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Background: Atrial fibrillation (AF) is the most common arrhythmia and increases cardiovascular risk in hypertensive patients. Therefore, in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) a prespecified objective was to compare the effects of valsartan and amlodipine on new-onset AF., Methods: A total of 15 245 hypertensive patients at high cardiovascular risk received valsartan 80-160 mg/day or amlodipine 5-10 mg/day combined with additional antihypertensive agents. Electrocardiograms were obtained every year and analyzed centrally for evidence of left ventricular hypertrophy and new-onset AF., Results: At baseline, AF was diagnosed in 2.6% of 7649 valsartan recipients and 2.6% of 7596 amlodipine recipients. During antihypertensive treatment the incidence of at least one documented occurrence of new-onset AF was 3.67% with valsartan and 4.34% with amlodipine [unadjusted hazard ratio 0.843, [95% confidence interval (CI): 0.713, 0.997], P = 0.0455]. The incidence of persistent AF was 1.35% with valsartan and 1.97% with amlodipine [unadjusted hazard ratio 0.683 (95% CI: 0.525, 0.889), P = 0.0046]., Conclusions: Valsartan-based treatment reduced the development of new-onset AF, particularly sustained AF in hypertensive patients, compared with amlodipine-based therapy. These findings suggest that angiotensin II receptor blockers may result in greater benefits than calcium antagonists in hypertensive patients at risk of new-onset AF.

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.

In the main Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) report, we investigated outcomes in 15 245 high-risk hypertensive subjects treated with valsartan- or amlodipine-based regimens. In this report, we analyzed outcomes in 7080 patients (46.4%) who, at the end of the initial drug adjustment period (6 months), remained on monotherapy. Baseline characteristics were similar in the valsartan (N=3263) and amlodipine (N=3817) groups. Time on monotherapy was 3.2 years (78% of treatment exposure time). The average in-trial blood pressure was similar in both groups. Event rates in the monotherapy group were 16% to 39% lower than in the main VALUE trial. In the first analysis, we censored patients when they discontinued monotherapy ("censored"); in the second, we counted events regardless of subsequent therapy (intention-to-treat principle). We also assessed the impact of duration of monotherapy on outcomes. No difference was found in primary composite cardiac end points, strokes, myocardial infarctions, and all-cause deaths with both analyses. Heart failure in the valsartan group was lower both in the censored and intention-to-treat analyses (hazard ratios: 0.63, P=0.004 and 0.78, P=0.045, respectively). Longer duration of monotherapy amplified between-group differences in heart failure. New-onset diabetes was lower in the valsartan group with both analyses (odds ratios: 0.78, P=0.012 and 0.82, P=0.034). Thus, despite lower absolute event rates in monotherapy patients, the relative risks of heart failure and new-onset diabetes favored valsartan. Moreover, these findings support the feasibility of comparative prospective trials in lower-risk hypertensive patients.

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.

Background: 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., Methods: 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., Findings: 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)., Interpretation: 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.

The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test whether, for the same achieved blood pressures, regimens based on valsartan or amlodipine would have differing effects on cardiovascular endpoints in high risk hypertension. But inequalities in blood pressure, favouring amlodipine, throughout the multiyear trial precluded comparison of outcomes. A technique of serial median matching, applied at 6 months when treatment adjustments intended to achieve control of blood pressure were complete, created 5006 valsartan-amlodipine patient pairs matched exactly for systolic blood pressure, age, sex, and the presence or absence of previous coronary disease, stroke, or diabetes. Subsequent combined cardiac events, myocardial infarction, stroke, and mortality were almost identical in the two cohorts, but admission to hospital for heart failure was significantly lower with valsartan. Reaching blood pressure control (systolic <140 mm Hg) by 6 months, independent of drug type, was associated with significant benefits for subsequent major outcomes; the blood pressure response after just 1 month of treatment predicted events and survival.

Intensive blood pressure control is a desirable and obtainable goal in patients with hypertension, according to the most recent treatment guidelines from Europe and the US. Achieving target blood pressure depends on the efficacy of antihypertensive treatment and patient compliance. Olmesartan medoxomil, a non-peptidergic angiotensin AT1 receptor antagonist, has been shown to be effective and well tolerated. Continuation of initial treatment is higher with AT1 receptor antagonists than for any other class of antihypertensive drugs. Olmesartan medoxomil may also have end-organ protective effects that provide additional clinical benefit. Optimal blood pressure control may be achieved faster if initial treatment contains the most efficacious and well tolerated antihypertensive drug or drugs. The ongoing European study, known as OLMEBEST (Efficacy and safety of OLMEsartan: reduction of Blood pressure in the treatment of patients suffering from mild to moderate ESsenTial hypertension), will provide important information on the use of olmesartan medoxomil as an initial treatment for hypertension.

Prospective randomised trials have demonstrated convincingly the benefits of drug treatment of hypertension. Treatment with conventional antihypertensive agents reduces the incidence of cardiovascular events by about that which would be expected from epidemiological data for the achieved difference in blood pressure. Newer agents, such as angiotensin II receptor blockers, have potential for benefits beyond blood pressure reduction. This rationale is under evaluation in a number of long-term morbidity and mortality trials which will report over the next few years, with the largest, VALUE, due to provide results in 2004. The findings from these trials will be decisive in determining the future role of this important new class of drugs.