Early Initiation of Sacubitril/Valsartan in Patients With Acute Heart Failure and Renal Dysfunction: An Analysis of the TRANSITION Study.

BACKGROUND: Treatment of patients with heart failure with reduced ejection fraction (HFrEF) and renal dysfunction (RD) is challenging owing to the risk of further deterioration in renal function, especially after acute decompensated HF (ADHF). METHODS AND RESULTS: We assessed the effect of RD (estimated glomerular filtration rate of ≥30 to <60 mL/min/1.73 m2) on initiation, up-titration, and tolerability of sacubitril/valsartan in hemodynamically stabilized patients with HFrEF admitted for ADHF (RD, n = 476; non-RD, n = 483). At week 10, the target dose of sacubitril/valsartan (97/103 mg twice daily) was achieved by 42% patients in RD subgroup vs 54% in non-RD patients (P < .001). Sacubitril/valsartan was associated with greater estimated glomerular filtration rate improvements in RD subgroup than non-RD (change from baseline least squares mean 4.1 mL/min/1.73 m2, 95% confidence interval 2.2-6.1, P < .001). Cardiac biomarkers improved significantly in both subgroups; however, compared with the RD subgroup, the improvement was greater in those without RD (N-terminal pro-brain natriuretic peptide, -28.6% vs -44.8%, high-sensitivity troponin T -20.3% vs -33.9%) (P < .001). Patients in the RD subgroup compared with those without RD experienced higher rates of hyperkalemia (16.3% vs 6.5%, P < .001), investigator-reported cardiac failure (9.7% vs 5.6%, P = .029), and renal impairment (6.4% vs 2.1%, P = .002). CONCLUSIONS: Most patients with HFrEF and concomitant RD hospitalized for ADHF tolerated early initiation of sacubitril/valsartan and showed significant improvements in estimated glomerular filtration rate and cardiac biomarkers. CLINICAL TRIAL REGISTRATION: NCT02661217.

Vitamin D and progression of carotid intima-media thickness in HIV-positive Canadians.

OBJECTIVES: Based on a growing body of evidence implicating low vitamin D status in the development of cardiovascular disease (CVD), we hypothesized that in Canadian HIV-positive adults, low 25-hydroxyvitamin D (25(OH)D) concentration would be associated with increased subclinical vascular disease progression. METHODS: We prospectively studied the relationship between baseline 25(OH)D and subsequent progression of carotid intima-media thickness (CIMT) between 2002 and 2011, in the Canadian HIV Vascular Study using stored blood specimens. RESULTS: Of the 128 participants, 89.1% were men, the mean age (standard deviation [SD]) was 46.5 (8.2) years, 93.8% were white, and 36.7% were current smokers. Mean (SD) annual CIMT follow-up was 5.9 (1.8) years (maximum 8.5 years), providing approximately 750 patient-years of follow-up. Mean (SD) CIMT progression was 0.027 (0.030) mm/year. Mean (SD) 25(OH)D was 95.0 (46.9) nmol/L. Only 13.3% of participants were vitamin D deficient (25(OH)D < 50 nmol/L), whereas 61.7% had a 25(OH)D exceeding the sufficiency threshold (75 nmol/L). Vitamin D quartiles were inversely associated with body mass index (BMI) (P = 0.034), total cholesterol to high-density lipoprotein (HDL) cholesterol ratio (P = 0.001) and parathyroid hormone concentration (P = 0.003), but not efavirenz exposure (P = 0.141). In linear regression analyses, baseline 25(OH)D as a continuous variable was inversely associated with CIMT progression in univariable (P < 0.001) and multivariable (P < 0.001) models. CONCLUSIONS: Baseline 25(OH)D was associated with CIMT progression in this relatively vitamin D replete, predominately white and male, Canadian HIV-positive population. Future research needs to establish causality as this may warrant more targeted screening or supplementation.

Novel approaches in primary cardiovascular disease prevention: the HOPE-3 trial rationale, design, and participants' baseline characteristics

AbstractBACKGROUND:Cholesterol and blood pressure (BP) can be effectively and safely lowered with statin drugs and BP-lowering drugs, reducing major cardiovascular (CV) events by 20%-30% within 5 years in high-risk individuals. However, there are limited data in lower-risk populations. The Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial is evaluating whether cholesterol lowering with a statin drug, BP lowering with low doses of 2 antihypertensive agents, and their combination safely reduce major CV events in individuals at intermediate risk who have had no previous vascular events and have average cholesterol and BP levels.METHODS:A total of 12,705 women 65 years or older and men 55 years or older with at least 1 CV risk factor, no known CV disease, and without any clear indication or contraindication to the study drugs were randomized to rosuvastatin 10 mg/d or placebo and to candesartan/hydrochlorothiazide 16/12.5 mg/d or placebo (2 × 2 factorial design) and will be followed for a mean of 5.8 years. The coprimary study outcomes are the composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke and the composite of CV death, nonfatal MI, nonfatal stroke, resuscitated cardiac arrest, heart failure, and arterial revascularization.RESULTS:Participants were recruited from 21 countries in North America, South America, Europe, Asia, and Australia. Mean age at randomization was 66 years and 46% were women.CONCLUSIONS:The HOPE-3 trial will provide new information on cholesterol and BP lowering in intermediate-risk populations with average cholesterol and BP levels and is expected to inform approaches to primary prevention worldwide (HOPE-3 ClinicalTrials.govNCT00468923).

Low resting heart rates are associated with new-onset atrial fibrillation in patients with vascular disease: results of the ONTARGET/TRANSCEND studies.

BACKGROUND: Elevated systolic blood pressure (SBP) and high resting heart rate (HR) are associated with cardiovascular end-points. Although the association between atrial fibrillation (AF) and SBP is well established, the relation between AF and HR remains unclear. METHODS: In patients from the ONTARGET and TRANSCEND studies with high cardiovascular disease risk (n = 27 064), new-onset AF was evaluated in relation to mean SBP, visit-to-visit variation in SBP (SBP-CV; i.e. SD/mean × 100%), mean HR and visit-to-visit variation in HR (HR-CV). RESULTS: Low mean HR (P < 0.0001) and high SBP (P = 0.0021) were associated with incident AF. High SBP-CV (P = 0.031) and HR-CV (P < 0.0001) were also associated with incident AF. After adjustment for confounders, SBP and SBP-CV were no longer significantly associated with AF. The detrimental effect of low HR was particularly evident in subjects who were not receiving treatment with beta-blockers (P = 0.014 for interaction between beta-blocker use and mean HR). In addition to low HR, high HR-CV and high SBP had additive effects on incident AF. CONCLUSIONS: Low mean HR (<60 beats min(-1) ) is independently associated with incident AF, and low HR-CV and high SBP further increase the incidence of new-onset AF in patients at high risk of cardiovascular disease.

Resting heart rate is associated with renal disease outcomes in patients with vascular disease: results of the ONTARGET and TRANSCEND studies.

BACKGROUND: Resting heart rate (RHR) is associated with cardiovascular disease outcomes in high-risk patients. It is not known whether RHR is predictive of renal outcomes such as albuminuria, end-stage renal disease (ESRD) or doubling of creatinine. We evaluated whether RHR could predict renal endpoints in patients at a high risk of cardiovascular disease. We also tested the effects of RHR at different levels of systolic blood pressure (SBP). METHODS: We analysed data from 28 757 patients in the ONTARGET and TRANSCEND trials. RHR and SBP were available for a mean of 4.9 ± 0.4 visits (range 3-5) within the first 2 years of the studies. Albuminuria was determined at baseline, at 2 years and at study end. RESULTS: Mean RHR was predictive of incident micro-albuminuria [hazard ratio (HR) for RHR ≥80 vs. <60 beats min(-1) 1.49, 95% confidence interval (CI) 1.29-1.71, P < 0.0001], incident macro-albuminuria (HR 1.84, 95% CI 1.39-2.42, P < 0.0001), doubling of creatinine (HR 1.47, 95% CI 1.00-2.17, P = 0.050) and ESRD (HR 1.78, 95% CI 1.00-3.16, P = 0.050), and the combined renal end-point (HR 1.51, 95% CI 1.32-1.74, P < 0.0001). Associations were robust at SBPs from <120 to ≥150 mmHg, with the lowest risk at a SBP of 130-140 mmHg. CONCLUSION: Resting heart rate is a potent predictor of these renal outcomes, as well as their combination, in patients with cardiovascular disease. RHR at all SBP levels should be considered as a possible renal disease risk predictor and should be investigated as a treatment target with RHR-reducing agents.

A comparison of the assessment and management of cardiometabolic risk in patients with and without type 2 diabetes mellitus in Canadian primary care.

AIM: To investigate the cardiometabolic risk (CMR) assessment and management patterns for individuals with and without type 2 diabetes mellitus (T2DM) in Canadian primary care practices. METHODS: Between April 2011 and March 2012, physicians from 9 primary care teams and 88 traditional non-team practices completed a practice assessment on the management of 2461 patients >40 years old with no clinical evidence of cardiovascular disease and diagnosed with at least one of the following risk factor-T2DM, dyslipidaemia or hypertension. RESULTS: There were 1304 individuals with T2DM and 1157 without. Pharmacotherapy to manage hyperglycaemia, dyslipidaemia and hypertension was widely prescribed. Fifty-eight percent of individuals with T2DM had a glycated haemoglobin (HbA1c) ≤7.0%. Amongst individuals with dyslipidaemia, median low-density lipoprotein cholesterol (LDL-C) was 1.8 mmol/l for those with T2DM and 2.8 mmol/l for those without. Amongst individuals with hypertension, 30% of those with T2DM achieved the <130/80 mmHg target, whereas 60% of those without met the <140/90 mmHg target. The composite glycaemic, LDL-C and blood pressure (BP) target outcome was achieved by 12% of individuals with T2DM. Only 17% of individuals with T2DM and 11% without were advised to increase their physical activity. Dietary modifications were recommended to 32 and 10% of those with and without T2DM, respectively. CONCLUSIONS: Patients at elevated CMR were suboptimally managed in the primary care practices surveyed. There was low attainment of recommended therapeutic glycaemic, lipid and BP targets. Advice on healthy lifestyle changes was infrequently dispensed, representing a missed opportunity to educate patients on the long-term benefits of lifestyle modification.

Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.

Increased cardiovascular risk after pre-eclampsia in women with dysglycaemia.

AIMS: Compared with women with uncomplicated pregnancies, women with a history of pre-eclampsia have two to five times the risk of cardiovascular disease. It is not known whether this risk is related to albuminuria, a known cardiovascular risk factor that is part of the definition of pre-eclampsia and that often persists after delivery. Our objective was to determine if the high risk of cardiovascular disease in women with pre-eclampsia is accounted for by known cardiovascular risk factors including albuminuria. METHODS: We performed a cross-sectional analysis of 4080 dysglycaemic women enrolled in a large randomized controlled trial who provided an obstetric history and had at least one delivery. Blood pressure, height, weight, waist circumference and hip circumference were measured. An oral glucose tolerance test, lipids, an electrocardiogram and an albumin/creatinine ratio from a first morning urine sample were obtained. RESULTS: There were 3613 women with no history of pre-eclampsia during their pregnancies, 108 with severe pre-eclampsia and 359 with non-severe pre-eclampsia. Women with a history of severe pre-eclampsia had higher rates of previous cardiovascular disease than women with non-severe pre-eclampsia or women without pre-eclampsia (87, 72 and 72%, P = 0.0019). The high risk of previous cardiovascular disease in women with a history of severe pre-eclampsia (odds ratio 2.67, 95% CI 1.52-4.70) persisted after adjustment for albuminuria (odds ratio 2.74, 95% CI 1.55-4.83) and also after adjusting for other covariates including albuminuria (odds ratio 3.03, 95% CI 1.69-5.44). CONCLUSION: Even after accounting for cardiovascular risk factors including albuminuria, a history of severe pre-eclampsia is independently associated with a threefold higher risk of cardiovascular disease.

Risk of premature stroke in recent immigrants (PRESARIO): population-based matched cohort study.

BACKGROUND: New immigrants to North America, most of whom are under age 50 years, exhibit fewer risk factors for cardiovascular disease than their native-born counterparts, yet the stress of resettlement may conceivably place them at higher risk of stroke. We determined the risk of acute stroke associated with recency of immigration. METHODS: We completed a population-based matched cohort study in Ontario, the largest province in Canada, from April 1, 1995, to March 31, 2007. Overall, 965,829 new immigrants were matched to 3,272,393 long-term residents by year of birth, sex, and location. New immigrants were identified as new recipients of universally available public health insurance, and long-term residents were those insured for 5 years or longer. RESULTS: The mean age of the participants at study entry was about 34 years and the total number of observed strokes was 6,216 after a median duration of follow-up of about 6 years. The incidence rate of acute stroke was 1.69 per 10,000 person-years among new immigrants and 2.56 per 10,000 person-years among long-term residents (crude hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.62-0.71). After adjusting for age, income quintile, urban vs rural residence, history of hypertension, diabetes mellitus and smoking, and number of health insurance claims, the HR for stroke was 0.69 (95% CI 0.64-0.74). Similar risk estimates were seen for both ischemic and hemorrhagic stroke subtypes. CONCLUSION: New immigrants appear to be at lower risk of premature acute stroke than long-term residents. This finding does not appear to be explained by the availability of health care services or income level.

Myocardial infarction associated with recency of immigration to Ontario.

BACKGROUND: New immigrants to North America exhibit lower rates of obesity and hypertension than their native-born counterparts. Whether this is reflected by a lower relative risk of acute myocardial infarction (AMI) is not known. OBJECTIVE: To determine the risk of AMI among new immigrants compared to long-term residents, and, among those who develop AMI, their short- and long-term mortality rate. DESIGN: Population-based, matched, retrospective cohort study. SETTING: Entire province of Ontario, the most populated province in Canada, from 1 April 1995 to 31 March 2007. PARTICIPANTS: A total of 965,829 new immigrants were matched to 3,272,393 long-term residents by year of birth, sex and geographic location. MEASUREMENTS: The main study outcome was hospitalization with a most responsible diagnosis of AMI. Secondary study outcomes among those who sustained an AMI were in-hospital, 30-day and 1-year mortality. RESULTS: The mean age of the participants at study entry was approximately 34 years. The incidence rate of AMI was 4.14 per 10,000 person-years among new immigrants and 6.61 per 10,000 person-years among long-term residents. After adjusting for age, income quintile, urban vs. rural residence, history of hypertension, diabetes mellitus and smoking and number of health insurance claims, the hazard ratio for AMI was 0.66 [95% confidence interval (CI): 0.63-0.69]. CONCLUSION: New immigrants appear to be at lower risk of AMI than long-term residents. This finding does not appear to be explained by the availability of health-care services or income level.

Cardiovascular risk factors and non-invasive assessment of subclinical atherosclerosis in youth.

UNLABELLED: Our understanding of the natural history of atherosclerosis in childhood and its response to cardiovascular (CV) risk factor reduction have been hampered by the lack of a reliable, non-invasive measure of atherosclerosis. Carotid intima media thickness (IMT), a surrogate marker of atherosclerosis in adults, is increased in youth heterozygous for familial hypercholesterolemia (FH) and declines with lipid lowering pharmacotherapy. The age at which vascular changes can be reliably identified using IMT and the influence of CV risk factors beyond FH on IMT remains unclear. OBJECTIVE: To examine the influence of demographic, family history, anthropometric characteristics and traditional CV risk factors on IMT in children 5-16 years of age (mean age 11 year). METHODS: In a cross-sectional study, we assessed IMT in 148 children (51 with elevated low density lipoprotein (LDL)-cholesterol, 44 with overweight and 53 controls). Measures included: family history of premature coronary heart disease (CHD), physical activity, pubertal stage, smoking history, fasting glucose, insulin, lipid profile, apolipoproteins A1 and B, anthropometry, blood pressure and IMT. RESULTS: The groups were similar for age and family history of premature CHD. Compared to controls, average maximum IMT (0.403+/-0.04 vs 0.387+/-0.029) and average mean IMT were elevated in the hyperlipidemia group (p<0.05), but not in the overweight group (max IMT 0.393+/-0.034; p vs control=0.17). Using multiple regression modelling, age, family history of premature CHD and apoliprotein A1 and B predicted 17% of the variability in IMT. No measure of adiposity predicted IMT. CONCLUSION: Age is an important predictor of IMT in youth. Among traditional CV risk factors, dyslipidemia and family history of premature CHD are independent predictors of IMT.

Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.

OBJECTIVE: Impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are risk factors for diabetes, cardiovascular disease (CVD), and kidney disease. We determined the effects of ramipril and rosiglitazone on combined and individual CVD and renal outcomes in people with IGT and/or IFG in the Diabetes REduction Assessment With ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGN AND METHODS: A total of 5,269 people aged >or=30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up. RESULTS: Compared with placebo, neither ramipril (15.7% [412 of 2,623] vs. 16.0% [424 of 2,646]; hazard ratio [HR] 0.98 [95% CI 0.84-1.13]; P = 0.75) nor rosiglitazone (15.0% [394 of 2,635] vs. 16.8% [442 of 2,634]; 0.87 [0.75-1.01]; P = 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08%; HR 7.04 [95% CI 1.60-31.0]; P = 0.01) but reduced the risk of the renal component (0.80 [0.68-0.93]; P = 0.005); prevention of diabetes was independently associated with prevention of the renal component (P < 0.001). CONCLUSIONS: Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure.

Venous thromboembolism in association with features of the metabolic syndrome.

BACKGROUND: Central obesity, diabetes mellitus, dyslipidaemia and chronic hypertension--features of the metabolic syndrome--have been individually associated with venous thromboembolism (VTE). However, whether each of these factors additively increases the risk of VTE is uncertain. AIM: To determine whether features of the metabolic syndrome independently increase the risk of VTE. DESIGN: Prospective cohort study derived from the Heart Outcomes Prevention Evaluation 2 (HOPE-2) randomized clinical trial. SETTING: One hundred and forty-five clinical centres in 13 countries. METHODS: We studied 5522 adults aged > or =55 years with cardiovascular disease or diabetes mellitus. At enrollment, 35% had 0-1 features of the metabolic syndrome, 30% had two, 24% had three and 11% had four. We defined symptomatic VTE as an objectively confirmed new episode of deep-vein thrombosis or pulmonary embolism. RESULTS: VTE occurred in 88 individuals during a median 5.0 years of follow-up. The incidence rate of VTE (per 100 person-years) was 0.30 with 0-1 features, 0.36 with two features, 0.38 with three features and 0.40 with four features of the metabolic syndrome (trend p = 0.43). Relative to the presence of 0-1 features of the metabolic syndrome, the adjusted hazard ratio (95%CI) for VTE was 1.22 (0.71-2.08) with two features, 1.25 (0.70-2.24) with three features, and 1.26 (0.59-2.69) with four features. DISCUSSION: The number of features of the metabolic syndrome present was not a clinically important risk factor for VTE in older adults with vascular arterial disease.

Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and B12 in high-risk patients: the Heart Outcomes Prevention Evaluation (HOPE)-2 trial.

BACKGROUND: Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular (CV) disease. Simple, inexpensive and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by approximately 25% to 30% and may reduce CV events. Therefore, a large, randomized clinical trial--the Heart Outcomes Prevention Evaluation (HOPE)-2 study--is being conducted to evaluate this therapy in patients at high risk for CV events. OBJECTIVES: To evaluate whether long-term therapy with folic acid and vitamins B6 and B12 reduces the risk of major CV events in a high-risk population. The primary study outcome is the composite of death from CV causes, myocardial infarction and stroke. METHODS: A total of 5522 patients aged 55 years or older with pre-existing CV disease or with diabetes and additional risk factor(s) at 145 centres in 13 countries were randomly assigned to daily therapy with combined folic acid 2.5 mg, vitamin B6 50 mg and vitamin B12 1 mg, or to placebo. Follow-up will average five years, to be completed by the end of 2005. RESULTS: The patients' baseline characteristics confirmed their high-risk status. Baseline homocysteine levels varied between countries and regions. HOPE-2 is one of the largest trials of folate and vitamins B6 and B12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention.

The relationship between dysglycaemia and cardiovascular and renal risk in diabetic and non-diabetic participants in the HOPE study: a prospective epidemiological analysis.

AIMS/HYPOTHESIS: Emerging data suggest that different indices of glycaemia are risk factors for clinical events. The aim of this analysis was to investigate the relationship between fasting plasma glucose or glycated haemoglobin (GHb) levels and incident cardiovascular (CV) outcomes, death, heart failure and overt nephropathy in diabetic and non-diabetic individuals enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study. MATERIALS AND METHODS: The adjusted 4.5-year risk of CV events (myocardial infarction or stroke or CV death), heart failure, death and overt nephropathy was analysed in relation to baseline and updated GHb levels (in 3,529 diabetic HOPE study participants) and baseline fasting plasma glucose levels (in 1,937 non-diabetic and 1,013 diabetic participants). RESULTS: In diabetic participants, a 1% absolute rise in the updated GHb predicted future CV events (relative risk [RR]=1.07, 95% CI 1.01-1.13; p=0.014), death (RR=1.12, 95% CI 1.05-1.19; p=0.0004), heart failure (RR=1.20, 95% CI 1.08-1.33; p=0.0008) and overt nephropathy (RR=1.26, 95% CI 1.17-1.36; p<0.0001) after adjusting for age, sex, diabetes duration, blood pressure, WHR, hyperlipidaemia and ramipril. Similarly, a 1 mmol/l rise in fasting plasma glucose was related to an increased risk of CV outcomes (RR=1.09, 95% CI 1.05-1.13; p<0.0001), death (RR=1.06, 95% CI 1.01-1.12; p=0.017), heart failure (RR=1.16, 95% CI 1.06-1.13; p=0.0007) and overt nephropathy (RR=1.34, 95% CI 1.23-1.45; p<0.0001) in the group composed of diabetic and non-diabetic individuals. The significant relationship between fasting plasma glucose and CV outcomes persisted after adjustment for diabetes status (RR=1.06, 95% CI 1.00-1.12; p=0.043). CONCLUSIONS/INTERPRETATION: There is an independent progressive relationship between indices of glycaemia and incident CV events, renal disease and death. Clinical trials of glucose lowering to prevent these outcomes in diabetic and non-diabetic individuals are indicated.

The HOPE (Heart Outcomes Prevention Evaluation) Study and its consequences.

The HOPE study was a 19 country, prospective randomized trial in which the ACE-inhibitor Ramipril but not Vitamin E significantly reduced the risk of future cardiovascular events in a high-risk population of men and women, including many with diabetes. The benefits were present in all sub-groups, independent of the presence or absence of diabetes, hypertension, evidence of cardiovascular disease, microalbuminuria, blood pressure lowering, the use of aspirin, lipid-lowering or antihypertensive medication. It provided clear evidence that Ramipril should safely and cost-effectively be used in individuals not known to have low ventricular ejection fraction or heart failure but at high-risk of cardiovascular events. It was also beneficial in patients with renal insufficiency, reducing progression of proteinuria and development of new microalbuminuria. It provided micro- and macrovascular benefits in people with diabetes, reduced the development of new cases of diabetes and showed a positive and graded association between the waist-to-hip ratio and the risk of developing diabetes. Sub-studies completed and on-going into the predictive role of natriuretic peptides, infectious and inflammatory markers, provide insight into possible mechanisms of action of Ramipril.

Serum potassium, cardiovascular risk, and effects of an ACE inhibitor: results of the HOPE study.

BACKGROUND: Both hyper- and hypokalemia increase cardiovascular risk. Modest hyperkalemia is common with angiotensin-converting enzyme inhibition. We studied post-hoc the association of an initial, on-treatment serum potassium measurement with subsequent cardiovascular outcomes over 4.5 years in 9297 individuals at high cardiovascular risk, randomized to an ACE inhibitor or to placebo. METHODS: Post-hoc analysis of cardiovascular outcomes, as related to serum potassium levels, in the HOPE (Heart Outcomes and Prevention Evaluation) study which compared ramipril to placebo, and included 692 patients with a serum potassium level >5.0 mM and 137 with a serum potassium level <3.5 mM, defined as hyper- and hypokalemia, respectively. Serum potassium was measured 1 month after start of randomized treatment. RESULTS: With hyperkalemia, the primary event rate was unchanged compared to normokalemia (15.5 vs 15.7%, p > 0.4, respectively), with hypokalemia, the primary event rate was higher (22.6% vs 15.5%, respectively, p = 0.023). The hazard ratio for the primary outcome associated with this initial hypokalemia was 1.44 (1.00-2.06) on multivariate analysis. The combined primary outcome (myocardial infarction, cardiovascular death, stroke) was not different throughout deciles of serum potassium but the lowest and highest deciles included many with normokalemia. Randomized treatment was withheld because of hyperkalemia in 8 and 6 people allocated to ramipril and placebo, respectively. The benefit of ramipril on cardiovascular outcomes was independent of serum potassium, but ramipril reduced hypokalemia in the entire cohort (1.15 vs 1.86% with placebo, p = 0.005), particularly in those participants on diuretics (3.8% vs 6.5%, p = 0.07). CONCLUSIONS: In patients at high cardiovascular risk, modest hypokalemia predicts a less favorable outcome while modest hyperkalemia does not. Ramipril reduces hypokalemia and decreases risk.