Microalbuminuria in subjects with hypertension attending specialist blood pressure clinics.

Albuminuria is associated with increased risk of cardiovascular disease and target organ damage in patients with diabetes mellitus. In nondiabetic hypertensive patients, the threshold at which microalbuminuria (MAU) increases risk is unclear and there is evidence that cardiovascular risk may be increased in individuals with MAU levels lower than the usual recommended screening thresholds. We compared two definitions of MAU (on the basis of three early morning urine samples) in a cohort of hypertensive patients attending two specialist clinics in Scotland: conventional (MAU(C)) albumin-to-creatinine ratio (ACR) >2.5-25 mg mmol(-1) in males or >3.5-25 mg mmol(-1) in females; and low-grade (MAU(L)) ACR 1.2-2.5 in males or 1.7-3.5 mg mmol(-1) in females. Of the 1059 subjects screened, 786 (74%) were nondiabetic, with estimated glomerular filtration rate ⩾30 ml min(-1) per 1.73 m(2) and without gross proteinuria (low-risk subset). The average age was 58±15 years, body mass index 30±6 kg m(-2) and 46% were males. The prevalence of MAU(C) was 11% and 9.5% in the overall and low-risk subset, respectively, whereas MAU(L) prevalence was 11.1% and 10% respectively. The prevalence of cardiovascular disease was higher (24%) with albuminuria (both MAU(C) and MAU(L)) compared with 14% among those without albuminuria. The use of MAU(L) doubled the number of hypertensive subjects with increased cardiovascular risk who can be targeted for more rigorous risk reduction strategies. Consideration should be given to reducing the current threshold for MAU.

Do we need more long-term outcome trials for the treatment of hypertension?

The epidemiology of arterial hypertension and its treatment has been underlined by a huge research literature. Consistently raised arterial blood pressure in a clinic or home setting is a simple clinical observation that marks a predilection to a variety of fatal and non-fatal vascular disease events. Over the past 50 years tolerable, safe and effective primary and secondary medicines to offset a substantial amount of the associated morbidity and mortality risk of elevated blood pressure have emerged. Due to the nature of the population-relative risk and low absolute risk of this phenomenon it has often taken very large numbers of patients recruited from multiple centres in several countries and huge financial investment to define these profiles. Few national clinical research funds have invested in this process and it has often been left to a relatively small group of investigators to work closely with the commercial producers of new medicines to complete the essential outcome trials on which much of contemporary cardiovascular medical practice is based. Currently there are few, if any, significant new drug entities relevant to raised blood pressure under development. Most of the underlying clinical management principles and associations are clear. Achieved blood pressure, through patient adherence and variable prescriber practice, defines outcomes for individuals. The theoretical likelihood of a major step forward in the understanding of raised arterial blood pressure or a preferred means for population management is low. Moreover, with few new drug entities, investment in major outcome trials is unlikely to be proposed and the target for new trials is perhaps less apparent. While there can be no doubt that few areas in recent medical practice have benefited more from such huge achievements in underlining treatment, is it time to move on from the cardiovascular mega trial in hypertension?

Comparison of the efficacy of candesartan and losartan: a meta-analysis of trials in the treatment of hypertension.

Informed by the findings from prospective observational studies and randomized outcome trials, guidelines for the management of hypertension acknowledge that the benefit of treatment can be attributed largely to blood pressure (BP) reduction. Therefore, quantification of differential BP lowering of different agents within classes of anti-hypertensives is of practical importance. The objective of this analysis was to compare the efficacy of candesartan and losartan with respect to reduction in systolic and diastolic BP (SBP and DBP). A systematic literature search of databases from 1980 to 1 October 2008 identified 13 studies in which candesartan and losartan were compared in randomized trials in hypertensive patients. Data from 4066 patients were included in the analysis using a random effect model. Mean changes in SBP and DBP were compared for each drug alone and after stratification for dose and for combination with hydrochlorothiazide (HCTZ). On the basis of all the data, the weighted mean difference favoured candesartan-3.22 mm Hg (95% confidence interval (CI) 2.16, 4.29) for SBP and 2.21 mm Hg (95% CI 1.34, 3.07) for DBP. These findings were consistent when analyses according to dose and combination with HCTZ were carried out. Thus, it can be concluded that at currently recommended doses, candesartan is more effective than losartan in lowering BP.

Statin administration prior to ischaemic stroke onset and survival: exploratory evidence from matched treatment-control study.

In addition to their lipid-lowering effects, it has been speculated that statins may also have beneficial effects on cerebral circulation and brain parenchyma during ischaemic stroke and reperfusion. We hypothesized that patients who had taken statins prior to stroke onset may have a better survival rate at 1 month and during the follow-up period. We retrospectively studied consecutive ischaemic stroke patients admitted to an acute stroke unit and at least a month's follow-up. From these, we included those patients who, at admission, had reported the use of a statin prior to the stroke onset in the statin group (n = 205). Each patient in the statin group was matched with two patients who reported no statin use (n = 410). Using logistic regression and Cox proportional hazards models, we adjusted for variables that significantly differed between treatment groups or that independently predicted mortality. After adjusting for those variables, statin use was associated with reduced mortality at 1 month [odds ratio 0.24; 95% confidence interval (CI) 0.09-0.67] and during the follow-up period (hazard ratio 0.57; 95% CI 0.35-0.93). The use of statins prior to stroke onset is associated with improved stroke survival within this cohort study with matched controls.

Angiotensin-II receptor blockers: benefits beyond blood pressure reduction?

Effective treatment of hypertension is essential to reduce the risk of renal and cardiovascular (CV) morbidity. The risks associated with hypertension are modulated by the presence of other factors. This has prompted the quest for agents that have benefits beyond blood pressure (BP) lowering. The angiotensin II receptor blocker (ARB) class of antihypertensive agents represents an important addition to the therapeutic options for elevated BP. Their ability to control BP is equivalent to existing therapies and there is a considerable and mounting evidence-base for their ability to reduce hypertension-associated target organ damage and comorbidities. Studies show that ARBs have clinical benefits across the spectrum of disease severity. In particular, recent large studies have demonstrated that these benefits extend to patients with conditions predisposing to CV events, such as diabetes, left ventricular hypertrophy and microalbuminuria, and where risk factors coexist. Data from these studies suggest that the CV protective effects of ARBs are at least, in part, independent from the BP lowering action. In addition, ARBs are extremely well tolerated, and strong evidence suggests that compliance with therapy--a key factor in achieving adequate BP control--with ARBs is higher than with other antihypertensive agents. Furthermore, flexible dosing and good tolerability profile mean that, where necessary, ARBs can be combined with other classes of antihypertensive agents to achieve adequate BP control and reduce the risk of hypertension-associated morbidity.

Why not prescribe the best drugs for hypertension now?

As Westernised societies have become more affluent, the attitudes of the population have become more risk-aware. People are now intolerant of small risks as well as the physical or mental discomforts from drug side effects. Safety and tolerability are now major forces driving the development of new medicines for the treatment of chronic illnesses and the prevention of increasingly rare events. For example, over the past decades, lower and lower treatment thresholds have been recommended in hypertension. Public perception of risk strongly influences the acceptability of lifetime treatment, especially for mild hypertension. This era has also witnessed great advances in the development of antihypertensive drugs that combine efficacy with unsurpassed tolerability. However, the philosophy of Scottish teachers of Materia medica still appears to be followed-'never be the first or the last to prescribe a new drug'. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists are as safe and as efficacious as other antihypertensive medications and better tolerated. Large trials (HOT, HOPE, UKPDS and PROGRESS) point to the need for rigorous control of blood pressure particularly in high-risk individuals. Antihypertensive drugs that act on the renin-angiotensin system will probably impact significantly on achieving optimal blood pressure levels. Should it not now be accepted that high-risk patients should have ACE inhibitors and angiotensin II receptor antagonists prescribed as first-line agents? We review the evidence for the use of ACE inhibitors and angiotensin II receptor antagonists as antihypertensive agents.

Clinical potential: angiotensin converting enzyme inhibitor or angiotensin II antagonist?

Blockade of the renin-angiotensin system by angiotensin converting enzyme (ACE) inhibitors has an established role in the management of hypertension, heart failure, patients post-myocardial infarction and renal impairment. The mechanism of action of angiotensin II antagonists offers the potential of more complete blockade of angiotensin II, selective inhibition of the AT1 receptor and specificity for the renin-angiotensin system. Whether these mechanistic differences enhance the clinical potential of these drugs remains to be established. Preliminary evidence suggests that ACE inhibitors and angiotensin II antagonists have similar antihypertensive, haemodynamic and nephroprotective effects. Several major outcome trials with angiotensin II antagonists are underway and these should determine the eventual clinical potential of this class. Early results suggest equivalence with ACE inhibitors but further direct comparisons are needed. Angiotensin II antagonists have one undisputed advantage--excellent tolerability. Given the continuing under-use of ACE inhibitors because of concerns about adverse effects, this property alone may prove decisive in ensuring that angiotensin II antagonists yield the full clinical potential from blockade of the renin-angiotensin system.

Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. ASCOT investigators.

OBJECTIVE: To test the primary hypothesis that a newer antihypertensive treatment regimen (calcium channel blocker +/- an angiotensin converting enzyme inhibitor) is more effective than an older regimen (beta-blocker +/- a diuretic) in the primary prevention of coronary heart disease (CHD). To test a second primary hypothesis that a statin compared with placebo will further protect against CHD endpoints in hypertensive subjects with a total cholesterol < or = 6.5 mmol/l. DESIGN: Prospective, randomized, open, blinded endpoint trial with a double-blinded 2 x 2 factorial component. SETTING: Patients were recruited mainly from general practices. PATIENTS: Men and women aged 40-79 were eligible if their blood pressure was > or = 160 mmHg systolic or > or = 100 mmHg diastolic (untreated) or > or = 140 mmHg systolic or > or = 90 mmHg diastolic (treated) at randomization. INTERVENTIONS: Patients received either amlodipine (5/ 10 mg) +/- perindopril (4/8 mg) or atenolol (50/ 100 mg) +/- bendroflumethiazide (1.25/2.5 mg) +K+ with further therapy as required to reach a blood pressure of < or = 140 mmHg systolic and 90 mmHg diastolic. Patients with a total cholesterol of < or = 6.5 mmol/l were further randomized to receive either atorvastatin 10 mg or placebo daily. MAIN OUTCOME MEASURE: Non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD). RESULTS: 19 342 men and women were initially randomized, of these 10297 were also randomized into the lipid-lowering limb. All patients had three or more additional cardiovascular risk factors. CONCLUSIONS: The study has 80% power (at the 5% level) to detect a relative difference of 20% in CHD endpoints between the calcium channel blocker-based regimen and the beta-blocker-based regimen. The lipid-lowering limb of the study has 90% power at the 1% level to detect a relative difference of 30% in CHD endpoints between groups.

Effects of individual risk factors on the incidence of cardiovascular events in the treated hypertensive patients of the Hypertension Optimal Treatment Study. HOT Study Group.

BACKGROUND: The Hypertension Optimal Treatment (HOT) Study has provided information about cardiovascular events in 18790 hypertensives, subjected to pronounced blood pressure (BP) lowering for a mean of 3.8 years. The HOT study data have subsequently been analysed after stratification of the patients according to global cardiovascular risk, and it has been found that, despite intensive blood pressure lowering in all risk strata, morbid event rates increased with increasing risk stratum. OBJECTIVES: Previously analysed global risk strata were based on combinations of risk factors. The analyses presented here were intended to provide information on the relative role that the presence of each individual factor may have in increasing cardiovascular risk, despite good BP control. METHODS: Risk ratios (RR) for patients with and those without a risk factor were calculated with 95% confidence intervals (CI) using a Cox proportional hazard model, and adjusted for all variables except the one under examination. RESULTS: For all risk factors considered and for all types of event, RR were always greater than 1, indicating a greater risk in the presence, compared with that in the absence of each factor. The male gender was a statistically significant risk for cardiovascular (CV) events, CV and total mortality and particularly for myocardial infarction (MI); age > or = 65 years for CV events, stroke, CV and particularly total mortality; smoking for all events analysed, but particularly for total mortality (twice higher in smokers than in non-smokers); high serum cholesterol (> 6.8 mmol/l) for CV events, MI and CV mortality; high serum creatinine (> 155 micromol/l) for CV events, stroke, CV and total mortality; diabetes for CV events, stroke, total mortality and particularly CV mortality; and ischaemic heart disease for all events analysed. Adjusted RR were often close to or greater than 2. CONCLUSIONS: Each of the risk factors considered was found to be an important cause of residual risk, despite good BP control. These findings emphasize the importance of addressing other correctable risk factors, e.g. smoking, hypercholesterolaemia and diabetes, as well as rigorous control of blood pressure, and of initiating antihypertensive therapy before cardiovascular and renal damage becomes manifest.