Risk of recurrent stroke and dementia following acute stroke by changes in kidney function: results from the Perindopril Protection Against Recurrent Stroke Study.

BACKGROUND: Limited data exist on the relationship between declining kidney function and cardiovascular events, dementia, and mortality in patients with a history of stroke.Thus the aims of the study were to investigate functional relationships between dynamic kidney function change and cardiovascular outcomes, and clarify whether adding kidney parameters to conventional cardiovascular risk factors improves model discrimination. METHODS: Post hoc analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) clinical trial of blood pressure lowering for the secondary prevention of stroke. We examined the association between dynamic kidney function defined as percentage change (declines of >30%, and >0 to ≤30%, and increases of ≥0 to <30%, and ≥30%) in estimated glomerular filtration rate (eGFR) over 2 years and recurrent stroke, major cardiovascular events, dementia and all-cause death over the next 2 years using Cox proportional hazard models controlling for eGFR at registration and potential confounders. Restricted cubic splines were used to assess the functional relationships. C-statistics and Net Reclassification Improvement (NRI) at 2 years were used to assess model discrimination. RESULTS: In 4591 patients followed for a mean of approximately 2 years, 254 (5.5%) developed recurrent stroke, 391 (8.5%) had a major cardiovascular event, 221 (4.8%) developed dementia, and 271 (5.9%) died. Reverse J-like or U-like relationships were observed for percent declines in eGFR and outcomes. Using declines in eGFR of >0 to ≤30% as a reference, increased risks were evident for a greater decline (>30%) in relation to recurrent stroke [adjusted hazard ratio 1.85, 95% confidence interval (CI) 1.20-2.85], major cardiovascular event (2.24, 1.62-3.10) and all-cause death (2.09, 1.39-3.15). A larger increase (≥30%) in eGFR was also associated with a greater risk of all-cause death (1.96, 1.14-3.37). Improvements in the C-statistic were found by adding baseline eGFR and percent change compared with a model with conventional cardiovascular risk factors alone, for major cardiovascular events, dementia, and all-cause mortality. CONCLUSION: Declining kidney function following an incident cerebrovascular event is associated with additional risk of a major cardiovascular events, dementia, and 2-year mortality. However, a large increase in kidney function was also found to be associated with a higher risk of mortality.

The global burden of hypertension exceeds 1.4 billion people: should a systolic blood pressure target below 130 become the universal standard?

: In 2010, 1.4 billion people globally had hypertension, with 14% controlled to systolic blood pressure (SBP, mmHg) below 140, which contributes to 18 million cardiovascular deaths annually. Recent hypertension guidelines endorsed SBP targets below 130 or lower for all or some hypertensive patients to reduce cardiovascular events (CVEs) more than the prior SBP target less than 140. In 2016, the Australian Guideline strongly recommended target SBP below 120 for adults at very high risk for CVE or aged above 75 years. In 2017 and 2018, the Canadian Guideline recommended automated office SBP (AOSBP) below 120 in adults at high risk and aged above 75 years (grade B). In 2017, the US Guideline recommended SBP below 130 for all adults (moderate-to-high risk class I; lower-risk grade IIb). In 2018, the European Guideline recommended SBP below 140 for all adults, and, if tolerated, a SBP range of 120-129 for adults aged below 65 years and 130-139 for adults aged at least 65 years (class I). The guidelines were variably influenced by Systolic blood PRessure INTervention trial and meta-analyses indicating fewer CVE when mean in-trial SBP was below 130 versus above 130. Clinicians considering lower SBP targets should be aware that: AOSBP preceded by 5-min rest is approximately 10-15 mmHg lower than usual office SBP; hypertensive patients with office SBP consistently versus intermittently below 140 have fewer CVE; benefits of mean office SBP or AOSBP below 120 remain unproven and could increase adverse events. Clinicians worldwide will do well to control SBP to below 140 in most hypertensive patients on most visits, which should lead to mean in-clinic SBP of 120-129.

Heart rate and blood pressure interactions in the development of erectile dysfunction in high-risk cardiovascular patients.

AIMS: Erectile dysfunction (ED) is associated with cardiovascular risk factors as elevated systolic blood pressure (SBP), resting high heart rate (HR), and endothelial dysfunction and predicts cardiovascular events. However, the interaction between high HR and SBP and the development of ED remains unclear. METHODS AND RESULTS: We evaluated 1015 male patients enrolled in the ED substudy of ONTARGET and TRANSCEND, examining the influence of mean HR and mean SBP obtained over all study visits (mean 10.9±1.4 study visits) and their interaction with ED. In patients without pre-existing ED, new onset ED was detected in 29% of patients below, and 41% of patients above, the median of mean HR (OR 1.72, 95% CI 1.8-2.5, p = 0.0047). In patients with pre-existing ED, high HR had no add-on effect. With or without pre-existing ED, high SBP had no influence after adjustment for covariates (OR 1.03, 95% CI 0.66-1.59, p = 0.91). In a continuous model, it was shown that effects of high HR were prominent at low Kölner (Cologne) Evaluation of Erectile Function (KEED) score baseline values and in the presence of SBP above the median. CONCLUSIONS: In patients at risk for cardiovascular events, high HR is associated with ED, whereas the effect of high SBP was not significant. High resting HR might represent a cardiovascular risk indicator. Whether HR represents a potential treatment target to improve ED in high-risk individuals must be scrutinized in prospective trials.

Stroke mortality and trends from 1990 to 2006 in 39 countries from Europe and Central Asia: implications for control of high blood pressure.

AIMS: The aim of the present study was to extend our understanding of international trends in stroke and major sequelae in Europe and countries peripheral to Europe by assessing: (1) current mortality rates, (2) the most recent 15-year prevalence trends, and (3) the relationship between systolic blood pressure in community surveys and national stroke mortality. METHODS AND RESULTS: Data were obtained from the World Health Organization (WHO www.who.int/whosis/database/mort/table.cfm), and represent national vital statistics as reported by 39 countries (European and Central Asian countries) using a standard format and population-based cardiovascular surveys. Total numbers of deaths by stroke (International Classification of Diseases 430-438, 444) and the age, sex-adjusted incidence rates were obtained and grouped according to three standard demographic categories: A, B, and C (WHO). A Bayesian linear mixed effect model was fitted to the annual mortality rates. Higher rates of stroke mortality were observed for B and C group countries as compared with those countries belonging to Group A (e.g. Bulgaria 273.9 and 281.1; Israel 37.7 and 45.4 per 100 000 men and women, respectively). Even though the mortality rates within the country groupings were relatively similar, countries with marked deviation from the average were observed, mainly in Groups B and C. Stroke mortality decreased sharply in Group A during the period of study; conversely it had increased substantially in Group B and to a lesser extent in Group C. For both sexes markedly higher rates were noted moving from west to east, with some exceptions. CONCLUSION: We have entered a period of rapidly increasing international inequality in stroke risk, where countries with low adult mortality in the latter 20th century extended their downward trend and countries with moderate as well as high mortality have on average seen unprecedented increases in death rates from stroke.

Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: New results from the ADVANCE trial.

OBJECTIVE: To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-standing type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a multicenter, factorial randomized trial of perindopril-indapamide versus placebo (double-blind comparison) and intensive glucose control with a gliclazide MR-based regimen (target A1C 0.1): the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale. Compared with neither intervention, combination treatment reduced the risk of new or worsening nephropathy by 33% (95% CI 12-50%, P = 0.005), new onset of macroalbuminuria by 54% (35-68%, P < 0.0001), and new onset of microalbuminuria by 26% (17-34%). Combination treatment was associated with an 18% reduction in the risk of all-cause death (1-32%, P = 0.04). CONCLUSIONS: The effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.

Effect of rimonabant on blood pressure in overweight/obese patients with/without co-morbidities: analysis of pooled RIO study results.

OBJECTIVE: Rimonabant, the first selective cannabinoid type 1 (CB1) receptor blocker, has been shown to improve multiple cardiometabolic risk factors in overweight/obese patients. This analysis assessed the impact of rimonabant on blood pressure in the pooled population from four large trials with similar design - the Rimonabant-In-Obesity (RIO) programme. METHODS: RIO-Europe (n = 1507) and RIO-North America (n = 3040) recruited overweight/obese patients, and RIO-Lipids (n = 1033) and RIO-Diabetes (n = 1045) recruited overweight/obese patients with untreated dyslipidaemia or type 2 diabetes, respectively. At study entry (screening), 37.2% (n = 2463) of patients had hypertension, 71.4% (n = 1757) of whom were taking an antihypertensive treatment. RESULTS: After 1 year of treatment, mean change in systolic blood pressure (SBP) from baseline was -0.8 mmHg for rimonabant 20 mg versus +0.3 mmHg for placebo (P = 0.007); diastolic blood pressure (DBP) decreased by -0.8 versus -0.3 mmHg (P = 0.029) respectively. In the subgroup of patients with high blood pressure at baseline, SBP change was -7.5 mmHg for rimonabant 20 mg versus -4.7 mmHg for placebo (P = 0.005); DBP change was -5.2 versus -3.0 mmHg (P < 0.001). Reductions were more pronounced in patients with dyslipidaemia and type 2 diabetes. There was no effect of rimonabant 20 mg on blood pressure beyond that expected from weight loss alone. Overall, there was a similar incidence of adverse events (AEs) at 1 year in the placebo (81.8%) and rimonabant 20 mg (86.0%). The most common AEs occurring with rimonabant were nausea, dizziness, arthralgia and diarrhoea. A slightly higher proportion of patients in the rimonabant 20 mg group discontinued as a result of AEs (13.8%) versus placebo (7.2%). CONCLUSIONS: Rimonabant 20 mg led to modest, but significant SBP and DBP reductions in overweight/obese patients. The effect of rimonabant on blood pressure appears to be mediated by weight loss.

Effects of nifedipine GITS and diuretics in isolated systolic hypertension--a subanalysis of the INSIGHT study.

AIMS: This study tested the effects on cardiovascular outcomes of treatments based on nifedipine gastrointestinal therapeutic system (GITS) compared with the diuretic combination co-amilozide in a pre-specified subset of patients with isolated systolic hypertension (ISH) enrolled in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study. MAJOR FINDINGS: Of 6321 randomized patients, 1498 (23.7%) had ISH with a baseline mean BP of 173/88 mmHg in both treatment groups. Mean BP fell by 29/10 mmHg in the nifedipine and 30/10 mmHg in the diuretic group to a mean BP of 144/78 mmHg and 143/79 mmHg, respectively, at endpoint. The percentage of primary outcomes in patients with ISH was not significantly different between the two treatment groups (nifedipine GITS 6.0%, co-amilozide 6.6%). The number of ISH patients with composite secondary outcomes was 90 (12.2%) in the nifedipine GITS group and 110 (14.5%) in the co-amilozide group (not significant). The incidence rates of primary and secondary outcomes were similar in patients without ISH. CONCLUSION: In patients with ISH, nifedipine GITS and co-amilozide had similar effects on clinical outcomes and BP lowering. They lend support to international guidelines for the treatment of hypertension recommending the use of long-acting dihydropyridine calcium-channel blockers as one treatment option for patients with ISH.

Design of the Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial.

The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial is a large clinical trial of omapatrilat, a vasopeptidase inhibitor, in patients with stage 1 isolated systolic hypertension (ISH). OPERA is the first study to examine whether effective antihypertensive treatment can provide survival and clinical end point benefits in older persons with this common condition. This 5-year multinational, randomized, double-blind, parallel-group, placebo-controlled, forced-titration study will be conducted in approximately 12,600 subjects randomized by approximately 1100 study centers worldwide over a recruitment period of approximately 2 years. The primary objective of OPERA is to determine whether treatment with once-daily omapatrilat (target dose 40 mg) will reduce cardiovascular (CV) morbidity and mortality in older (> or = 65 years) men and women with enhanced risk for atherosclerotic events due to stage 1 ISH plus other risk factors for which currently there is no evidence-based requirement for treatment. Blood pressure inclusion criteria are systolic blood pressure (SBP) 140 to 159 mm Hg (SBP 125 to 139 mm Hg in diabetic individuals) and diastolic blood pressure (DBP) <90 mm Hg. The primary end point is defined as the composite of fatal/nonfatal stroke, fatal/nonfatal myocardial infarction, fatal/nonfatal heart failure, and other CV mortality. Secondary end points include the individual components of the primary end point, CV mortality, and major cardiovascular end points, as well as effects on cognitive function and initiation of treatment for diabetes. Additional analyses will be conducted in men and women, in diabetic patients, in different risk classes and according to prior evidence of vascular disease.