Valsartan Antihypertensive Long-term Use Research Articles

The angiotensin receptor antagonist valsartan: a review of the literature with a focus on clinical trials

Valsartan is an angiotensin receptor antagonist that specifically blocks the angiotensin II type 1 receptors. It is an effective and well-tolerated once-daily antihypertensive agent, with a tolerability profile similar to placebo. A recent series of large-scale clinical trials have shown the benefits of valsartan in disease states beyond hypertension. Based on the results of the Val-HeFT (Valsartan in Heart Failure Trial) and VALIANT (Valsartan in Acute Myocardial Infarction Trial) studies, valsartan is indicated for use in patients with heart failure and in patients post-myocardial infarction. Recently, in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial, valsartan was no more cardioprotective than calcium channel blockers, but was shown to reduce the risk of developing new-onset diabetes in hypertensive patients at high risk of cardiac events compared with calcium antagonist treatment. In diabetic patients with microalbuminuria, valsartan has been shown to have benefits beyond those attributable to blood pressure lowering alone.

Angiotensin Receptor Blockers: Cardiovascular Protection in the Metabolic Syndrome

It is well recognised that the metabolic syndrome, a constellation of risk factors including obesity, hypertension, insulin resistance and dyslipidaemia, is associated with an increased risk of cardiovascular complications and the development of Type 2 diabetes. Consequently, timely identification and management of all components of the metabolic syndrome is warranted. In particular, guidelines have emphasised the importance of targeting elevated blood pressure (BP) and dyslipidaemia as a method of reducing global cardiovascular risk. Findings from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial show that the angiotensin receptor blocker, valsartan, reduces cardiovascular events and the development of Type 2 diabetes in high-risk individuals. This profile is being further explored in the ongoing Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Given the potential advantages to patients and physicians of tackling more than one of the components of the metabolic syndrome, antihypertensive agents such as valsartan would appear to be and important addition to the management of vulnerable patients at high risk of cardiovascular events.

The importance of early antihypertensive efficacy: the role of angiotensin II receptor blocker therapy

Desirable features of antihypertensive agents include efficacy, tolerability, prolonged duration of action and rapid achievement of target blood pressure (BP). Recent studies have examined the relationship between the onset of antihypertensive effect and cardiovascular events. Data from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE), the Study on Cognition and Prognosis in the Elderly (SCOPE), and the Systolic Hypertension in Europe (Syst-Eur) trials support the hypothesis that the time it takes to reach target BP influences cardiovascular outcomes. VALUE, which compared BP-lowering and clinical event rates between patients treated with the angiotensin II receptor blocker (ARB) valsartan or the calcium channel blocker (CCB) amlodipine as well as between those who achieved immediate or delayed BP control, provides the strongest evidence of this to date. Additional data from SCOPE and Syst-Eur suggest that delays of 3 months to 2 years in starting antihypertensive therapy can increase the risk of certain cardiovascular end points, especially stroke. These data suggest that it may be beneficial to examine the efficacy of antihypertensive agents, not only long term, but also at earlier times to assess the onset and impact of early antihypertensive effect. The ARB olmesartan medoxomil (olmesartan) and the CCB amlodipine were compared in a randomized, double-blind, placebo-controlled clinical trial, which demonstrated that the onset of antihypertensive effect of olmesartan is comparable with that of amlodipine. Another study demonstrated that more patients treated with olmesartan achieved target BPs within 2 weeks of treatment compared with the ARBs losartan, valsartan and irbesartan.

New Onset of Type 2 Diabetes Mellitus during Antihypertensive Therapy

Hypertension is a widely diffused clinical condition in the general population and it is often associated with people who are overweight (i.e. have abdominal adiposity) or obese and with metabolic syndrome. Evidence shows that hypertensive patients are at increased risk of developing type 2 diabetes mellitus (T2DM) since angiotensin II is involved in the pathogenesis of hypertension and insulin resistance, which are both the key components of metabolic syndrome. The preventive effect of renin-angiotensin system (RAS) inhibition on the development of T2DM could reflect the closely linked mechanisms of blood pressure and blood glucose homeostasis. Since hyperglycaemia is a consequence of insulin resistance and β-cell dysfunction, preventing T2DM by RAS inhibition may result from an improvement of β-cell function and/or an enhancement of insulin sensitivity, which are secondary to modifications in microcirculation and changes in ionic status. On the basis of this hypothesis, several trials in treating hypertensive patients have shown a positive effect of drugs inhibiting RAS in reducing the number of hypertensive patients that develop T2DM. We analysed the results of the following clinical studies that found a reduction in the incidence of new-onset T2DM in hypertensive patients using angiotensin II type 1 receptor blockers (ARBs): LIFE (Losartan Intervention For Endpoint reduction in hypertension) [losartan]; SCOPE (Study on COgnition and Prognosis in the Elderly) [candesartan]; ALPINE (Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation) [candesartan]; CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) [candesartan]; and VALUE (Valsartan Antihypertensive Long-term Use Evaluation) [valsartan]. We analysed the results of the following clinical studies that found a reduction in the incidence of new-onset T2DM in hypertensive patients using angiotensin II type 1 receptor blockers (ARBs): LIFE (Losartan Intervention For Endpoint reduction in hypertension) [losartan]; SCOPE (Study on COgnition and Prognosis in the Elderly) [candesartan]; ALPINE (Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation) [candesartan]; CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) [candesartan]; and VALUE (Valsartan Antihypertensive Long-term Use Evaluation) [valsartan]. Evidence shows that blood pressure reduction, when associated with lifestyle modifications (especially in high-risk patients), is more important than the mechanism of action of the antihypertensive drugs, which is to normalise blood pressure and thus reduce the incidence of cardiovascular events. In this regard, the identification of the potential influence of RAS inhibition in preventing new-onset T2DM in hypertensive subjects is a promising topic for the healthcare system. In the future, data from the ongoing trials, where prevention of diabetes is the primary endpoint, may prove to what extent this class of drugs is actually effective. However, in the previously mentioned clinical trials, the superior effectiveness of ARBs in preventing T2DM is associated with a lower efficacy in preventing cardiovascular events, because of their lesser capacity in lowering blood pressure. Evidence so far suggests the use of ARBs preferably in association with other classes of antihypertensive drugs and under a constant control of blood pressure. In this latter regard, in the recently published ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm) study, a combination therapy based on a drug inhibiting RAS (perindopril) and a calcium-channel blocker (amlodipine) significantly reduced the incidence of major cardiovascular events and new onset of diabetes in high-risk hypertensive patients, compared with a combination therapy based on thiazide diuretic and a β-blocker.

The value of lowering blood pressure

According to the Canadian Heart Health Survey, only 14% of Canadian hypertensive patients are aware of their disease and are treated appropriately. One of the reasons for this could be that physicians are confused by an excess of confusing and contradictory information regarding the choice of drugs. Two recent publications may contribute to a much-needed simplification of the problem. The Blood Pressure Lowering Treatment Trialists' Collaboration published a meta-analysis based on 29 randomized trials that comprised a total of more that 162,000 participants. The treatment regimens were based on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, beta-blockers and calcium channel blockers. The main finding of the meta-analysis was that treatment with any of the blood pressure-lowering regimens reduced the risk of major cardiovascular events, and the extent of these risk reductions was directly related to the degree of blood pressure lowering. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) compared valsartan with amlodipine. At the end of the study, the reductions in blood pressure from baseline were 17.3/9.9 mmHg in the amlodipine group and 15.2/8.2 mmHg in the valsartan group (P<0.0001). There was a significantly lower incidence of myocardial infarction in the amlodipine group (4.1%) than in the valsartan group (4.8%). From these two studies, it would be reasonable to conclude that the treatment of elevated blood pressure has two main goals: to achieve a normal blood pressure and to produce a happy patient. The agent or agents used to obtain these goals are relatively unimportant.

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Development of Diabetes With Thiazide Diuretics: The Potassium Issue

Development of Diabetes With Thiazide Diuretics: The Potassium Issue

Advantages of new cardiovascular risk-assessment strategies in high-risk patients with hypertension

Background: Accurate assessment of cardiovascular 1026 disease (CVD) risk in patients with hypertension is important when planning appropriate treatment of modifiable risk factors. The causes of CVD are multifactorial, and hypertension seldom exists as an isolated risk factor. Classic models of risk assessment are more accurate than a simple counting of risk factors, but they are not generalizable to all populations. In addition, the risk associated with hypertension is graded, continuous, and independent of other risk factors, and this is not reflected in classic models of risk assessment. Objective: This article is intended to review both1026 classic and newer models of CVD risk assessment. Methods: MEDLINE was searched for articles published1026 between 1990 and 2005 that contained the terms cardiovascular disease, hypertension, or risk assessment. Articles describing major clinical trials, new data about cardiovascular risk, or global risk stratification were selected for review. Results: Some patients at high long-term risk for 1026 CVD events (eg, patients aged <50 years with multiple risk factors) may go untreated because they do not meet the absolute risk-intervention threshold of 20% risk over 10 years with the classic model. Recognition of the limitations of classic risk-assessment models led to new guidelines, particularly those of the European Society of Hypertension-European Society of Cardiology. These guidelines view hypertension as one of many risk and disease factors that require treatment to decrease risk. These newer guidelines include a more comprehensive range of risk factors and more finely graded blood pressure ranges to stratify patients by degree of risk. Whether they accurately predict CVD risk in most populations is not known. Evidence from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study, which stratified patients by several risk and disease factors, highlights the predictive value of some newer CVD risk assessments. Conclusion: Modern risk assessments, which include1026 blood pressure along with a wide array of modifiable risk factors, may be more accurate than classic models for CVD risk prediction.

Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension

Angiotensin receptor blockers (ARBs), also known as sartans, block the activation of angiotensin type 1 receptors and have a recognised role in the treatment of heart failure and nephropathy. Since 2002, there have been three major outcome trials of ARBs in hypertension. We performed a meta-analysis to evaluate the impact of ARB on major outcomes. Randomised controlled trials of ARBs in hypertensive subjects with an average follow-up of at least 2 years and at least 100 major cardiovascular events were included. For each trial, the ARB used, number and characteristics of subjects, baseline and change in blood pressure, cardiovascular and noncardiovascular outcomes were recorded. Three trials involving 29 375 subjects were included in the meta-analysis. In Losartan Intervention For Endpoint (LIFE) and Study on Cognition and Prognosis in the Elderly (SCOPE) but not in Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE), an ARB reduced the occurrence of the primary end point and stroke compared to control. Compared to other antihypertensive drugs, ARB treatment was associated with no significant change in all-cause mortality (relative risk ratio (RRR) 0.96, 95% CI: 0.88-1.06, P = 0.45). There was an increase in myocardial infarction (RRR, 1.12, 95% CI: 1.01-1.26, P = 0.041), but a decrease in new-onset diabetes mellitus (RRR, 0.80, 95% CI: 0.74-0.86, P < 0.0000001). In conclusion, the reduction in new-onset diabetes partly offsets any increase in the risk of myocardial infarction. Most hypertensive patients require more than one class of drugs. Small differences in treatment outcome should not over-ride the importance of good blood pressure control.

Noncardiovascular Illness as Barrier to Antihypertensive Treatment

Control rates of hypertension vary from one country to another, but in general, they are much lower than would be desirable. In the United States, the National Health and Nutrition Examination Survey1 showed that the awareness of the hypertensive population improved from 50% in the 1970s to 70% in the 1990s. Over the same time interval, the proportion of treated hypertensive patients with normalized blood pressure rose from 10% to 29%. Recent studies in Europe2 and other parts of the world3 confirmed that the rule of halves still exists and that the fractions of hypertensive patients with properly controlled blood pressure range from ≈5% to 45%.4,5 Patients with high blood pressure not carrying out recommended therapy is a pervasive phenomenon that contributes worldwide to the low control rates of hypertension. Adherence, in a more judgmental way, also termed compliance, is the extent to which a patient’s behavior coincides with the clinical prescription.6 It usually increases with higher education, affluence, social support, and the frequency and quality of the interactions with the care providers, but it diminishes with the number of tablets to be taken.7 Other frequently cited reasons for not filling prescriptions are the …

Therapeutic Controversies in Hypertension

Although numerous prospective randomized trials since the Veterans Administration studies clearly have attested to the efficacy and safety of antihypertensive therapy, there remain some controversial issues with all classes of antihypertensive drugs. Thiazide diuretics increase the risk for new-onset diabetes and their long-term safety has been questioned. Alpha-blockers do not reduce morbidity and mortality in uncomplicated hypertension but are well known to cause a variety of poorly tolerated side effects. The safety of calcium antagonists has been questioned for many years, although recent large prospective randomized trials such as Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, International Verapamil-Trandolapril Study, Intervention as a Goal in Hypertension, Valsartan Antihypertensive Long-Term Use Evaluation and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) have attested to their safety and efficacy. Angiotensin-converting enzyme inhibitors, in general, are well tolerated but have potentially fatal adverse effects in a few patients. Angiotensin-receptor blockers are exceedingly well tolerated, but may be less-efficacious antihypertensive agents than other drug classes. Most antihypertensive drug classes have an effect on new-onset diabetes that should be taken into account in patients at risk. No head-to-head comparison of combination therapy looking at efficacy and safety has been available. The long-term safety of antihypertensive therapy is documented poorly because most trials only last 4 to 6 years. Despite these drawbacks and concerns, the benefits of antihypertensive therapy clearly outweigh its potential risk.

An updated clinical primer on large artery mechanics: implications of pulse waveform analysis and arterial tonometry

The use of pulse wave analysis with arterial tonometry has accelerated over the last year. Despite approval from the US Food and Drug Administration in 2001 on the use of generalized transfer function to generate the central (aortic) pressure wave from the radial waveform, this technique is still questioned. This review summarizes major findings on (a) value of arterial tonometry in determining indices of cardiovascular function, (b) use of these indices in outcome and drug studies, (c) relevance to major trials on blood pressure reduction. Pulse pressure has emerged as a better predictor of cardiac ischemic events than systolic, diastolic, and mean brachial pressure. Central systolic and pulse pressure and augmentation index have shown an even better relation with cardiovascular events and with outcomes. The claim by specific angiotensin-converting enzyme inhibitor and angiotensin receptor blocker drugs of their benefits "beyond blood pressure lowering" has been challenged on the basis of greater reduction in central and aortic pressure compared with brachial pressure measured by cuff sphygmomanometer, as shown by the pREterax in regression of Arterial Stiffness in a contrOlled double-bliNd study. Augmentation index is higher in hypertension, is inversely related to body height, and can be reduced by exercise. Augmentation index shows a linear relation with age up to 60 years. Regrettably, recent major trials such as the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis, Prevention of Events with Angiotensin Converting Enzyme Inhibition, and Valsartan Antihypertensive Long-term Use Evaluation studies have not included pulse wave analysis to distinguish the relative benefit of different drugs. Pulse wave analysis will assist in a better understanding of hypertension as well as in establishing the extent of cardiovascular disease and for monitoring therapy.

Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension

Angiotensin receptor blockers (ARBs), also known as sartans, block the activation of angiotensin type 1 receptors and have a recognised role in the treatment of heart failure and nephropathy. Since 2002, there have been three major outcome trials of ARBs in hypertension. We performed a meta-analysis to evaluate the impact of ARB on major outcomes. Randomised controlled trials of ARBs in hypertensive subjects with an average follow-up of at least 2 years and at least 100 major cardiovascular events were included. For each trial, the ARB used, number and characteristics of subjects, baseline and change in blood pressure, cardiovascular and noncardiovascular outcomes were recorded. Three trials involving 29 375 subjects were included in the meta-analysis. In Losartan Intervention For Endpoint (LIFE) and Study on Cognition and Prognosis in the Elderly (SCOPE) but not in Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE), an ARB reduced the occurrence of the primary end point and stroke compared to control. Compared to other antihypertensive drugs, ARB treatment was associated with no significant change in all-cause mortality (relative risk ratio (RRR) 0.96, 95% CI: 0.88-1.06, P = 0.45). There was an increase in myocardial infarction (RRR, 1.12, 95% CI: 1.01-1.26, P = 0.041), but a decrease in new-onset diabetes mellitus (RRR, 0.80, 95% CI: 0.74-0.86, P < 0.0000001). In conclusion, the reduction in new-onset diabetes partly offsets any increase in the risk of myocardial infarction. Most hypertensive patients require more than one class of drugs. Small differences in treatment outcome should not over-ride the importance of good blood pressure control.

Avoiding adverse cardiovascular outcomes with prompt blood pressure control: An economic analysis based on the valsartan antihypertensive long-term use evaluation (VALUE) trial

Improved outcomes in hypertensive patients are usually ascribed to the benefit of gradual blood pressure (BP) control over the long-term. There is a paucity of data on the effects of prompt BP lowering on cardiovascular (CV) outcomes over the short-term. Recent results from the VALUE trial demonstrate significant reductions in CV events in patients at high CV risk, associated with BP lowering over the first 3 months. This analysis therefore examines the cost-effectiveness of antihypertensive therapy, based on CV event rate reduction in the first 3 months of the VALUE trial. An economic model was developed to determine costs per event avoided for stroke and all-cause mortality in the 0–3 month period of the VALUE trial (the only discrete outcomes showing significant differences between regimens in the early treatment period). Drug utilization was determined from the VALUE publication (Julius et al. Lancet, 2004; 363:2022); drug costs were taken from public sources reflecting retail pharmacy pricing. Stroke and all-cause mortality event rates were determined from the published paper using Kaplan-Meier graphs and reported odds ratios (OR) with 95% confidence intervals (CI), for valsartan vs amlodipine: stroke 1.94 (1.10–3.42); all-cause mortality 2.84 (1.51–5.34). Sensitivity analyses were conducted based on the upper and lower bounds of the CI for the OR and ±20% on event rates. Over 3 months, amlodipine-based treatment reduced mean systolic BP by 3.8 mm Hg more than valsartan-based treatment, leading to reduction of 36 strokes and 53 fewer deaths per 15,000 patients. Associated drug cost is $9.67 higher per patient with amlodipine vs. valsartan. Cost per stroke averted is $4,003 and cost per all-cause death avoided is $2,742. Sensitivity analyses demonstrated a range of $2,282-$26,698 per stroke averted and $1,821-$6,582 per all-cause death avoided. All antihypertensive regimens may not be equally efficacious at rapidly reducing BP to goal. Among patients at relatively high risk for CV events, prompt BP reduction with amlodipine-based therapy as seen in VALUE, can reduce stroke and all-cause mortality within the first 3 months. These results reinforce the cost-effectiveness of optimal combination antihypertensive therapy for early and aggressive BP lowering to reduce CV events.

Prevention and Health Services Delivery

The burden of stroke to the health care system in the United States continues to increase. Stroke-related hospital admissions grew from 580 000 in 1988 to 820 000 in 1997, an 18.6% increase after age adjustment.1 More effective stroke prevention provides the primary means of reducing these alarming statistics. This can be accomplished through better implementation of known preventive strategies2 and through research into new approaches to stroke prevention. Diet can affect stroke risk, with epidemiological studies indicating an inverse relationship between fruit and vegetable consumption and cardiovascular events.2 For example, one study including individuals free of cardiovascular disease at baseline found that the relative risk (RR) of stroke was reduced by 31% (RR, 0.69; 95% CI, 0.52 to 0.92) for persons in the highest quintile of fruit and vegetable intake.3 Analysis of data from the National Health and Nutrition Examination Survey (NHANES) Epidemiologic Follow-up Study supports these results.4 The study included 9608 adults aged 25 to 74 years who were free of cardiovascular disease at a baseline evaluation between 1971 and 1975. Consumption of fruits and vegetables ≥3 times per day compared with <1 time per day was associated with a 27% lower stroke incidence (RR, 0.73; 95% CI, 0.57 to 0.95) after adjustment for potential confounders, suggesting the benefit is not attributable to a healthy-user effect. The results reinforce present recommendations for an intake of 5 servings of fruits and vegetables daily. Because fruits and vegetables contain antioxidants, antioxidant food supplements might be expected to have similar benefits. However, a 3-year study of patients with coronary heart disease, low levels of high-density lipoprotein cholesterol, and normal levels of low-density lipoprotein cholesterol found no reduction in cardiovascular end points (death, myocardial infarction, stroke, and revascularization procedures) with the use of antioxidant supplements (800 IU …

Left Ventricular Hypertrophy and Angiotensin II Receptor Blocking Agents

Angiotensin II plays a significant role in cell growth and proliferation in model systems and in humans. Numerous studies have shown that left ventricular hypertrophy (LVH) increases the risk of coronary heart disease, congestive heart failure, stroke or transient ischemic attack; all-cause deaths, and sudden death. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has provided beneficial effects on LVH regression and on cardiac remodeling in the presence of hypertension and heart failure. The new class of ARBs appears to provide cardioprotective effects that are similar to those of the ACE inhibitors. Most of the beneficial effects provided by these agents appear to be related to a more complete blockade of the angiotensin II type 1 (AT1) receptor. However, costimulation of the angiotensin II type 2 (AT2) receptor appears to increase nitric oxide and thus causes some bradykinin-like effects. Evidence for the role of angiotensin II in promoting LVH as well as abnormal regulation of the angiotensin II signal transduction pathways in model systems and in humans has been reviewed. Secondly, the mechanisms for the beneficial effects of angiotensin II receptor blockers studied in model systems and in humans, including possible involvement in the formation of reactive oxygen species by mononuclear cells, are presented. Finally, results from large-scale interventions such as the Losartan Intervention For Endpoint reduction (LIFE) study, as well as an overview of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial involving the use of ARB in high-risk patients, are presented.

Fixed-Dose Combinations in the Management of Hypertension

We discuss combination therapy with angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics in light of the independent actions of both types of agents, and the adverse effects of both agents independently and in the context of the physiologic synergy achieved in using these agents together. ARBs counteract many of the adverse events associated with the use of thiazide diuretics and have been shown to reduce the occurrence of new-onset diabetes mellitus. We also review outcome trials in patients with hypertension (such as LIFE [Losartan Intervention For Endpoint reduction in hypertension], VALUE [Valsartan Antihypertensive Long-term Use Evaluation], and SCOPE [Study on COgnition and Prognosis in the Elderly]), in which losartan, valsartan, and candesartan cilexetil were used in combination with hydrochlorothiazide. Fixed combination ARB/hydrochlorothiazide agents make sense as initial therapy for patients in whom BP is >20/10 mm Hg above goal.

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

The VALUE trial: a commentary

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial compared coronary heart disease outcome in two anti-hypertensive treatment strategies based on either an angiotensin receptor blocker, valsartan, or a calcium channel blocker (CCB), amlodipine. In both patient groups a diuretic was added, if necessary, in an attempt to achieve blood pressure (BP) goals. Follow-up of over 15,000 patients was maintained for 4.2 years. There were no differences in the primary composite endpoint of cardiac morbidity and mortality (which included interventional procedures, hospitalised heart failure, non-fatal myocardial infarction and fatal coronary heart disease, however myocardial infarction and stroke events occurred less commonly on amlodipine than on valsartan the former achieving statistical significance [p=0.02 and p=0.08 respectively]). There was a non-significant excess of hospitalised heart failure on amlodipine (p=0.012). However, lower BPs early in the trial probably accounted for most of the observed benefits in favour of the CCB. The angiotensin receptor blocker arm was associated with less new onset diabetes. The results of VALUE add further support to the evidence that blood pressure control is the major determinant in outcome in trials of antihypertensive therapy.

Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial

The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test the hypothesis that for the same blood-pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk. 15?245 patients, aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a randomised, double-blind, parallel-group comparison of therapy based on valsartan or amlodipine. Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint, defined as a composite of cardiac mortality and morbidity. Patients from 31 countries were followed up for a mean of 4.2 years. Blood pressure was reduced by both treatments, but the effects of the amlodipine-based regimen were more pronounced, especially in the early period (blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month; 1.5/1.3 mm Hg after 1 year; p<0.001 between groups). The primary composite endpoint occurred in 810 patients in the valsartan group (10.6%, 25.5 per 1000 patient-years) and 789 in the amlodipine group (10.4%, 24.7 per 1000 patient-years; hazard ratio 1.04, 95% CI 0.94-1.15, p=0.49). The main outcome of cardiac disease did not differ between the treatment groups. Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes. The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk.