium Excretion and Cardiovascular Diseases in Patients with Chronic Kidney Disease: the Chronic Renal Insufficiency Cohort study

Introduction: Chronic kidney disease (CKD) patients are at an increased risk of cardiovascular disease (CVD) compared to the general population. Prior studies have produced contradictory results for the associations of sodium and potassium intake with the risk of CVD. In addition, these associations have not been investigated in patients with CKD. Hypothesis: We assessed the prospective associations between urinary sodium and potassium excretion and CVD event rates among patients with CKD. Methods: The Chronic Renal Insufficiency Cohort Study (CRIC) is a prospective cohort study of 3,939 participants with CKD from seven locations in the United States. Dietary sodium and potassium intake are assessed by averaging three 24-hour urinary measures and calibrating to sex-specific mean 24-hour urinary creatinine excretion. Composite CVD event is defined as myocardial infarction (MI), stroke, or congestive heart failure (CHF). CVD events are reported every six months and confirmed by medical record adjudication. Results: Over an average 6.5 years of follow-up, 660 CVD events were observed. The highest quartile (>197.7 mmol/24 hours) of adjusted sodium excretion had a hazard ratio (HR) of 1.52 (95% confidence interval 1.23, 1.88; p for trend across quartiles 70.5 mmol/24 hours) of adjusted potassium excretion had a HR of 1.46 (1.14, 1.87; p for trend across quartiles 0.0009) for composite CVD events compared to the lowest quartile (≤41.2 mmol/24 hours). When modeled continuously, every 100-mmol/24 hours higher adjusted sodium excretion was associated with an increased HR of 1.25 (1.14, 1.36) for composite CVD events, 1.25 (1.13, 1.39) for CHF, 1.32 (1.08, 1.61) for stroke, and 1.09 (0.93, 1.27) for MI. In addition, every 50-mmol/24 hour higher adjusted potassium intake was associated with an increased HR of 1.25 (1.10, 1.41) for composite CVD events, 1.32 (1.15, 1.52) for CHF, 1.11 (0.81, 1.54) for stroke, and 1.00 (0.79, 1.27) for MI. Conclusions: Our study found that high dietary sodium and potassium are both associated with an increased risk of CVD among patients with CKD. These findings suggest that reductions in high dietary sodium and potassium intake might reduce the risk of CVD among patients with CKD.

Effects of antihypertensive treatment in Asian populations: A meta-analysis of prospective randomized controlled studies (CARdiovascular protectioN group in Asia: CARNA)

To examine the effects of antihypertensive treatment on cardiovascular disease (CVD) in Asian populations, we systematically evaluated prospective randomized studies carried out in Asia (1991–2013). We identified 18 trials with 23,215 and 21,986 hypertensive patients in the intervention (ie, strict blood pressure [BP] lowering or add-on treatment) and reference groups, respectively (mean age, 65 years; follow-up duration, 3.2 years). Analysis was performed through 1) first subgroup: eight trials that compared active antihypertensive treatment with placebo or intensive with less intensive BP control and 2) second subgroup: 10 trials that compared different antihypertensive treatments. In the first subgroup analysis, BP was reduced from 160.3/87.3 mm Hg to 140.2/78.4 mm Hg in the intervention group with a −6.7/−2.2 mm Hg (P < .001) greater BP reduction than the reference group. Compared with the reference group, the intervention group had a lower risk of composite CVD events (odd ratio [OR], 0.73; 95% confidence interval [CI], 0.66–0.81), myocardial infarction (OR, 0.79; 95% CI, 0.63–1.0), stroke (OR, 0.71; 95% CI, 0.63–0.80), and CVD mortality (OR, 0.81; 95% CI, 0.68–0.97; all P ≤ .05). In the second subgroup analysis, no difference was found for any outcome between renin-angiotensin blockers and calcium-channel blockers or diuretics. The meta-regression line among the 18 trials indicated that a 10 mm Hg reduction in systolic BP was associated with a reduced risk for composite CVD events (−39.5%) and stroke (−30.0%). Our meta-analysis shows a benefit when a BP target of less than 140/80 mm Hg is achieved in Asian hypertensives. BP reduction itself, regardless of BP lowering agents, is important for achieving CVD risk reduction.

Effects of Valsartan Versus Amlodipine in Diabetic Hypertensive Patients With or Without Previous Cardiovascular Disease

Recently, we reported that angiotensin II receptor blocker (ARB), valsartan, and calcium channel blocker (CCB), amlodipine, had similar effects on the prevention of cardiovascular disease (CVD) events in diabetic hypertensive patients. We assessed the difference of cardiovascular protective effects between ARB and CCB in patients with and without previous CVD, respectively. A total of 1,150 Japanese diabetic hypertensive patients were randomized to either valsartan or amlodipine treatment arms, which were additionally divided into 2 groups according to the presence of previous CVD at baseline (without CVD, n= 818; with CVD, n= 332). The primary composite outcomes were sudden cardiac death, acute myocardial infarction, stroke, coronary revascularization, or hospitalization for heart failure. The incidence of primary end point events in patients with previous CVD was 3.5-times greater than that in patients without previous CVD (64.1 vs 17.9/1,000 person-years). The ARB- and the CCB-based treatment arms showed similar incidence of composite CVD events in both patients without previous CVD (hazard ratio [HR] 1.35, 95% confidence interval [CI] 0.76 to 2.40) and those with previous CVD (HR 0.79, 95% CI 0.48 to 1.31). The ARB-treatment arm showed less incidence of stroke compared with the CCB-based treatment arm in patients with previous CVD (HR 0.24, 95% CI 0.05 to 1.11, p= 0.068), whereas the 2 treatment arms showed similar incidence of stroke in patients without previous CVD (HR 1.52, 95% CI 0.59 to 3.91). In conclusion, the ARB- and the CCB-based treatments exerted similar protective effects of CVD events regardless of the presence of previous CVD. For stroke events, the ARB may have more protective effects than the CCB in diabetic hypertensive patients with previous CVD.

Short‐Term Perioperative All‐Cause Mortality and Cardiovascular Events in Women With Systemic Lupus Erythematosus

Persons with systemic lupus erythematosus (SLE) are at an increased risk of cardiovascular disease (CVD) events, but this excess CVD burden in the perioperative setting is yet to be determined. We aimed to determine the risk of perioperative short-term all-cause mortality and CVD events among women with SLE compared to those without SLE. We conducted a cross-sectional analysis of pooled hospital discharge data of the Nationwide Inpatient Sample from 1998-2002. We abstracted diseases and procedures using International Classification of Diseases, Ninth Revision, Clinical Modification codes. The principal procedure was categorized into either a low, intermediate, or high risk level. Survey logistic regression adjusting for potential confounders provided estimates for stratum-specific odds of adverse events in women with SLE relative to those without SLE for each procedure risk level. All-cause mortality was significantly greater among women with SLE having a low- (odds ratio [OR] 1.54, 95% confidence interval [95% CI] 1.00-2.37) or a high-risk principal procedure (OR 2.52, 95% CI 1.34-4.75) relative to women without SLE, but did not differ significantly among persons with intermediate-risk procedures. Women with SLE with a low-risk procedure were also more likely to experience a composite CVD event relative to women without SLE (OR 1.40, 95% CI 1.04-1.87). Women with SLE are at an increased risk for short-term perioperative adverse events. These results highlight a need for greater scrutiny during perioperative evaluation and management of women with SLE.

Associations among Darbepoetin-α, CD34+ Cells and Cardiovascular Disease Events in Patients on Hemodialysis

Background and Objectives: Erythropoiesis-stimulating agents (ESAs) might moderate circulating CD34-positive hematopoietic stem (CD34⁺) cells. We assessed associations between ESA therapy and CD34⁺ cells and their impact on cardiovascular disease (CVD) events in patients on prevalent hemodialysis (HD). Design, Setting, Participants and Measurements: We analyzed 95 patients on prevalent HD who received the ESAs epoetin-β (n = 22), darbepoetin-α (n = 60), or neither (control; no ESA, n = 13). Baseline values for CD34⁺ cells, high-sensitivity C-reactive protein, interleukin-6, vascular endothelial growth factor, inter-cellular adhesion molecule-1, and carotid intima-media thickness were determined. The numbers of CD34⁺/erythropoietin receptor (EPOR)⁺ cells were determined in 35 and 8 patients in the darbepoetin-α and control groups, respectively. CD34⁺ cells were counted after 6 and 12 months of darbepoetin-α treatment (n = 35). All patients were followed up for a mean of 28 months. Results: Hemoglobin levels were lower, carotid intima-media thickness was more pronounced, and the ESA dose was higher in patients with a low, than with a high, CD34⁺ cell count. The ratio of CD34⁺/EPOR⁺ to CD34⁺ cells positively correlated with the darbepoetin-α dose. A low, but not a high, dose of darbepoetin-α for 6 and 12 months was associated with more CD34⁺ cells. Although high-dose darbepoetin-α therapy was an independent predictor of composite CVD events, this association disappeared when adjusted for the CD34⁺ cell count with other confounders. Conclusions: High-dose ESA therapy is associated with a low CD34⁺ cell count and comprises a risk factor for CVD events in patients on prevalent HD.

Oxidized high-density lipoprotein as a risk factor for cardiovascular events in prevalent hemodialysis patients

Background and objectives Here, we assessed the impact of oxidized high-density lipoprotein (oxHDL), dysfunctional HDL, on mortality and cardiovascular disease (CVD) events in prevalent HD patients and compared oxHDL to interleukin-6 (IL-6), a strong predictor of CVD events in HD patients. Design, setting, participants, and measurements This prospective study examined a cohort of prevalent HD patients ( n = 412). Blood samples were obtained at baseline to measure lipids, high-sensitive C-reactive protein (hsCRP), IL-6, oxidized low-density lipoprotein, N-terminal pro B-type natriuretic peptide, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase, adiponectin, and oxHDL. Carotid intima-media thickness (CIMT) was assessed at baseline and 3-year follow-up. Nutritional status was assessed by subjective global assessment (SGA), body mass index, and geriatric nutritional risk index (GNRI). After the baseline assessment, study patients were prospectively followed up (mean observational period, 40 months). Results At baseline, patients with high oxHDL had a worse nutritional state and higher HDL-cholesterol (HDL-chol), ICAM-1, and adiponectin levels and a higher oxHDL/HDL-chol ratio than low oxHDL patients. A combination of high oxHDL and high IL-6 was significantly associated with increased CIMT at baseline and a larger increase in CIMT at 3-year follow-up. High oxHDL did not predict all-cause mortality; however, it was significantly associated with CVD-related mortality and composite CVD events, particularly with concomitant high IL-6. These associations were confirmed in multivariate Cox hazard models adjusted with confounding variables. Conclusions High oxHDL, particularly with concomitant high IL-6, may be associated with an increased risk of CVD events and CVD-related mortality in prevalent HD patients.

Antihypertensive Treatment and Secondary Prevention of Cardiovascular Disease Events Among Persons Without Hypertension

Cardiovascular disease (CVD) risk increases beginning at systolic blood pressure levels of 115 mm Hg. Use of antihypertensive medications among patients with a history of CVD or diabetes and without hypertension has been debated. To evaluate the effect of antihypertensive treatment on secondary prevention of CVD events and all-cause mortality among persons without clinically defined hypertension. Meta-analysis with systematic search of MEDLINE (1950 to week 3 of January 2011), EMBASE, and the Cochrane Collaboration Central Register of Controlled Clinical Trials and manual examination of references in selected articles and studies. From 874 potentially relevant publications, 25 trials that fulfilled the predetermined inclusion and exclusion criteria were included in the meta-analysis. Information on participant characteristics, trial design and duration, treatment drug, dose, control, and clinical events were extracted using a standardized protocol. Outcomes included stroke, myocardial infarction (MI), congestive heart failure (CHF), composite CVD outcomes, CVD mortality, and all-cause mortality. Compared with controls, participants receiving antihypertensive medications had a pooled relative risk of 0.77 (95% confidence interval [CI], 0.61 to 0.98) for stroke, 0.80 (95% CI, 0.69 to 0.93) for MI, 0.71 (95% CI, 0.65 to 0.77) for CHF, 0.85 (95% CI, 0.80 to 0.90) for composite CVD events, 0.83 (95% CI, 0.69 to 0.99) for CVD mortality, and 0.87 (95% CI, 0.80 to 0.95) for all-cause mortality from random-effects models. The corresponding absolute risk reductions per 1000 persons were -7.7 (95% CI, -15.2 to -0.3) for stroke, -13.3 (95% CI, -28.4 to 1.7) for MI, -43.6 (95% CI, -65.2 to -22.0) for CHF events, -27.1 (95% CI, -40.3 to -13.9) for composite CVD events, -15.4 (95% CI, -32.5 to 1.7) for CVD mortality, and -13.7 (95% CI, -24.6 to -2.8) for all-cause mortality. Results did not differ according to trial characteristics or subgroups defined by clinical history. Among patients with clinical history of CVD but without hypertension, antihypertensive treatment was associated with decreased risk of stroke, CHF, composite CVD events, and all-cause mortality. Additional randomized trial data are necessary to assess these outcomes in patients without CVD clinical recommendations.

Piecing the Puzzle Together: ACCORDing to Whom?

For many people, the Diabetes Control and Complications Trial (DCCT) report 15 yr ago ended controversy about the relationship between glucose control and microvascular complications (1). At the time, this debate was a one-piece puzzle, seemingly solved by the study. However, to others, the puzzle was more complex. Because DCCT was a type 1 study, concerns were raised that the weight gain often seen with intensive therapy could result in more cardiovascular events in patients with type 2 diabetes. These concerns were alleviated with the report of the United Kingdom Prospective Diabetes Study (UKPDS) 10 yr ago (2). Like the DCCT, improvements in glycemia resulted in a reduced microvascular burden, but in this older type 2 population, there was also a nonsignificant 16% reduction in myocardial infarctions. Yet another piece to the puzzle was added with a Japanese report confirming the relationship between tight glucose control and microvascular complications. This trial also noted twice the number of macrovascular events in the conventional therapy group as opposed to those intensively managed, but the number of events was small (1.3 vs. 0.6 events per 100 patient-years), as would have been expected in this relatively young cohort (3). It was surprising to some that intensive therapy of glycemia did not more convincingly reduce cardiovascular events in type 2 diabetes. Some argued we were using the wrong agents and suggested that perhaps using a novel drug class such as thiazolidinediones would improve cardiovascular event rates. Unfortunately, the use of pioglitazone in the PROactive study did not improve a composite cardiovascular disease (CVD) primary endpoint (4), and interpretation of the study results generated much controversy. Perhaps a better way to solve the puzzle is by using a more comprehensive strategy of treating not just glycemia but also blood pressure and lipids in patients with type 2 diabetes. The group from the Steno Diabetes Center recently published their 13.3-yr follow-up of 160 subjects with type 2 diabetes and microalbuminuria (5). The results after completion of the intervention addressing all three risk factors, including behavior modification with more physical activity, were reported in 2003 after 7.8 yr of treatment (6). At that time, it was noted that the multicomponent intervention reduced CVD and microvascular events by about 50%. The more recent report, which was simply a follow-up observation study without active intervention, noted that the intensive therapy group had a reduction in mortality (hazard ratio 0.54; 95% confidence interval 0.32–0.89; P 0.02) (5). Intensive therapy was also associated with a lower risk of CVD deaths and events as well as reductions in the microvascular outcomes of end-stage renal disease and need for retinal photocoagulation. Before leaving this part of the puzzle, several points need to be emphasized. First, the Steno-2 population is a very specific population: white, microalbuminuric patients who at the beginning of the study were 55 yr old. For glycemic control of the intensive therapy group, fewer than 20% were able to achieve the target of less than 6.5% hemoglobin A1c (A1C), and overall mean A1C was about 8% for these subjects during both the intervention and the follow-up (5, 6). The difference in A1C of 0.7% between these two groups during the intervention likely explains part, if not most, of the microvascular benefit. Importantly, like the Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up of the type 1 DCCT cohort (7), there was continuing microvascular benefit years later for those patients randomized to intensive therapy, despite the fact that A1C levels were no different after the intervention. Besides the importance of metabolic memory, which was initially described for the EDIC patients with type 1 diabetes, this effect further speaks to the clinical importance that any improvement in glycemic control will be important, even if A1C levels are not at target. The Steno-2 conventionally treated patients also remind us just how poor the prognosis of type 2 diabetes with microalbuminuria really is; at the end of the follow-up period, the rate of death was 50% (5). The good news is there was an absolute risk reduction of 20% for death from any cause and 29% for any cardiovascular event with this intensive therapy. It is difficult to quantify the contribution of each component of therapy to the

Angiopoietin‐2 levels as a biomarker of cardiovascular risk in patients with hypertension

Background. Abnormal angiogenesis is a pathophysiological component of cardiovascular disease (CVD), where circulating biomarkers of angiogenesis are associated with increased CVD risk in hypertension. We hypothesized that raised levels of angiopoietin (Ang)‐1 and ‐2 would predict events in patients with hypertension treated for CVD.Methods. We measured angiopoietin levels by enzyme‐linked immunosorbent assay (ELISA) in 251 hypertensive participants (85% male; mean age 63.5 years; 192 free of previous CVD events). Plasma angiopoietin levels were related to the subsequent CVD events over a mean follow‐up period of 57.1 (SD 11) months.Results. There were 11 cases of myocardial infarction (MI) and 18 cases of stroke during follow‐up. Ang‐2 was a significant predictor of MI, stroke, and composite CVD events, with the greatest event‐free survival amongst those in the lower tertile (all P<0.05). Ang‐1 was not predictive of CVD outcomes. Of CVD risk factors at recruitment (blood pressure, body mass index, plasma glucose, serum and high‐density lipoprotein (HDL)‐cholesterol), Ang‐2 was the only discriminator of incident MI (area under curve (AUC) = 73%, P = 0.013), where a value >4.3 ng/mL optimized specificity and sensitivity. On Cox regression analysis (CVD treatments and risk factors), raised Ang‐2 was an independent predictor of MI, P<0.05, but not stroke or composite outcomes.Conclusions. Among patients with hypertension, raised levels of Ang‐2 were predictive of MI, and further study is warranted to evaluate the use of this biomarker in CVD management, risk stratification, and prevention.