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.

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.

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.

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.

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.

Are fixed-dose combination antihypertensives suitable as first-line therapy?

OBJECTIVE: To contemplate how initial antihypertensive therapy with fixed-dose combinations (FDC) might be incorporated into clinical practice, based on a compilation of evidence comparing FDCs with monotherapy and loose-dose combinations in varying patient populations. METHODS: A non-systematic search of PubMed (from 2007 to 2012) was performed for randomized, controlled trials in order to capture the evidence on FDC versus monotherapy and loose-dose combinations as first-line therapy. The literature search focused on calcium channel blocker (CCB)-renin angiotensin system (RAS) blocker combinations. Additionally, any relevant papers known to the authors were included. International recommendations from published hypertension treatment guidelines were also consulted. RESULTS: The results of this literature review identified two emergent issues. Firstly, there is a discord between antihypertensive use and actual blood pressure (BP) control achieved - despite an increase in the use of antihypertensives over the last 10 years, BP control rates remain low. Secondly, a greater association between BP and cardiovascular risk in Asians may magnify this discrepancy. A number of international guidelines are recommending early combination therapy, such as CCB-RAS blocker combinations in the majority of patients based on the available evidence, with such combinations showing benefits in terms of compliance, BP lowering and control, and safety. Additionally, recent studies have indicated that improved BP control may be achieved with simplified guidelines and the use of FDCs. Overall, these findings indicate that FDC could be used as first-line. CONCLUSIONS: The findings from this literature review suggest that physicians may need to readdress their approach to antihypertensive treatment. Earlier use of antihypertensive FDC (including first-line) may help to shrink the current gap between antihypertensive use and BP target control achieved. Most guidelines acknowledge that combination therapy is required in the majority of patients, and FDC are regarded as a suitable alternative, having demonstrated better compliance compared with loose-dose combinations.

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.

Hematocrit predicts long-term mortality in a nonlinear and sex-specific manner in hypertensive adults.

Hematocrit has been inconsistently reported to be a risk marker of cardiovascular morbidity and mortality. The Glasgow Blood Pressure Clinic Study cohort included 10951 hypertensive patients, who had hematocrit measured at their initial clinic visit and followed for ≤35 years. Cox proportional hazards models were used to estimate hazard ratios for all-cause, cardiovascular, ischemic heart disease, stroke, and noncardiovascular mortality. There were 3484 deaths over a follow-up period of 173245 person-years. Hematocrit was higher in men (median, 0.44; interquartile range, 0.42-0.47) than in women (median, 0.41; interquartile range, 0.38-0.43). The lowest risk for all-cause mortality was seen in quartile 2 for men (range, 0.421-0.440) and women (range, 0.381-0.400). Compared with quartile 2, the adjusted hazard ratios for quartiles 1, 3, and 4 were, respectively, 1.11 (range, 0.97-1.28), 1.19 (range, 1.04-1.37), and 1.22 (range, 1.06-1.39) in men and 1.17 (range, 1.01-1.36), 0.97 (range, 0.83-1.13), and 1.19 (range, 1.04-1.37) in women. Men showed a J-shaped pattern for cardiovascular mortality and a linear pattern for noncardiovascular mortality in cause-specific analysis, whereas in women a U-shaped pattern was observed for noncardiovascular mortality only. Higher baseline hematocrit was associated with higher on-treatment blood pressure during follow-up. Baseline hematocrit did not affect the time to reach target blood pressure. The increased risk of death attributed to higher hematocrit was seen in men and women irrespective of their achievement of target blood pressure, indicating that the risk is independent of the effect of hematocrit on blood pressure. Hypertensive patients with hematocrit levels outside of the sex-specific reference ranges identified in this study should be targeted for more aggressive blood pressure and cardiovascular risk reduction treatment.

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.

Improving blood pressure control in patients with diabetes mellitus and high cardiovascular risk.

Patients with diabetes mellitus and symptomatic coronary artery disease are also likely to be hypertensive and, overall, are at very high cardiovascular (CV) risk. This paper reports the findings of a posthoc analysis of the 1113 patients with diabetes mellitus in the ACTION trial: ACTION itself showed that outcomes in patients with stable angina and hypertension were significantly improved when a long-acting calcium channel blocking drug (nifedipine GITS) was added to their treatment regimens. This further analysis of the ACTION database in those patients with diabetes has identified a number of practical therapeutic issues which are still relevant because of potential outcome benefits, particularly in relation to BP control. For example, despite background CV treatment and, specifically, despite the widespread use of ACE Inhibitor drugs, the addition of nifedipine GITS was associated with significant benefits: improvement in BP control by an average of 6/3 mmHg and significant improvements in outcome. In summary, this retrospective analysis has identified that the addition of nifedipine GITS resulted in improved BP control and significant outcome benefits in patients with diabetes who were at high CV risk. There is evidence to suggest that these findings are of direct relevance to current therapeutic practice.

Benefits of nifedipine GITS in stable coronary artery disease: Further analysis of the "ACTION" database.

INTRODUCTION: Retrospective analyses of specific subgroups of patients from the database of the ACTION study have evaluated the effectiveness of a nifedipine gastrointestinal therapeutic system (GITS) on clinical outcomes. These subgroups included those patients receiving: 1) full "optimal" therapy at baseline; 2) full "optimal" therapy at baseline but excluding renin angiotensin system (RAS)-blocking drugs; 3) treatment with nifedipine GITS who were not treated with RAS blockers versus those treated with RAS blockers but not nifedipine GITS. METHODS: Analyses were performed on an intention-to-treat basis. Treatment groups were compared by log-rank test without adjustment for covariates. Hazard ratios with 95% confidence intervals were obtained using Cox proportional hazards models with treatment allocation as the only covariate. RESULTS: 2461 patients randomized in ACTION were receiving optimal therapy (beta blockers, nitrates, aspirin, statins) excluding RAS blockers at baseline. There were reductions associated with nifedipine GITS compared with placebo in all prespecified endpoints but statistical significance was only achieved for debilitating stroke (48%; P<0.02) and coronary angiography (14%; P<0.05). These benefits were paralleled by a -4.1 and -2.8 mmHg difference between the groups for systolic and diastolic blood pressure, respectively. Patients randomized to nifedipine GITS but no RAS blockers (n=2966) when compared to those receiving RAS blockers but no nifedipine GITS (n=880) had highly statistically significant reductions in cardiovascular events (22%), new-onset heart failure (53%), and debilitating stroke (45%). However, the groups differed in their baseline characteristics. CONCLUSION: Addition of nifedipine GITS to the treatment regimen of selected patient groups with symptomatic coronary artery disease results in a significant reduction of cardiovascular morbidity. While the interpretation of these subgroup analyses must obviously be cautious, there is a clear message relating to "best practice" treatment of angina, which suggests that "reliance" on RAS blockade may be misplaced and greater attention should be directed towards control of blood pressure.

Potential concerns about generic substitution: bioequivalence versus therapeutic equivalence of different amlodipine salt forms.

BACKGROUND AND SCOPE: Whether generic drug products are truly therapeutically identical and interchangeable with their innovator counterparts is still a matter of debate. This review discusses the controversies related to the criteria for bioequivalence and therapeutic equivalence. These concerns are illustrated by using the calcium antagonist amlodipine besylate (innovator drug) versus amlodipine maleate (generic), indicated for the treatment of hypertension and angina pectoris, as an example. METHODS: English-language publications were searched in Medline and EMBASE to retrieve all references on amlodipine maleate and literature related to the regulatory guidelines for bioequivalence and therapeutic equivalence to August 2008. Websites from the European and US regulatory authorities were also consulted. FINDINGS: According to regulatory definitions, generic drug products need to be identical to their reference with respect to the active substance, the route of administration as well as quality standards. In contrast to innovator drugs, which have to demonstrate their clinical efficacy and safety, generics are considered therapeutically equivalent based on simple bioequivalence testing. In addition, bioequivalence is established with a disputable study method (single dose in a small group of healthy subjects) and statistics (broad acceptance intervals). Consequently, a potential negative impact of alternative salt forms or excipients on the clinical profile of a drug may remain undetected. To exemplify this, although amlodipine maleate is known to contain (degradation) impurities with (potential) biological activity, it is found per definition bioequivalent to its innovator drug, amlodipine besylate. However, only two clinical studies compared the antihypertensive and safety profiles of both drugs up to 3 months, without CV event endpoints. CONCLUSIONS: The validity of the current criteria for interchangeability of generic and innovator drugs remains controversial and may compromise the response and/or safety of patients. In the case of amlodipine, thorough long-term clinical investigations of commercial amlodipine maleate salt preparations including hard endpoints may be needed to justify their use.

Clinical outcomes according to baseline blood pressure in patients with a low ejection fraction in the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) Program.

OBJECTIVES: This study sought to investigate the efficacy and tolerability of candesartan, according to baseline blood pressure (BP), in the 4,576 patients with a low ejection fraction (EF) (or=141 mm Hg) and 4 DBP categories (or=81 mm Hg). RESULTS: Low SBP and DBP were associated with worse clinical outcomes. Baseline BP did not modify the effects of candesartan on clinical outcomes: the interaction p value between SBP category and treatment was 0.38 (0.22 for DBP category). For both placebo and candesartan, study drug discontinuation for adverse effects (especially hypotension) was highest in patients in the lowest baseline BP categories. However, the relative risk of discontinuation for hypotension, renal dysfunction, and hyperkalemia in the candesartan compared with placebo group was not increased in patients with a low baseline BP. CONCLUSIONS: In patients with low EF heart failure, the relative risks and benefits of candesartan treatment were similar in patients with a low BP compared to those with a higher BP.

Candesartan cilexetil--a review of effects on cardiovascular complications in hypertension and chronic heart failure.

UNLABELLED: Therapeutic interventions that block the renin-angiotensin-aldosterone system (RAAS) have an important role in slowing the progression of cardiovascular risk actors to established cardiovascular diseases. In recent years, angiotensin receptor blockers (ARBs) have emerged as effective and well-tolerated alternatives to an angiotensin-converting enzyme inhibitor (ACEi) for RAAS blockade. The ARB candesartan was initially established as an effective once-daily antihypertensive treatment, providing 24-h blood pressure (BP) control with a trough:peak ratio close to 100%. SCOPE: A Medline literature search was undertaken to identify randomised, controlled trials that examined the efficacy and cardiovascular outcomes associated with candesartan cilexetil in hypertension and chronic heart failure (CHF). FINDINGS: Compared with other ARBs, candesartan demonstrates the strongest binding affinity to the angiotensin II type 1 receptor. Clinical trials have demonstrated that candesartan is well tolerated in combination with diuretics or calcium channel blockers (CCBs), making it a suitable treatment option for patients whose hypertension is not adequately controlled by monotherapy. Subsequently, candesartan became the only ARB licensed in the UK to treat patients with CHF and left ventricular ejection fraction < or = 40% as add-on therapy to an ACEi or when an ACEi is not tolerated. Studies in patients with symptomatic HF have indicated that candesartan treatment was associated with significant relative risk reductions in cardiovascular mortality and hospitalisation due to CHF. CONCLUSIONS: There are clear indications that the clinical benefits of candesartan may extend beyond its proven antihypertensive effects to a wider range of complications across the cardiovascular continuum, including diabetes, left ventricular hypertrophy, atherosclerosis and stroke. Such results suggest that candesartan treatment may offer significant patient benefits as well as practical advantages over conventional treatment.

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