Importance of sustained and "tight" blood pressure control in patients with high cardiovascular risk.

A retrospective further analysis of the ACTION database evaluated the relationship between cardiovascular outcomes and the "quality" of the control of blood pressure (BP). The study population (n = 6287) comprised those patients with four BP measurements during year 1 subdivided according to the proportion of visits in which BP was controlled in relation to two BP targets: < 140/90mmHg and < 130/80 mmHg. Differences between the BP control groups for the major prespecified ACTION outcomes were investigated with Cox proportional hazards models. For all the prespecified cardiovascular endpoints the incidence declined as the proportion of visits with BP control increased. The greatest differences in outcomes between the different BP control groups were observed for the risk of stroke but were still apparent for all the other endpoints. For example, the risks for the primary outcome [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.67 to 0.90] were significantly less in the group with >_75% of visits with BP control than in the group with < 25% of visits with BP control. There were no significant treatment-related differences. Retrospective analyses are not definitive but these results highlight the importance of the attainment of BP control targets and the consistency of BP control during long-term follow-up.

Prognostic importance of pretreatment and on-treatment blood pressure: Further analysis of the ACTION database and the effect of nifedipine gastrointestinal therapeutic system.

This retrospective further analysis of the ACTION database evaluated the relationships between baseline blood pressure (BP), on-treatment BP (after 6 weeks) and subsequent cardiovascular outcomes. Analyses were performed using multivariate Cox proportional hazard models. Statistically significant (p < 0.001) and consistent patterns were noted between the risk of major cardiovascular endpoints and both baseline SBP and on-treatment SBP. The lowest risk of debilitating stroke was apparent in those patients with baseline SBP < 120mmHg, with a hazard ratio in this lowest BP group of 0.45 (95% confidence interval 0.28, 0.72), compared to the referent highest BP group (SBP < 150mmHg). Adjusting the model for treatment (nifedipine or placebo) did not modify the conclusions in any statistical or clinically meaningful way. Corresponding and similar results were obtained for pulse pressure but diastolic blood pressure (DBP) was not a consistently useful predictor of outcome. These data confirm the predictive importance of on-treatment SBP (but not DBP) and contribute to the debate about treatment-related BP targets. In this analysis, treatment with nifedipine gastrointestinal therapeutic system in high-risk patients with coronary artery disease was not associated with any increase in cardiovascular risk, even with baseline SBP5120mmHg.

Once daily nifedipine: the formulation dictates the pharmacokinetic characteristics and the therapeutic responses.

Nifedipine as a pharmacologic agent for treating hypertension and angina pectoris has been available worldwide since the early 1980's. However, the formulation of nifedipine has undergone a number of modifications over time to improve the pharmacokinetic profile and administration regimen from 3 times daily to once daily. Nifedipine Gastrointestinal Therapeutic System (GITS) is the most widely studied of the once daily formulations from both a pharmacokinetic and clinical perspective. Nifedipine GITS was registered in most major countries worldwide based on both clinical pharmacology and clinical trial data in adequately powered studies. Moreover, outcome trials in both hypertension (INSIGHT) and angina pectoris (ACTION) have been completed and published. Other once daily modified release nifedipine formulations are available in a number of countries but limited published data is available on these formulations. A Pubmed (Medline) search using the terms "nifedipine pharmacokinetics" yielded 162 articles of which 7 provided detailed pharmacokinetic values in head to head comparisons of nifedipine GITS and another once a day formulation. These published pharmacokinetic studies have failed to show that any of the other formulations is consistently bioequivalent to the reference formulation, nifedipine GITS. In addition, other Pubmed searches yielded limited data from comparative clinical studies, which show significant differences in favor of the nifedipine GITS formulation in terms of blood pressure control and activation of the sympathetic nervous system. With limited data comparing once daily formulations of nifedipine to nifedipine GITS and no data comparing between other once a day formulations, for both pharmacokinetic and therapeutic reasons, the evidence indicates that patients should not be switched between once daily formulations of nifedipine.

Long-acting dihydropyridine calcium-channel blockers and sympathetic nervous system activity in hypertension: a literature review comparing amlodipine and nifedipine GITS.

Calcium-channel blockers (CCBs) constitute a diverse group of compounds but are often referred to as a single homogeneous class of drug and the clinical responses indiscriminately summarized. Even within the dihydropyridine subgroup, there are significant differences in formulations, pharmacokinetics, durations of action and their effects on blood pressure, heart rate, end organs and the sympathetic nervous system. Amlodipine and nifedipine in the gastrointestinal therapeutic system (GITS) formulation are the most studied of the once-daily CCBs. Amlodipine has an inherently long pharmacokinetic half-life, whereas, in contrast, nifedipine has an inherently short half-life but in the GITS formulation the sophisticated delivery system allows for once-daily dosing. This article is derived from a systematic review of the published literature in hypertensive patients. The following search terms in three main databases (MEDLINE, Embase, Science Citation Index) from 1990 to 2011 were utilized: amlodipine, nifedipine, sympathetic nervous system, sympathetic response, sympathetic nerve activity, noradrenaline, norepinephrine and heart rate. More than 1500 articles were then screened to derive the relevant analysis. As markers of sympathetic nervous system activation, studies of plasma norepinephrine concentrations, power spectral analysis, muscle sympathetic nerve activity and norepinephrine spillover were reviewed. Overall, each drug lowered blood pressure in hypertensive patients in association with only small changes in heart rate (i.e. <1 beat/min). Plasma norepinephrine concentrations, as the most widely reported marker of sympathetic nervous system activity, showed greater increases in patients treated with amlodipine than with nifedipine GITS. The evidence indicates that both these once-daily dihydropyridine CCBs lower blood pressure effectively with minimal effects on heart rate. There are small differences between the drugs in the extent to which each activates the sympathetic nervous system with an overall non-significant trend in favour of nifedipine GITS.

From hypertension to heart failure -- are there better primary prevention strategies?

Although in the developed world the incidence of and mortality from coronary heart disease (CHD) and stroke have been declining over the last 15 years, heart failure is increasing in incidence, prevalence and overall mortality, despite advances in the diagnosis and management of the condition. Hypertension, alone or in combination with CHD, precedes the development of heart failure in the majority of both men and women. Whilst there have been improvements in the overall management of hypertension, as reflected in rates of diagnosis, awareness, treatment and control of blood pressure (BP), there are still many patients with hypertension who remain undiagnosed or untreated and of those who do receive treatment many fail to achieve current targets for BP control. Placebo-controlled trials in hypertension, largely based on diuretic and beta-blocker-based regimens, have unequivocally demonstrated that the treatment of hypertension can significantly reduce the incidence of heart failure. Newer treatment strategies offer theoretical and proven practical advantages over established antihypertensive therapy. In particular, AT1-receptor blockers appear to provide benefits beyond BP control and are effective in the treatment of both hypertension and heart failure. Thus, the primary prevention of heart failure in hypertensive patients should be based upon strategies that provide tight and sustained BP control necessitating the use of multiple drugs. However, there is now compelling evidence to suggest that this therapy should include an antihypertensive agent that inhibits the reninangiotensin- aldosterone system (RAAS).

Controlled-release doxazosin as combination therapy in hypertension: the GATES study.

Doxazosin gastrointestinal therapeutic system (GITS) or placebo was added to the antihypertensive therapy of uncontrolled hypertensive patients in a prospective, randomized, double-blind trial. Patients received doxazosin GITS 4 mg/d (n=89) or placebo (n=86) for 6 weeks in addition to entry antihypertensive medication. Doxazosin GITS was increased to 8 mg/d after 2 or 4 weeks if patients did not respond (sitting blood pressure <140/90 mm Hg and 10/10-mm Hg decrease from baseline). Reductions from baseline in sitting and standing blood pressures were greater with doxazosin GITS than placebo at all time points (p

Angiotensin II receptor antagonists alone and combined with hydrochlorothiazide: potential benefits beyond the antihypertensive effect.

Angiotensin II receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics have an accepted place in the management of hypertension. Most patients require combination therapy with two or more drugs to adequately control blood pressure to targets recommended by European and international guidelines. ARBs and the thiazide diuretic hydrochlorothiazide have complementary modes of action. Fixed-dose combinations of an ARB and low-dose hydrochlorothiazide provide a convenient and effective treatment option for patients who do not achieve blood pressure targets on monotherapy, without compromising the placebo-like tolerability of ARBs. In Europe, fixed-dose combinations with hydrochlorothiazide currently are available for the ARBs candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan. Recently, a number of studies have focused on the use of ARBs in monotherapy and in combination therapy, in conditions including congestive heart failure, post-myocardial infarction management, hypertension with cardiovascular risk factors, and diabetic and non-diabetic nephropathy. Evidence from these studies suggests a beneficial role beyond the antihypertensive effect of these therapies in providing protection against cardiovascular, renovascular, and cerebrovascular events.

Acetaminophen use and risk of myocardial infarction and stroke in a hypertensive cohort.

Recent data suggest that self-reported acetaminophen use is associated with increased risk of cardiovascular events and that acetaminophen causes a modest blood pressure rise. There are no randomized trials or studies using verified prescription data of this relationship. We aimed to assess the relationship between verified acetaminophen prescription data and risk of myocardial infarction or stroke in patients with hypertension. We performed a retrospective data analysis using information contained within the UK Clinical Research Practice Datalink. Multivariable Cox proportional hazard models were used to estimate hazard ratios for myocardial infarction (primary end point), stroke, and any cardiovascular event (secondary end points) associated with acetaminophen use during a 10-year period. Acetaminophen exposure was a time-dependent variable. A propensity-matched design was also used to reduce potential for confounding. We included 24,496 hypertensive individuals aged ≥ 65 years. Of these, 10,878 were acetaminophen-exposed and 13,618 were not. There was no relationship between risk of myocardial infarction, stroke, or any cardiovascular event and acetaminophen exposure on adjusted analysis (hazard ratio, 0.98; 95% confidence interval, 0.76-1.27; hazard ratio, 1.09; 95% confidence interval, 0.86-1.38; and hazard ratio, 1.17; 95% confidence interval, 0.99-1.37; respectively). Results in the propensity-matched sample (n=4000 per group) and when men and women were analyzed separately were similar. High-frequency users (defined as receiving a prescription for >75% of months) were also not at increased risk. After allowance for potentially confounding variables, the use of acetaminophen was not associated with an increased risk of myocardial infarction or stroke in a large cohort of hypertensive patients.

Dihydropyridine calcium channel blockers: basic pharmacological similarities but fundamental therapeutic differences.

Recent trials indicate that treatment with calcium channel blockers (CCBs) reduces cardiovascular morbidity and mortality in hypertensive patients (including those with significant coronary artery disease). Since the fundamental mechanism of action of all CCBs is the same, it might be assumed that the findings of these outcome studies can be generalized to all types of CCB. However, in the light of the well-recognized clinical pharmacological differences between the 'rate-limiting' agents, verapamil and diltiazem, and the dihydropyridine group of CCBs, this must be considered to be a misconception. Less well-recognized, and often ignored, are the significant differences between agents within the dihydropyridine group. These differences translate to distinct differences in the therapeutic profiles and may well translate into differences in outcome during long-term treatment. Thus, the differences in pharmacokinetic, pharmacodynamic and therapeutic profiles make it clear that caution should be exercised in assuming that all dihydropyridine CCBs licensed for once-daily administration are equivalent in terms of their durations of action and overall antihypertensive efficacy.

Bioequivalence and other unresolved issues in generic drug substitution.

BACKGROUND: Substitution of generic drugs for brand-name products is highly controversial and often is met with suspicion by health care providers and patients. Historically, the debate has focused on the issue of bioequivalence, and clinical practice has identified a number of drug classes for which generic substitution should be approached with caution. Current bioequivalence requirements are based on a measure of average bioequivalence; however, there are fears that use of this measure may be inappropriate in the case of a drug with a narrow or wide therapeutic range or high intrasubject or intersubject variability. Under these circumstances, measures of individual and population bioequivalence are proposed to be more accurate than measures of average bioequivalence. OBJECTIVE: This paper addresses issues of bioequivalence and other concerns with generic drug substitution. METHODS: I conducted a MEDLINE search of the English-language literature containing the key terms generic, multisource, quality, and brand and published between 1973 and 2003. The names of branded pharmaceuticals whose patents had recently expired (eg, Ventolin HFA, Adalat, Capoten, Tagamet HB 200, and Valium) also were used to search for articles on generic substitution. Reference lists of relevant articles also were searched. Bioequivalence issues are presented together with more general concerns over generic drug substitution, such as consumer perception of risk, differences in product and packaging appearance, and differences in excipients. RESULTS: The literature reviewed act to highlight a number of different drug categories and patient subpopulations for which generic substitution can still prove to be problematic. CONCLUSION: I recommend that health care providers continue to exercise caution in the consideration of generic drug substitution under certain circumstances.

Efficacy and tolerability of long-term rilmenidine treatment in hypertensive diabetic patients. A retrospective analysis of a general practice study.

INTRODUCTION: Rilmenidine is a centrally acting antihypertensive which differs from the other representatives of this class by its very high specificity for the imidazoline I1 receptors and its good tolerability. Recent studies have shown rilmenidine improves glucose tolerance and reduces micro-albuminuria in patients with diabetes mellitus. METHODOLOGY: The evidence of these potentially favorable characteristics encouraged a secondary retrospective analysis of a subgroup of 2738 diabetic patients included in a previous long-term open study of rilmenidine alone, or in combination with other classes of antihypertensives. RESULTS: The antihypertensive efficacy of rilmenidine demonstrated previously in controlled studies was confirmed during the 12-month follow-up. In addition, favorable effects of drug treatment on fasting blood glucose and plasma triglyceride levels were consistent with an improvement in glucose and lipid metabolism during treatment. The profile of adverse events was similar to that observed in the nondiabetic population, the occurrence of postural hypotension being observed in <1% of patients and not necessitating any withdrawals from the study. CONCLUSION: Diabetic hypertensive patients frequently require the use of multiple medications and consideration of the metabolic interactions between treatments. The results of this retrospective analysis support the use of rilmenidine in patients with hypertension and diabetes mellitus and should encourage the conduct of controlled trials of cardiovascular and renal protection and outcome with this compound.

A putative placebo comparison of the SCOPE and LIFE trials.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial and the Study on Cognition and Prognosis in the Elderly (SCOPE) superficially produced comparable outcomes, with effects on stroke greater than those anticipated from blood pressure (BP) lowering alone. This, however, ignores important features of both studies. It ignores firstly the disparate comparator agents - atenolol in LIFE and predominantly hydrochlorthiazide in SCOPE, secondly the small, but potentially important BP differential between the treatment arms in SCOPE and finally the small, statistically non-significant increase in coronary heart disease (CHD) in both trials. This analysis compares the major cardiovascular outcomes in these trials with reference to placebo. Two alternative reference populations were employed to calculate the imputed placebo, firstly the MRC Trial in Elderly Hypertensives and secondly a meta-analysis of trials in the elderly, which included comparisons between diuretic- and b-blocker-based regimens. Overall, the choice of 'comparator placebo' did not substantially influence the derived results. Accounting for BP differences and based on the meta-analysis, both trials demonstrated statistically significant reductions in fatal/non-fatal stroke compared with placebo - relative risks (95% confidence intervals [CI]) of 0.53 (0.39, 0.73) and 0.56 (0.41, 0.76) for SCOPE and LIFE, respectively. For fatal/non-fatal MI, there were greater discrepancies between the studies, but with neither achieving statistical significance compared with placebo - relative risks of 0.85 (0.59, 1.24) and 1.08 (0.80, 1.46) for SCOPE and LIFE, respectively. This analysis clearly demonstrates that both candesartan in SCOPE and losartan in LIFE are associated with reductions in stroke events compared with placebo, greater than that observed in the well-established meta-analysis of placebo-controlled hypertensive trials. However, the CIs are such that it is not possible to suggest definitively that this is a benefit beyond BP reduction alone. Neither trial is sufficiently 'powered' to demonstrate a benefit in CHD outcomes, but with SCOPE there was a trend towards benefit with a point estimate compatible with the major meta-analysis.

Achieving Quality 24-h Blood Pressure Control with Candesartan Cilexetil.

Epidemiological evidence suggests that optimal blood pressure control requires strategies that lower blood pressure consistently and fully throughout 24 h. In order to maximize compliance, antihypertensive agents also need to be well tolerated and effective when administered at a convenient once-daily dose. The new angiotensin II type 1 (AT 1 ) receptor blocker candesartan binds tightly to, and dissociates slowly from, the AT1-receptor and thereby provides long-lasting suppression of the renin-angiotensin system. This is likely to explain its pronounced antihypertensive efficacy, which is maintained smoothly over 24 h. The trough-to-peak ratio is a useful measure of the persistence of antihypertensive efficacy at the end of the dosing interval. This ratio was found to be close to the ideal of 1.0 for candesartan cilexetil, -8 and 16 mg, whereas it was 0.7 for the prototype AT 1 -receptor blocker losartan, 50 mg. The antihypertensive effect of candesartan cilexetil, 16 mg, was also significantly greater than that of losartan, 100 mg, as demonstrated by ambulatory blood pressure measurements 0-36 h after dosing and by clinic measurements 48 h after dosing. By controlling blood pressure well beyond the normal dosing interval, candesartan cilexetil provides cardiovascular protection even in those patients who may occasionally miss doses.

A chronotherapeutic approach to effective blood pressure management.

The major randomized trials in hypertension have unequivocally demonstrated the benefits of treatment. None of these trials have sought to address the issue of the potential superiority of 24-hour blood pressure control. However, there is a volume of epidemiologic evidence to suggest that prevention of target organ damage requires the sustained reduction of blood pressure throughout the full 24-hour period between doses. Historically, some antihypertensive drugs have been approved for use at high doses to achieve apparent blood pressure control at the end of the once-daily dosing interval. This approach is flawed; attention is focused on this single time point at the end of the dosing interval, without due regard to the antihypertensive response during the rest of the dosing interval. Subsequently, guidelines formulated by the US Food and Drug Administration suggest that all antihypertensive drugs should consistently achieve a trough:peak ratio decline in blood pressure of at least 50%. Evidence suggests that antihypertensive drugs, such as calcium antagonists and angiotensin II receptor blockers, differ in their ability to provide 24-hour blood pressure control. For example, unlike some other angiotensin II receptor blockers, telmisartan provides consistent reduction of blood pressure during the 24-hour period.

Thrapeutic equivalence in the treatment of hypertension: Can lercanidipine and nifedipine GITS be considered to be interchangeable?

AIM: To undertake a review of the evidence that nifedipine GITS and lercanidipine are therapeutically equivalent in the management of essential hypertension. METHODS: A systematic review of the published literature was prompted by the findings of two meta-analyses which indicated that there was a lower incidence of peripheral (ankle) oedema with lercanidipine. However, neither meta-analysis gave detailed attention to comparative antihypertensive efficacy or cardiovascular protection. Accordingly, a systematic, detailed and critical review was undertaken of individual published papers. The review started with those studies incorporated into the 2 meta-analyses and then all other salient and directly relevant papers identified through the following search criteria: all randomized controlled trials in which the therapeutic profile and antihypertensive effects of lercanidipine were directly compared with those of nifedipine GITS (in hypertensive patients). The search strategy was focused on the reports of clinical trials of lercanidipine vs nifedipine GITS, which were identified through a systematic search of PubMed (from 1966 to October 2012), Embase (from 1980 to October 2012) and the Cochrane library (from 1 October 2008 to end October 2013). The search combined terms related to lercanidipine vs nifedipine GITS (including MeSH search using calcium antagonists, calcium channel blockers and dihydropyridines). RESULTS: With regard to blood pressure (BP) control and the consistency of BP control throughout 24-h, there is limited published evidence. However, two studies using 24 h ambulatory blood pressure monitoring clearly identified the dose-dependency of BP lowering with lercanidipine and its variably sustained 24-h efficacy. In contrast, there is evidence of a consistent antihypertensive effect throughout 24 h with nifedipine GITS. The incidence of the most common "side effect", i.e., peripheral (ankle) oedema can be estimated as follows. For every 100 patients treated with lercanidipine, 2.5 will report oedema compared to 6 patients treated with nifedipine GITS. However, 98 or 99 patients will continue treatment with nifedipine GITS, compared with 99.5 patients on lercanidipine. Finally, with regard to outcome studies of cardiovascular (CV) morbidity and mortality, there is definitive outcome evidence for nifedipine GITS but there is no evidence that treatment with lercanidipine leads to reductions in CV morbidity and mortality. CONCLUSION: There is no evidence in terms of long-term BP control and CV protection to justify the contention that lercanidipine is therapeutically equivalent to nifedipine GITS.

A review of the gastrointestinal therapeutic system (GITS) formulation and its effectiveness in the delivery of antihypertensive drug treatment (focus on nifedipine GITS).

Hypertension treatment guidelines do not discriminate within drug classes and, furthermore, do not consider whether or not all of the formulations of any given drug licensed for once-daily administration can be considered to be therapeutically interchangeable. This article focuses on this issue with respect to nifedipine and the development of the gastrointestinal therapeutic system (GITS) formulation. Nifedipine GITS is regarded as the gold standard once-daily formulation of nifedipine and, as such, it is anticipated that alternative formulations will be therapeutically equivalent to nifedipine GITS. In general, this depends on demonstrating pharmacokinetic bioequivalence. This article is intended to focus attention on generic substitution and, in particular, on aspects of the scientific basis for the substitution of generic products in place of branded products. Such substitution is required for cost-saving or cost-containment reasons and is justified on the basis that the generic (substitute) drug is "therapeutically" equivalent to the branded drug. Unfortunately, there are serious shortcomings in the current methods of assessment insofar as they are typically based on statistical comparisons of average pharmacokinetic parameter values, using arbitrary comparative criteria. This article illustrates the shortcomings of the current approaches to generic substitution and concludes that, in regulatory terms, either more rigorous pharmacokinetic criteria are required or pharmacodynamic indices should be added to reinforce the regulatory criteria. Generic substitution is a balancing act but, at the moment, the cost issue is dominant. To restore the balance, equivalent efficacy must be confirmed. At present, therefore, in the absence of such regulatory rigor, the obvious course is to prefer the branded product, the therapeutic efficacy of which (including outcome benefits) has been established.

Acetaminophen use and change in blood pressure in a hypertensive population.

OBJECTIVE: Recent data suggest that self-reported acetaminophen use is associated with increased risk of cardiovascular events and a rise in arterial blood pressure (BP). We investigated the association between acetaminophen use and BP in a large cohort of patients with hypertension using verified prescription data. METHODS: We extracted data from the UK General Practice Research Database for all hypertensive patients aged 65 years or older who were prescribed acetaminophen and had BP measured both before and during acetaminophen treatment. Patients were grouped according to whether their antihypertensive treatment remained unchanged or not during the study period. The change in SBP and DBP during acetaminophen use was determined and compared with the change in BP in a group of nonacetaminophen-exposed people identified using propensity matching. RESULTS: A total of 2754 acetaminophen-exposed individuals were included. BP rose slightly during the period of acetaminophen treatment wherein antihypertensive treatment was unchanged [change in SBP 1.6 [95% confidence interval (CI) 0.7-2.5) mmHg and change in DBP 0.5 (95% CI 0.1-1.0) mmHg)]. BP fell when new antihypertensive medications were prescribed. These BP changes were no different to those seen in matched nonacetaminophen-exposed individuals [between-group difference wherein antihypertensive treatment was unchanged was 0.6 (95% CI -0.6 to 1.9) mmHg and 0.5 (-0.1 to 1.1) mmHg for change in SBP and DBP, respectively]. CONCLUSION: We found no evidence of a sustained rise in blood pressure caused by acetaminophen treatment in a large population of patients with treated hypertension.

Long-term and ultra long-term blood pressure variability during follow-up and mortality in 14,522 patients with hypertension.

Recent evidence indicates that long-term visit-to-visit blood pressure variability (BPV) may be an independent cardiovascular risk predictor. The implication of this variability in hypertension clinical practice is unclear. BPV as average real variability (ARV) was calculated in 14,522 treated patients with hypertension in 4 time frames: year 1 (Y1), years 2 to 5 (Y2-5), years 5 to 10 (Y5-10), and years >10 (Y10+) from first clinic visit. Cox proportional hazards models for cause-specific mortality were used in each time frame separately for long-term BPV, across time frames based on ultra long-term BPV, and within each time frame stratified by mean BP. ARV in systolic blood pressure (SBP), termed ARV(SBP), was higher in Y1 (21.3±11.9 mm Hg) in contrast to Y2-5 (17.7±9.9 mm Hg), Y5-10 (17.4±9.6 mm Hg), and Y10+ (16.8±8.5 mm Hg). In all time frames, ARV(SBP) was higher in women (P<0.01) and in older age (P<0.001), chronic kidney disease (P<0.01), and prevalent cardiovascular disease (P<0.01). Higher long-term and ultra long-term BPV values were associated with increased mortality (all-cause, cardiovascular, and noncardiovascular mortality; P for trend, <0.001). This relationship was also evident in subgroups with mean SBP<140 mm Hg in all time frames. Monitoring BPV in clinical practice may facilitate risk reduction strategies by identifying treated hypertensive individuals at high risk, especially those with BP within the normal range.