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.

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.

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.

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.

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.

Persistence of antihypertensive efficacy after missed doses: comparison of amlodipine and nifedipine gastrointestinal therapeutic system.

OBJECTIVE: In this randomized, double-blind, crossover study, the antihypertensive efficacy of amlodipine and nifedipine gastrointestinal therapeutic system (GITS) was compared following missed doses. Design and methods In a randomized crossover design, 42 patients were randomized to receive amlodipine (5-10 mg) or the GITS formulation of nifedipine (nifedipine GITS) (30-60 mg) once daily for 12 weeks, then vice versa. During weeks 8, 10 and 12 of each treatment period, compliance failures were simulated by patients missing 0, 1 or 2 doses of their medication, and ambulatory systolic (SBP) and diastolic (DBP) blood pressure measurements were obtained. RESULTS: Following steady-state treatment (i.e. 'perfect compliance'), there was no difference between amlodipine and nifedipine GITS in SBP (140.1 versus 134.2 mmHg) or DBP (84.0 versus 85.8 mmHg) at 0-24 h post-dose. When compliance was not perfect, i.e. when one or two doses were missed, DBP was maintained at a significantly lower level with amlodipine compared with nifedipine GITS at 24-48 h post-dose (83.1 versus 86.4 mmHg, P = 0.005) and at 48-72 h post-dose (84.2 versus 89.7 mmHg, P < 0.001). Plasma concentrations of amlodipine were better maintained than those of nifedipine GITS. At 72 h post-dose, the plasma concentration of amlodipine was 61% (17.0 +/- 11.2 ng/ml) compared with < 25% (28.3 +/- 49.9 ng/ml) for nifedipine GITS. CONCLUSION: During short periods of non-compliance, antihypertensive efficacy remains more predictable with amlodipine than with nifedipine GITS.