Latin American Consensus on the management of hypertension in the patient with diabetes and the metabolic syndrome.

: The prevalence of hypertension, type 2 diabetes mellitus (DM2) and the metabolic syndrome continues to increase in Latin America, while the rates of diagnosis, treatment and control of these disorders remain low. The frequency of the risk factors that constitute the metabolic syndrome and are associated with an increased risk of cardiovascular disease has not diminished since the publication of the previous consensus. This document discusses the socioeconomic, demographic, environmental and cultural characteristics of most associated Latin American countries and partially explains the lack of better results in improving clinical and public health actions that allow high morbidity and mortality rates caused by cardiovascular diseases and DM2 to be reduced through programs aligned with the so-called precision medicine, which should be predictive, preventive, personalized and participatory. The Consensus ratifies the diagnostic criteria expressed in the previous consensus to define hypertension and DM2 but, for the metabolic syndrome, and in the absence of evidence, the recommendation is to implement a cohort study that determines the abdominal perimeter value associated with hard outcomes, such as DM2 and CVD. Meanwhile, we recommend modifying the criterion to more than 94 cm in men and more than 84 cm in women according to WHO recommendations. We also recommend the carrying out of a study that identifies the situation of hypertension and DM2 in people of African ancestry who, in Latin America, exceed 75 million and whose epidemiology does not include solid studies. With respect to the proposed therapeutic targets, we recommended maintaining those defined in the previous consensus, but insisting that early pharmacological management of prediabetes with metformin should be introduced, as should the treatment of diabetic hypertensive patients with a combination therapy of two fixed-dose antihypertensive drugs and management with statins. To increase adherence, the use of different drugs combined in a single pill (polypill) is recommended. The simplification of the therapeutic regimen is accompanied by greater control of cardiovascular risk factors, both in primary and secondary prevention, and has been shown to be cost-effective. The consensus recommends the use of the currently available polypill combining an angiotensin-converting enzyme inhibitor, a statin and aspirin for secondary cardiovascular prevention and in patients with a high cardiovascular risk, such as hypertension patients with DM2.

Osmotic indices and kidney concentrating activity: population-based data on correlates and prognostic power.

Background: Research data are limited on indices of osmotic equilibrium and of kidney concentrating activity (KCA). This study investigated correlates and prognostic power of these indices in a sample of the general population. Methods: Urine osmolality (U-osm), plasma osmolality (P-osm), plasma creatinine and other variables were measured by the Gubbio Study for the 1988-92 exam (baseline). Plasma creatinine and other variables were re-measured in the 2001-07 exam (follow-up). KCA was assessed as the U-osm/P-osm ratio and kidney function as estimated glomerular filtration rate (eGFR). Results: Baseline data were complete in 4220 adults, of whom 852 died before follow-up and 2795 participated in the follow-up. At baseline, the following independent cross-sectional associations were identified: female sex and higher urine flow with lower values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); obesity with higher values of U-osm, P-osm and U-osm/P-osm ratio (P < 0.01); older age and lower eGFR with lower U-osm, lower U-osm/P-osm ratio and higher P-osm (P < 0.05); hypertension and smoking with lower U-osm and lower U-osm/P-osm ratio (P < 0.05) but not with P-osm. From baseline to follow-up, the annualized rate was 1.26% for mortality and -0.74 ± 0.76 mL/min × 1.73 m2 for eGFR change. Mortality was independently predicted by baseline U-osm and baseline U-osm/P-osm ratio (hazard ratio for one higher standard deviation was ≤0.91, 95% confidence interval was ≤0.97, P < 0.01), but not by baseline P-osm. The eGFR change was not independently predicted by baseline values of U-osm, P-osm and U-osm/P-osm ratio (P ≥ 0.4). Conclusions: Sex, age, obesity, eGFR, urine flow, hypertension and smoking independently associated with U-osm and KCA. U-osm and KCA independently predicted mortality, but not kidney function change over time.

Effects of pentoxifylline on inflammatory markers and blood pressure: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Pentoxifylline is a xanthine derivative with potential cardiovascular benefits. AIM: To evaluate the impact of pentoxifylline on blood pressure (BP) and plasma TNF-α, C-reactive protein (CRP) and IL-6 through a systematic review and meta-analysis of randomized controlled trials. METHODS: The protocol was registered (PROSPERO: CRD42016035988). The search included PUBMED, ProQuest, Scopus and EMBASE until 1 September 2015 to identify trials reporting BP or inflammatory markers during pentoxifylline therapy. Quantitative data synthesis was performed using a random-effects model, with weighted mean difference (WDF) and 95% confidence intervals (CIs) as summary statistics. RESULTS: Fifteen studies (16 treatment arms) were found to be eligible for inclusion. Meta-analysis did not suggest any effect of pentoxifylline on either SBP or DBP. Pentoxifylline treatment was associated with a significant reduction in plasma concentrations of TNF-α (WDF: -1.03 pg/ml, 95% CI: -1.54, -0.51; P < 0.001, 11 treatment arms) and CRP (WDF: -1.39 mg/l, 95% CI: -2.68, -0.10; P = 0.034, five treatment arms). No alteration in plasma IL-6 concentration was observed. The impact of pentoxifylline on plasma TNF-α levels was found to be positively associated with treatment duration (slope: 0.031; 95% CI: 0.004, 0.057; P = 0.023) but independent of pentoxifylline dose (slope: -0.0003; 95% CI: -0.002, 0.001; P = 0.687). CONCLUSION: Pentoxifylline did not alter BP or plasma IL-6 concentration, but significantly reduced circulating TNF-α and CRP concentrations.

No evidence for a J-shaped curve in treated hypertensive patients with increased cardiovascular risk: The VALUE trial.

Previous studies have debated the notion that low blood pressure (BP) during treatment, particularly diastolic (DBP), is associated with increased risk of cardiovascular disease. We evaluated the impact of low BP on cardiovascular outcomes in a high-risk population of 15,244 hypertensive patients, almost half of whom had a history of coronary artery disease (CAD). In the prospective Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, patients were randomized to valsartan or amlodipine regimens and followed for 4.2 years (mean) with no difference in the primary cardiovascular endpoint. A Cox proportional hazards model was used to evaluate the relationship between average on-treatment BP and clinical outcomes. The relationship between BP and cardiovascular events was adjusted for age, gender and body mass index, and baseline qualifying risk factors and diseases (smoking, high total cholesterol, diabetes mellitus, proteinuria, CAD, previous stroke and left ventricular hypertrophy). DBP ≥ 90 mmHg, compared with < 90 mmHg, was associated with increased incidence of the primary cardiovascular endpoint (all cardiac events); however, DBP < 70 mmHg, compared with ≥ 70 mmHg, was not associated with increased incidence after covariate adjustment (no J-shaped curve). Similar results were observed for death, myocardial infarction (MI), heart failure and stroke, considered separately. Nadir for MI was at DBP of 76 mmHg and for stroke 60 mmHg. The ratio of MI to stroke increased with lower DBP. In CAD patients the MI to stroke ratio was more pronounced than in patients without CAD but there was no significant J-curve in either group. Systolic BP ≥ 150 but not < 130 mmHg, compared with 130-149 mmHg, similarly was associated with increased risk for primary outcome. In conclusion, patients in BP strata ≥ 150/90 mmHg, but not patients in BP strata < 130/70 mmHg, were at increased risk for adverse outcomes in this hypertensive, high-risk population. Although benefit in preventing MI in relation to preventing stroke levels off for the lowest BPs, these data provide no support for a J-curve in the treatment of high-risk hypertensive patients . The increase in the ratio of MI to stroke with lower DBP indicates target organ heterogeneity in that the optimal on-treatment DBP for cerebroprotection is below that for cardioprotection.

Consenso latino-americano de hipertensão em pacientes com diabetes tipo 2 e síndrome metabólica / Latin American consensus on hypertension in patients with diabetes type 2 and metabolic syndrome

O presente documento foi preparado por um grupo de especialistas, membros das Sociedades de Cardiologia, Endocrinologia, Medicina Interna, Nefrologia e Diabetes dos países da América Latina, para que sirva de diretriz para médicos que cuidam de pacientes com diabetes, hipertensão e fatores de risco concomitantes ou complicações de ambas as condições. Embora o conceito de síndrome metabólica seja atualmente muito discutido, a alta prevalência na América Latina do conjunto de alterações metabólicas que a compõem sugere que a síndrome metabólica é uma entidade nosográfica útil no contexto da medicina latino-americana. Devido a isso, no presente documento presta-se especial atenção a essa síndrome com a finalidade de alertar aos médicos sobre uma população particularmente de alto risco, que, por ser subestimada, não é tratada de forma adequada para os fatores de risco que constituem a síndrome metabólica. As recomendações deste documento são o resultado de apresentações e debates que ocorreram durante um encontro de dois dias em Bucaramanga (Colômbia), em outubro de 2012. Todos os participantes aprovaram as decisões finais. Os autores reconhecem que a publicação e difusão das diretrizes não serão suficientes para alcançar as mudanças recomendadas tanto em estratégias diagnósticas como terapêuticas, por isso programaram intervenções que permitirão identificar as barreiras do conhecimento, as atitudes e comportamento, o que permitirá tanto aos médicos como aos pacientes uma adequada adesão às recomendações sugeridas nestas diretrizes. Arq Bras Endocrinol Metab. 2014;58(3):205-25.

The present document has been prepared by a group of experts, members of cardiology, endocrinology, internal medicine, nephrology and diabetes societies of Latin American countries, to serve as a guide to physicians taking care of patients with diabetes, hypertension and comorbidities or complications of both conditions. Although the concept of metabolic syndrome is currently disputed, the higher prevalence in Latin America of that cluster of metabolic alterations has suggested that metabolic syndrome is a useful nosography entity in the context of Latin American medicine. Therefore, in the present document, particular attention is paid to this syndrome in order to alert physicians on a particular high-risk population, usually underestimated and undertreated. These recommendations result from presentations and debates by discussion panels during a 2-day conference held in Bucaramanga, in October 2012, and all the participants have approved the final conclusions. The authors acknowledge that the publication and diffusion of guidelines do not suffice to achieve the recommended changes in diagnostic or therapeutic strategies, and plan suitable interventions overcoming knowledge, attitude and behavioural barriers, preventing both physicians and patients from effectively adhering to guideline recommendations. Arq Bras Endocrinol Metab. 2014;58(3):205-25.

Typical and atypical coronary heart disease deaths and their different relationships with risk factors. The Gubbio residential cohort study.

OBJECTIVES: The Seven Countries Study showed that fatal coronary heart disease (CHD) with only chronic heart failure, arrhythmia or blocks (atypical CHD, A-CHD) may represent a distinct disease as compared to fatal CHD cases with angina pectoris, acute myocardial infarction (AMI) or sudden death (typical CHD, T-CHD). We aimed at validating this, using identical diagnostic criteria, in a separate residential cohort first examined in 1983-85 in Gubbio, central Italy. MATERIAL AND METHODS: Forced Cox's models were run to assess 9 classic risk factors and their 20-year predictivity of A-CHD versus T-CHD, in the entire cohort or separately for men and women. RESULTS: There were 3229 subjects aged 30-79 years. Entry mean age was slightly higher in women than men although age at death was lower in men than in women for both T-CHD (71.99 ± 11.38 versus 81.20 ± 9.35 years, p<0.0001) and A-CHD (80.22 ± 9.44 versus 84.98 ± 8.13 years, p<0.0001). T-CHDs were predicted by male gender, age, continued smoke, systolic blood pressure (SBP), blood glucose, total and HDL-cholesterol (protective). A-CHDs were predicted by age, continued smoke, SBP, body mass index and blood glucose but neither total nor HDL-cholesterol or gender was significant. In the entire cohort and in men there were predictive differences of T-CHD versus A-CHD fatalities only in relation to age (p<0.01), SBP (p<0.05) and total cholesterol (p<0.01). CONCLUSION: As age, SBP and total cholesterol had a different predictive role of T-CHD versus A-CHD fatalities also in the Gubbio cohort, the possibility is reinforced that a different etiology exists between these entities.

Serum uric acid and eGFR_CKDEPI differently predict long-term cardiovascular events and all causes of deaths in a residential cohort.

OBJECTIVES: Serum uric acid (SUA) and estimated glomerular filtration rate (eGFR) were separately assessed as risk factors for incident coronary hard (CHDH), cardiovascular disease (CVDH) or all-cause (ALL) deaths but never concomitantly in a residential cohort. MATERIAL AND METHODS: Men and women aged 35-74years, totaling 2888 subjects were followed 13.5-19.5years for incident CVDH, CHDH and ALL deaths. Systematic comparisons among different end-points were based on: age, gender, systolic blood pressure (SBP), total and HDL cholesterol, cigarette consumption, body mass index, blood glucose, SUA, eGFR from the Chronic Kidney Disease Prognosis Consortium (eGFR_CKDEPI) and (eGFR_CKDEPI)(2). RESULTS: Significant (p<0.00001) differences in SUA quintiles were seen for SBP, total and HDL cholesterol, body mass index and eGFR_CKDEPI whereas cigarettes and blood glucose were not statistically different. There were increasingly larger proportions of all events in SUA quintiles (0.05>p<0.0001). Among 4 major continuous variables, SUA was largely accurate (ROC>0.610) to predict all end-points whereas eGFR_CKDEPI was the worse univariate predictor. Multivariately, age, gender, SBP and cigarettes were significant predictors for all end-points. Total cholesterol was a significant predictor only for CHDH events. Blood glucose and SUA were contributors for CVDH events (RR, for 1mg/dl of SUA, 1.09, 95%CI 1.01-1.17), CVD deaths (RR 1.11, 95%CI 1.03-1.20) and ALL deaths (RR 1.08, 95%CI 1.03-1.14) whereas (eGFR_CKDEPI)(2) was for ALL deaths only (RR 1.02, 95%CI 1.00-1.04). CONCLUSION: SUA is a predictor of long-term incidence of cardiovascular events and deaths and all-cause mortality and should be considered for risk predictive purposes and instruments whereas eGFR_CKDEPI only predicts all-cause mortality by a U-shaped relation.

Consenso latinoamericano de hipertensión en pacientes con diabetes tipo 2 y síndrome metabólico / Latin american consensus of hypertension in patients with type 2 diabetes and metabolic syndrome

Resumen El presente documento ha sido preparado por un grupo de expertos, miembros de las sociedades de cardiología, endocrinología, medicina interna, nefrología y diabetes de los países de América Latina, para que sirvan de guía a los médicos que cuidan a pacientes con diabetes, hipertensión y enfermedades concomitantes o complicaciones de ambas condiciones. Aunque el concepto de síndrome metabólico actualmente es discutido, la alta prevalencia en América Latina del conjunto de alteraciones metabólicas que lo conforman sugiere que el síndrome metabólico es una entidad nosográfica común en el contexto de la medicina latinoamericana. Por lo tanto, en el presente documento se presta especial atención a este síndrome con el fin de alertar a los médicos de una particular población de alto riesgo, en la que por lo general es subestimada y no se tratan en forma optima los factores de riego que constituyen el síndrome metabólico. Las presentes recomendaciones son el resultado de las presentaciones y los debates en los paneles de discusión durante una reunión de dos días celebrada en Bucaramanga en octubre de 2012. Todos los participantes han aprobado las conclusiones finales. Los autores reconocen que la publicación y difusión de las guías no serán suficientes para alcanzar los cambios recomendados tanto en las estrategias diagnósticas como terapéuticas, por lo que se ha programado intervenciones que permitan identificar las barreras del conocimiento, de las actitudes y de comportamiento, lo que permitirá tanto a los médicos como a los pacientes una adecuada adherencia a las recomendaciones de las guías. (Acta MedColomb 2013; 38: 154-172).

Abstract The present document has been prepared by a group of experts, members of cardiology, endocrinology, internal medicine, nephrology and diabetes societies of Latin American Countries, to serve as a guide to physicians taking care of patients with diabetes, hypertension and comorbidities or complications of both conditions. Although the concept of metabolic syndrome is currently disputed, the higher prevalence in Latin America of that cluster of metabolic alterations has suggested that metabolic syndrome is useful nosography entity in the context of Latin American medicine. Therefore, in the present document, particular attention is paid to this syndrome in order to alert physicians on a particular high- risk population, usually underestimated and undertreated. These recommendations results from presentation and debates by discussion panels during a 2-day conference held in Bucaramanga, in October 2012, and all the participants have approved the final conclusions. The authors acknowledge that the publication and diffusion of guidelines do not suffice to achieve the recommended changes in diagnostic or therapeutic strategies, and plan suitable interventions overcoming both physicians and patients from effectively adhering to guideline recommendations. (Acta Med Colomb 2013; 38: 154-172)).

Consenso latinoamericano de hipertensión en pacientes con diabetes tipo 2 y síndrome metabólico / Latin american consensus on hypertension in patients with diabetes type 2 and metabolic syndrome

El presente documento ha sido preparado por un grupo de expertos, miembros de las sociedades de cardiología, endocrinología, medicina interna, nefrología y diabetes de los países de América Latina, para que sirvan de guía a los médicos que cuidan a pacientes con diabetes, hipertensión y enfermedades concomitantes o complicaciones de ambas condiciones. Aunque el concepto de síndrome metabólico actualmente es discutido, la alta prevalencia en América Latina del conjunto de alteraciones metabólicas que lo conforman sugiere que el síndrome metabólico es una entidad nosografías útil en el contexto de la medicina latinoamericana. Por lo tanto, en el presente documento se presta especial atención a este síndrome con el fin de alertar a los médicos de una particular población de alto riesgo, en la que por lo general se subestimada y no se trata en forma óptima los factores de riego que constituyen el síndrome metabólico. Las presentes recomendaciones son el resultado de las presentaciones y los debates en los paneles de discusión durante una reunión de 2 días celebrada en Bucaramanga en octubre de 2012. Todos los participantes han aprobado las conclusiones finales. Los autores reconocen que la publicación y difusión de las guías no serán suficientes para alcanzar los cambios recomendados tanto en las estrategias diagnósticas como terapéuticas, por lo que se ha programado intervenciones que permitan identificar las barreras del conocimiento, de las actitudes y de comportamiento, lo que permitirá tanto a los médicos como a los pacientes una adecuada adherencia a las recomendaciones de las guías(AU)

The present document has been prepared by a group of experts, members of cardiology, endocrinology, internal medicine, nephrology and diabetes societies of Latin American Countries, to serve as a guide to physicians taking care of patients with diabetes, hypertension and comorbidities or complications of both conditions. Although the concept of metabolic syndrome is currently disputed, the higher prevalence in Latin America of that cluster of metabolic alterations has suggested that metabolic syndrome is useful nosography entity in the context of Latin American medicine. Therefore, in the present document, particular attention is paid to this syndrome in order to alert physicians on a particular high- risk population, usually underestimated and undertreated. These recommendations results from presentation and debates by discussion panels during a 2-day conference held in Bucaramanga, in October 2012, and all the participants have approved the final conclusions. The authors acknowledge that the publication and diffusion of guidelines do not suffice to achieve the recommended changes in diagnostic or therapeutic strategies, and plan suitable interventions overcoming both physicians and patients from effectively adhering to guideline recommendations(AU)

Consenso latinommericano de hipertensión en pacentes con diabetes tipo 2 y sínndrome metabólico / Latin american consensus on hypertension in patients with type 2diabetes and meetabolic syndrome / Consenso latinoamericano de hipertensão em pacientes com diabetes tipo 2 e síndrome metabólico

El presente documento ha sido preparado por un grupo de expertos, miembros de las sociedades de cardiología, endocrinología, medicina interna, nefrología y diabetes de los países de América Latina, para que sirva de guía a los médicos que cuidan a pacientes con diabetes, hipertensión y enfermedades concomitantes o complicaciones de ambas condiciones. Aunque el concepto de síndrome metabólico actualmente es discutido, la alta prevalencia en América Latina del conjunto de alteraciones metabólicas que lo conforman sugiere que el síndrome metabólico es una entidad nosografías útil en el contexto de la medicina latinoamericana. Por lo tanto, en el presente documento se presta especial atención a este síndrome con el fin de alertar a los médicos de una particular población de alto riesgo, en la que por lo general se subestimada y no se trata en forma optima los factores de riego que constituyen el síndrome metabólico. Las presentes recomendaciones son el resultado de las presentaciones y los debates en los paneles de discusión durante una reunión de 2 días celebrada en Bucaramanga en octubre de 2012. Todos los participantes han aprobado las conclusiones finales. Los autores reconocen que la publicación y difusión de las guías no serán suficientes para alcanzar los cambios recomendados, tanto en las estrategias diagnósticas como terapéuticas, por lo que se ha programado intervenciones que permitan identificar las barreras del conocimiento, de las actitudes y de comportamiento, lo que permitirá tanto a los médicos como a los pacientes una adecuada adherencia a las recomendaciones de las guías.

The present document has been prepared by a group of experts, members of cardiology, endocrinology, internal medicine, nephrology and diabetes societies of Latin American Countries, to serve as a guide to physicians taking care of patients with diabetes, hypertension and comorbidities or complications of both conditions. Although the concept of metabolic syndrome is currently disputed, the higher prevalence in Latin America of that cluster of metabolic alterations has suggested that metabolic syndrome is useful nosography entity in the context of Latin American medicine. Therefore, in the present document, particular attention is paid to this syndrome in order to alert physicians on a particular high- risk population, usually underestimated and undertreated. These recommendations results from presentation and debates by discussion panels during a 2-day conference held in Bucaramanga, in October 2012, and all the participants have approved the final conclusions. The authors acknowledge that the publication and diffusion of guidelines do not suffice to achieve the recommended changes in diagnostic or therapeutic strategies, and plan suitable interventions overcoming both physicians and patients from effectively adhering to guideline recommendations.

O presente documento tem sido preparado por um grupo de expertos, membros das sociedades de cardiologia, endocrinologia, medicina interna, nefrologiae diabetes dospaíses da América Latina, para que sirva de guia aos médicos que tomam conta de pacientes com diabetes, hipertensãoe enfermidades concomitantes ou complicaçõesdas duas condições. Porémoconceito de síndrome metabólico atualmente é discutido, a alta prevalênciana América Latina do conjunto de alterações metabólicas que o conformam,sugereque o síndrome metabólico é uma entidade nosográfica útil no contexto da medicina latino americana. Pelo tanto, no presente documento se presta especial atenção a este síndrome comofim de alertar aos médicos de una particular população de alto risco,a qual pelo geralé subestimada e não se trata em forma ótimaosfatores de risco que constituemo síndrome metabólico. As presentes recomendações sãoo resultado das apresentaçõeseos debates nos painéis de discussão durante una reunião de 2 dias celebrada em Bucaramanga em outubro de 2012. Todosos participantes têm aprovado as conclusões finais. Os autores reconhecem que a publicaçãoe difusão dos guias no serão suficientes para alcançar os câmbios recomendados tanto nas estratégiasdiagnósticas quanto terapêuticas, pelo que se têm programadointervenções que permitam identificar as barreiras do conhecimento, das atitudes e de comportamento, o que permitirá tanto aos médicos quanto aos pacientes una adequada aderênciaàs recomendações dos guias.

Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials.

BACKGROUND: Daily aspirin reduces the long-term risk of death due to cancer. However, the short-term effect is less certain, especially in women, effects on cancer incidence are largely unknown, and the time course of risk and benefit in primary prevention is unclear. We studied cancer deaths in all trials of daily aspirin versus control and the time course of effects of low-dose aspirin on cancer incidence and other outcomes in trials in primary prevention. METHODS: We studied individual patient data from randomised trials of daily aspirin versus no aspirin in prevention of vascular events. Death due to cancer, all non-vascular death, vascular death, and all deaths were assessed in all eligible trials. In trials of low-dose aspirin in primary prevention, we also established the time course of effects on incident cancer, major vascular events, and major extracranial bleeds, with stratification by age, sex, and smoking status. RESULTS: Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio [OR] 0·85, 95% CI 0·76-0·96, p=0·008; 34 trials, 69,224 participants), particularly from 5 years onwards (92 vs 145; OR 0·63, 95% CI 0·49-0·82, p=0·0005), resulting in fewer non-vascular deaths overall (1021 vs 1173; OR 0·88, 95% CI 0·78-0·96, p=0·003; 51 trials, 77,549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35,535 participants), aspirin reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0·76, 95% CI 0·66-0·88, p=0·0003) in women (132 vs 176; OR 0·75, 95% CI 0·59-0·94, p=0·01) and in men (192 vs 245; OR 0·77, 95% CI 0·63-0·93, p=0·008). The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3·13 [95% CI 1·44-4·82] per 1000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control (8/203 vs 15/132; OR 0·32, 95% CI 0·12-0·83, p=0·009). INTERPRETATION: Alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extracranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer. FUNDING: None.

Effects of individual risk factors on the residual risk of cardiovascular events in a population of treated Chinese patients with hypertension: data from the Felodipine Event Reduction (FEVER) study.

BACKGROUND AND OBJECTIVES: The added cardiovascular risk conferred by risk factors or diseases accompanying hypertension has been investigated in Caucasian patients, and much less is known in Chinese patients. Furthermore, the residual risk persisting in hypertensive patients, despite blood pressure (BP) reduction, due to accompanying conditions has never been explored in Chinese, and whether they differ from Caucasians under this respect is unknown. METHODS: Felodipine Event Reduction (FEVER) study randomized 9711 Chinese hypertensive patients to more or less intense antihypertensive treatment for 40 months, with outcome monitoring. The present analyses provide information on the role that baseline presence of individual risk factors has in increasing outcome probability despite BP control. Risk ratios were calculated using Cox proportional hazard models, adjusted for a large number of baseline variables, except the one under examination, and also adjusted for on-treatment systolic and diastolic BP. RESULTS: Male sex, older age, diabetes and cardiovascular disease were accompanied by a significantly higher incidence of cardiovascular events (risk ratios 1.41-1.86 according to risk factor), stroke (risk ratios 1.42-1.72), cardiac events (risk ratios 1.40-2.70), all-cause death (risk ratios 1.51-2.16) and cardiovascular death (risk ratios 1.61-2.02). Higher baseline systolic BP and smoking conferred a significantly increased risk of cardiovascular events and strokes. Higher cholesterol was not found to increase any cardiovascular outcome. The same was the case for electrocardiographic left-ventricular hypertrophy and isolated systolic hypertension. CONCLUSIONS: A number of additional risk factors increased the residual risk of Chinese hypertensive patients despite effective antihypertensive treatment as much as described in Caucasians. High serum cholesterol was an exception: whether this is a Chinese characteristic or a more general phenomenon remains to be investigated.

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.

BACKGROUND: Low-dose aspirin is of definite and substantial net benefit for many people who already have occlusive vascular disease. We have assessed the benefits and risks in primary prevention. METHODS: We undertook meta-analyses of serious vascular events (myocardial infarction, stroke, or vascular death) and major bleeds in six primary prevention trials (95,000 individuals at low average risk, 660,000 person-years, 3554 serious vascular events) and 16 secondary prevention trials (17,000 individuals at high average risk, 43,000 person-years, 3306 serious vascular events) that compared long-term aspirin versus control. We report intention-to-treat analyses of first events during the scheduled treatment period. FINDINGS: In the primary prevention trials, aspirin allocation yielded a 12% proportional reduction in serious vascular events (0.51% aspirin vs 0.57% control per year, p=0.0001), due mainly to a reduction of about a fifth in non-fatal myocardial infarction (0.18%vs 0.23% per year, p<0.0001). The net effect on stroke was not significant (0.20%vs 0.21% per year, p=0.4: haemorrhagic stroke 0.04%vs 0.03%, p=0.05; other stroke 0.16%vs 0.18% per year, p=0.08). Vascular mortality did not differ significantly (0.19%vs 0.19% per year, p=0.7). Aspirin allocation increased major gastrointestinal and extracranial bleeds (0.10%vs 0.07% per year, p<0.0001), and the main risk factors for coronary disease were also risk factors for bleeding. In the secondary prevention trials, aspirin allocation yielded a greater absolute reduction in serious vascular events (6.7%vs 8.2% per year, p<0.0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (2.08%vs 2.54% per year, p=0.002) and in coronary events (4.3%vs 5.3% per year, p<0.0001). In both primary and secondary prevention trials, the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women. INTERPRETATION: In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds. Further trials are in progress. FUNDING: UK Medical Research Council, British Heart Foundation, Cancer Research UK, and the European Community Biomed Programme.

When should antihypertensive drug treatment be initiated and to what levels should systolic blood pressure be lowered? A critical reappraisal.

The evidence for two recommendations of all major guidelines on hypertension is critically discussed. The first recommendation is that of initiating antihypertensive drug treatment when systolic blood pressure is at least 140 or diastolic blood pressure at least 90 mmHg in patients with grade 1 hypertension and low or moderate total cardiovascular risk, and even when blood pressure is in the high normal range in patients with diabetes and previous cardiovascular disease. The second recommendation is that of achieving systolic blood pressure levels below 140 mmHg in all hypertensive patients, including the elderly, and values below 130 mmHg in patients having diabetes and high/very-high-risk patients. Critical analyses of the results of available trials show that the evidence is scanty for both recommendations. Nonetheless, they can be accepted as prudent statements, as antihypertensive agents are very well tolerated and lowering systolic blood pressure below 130 mmHg appears well tolerated. However, wisdom should not be taken for evidence, and simple trials should be designed to look for more solid evidence in favour of current recommendations.

Effects of antihypertensive treatment on ultrasound measures of myocardial fibrosis in hypertensive patients with left ventricular hypertrophy: results of a randomized trial comparing the angiotensin receptor antagonist, candesartan and the angiotensin-converting enzyme inhibitor, enalapril.

OBJECTIVE: To compare the effects of the angiotensin II receptor antagonist candesartan with the angiotensin-converting enzyme inhibitor enalapril on myocardial fibrosis evaluated by echoreflectivity analysis. METHODS: Hypertensive patients (n = 196) with echocardigraphically documented left ventricular hypertrophy were randomized to candesartan 8-16 mg/day (n = 91) or enalapril 10-20 mg/day (n = 105) with possible addition of hydrochlorothiazide (12.5-25 mg/day) for 48 weeks. Echoreflectivity analysis was performed on ultrasound two-dimensional tracings of the midapex septum with a specifically designed and validated software. Colour histograms were obtained; the primary outcome variable was the treatment-related change in histogram width (broadband), previously shown to correlate with collagen volume on endomyocardial biopsy; changes in mean colour scale were secondary outcome variable. RESULTS: Echoreflectivity analysis was feasible in 84 patients (48 candesartan, 36 enalapril). Broadband decreased significantly in the candesartan (-8.0 colour levels) and in the enalapril group (-12.9 colour levels) with no significant difference between treatments (P = 0.409); no significant changes occurred in mean colour scale. Patients under monotherapy (n = 46) showed similar trends as the larger intention to treat cohort, without significant difference between treatments. CONCLUSION: In hypertensive patients with left ventricular hypertrophy, both candesartan and enalapril induce a moderate but statistically significant reduction in an echoreflectivity index of myocardial fibrosis.

Twenty-year cardiovascular and all-cause mortality trends and changes in cardiovascular risk factors in Gubbio, Italy: the role of blood pressure changes.

AIMS: In an observational population study that lasted 20 years, the relationships between mortality trends and changes in cardiovascular risk factor levels were examined. METHODS AND RESULTS: In the town of Gubbio, in central Italy, population surveys for measurement of cardiovascular risk factors were performed 20 years apart. In a subset of the initial cohort (1927 men and 2333 women), mortality data were collected for 20 years. Cardiovascular risk factor levels were compared in individuals in the same age range (20-79 years) examined at the initial survey (1927 men and 2333 women) and at the final survey (1761 men and 2055 women). Age-adjusted rates significantly declined, by 28% among men and 51% among women, for all causes of death, and by 50% among men and 71% among women for cardiovascular disease deaths. Declines were observed in the levels of systolic blood pressure, serum cholesterol, resting heart rate, smoking habits, BMI, plasma glucose (the latter two only in women) and the estimated cardiovascular risk, together with increases in serum high-density lipoprotein cholesterol and in the proportion of treated and controlled hypertensive patients. CONCLUSION: Although similar but less impressive changes were recorded in Italy at large, the existence of the observational study in Gubbio might have motivated the general population and the medical profession towards actions promoting general health.

Definition of kidney dysfunction as a cardiovascular risk factor: use of urinary albumin excretion and estimated glomerular filtration rate.

BACKGROUND: Urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) have been used separately to provide information about cardiovascular risk. We analyzed whether UAE and eGFR used together provide complementary information. METHODS: We analyzed UAE, eGFR, cardiovascular risk factors, and incidence of cardiovascular disease in 1665 men and women of the Gubbio Population Study (aged 45-64 years). We designated UAE in the highest decile as high (>or= 18.6 microg/min in men and >or= 15.7 microg/min in women) and eGFR in the lowest decile as low (<64.20 mL/min/1.73 m(2) in men and <57.90 mL/min/1.73 m(2) in women). RESULTS: Kidney dysfunction defined using both markers was more frequent than using 1 marker (UAE alone or eGFR alone) (P< .001) because high UAE and low eGFR clustered in different individuals and were weakly associated with each other (P= .12). The hazard ratio (HR) for incident cardiovascular disease was elevated for both markers, independently of each other (HR for high UAE, 2.15; 95% confidence interval [CI], 1.33-3.49; HR for low eGFR, 2.14; 95% CI, 1.32-3.48). Kidney dysfunction defined by both markers predicted cardiovascular disease independently of sex, age, hypertension, hypercholesterolemia, smoking, diabetes mellitus, prior cardiovascular disease, left ventricular hypertrophy, and obesity (HR, 1.50; 95% CI, 1.05-2.14). The discriminant power of dysfunction defined by both markers was statistically significant (area under the receiver operating characteristic curve, 0.569 [P= .02]) and slightly higher than what was found with 1 marker of diabetes mellitus, prior cardiovascular disease, left ventricular hypertrophy, and obesity. CONCLUSIONS: High UAE and low eGFR provide complementary information in defining kidney dysfunction because they cluster in different individuals. Concomitant evaluation of both markers should be considered to adequately assess kidney dysfunction and cardiovascular risk.

Prevalence and correlates of multiple organ damage in a never-treated hypertensive population: role of ambulatory blood pressure.

AIM: Available evidence on multiple target organ damage (TOD) in the early phases of essential hypertension is scanty. We examined the prevalence and correlates of multiple TOD in never-treated patients with recently diagnosed hypertension. METHODS: A total of 602 consecutive outpatients with grades 1 and 2 hypertension underwent the following procedures: (i) routine examination, (ii) 24-h urine collection for microalbuminuria, (iii) ambulatory blood pressure monitoring over two 24-h periods within 4 weeks, (iv) echocardiography, (v) carotid ultrasonography. TOD at cardiac, vascular and renal levels was defined according to major international hypertension guidelines. RESULTS: Prevalence rates of patients negative for TOD (group I) or positive for one (group II), two (group III), or three (group IV) markers of TOD were as follows: 45, 33, 17 and 5%. In group II, alterations in left ventricular structure and geometry were more frequently present than carotid atherosclerosis and microalbuminuria; a similar trend was found in group III where a close association between cardiac and vascular, but not renal, signs of TOD was observed. In multiple regression analyses the risk of having three TOD was significantly related to age [odds ratio (OR): 2.11, 95% confidence interval (CI): 1.34-3.53], average 48-h systolic blood pressure (OR: 1.81, 95% CI: 1.22-2.95), smoking status (OR: 1.76, 95% CI: 1.22-2.86), male sex (OR: 1.36, 95% CI: 1.24-1.79), reproducible nondipping pattern (OR: 1.27, 95% CI: 1.12-1.61) and metabolic syndrome (OR: 1.16, 95% CI: 1.09-1.74). CONCLUSIONS: Our results show that: (i) a cluster of three TOD, namely at cardiac, carotid and renal levels, is not a common finding in a population of untreated essential hypertensive patients; a single TOD is present in about one-third of the patients and the parallel involvement of two organs in one-fifth of the cases; (ii) old age, ambulatory systolic blood pressure and smoking status are the most important predictors of multiple organ involvement.

Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: An analysis of findings from the VALUE trial.

BACKGROUND: In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial the primary outcome (cardiac morbidity and mortality) did not differ between valsartan and amlodipine-based treatment groups, although systolic blood pressure (SBP) and diastolic blood pressure reductions were significantly more pronounced with amlodipine. Stroke incidence was non-significantly, and myocardial infarction was significantly lower in the amlodipine-based regimen, whereas cardiac failure was non-significantly lower on valsartan. OBJECTIVES: The study protocol specified additional analyses of the primary endpoint according to: sex; age; race; geographical region; smoking status; type 2 diabetes; total cholesterol; left ventricular hypertrophy; proteinuria; serum creatinine; a history of coronary heart disease; a history of stroke or transient ischemic attack; and a history of peripheral artery disease. Additional subgroups were isolated systolic hypertension and classes of antihypertensive agents used immediately before randomization. METHODS: The 15,245 hypertensive patients participating in VALUE were divided into subgroups according to baseline characteristics. Treatment by subgroup interaction analyses were carried out by a Cox proportional hazard model. Within each subgroup, treatment effects were assessed by hazard ratios and 95% confidence intervals. RESULTS: For cardiac mortality and morbidity, the only significant subgroup by treatment interaction was of sex (P = 0.016), with the hazard ratio indicating a relative excess of cardiac events with valsartan treatment in women but not in men, but SBP differences in favour of amlodipine were distinctly greater in women. No other subgroup showed a significant difference in the composite cardiac outcome between valsartan and amlodipine-based treatments. For secondary endpoints, a sex-related significant interaction was found for heart failure (P < 0.0001), with men but not women having a lower incidence of heart failure with valsartan. CONCLUSION: As in the whole VALUE cohort, in no subgroup of patients were there differences in the incidence of the composite cardiac endpoint with valsartan and amlodipine-based treatments, despite a greater blood pressure decrease in the amlodipine group. The only exception was sex, in which the amlodipine-based regimen was more effective than valsartan in women, but not in men, whereas the valsartan regimen was more effective in preventing cardiac failure in men than in women.