Bryan Williams

Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.

BACKGROUND In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain. METHODS We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately. RESULTS After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001). CONCLUSIONS A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)

Differential Impact of Blood Pressure–Lowering Drugs on Central Aortic Pressure and Clinical Outcomes Principal Results of the Conduit Artery Function Evaluation (CAFE) Study

Background— Different blood pressure (BP)–lowering drugs could have different effects on central aortic pressures and thus cardiovascular outcome despite similar effects on brachial BP. The Conduit Artery Function Evaluation (CAFE) study, a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), examined the impact of 2 different BP lowering-regimens (atenolol±thiazide-based versus amlodipine±perindopril-based therapy) on derived central aortic pressures and hemodynamics. Methods and Results— The CAFE study recruited 2199 patients in 5 ASCOT centers. Radial artery applanation tonometry and pulse wave analysis were used to derive central aortic pressures and hemodynamic indexes on repeated visits for up to 4 years. Most patients received combination therapy throughout the study. Despite similar brachial systolic BPs between treatment groups (&Dgr;0.7 mm Hg; 95% CI, −0.4 to 1.7; P=0.2), there were substantial reductions in central aortic pressures with the amlodipine regimen (central aortic systolic BP, &Dgr;4.3 mm Hg; 95% CI, 3.3 to 5.4; P<0.0001; central aortic pulse pressure, &Dgr;3.0 mm Hg; 95% CI, 2.1 to 3.9; P<0.0001). Cox proportional-hazards modeling showed that central pulse pressure was significantly associated with a post hoc–defined composite outcome of total cardiovascular events/procedures and development of renal impairment in the CAFE cohort (unadjusted, P<0.0001; adjusted for baseline variables, P<0.05). Conclusions— BP-lowering drugs can have substantially different effects on central aortic pressures and hemodynamics despite a similar impact on brachial BP. Moreover, central aortic pulse pressure may be a determinant of clinical outcomes, and differences in central aortic pressures may be a potential mechanism to explain the different clinical outcomes between the 2 BP treatment arms in ASCOT.

MORTALITY AND MORBIDITY RESULTS FROM THE EUROPEAN WORKING PARTY ON HIGH BLOOD PRESSURE IN THE ELDERLY TRIAL

The latter was due to a reduction in cardiac mortality (−38%, p=0.036) and a nonsignificant decrease in cerebrovascular mortality (−32%, p=0.16). In the double-blind part of the trial, the total mortality rate was not significantly reduced (−26%, p=0.077). However, cardiovascular mortality was reduced in the actively treated group (−38%, p=0.023), owing to a reduction in cardiac deaths (−47%, p=0.048) and a non-significant decrease in cerebrovascular mortality (−43%, p=0.15). Deaths from myocardial infarction were reduced (−60%, p=0.043), and study-terminating morbid cardiovascular events were significantly reduced by active treatment (−60%, p=0.0064). Non-terminating cerebrovascular events were reduced (−52%, p=0.026), but the non-terminating cardiac events were not (+ 3%, p=0.98). In the patients randomised to active treatment there were 29 fewer cardiovascular events and 14 fewer cardiovascular deaths per 1000 patient years during the double-blind part of the trial.

Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV.

Summary of recommendationsProvide advice on life-style modifications for all people with high blood pressure (BP) and those with borderline or high-normal BP. Advice on effective nonpharmacological interventions is provided (A).Initiate antihypertensive drug therapy in people with sustained systolic BP (SBP) ⩾160 mmHg or sustained diastolic BP (DBP) ⩾100 mmHg (A).Make treatment decisions in people with sustained SBP between 140 and 159 mmHg and/or sustained DBP between 90 and 99 mmHg according to the presence or absence of cardiovascular disease, other target organ damage, or an estimated cardiovascular disease (CVD) risk of ⩾20% over 10 years, according to the Joint British Societies CVD risk assessment programme/risk chart (A).CVD risk replaces CHD risk estimation to reflect the importance of stroke prevention as well as CHD prevention. The new CVD risk threshold of ⩾20% is equivalent to a CHD risk of approximately ⩾15% over 10 years.In people with diabetes mellitus, initiate antihypertensive drug therapy if SBP is sustained ⩾140 mmHg and/or DBP is sustained ⩾90 mmHg (B).In nondiabetic people with hypertension, the optimal BP treatment goals are: SBP <140 mmHg and DBP <85 mmHg. The minimum acceptable level of control (Audit Standard) recommended is <150/<90 mmHg. Despite the best practice, these levels will be difficult to achieve in some hypertensive people (B).In people with diabetes and high BP, optimal BP goals are: SBP <130 mmHg and DBP <80 mmHg. The minimum acceptable level of control (Audit Standard) recommended is <140/<80 mmHg. Despite the best practice, these levels will be difficult to achieve in some people with diabetes and hypertension (B).Meta-analyses of BP-lowering trials have confirmed that, in general, the main determinant of benefit from BP-lowering drugs is the achieved BP, rather than choice of therapy. In some circumstances, there are compelling indications and contraindications for specific classes of antihypertensive drugs, and these are specified (A).Most people with high BP will require at least two BP-lowering drugs to achieve the recommended BP goals. A treatment algorithm (AB/CD) is provided to advise on the sequencing of drugs and logical drug combinations (C). When there are no cost disadvantages, fixed drug combinations are recommended to reduce the number of medications, which may enhance adherence to treatment (C).Other drugs that reduce CVD risk must also be considered, notably, low-dose aspirin and statin therapy (A).Unless contraindicated, low-dose aspirin (75 mg/day) is recommended for all people needing secondary prevention of ischaemic CVD, and primary prevention in people with hypertension over the age of 50 years who have a 10-year CVD risk ⩾20% and in whom BP is controlled to the audit standard (A).Statin therapy is recommended for all people with high BP complicated by CVD, irrespective of baseline total cholesterol or low-density lipoprotein (LDL)-cholesterol levels. Similarly, statin therapy is also recommended for primary prevention in people with high BP who have a 10-year CVD risk ⩾20%, estimated from the Joint British Societies CVD risk-assessment programme/chart. Optimal cholesterol lowering should reduce the total cholesterol by 25% or LDL-cholesterol by 30% or achieve a total cholesterol of <4.0 mmol/l or LDL-cholesterol of <2.0 mmol/l, whichever is the greatest reduction (A).Glycaemic control should be optimised in people with diabetes, for example, HbA1c <7% (A).Advice is provided on the clinical management of hypertension in specific patient groups, that is, the elderly, ethnic minorities, people with diabetes mellitus, chronic renal disease, and in women (pregnancy, oral contraceptive use and hormone-replacement therapy).Suggestions for the improved implementation and audit of these guidelines in primary care are provided.

British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary

Much new evidence has emerged on the importance of blood pressure as a risk factor for cardiovascular disease; the importance of lifestyle measures for the prevention and treatment of hypertension; the efficacy and safety of different drug classes; management of hypertension in groups at higher risk, including people with diabetes; the importance of assessing the total risk of cardiovascular disease; and additional benefits associated with the use of statins. Concern remains that national surveys continue to show substantial underdiagnosis, undertreatment, and poor rates of blood pressure control in the United Kingdom.1 A key reason for this is the predominant use of monotherapy by most doctors.1 To improve this suboptimal treatment, the British Hypertension Society recommends a treatment algorithm based on the AB/CD rule.2 Treatment of blood pressure alone will leave many hypertensive patients at unacceptably high risk of cardiovascular complications and death. This guideline reinforces the view that doctors should not focus solely on blood pressure but must also formally assess total risk of cardiovascular disease and use multifactorial interventions, including statins and aspirin, to reduce it. Most management of blood pressure and risk of cardiovascular disease will take place in primary care, and these guidelines are intended for general practitioners, practice nurses, and generalists in hospital practice. Detailed advice on implementation and the implications of the national service frameworks and the general medical services contract are contained in the full document (http://www.bhsoc.org/).3 These guidelines have been prepared by the guidelines working party of the British Hypertension Society on behalf of the society. The working party reviewed new data that have become available since the previous guidelines were published4 and amended the recommendations accordingly. Drafts of the full document were improved by consultation with …

Central Blood Pressure Measurements and Antihypertensive Therapy. A Consensus Document

The 2003 European Society of Hypertension/European Society of Cardiology guidelines for the management of arterial hypertension1 included 2 important novel recommendations: assessment of the total cardiovascular risk should be taken into account in the management of the hypertensive patient, and quantification of risk should include subclinical target organ damage. These guidelines acknowledged that central (aortic) blood pressure (BP), which is the pressure exerted on the heart and brain, may be different from the pressure that is measured at the arm. They also recognized that central pressure may be predictive of outcome in specific populations2 and differently affected by antihypertensive drugs. However, although these guidelines accepted that central augmentation index and pulse wave velocity may be important as measures of subclinical organ damage, they also stressed the need for prospective trials to establish their predictive values given that such studies were lacking at that time (2003). After publication of these guidelines, additional data have strengthened the pathophysiological importance of central BP. Clinical studies have indicated that central BP may have predictive value independent of the corresponding peripheral (brachial) BP. More importantly, recent large-scale trials have shown that central hemodynamics may provide a worthwhile treatment target. In addition, central hemodynamics can now be reliably assessed noninvasively with a number of devices. Accordingly, because arterial stiffening and central hemodynamics are markers and manifestations of organ damage, the pertinent key question is whether the balance of evidence on their importance and issues related to clinical practice allows for implementation in patient management. Central (aortic and carotid) pressures are pathophysiologically more relevant than peripheral pressures for the pathogenesis of cardiovascular disease.3,4 It is aortic systolic pressure that the left ventricle encounters during systole (afterload), and the aortic pressure during diastole is a determinant of coronary perfusion. Furthermore, the distending pressure in the …

Guidelines for management of hypertension: report of the third working party of the British Hypertension Society

Use non-pharmacological measures in all hypertensive and borderline hypertensive people.Initiate antihypertensive drug therapy in people with sustained systolic blood pressures (BP) ⩾160 mm Hg or sustained diastolic BP ⩾100 mm Hg.Decide on treatment in people with sustained systolic BP between 140 and 159 mm Hg or sustained diastolic BP between 90 and 99 mm Hg according to the presence or absence of target organ damage, cardiovascular disease or a 10-year coronary heart disease (CHD) risk of ⩾15% according to the Joint British Societies CHD risk assessment programme/risk chart.In people with diabetes mellitus, initiate antihypertensive drug therapy if systolic BP is sustained ⩾140 mm Hg or diastolic BP is sustained ⩾90 mm Hg.In non-diabetic hypertensive people, optimal BP treatment targets are: systolic BP <140 mm Hg and diastolic BP <85 mm Hg. The minimum acceptable level of control (Audit Standard) recommended is <150/<90 mm Hg. Despite best practice, these levels will be difficult to achieve in some hypertensive people.In diabetic hypertensive people, optimal BP targets are; systolic BP <140 mm Hg and diastolic BP <80 mm Hg. The minimum acceptable level of control (Audit Standard) recommended is <140/<90 mm Hg. Despite best practice, these levels will be difficult to achieve in some people with diabetes and hypertension.In the absence of contraindications or compelling indications for other antihypertensive agents, low dose thiazide diuretics or beta-blockers are preferred as first-line therapy for the majority of hypertensive people. In the absence of compelling indications for beta-blockade, diuretics or long acting dihydropyridine calcium antagonists are preferred to beta-blockers in older subjects. Compelling indications and contraindications for all antihypertensive drug classes are specified.For most hypertensives, a combination of antihypertensive drugs will be required to achieve the recommended targets for blood pressure control.Other drugs that reduce cardiovascular risk must also be considered. These include aspirin for secondary prevention of cardiovascular disease, and primary prevention in treated hypertensive subjects over the age of 50 years who have a 10-year CHD risk ⩾15% and in whom blood pressure is controlled to the audit standard. In accordance with existing British recommendations, statin therapy is recommended for hypertensive people with a total cholesterol ⩾5 mmol/L and established vascular disease, or 10-year CHD risk ⩾30% estimated from the Joint British Societies CHD risk chart. Glycaemic control should also be optimised in diabetic subjects.Specific advice is given on the management of hypertension in specific patient groups, ie, the elderly, ethnic subgroups, diabetes mellitus, chronic renal disease and in women (pregnancy, oral contraceptive use and hormone replacement therapy).Suggestions for the implementation and audit of these guidelines in primary care are provided.

Albuminuria and Kidney Function Independently Predict Cardiovascular and Renal Outcomes in Diabetes

There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.

Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people

Summary Background The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared. In this study, we aimed to analyse the associations of blood pressure with 12 different presentations of cardiovascular disease. Methods We used linked electronic health records from 1997 to 2010 in the CALIBER (CArdiovascular research using LInked Bespoke studies and Electronic health Records) programme to assemble a cohort of 1·25 million patients, 30 years of age or older and initially free from cardiovascular disease, a fifth of whom received blood pressure-lowering treatments. We studied the heterogeneity in the age-specific associations of clinically measured blood pressure with 12 acute and chronic cardiovascular diseases, and estimated the lifetime risks (up to 95 years of age) and cardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30, 60, and 80 years. This study is registered at ClinicalTrials.gov, number NCT01164371. Findings During 5·2 years median follow-up, we recorded 83 098 initial cardiovascular disease presentations. In each age group, the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90–114 mm Hg and diastolic blood pressure of 60–74 mm Hg, with no evidence of a J-shaped increased risk at lower blood pressures. The effect of high blood pressure varied by cardiovascular disease endpoint, from strongly positive to no effect. Associations with high systolic blood pressure were strongest for intracerebral haemorrhage (hazard ratio 1·44 [95% CI 1·32–1·58]), subarachnoid haemorrhage (1·43 [1·25–1·63]), and stable angina (1·41 [1·36–1·46]), and weakest for abdominal aortic aneurysm (1·08 [1·00–1·17]). Compared with diastolic blood pressure, raised systolic blood pressure had a greater effect on angina, myocardial infarction, and peripheral arterial disease, whereas raised diastolic blood pressure had a greater effect on abdominal aortic aneurysm than did raised systolic pressure. Pulse pressure associations were inverse for abdominal aortic aneurysm (HR per 10 mm Hg 0·91 [95% CI 0·86–0·98]) and strongest for peripheral arterial disease (1·23 [1·20–1·27]). People with hypertension (blood pressure ≥140/90 mm Hg or those receiving blood pressure-lowering drugs) had a lifetime risk of overall cardiovascular disease at 30 years of age of 63·3% (95% CI 62·9–63·8) compared with 46·1% (45·5–46·8) for those with normal blood pressure, and developed cardiovascular disease 5·0 years earlier (95% CI 4·8–5·2). Stable and unstable angina accounted for most (43%) of the cardiovascular disease-free years of life lost associated with hypertension from index age 30 years, whereas heart failure and stable angina accounted for the largest proportion (19% each) of years of life lost from index age 80 years. Interpretation The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range, and that diastolic and systolic associations are concordant, are not supported by the findings of this high-resolution study. Despite modern treatments, the lifetime burden of hypertension is substantial. These findings emphasise the need for new blood pressure-lowering strategies, and will help to inform the design of randomised trials to assess them. Funding Medical Research Council, National Institute for Health Research, and Wellcome Trust.

Management of hypertension: summary of NICE guidance.

Hypertension is one of the most important preventable causes of death worldwide and one of the commonest conditions treated in primary care in the United Kingdom, where it affects more than a quarter of all adults and over half of those over the age of 65 years.1 This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the management of hypertension,2 which updates the 2004 and 2006 clinical guidelines.3 4 5 NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Diagnosing hypertension (Updated recommendation) [ Based on the experience and opinion of the Guideline Development Group (GDG) ]