Preferential benefits of nifedipine GITS in systolic hypertension and in combination with RAS blockade: further analysis of the 'ACTION' database in patients with angina.

A retrospective analysis of the database from A Coronary Disease Trial Investigating Outcome with Nifedipine (ACTION) evaluated the effectiveness of nifedipine gastrointestinal therapeutic system (GITS) (i) in combination with renin angiotensin system (RAS) blockers and (ii) in patients with isolated systolic hypertension (ISH). Analysed on an intention-to-treat basis, treatment groups were compared by the log-rank test without adjustment for covariates and hazard ratios with 95% CIs were obtained using Cox proportional hazards models. Of 7665 randomized patients, 1732 patients were receiving RAS blockade at baseline, the addition of nifedipine GITS significantly reduced any cardiovascular (CV) event (-20%; P<0.05), the composite of death, any CV event and revascularization (-16%; P<0.05) and coronary angiography (-22%; P<0.01). These benefits were achieved with relatively small differences in systolic (3.2 mm Hg) and diastolic blood pressure (BP) (2.3 mm Hg). In 2303 patients (30.0%) who had ISH at baseline (1145 nifedipine GITS and 1158 placebo), nifedipine significantly reduced the primary efficacy end point (-18%; P<0.03), any CV event (-22%; P<0.01) and new heart failure (-40%; P<0.01). The benefits were associated with between-group differences in achieved BP of 4.7 and 3.3 mm Hg for systolic and diastolic BP, respectively. In summary, the lowest CV event rates were seen in those receiving (i) the combination of RAS blockade and nifedipine GITS and (ii) in those specifically treated for ISH.

Comparison of the efficacy of candesartan and losartan: a meta-analysis of trials in the treatment of hypertension.

Informed by the findings from prospective observational studies and randomized outcome trials, guidelines for the management of hypertension acknowledge that the benefit of treatment can be attributed largely to blood pressure (BP) reduction. Therefore, quantification of differential BP lowering of different agents within classes of anti-hypertensives is of practical importance. The objective of this analysis was to compare the efficacy of candesartan and losartan with respect to reduction in systolic and diastolic BP (SBP and DBP). A systematic literature search of databases from 1980 to 1 October 2008 identified 13 studies in which candesartan and losartan were compared in randomized trials in hypertensive patients. Data from 4066 patients were included in the analysis using a random effect model. Mean changes in SBP and DBP were compared for each drug alone and after stratification for dose and for combination with hydrochlorothiazide (HCTZ). On the basis of all the data, the weighted mean difference favoured candesartan-3.22 mm Hg (95% confidence interval (CI) 2.16, 4.29) for SBP and 2.21 mm Hg (95% CI 1.34, 3.07) for DBP. These findings were consistent when analyses according to dose and combination with HCTZ were carried out. Thus, it can be concluded that at currently recommended doses, candesartan is more effective than losartan in lowering BP.

¿Es hora de revisar las estrategias del tratamiento en las normas de hipertensión? / Is it time to review the treatment strategies in hypertension guidelines?

The major hypertension treatment guidelines all acknowledge that the benefit of treatment is largely associated with improved blood pressure control and that most patients require combination therapy. The guidelines from the USA (JNC 7) suggest that thiazide-type diuretics are most suitable for initiating treatment and as a component for combination therapy. In contrast, the European guidelines (ESH/ESC 2007) suggest that all five major classes of anti-hypertensives are suitable for mono and combination therapy. Furthermore, these guidelines suggest that, because many patients require more than one drug, emphasis on identification of the first class of drugs to be used is often irrelevant. With regard to cardiovascular outcome, there is compelling evidence from outcome studies that the combination of calcium channel blockade with blockade of the reninangiotensin system offers preferential benefit which cannot be solely attributed to superior blood pressure control. There is further evidence based upon new onset diabetes, regression of left ventricular hypertrophy, atrial fibrillation and persistence with long-term therapy that suggests that this combination of drug classes will maximize the benefits of antihypertensive therapy(AU)

Todas las principales guías para el tratamiento de la hipertensión reconocen que el beneficio del tratamiento está, en su mayor parte, asociado con el mejor control de la presión sanguínea y que la mayoría de los pacientes necesitan terapia combinada. Las guías de EE. UU (JNC 7) sugieren que los diuréticos tipo tiazida son los más apropiados para iniciar el tratamiento y como componente de tratamiento combinado. Por el contrario, las guías Europeas (ESH/ESC 2007) proponen que los cinco tipos de antihipertensivos son apropiados para tratamientos bien solos bien combinados. Además, estas guías sugieren que a menudo es irrelevante hacer hincaré sobre la identificación respeto a cuál de los medicamentos debe ser de primera elección, ya que muchos pacientes necesitan más de uno. En cuanto al resultado cardiovascular, existen pruebas convincentes basadas en los estudios sobre resultados de que la combinación de los bloqueadores de los canales del calcio con bloqueadores del sistema renina angiotensina ofrecen un beneficio preferencial que no se puede atribuir solamente a un control superior de la presión sanguina. Hay pruebas adicionales basadas en una diabetes de nueva aparición, regresión de hipertrofia ventricular izquierda, fibrilación auricular y persistencia con terapia a largo plazo que sugieren que esta combinación de clases de medicamentos aumenta los beneficios de la terapia antihipertensiva(AU)

Clinical comparative trials of angiotensin II type 1 (AT1)-receptor blockers.

Three characteristics of antihypertensive medication are pivotal in therapy for a patient with hypertension: potency and efficacy, duration of action, and the incidence of side-effects. The relatively new class of AT1-receptor blockers all display placebo-like tolerability and, as a class, their antihypertensive efficacy compares well with other antihypertensive classes. However, it is unclear whether clinically important differences in duration of action and antihypertensive efficacy exist within the AT1-receptor blocker class itself. The results of a number of head-to-head clinical comparisons between these agents suggest that candesartan cilexetil and irbesartan may be more effective than the prototype AT1-receptor blocker, losartan. In addition, studies using ambulatory blood pressure recording techniques have clarified the relative durations of antihypertensive action of the AT1-receptor blockers. In particular, studies mimicking the common event of a missed or delayed dose of antihypertensive medication, show that the antihypertensive effect of candesartan cilexetil extends well beyond the 24-h dosing interval, while the effect of losartan declines rapidly over this period. The available evidence therefore suggests that significant differences in efficacy and duration of action are apparent within the AT1-receptor blocker class, and that these differences may well translate into clinically relevant differences in cardiovascular outcome.

Is postural hypotension a real problem with antihypertensive medication?

Historically, postural hypotension has been cited as a consideration which might influence the selection of antihypertensive therapy. The common symptoms (dizziness, blackouts, syncope) give cause for concern but they are not attributed to every class of antihypertensive drug. For example, administration of a beta-blocker is not generally associated with symptomatic postural hypotension, whereas the alpha-blocker prazosin was particularly problematical, with a significant and well-recognized risk of first-dose postural effects. Titration from a low starting dose and careful selection/monitoring of patients have been successfully used to circumvent this problem. However, since there is a relatively high incidence of postural hypotensive symptoms in elderly patients in general, it may be a misconception to attribute such symptoms to any particular type of antihypertensive drug. Furthermore, with the newer alpha(1)-blockers, such as doxazosin, which have a more gradual onset of action, there is a markedly reduced tendency for postural hypotension to occur. Thus, it is perhaps time to reassess the real significance of iatrogenic postural hypotension in the selection of antihypertensive therapy.

Intrinsically long-acting agents compared with long-acting chronoformulations.

Intrinsically long-acting antihypertensive drugs may be characterized by long elimination half-lives with high trough: peak ratios for decreasing blood pressure. These agents are usually administered once daily in the morning, and at steady-state they provide 24 h blood pressure control, attenuate the early-morning surge in blood pressure, and maintain a normal circadian blood pressure pattern. In comparison, chronoformulations incorporate shorter-acting antihypertensive drugs into a delivery system that is delayed-onset or extended-release, or both. These agents, which are often designed to be given once daily at bedtime, deliver peak drug concentrations that coincide with the early-morning surge in blood pressure. Chronoformulations also provide 24 h blood pressure control. In highly compliant patients, both intrinsically long-acting drugs and chronoformulations are likely to provide comparable blood pressure control. However, in poorly compliant patients who miss doses of medication, intrinsically long-acting drugs are likely to be superior, because they sustain blood pressure control beyond the dosing interval.

The importance of sustained blood pressure control.

The case for antihypertensive drug regimens that produce consistent 24-h blood pressure control has largely been founded upon a series of epidemiological observations that were either cross-sectional or alternatively relatively small-scale follow-up studies. More recent data have unequivocally demonstrated, in a prospective study in hypertensive subjects with left ventricular hypertrophy, that the reduction in left ventricular mass index during the course of one year's antihypertensive treatment, was predicted much more closely by treatment-induced changes in ambulatory blood pressure than by changes in clinic blood pressure. This provides definitive and confirmatory data to support the aim of achieving blood pressure control, which is based upon a smooth and consistent antihypertensive effect over a full 24-h dosage interval. Regimens which provide such control may also offer the advantage of a sustained duration of effect beyond 24 h. This characteristic is attractive because even the most compliant patient may inadvertently miss at least one dose of medication each week. Evidence from a number of studies which have sought to mimic this pattern of suboptimal compliance by deliberately inserting a placebo phase into a steady-state treatment regimen, has clearly demonstrated the benefits of antihypertensive drugs with intrinsically long duration of action. Furthermore, there is evidence to suggest that following cessation of therapy there is a biphasic reversion of blood pressure towards baseline levels with a maintenance of a residual effect which is more pronounced with a long-acting agent when compared to a shorter-acting drug from the same therapeutic class. There is increasing evidence, albeit not derived from prospective outcome studies, that indicates that the benefits of antihypertensive therapy are likely to be maximized by treatment regimens which result in sustained blood pressure control.

Evaluation of an antihypertensive therapy utilising meta-analysis of a clinical trial database.

The emphasis on evidence-based medicine and the use of safe, cost-effective therapeutic strategies demands that management decisions be based upon evidence derived from clinical studies. Whilst prospective double blind clinical trials are regarded as the gold standard, there is no doubt that meta-analysis has proved valuable in defining the benefits of antihypertensive therapy. The antihypertensive efficacy of lacidipine has been assessed in a retrospective meta-analysis of a series of clinical studies in which the drug was compared with placebo and all the major classes of antihypertensive agent. All of the studies entered into the meta-analysis were parallel group double blind trials. Efficacy was based upon the reduction in both systolic and diastolic blood pressure and the effect on heart rate at trough immediately prior to dosing during maintenance therapy. In placebo controlled trials a clear dose response relationship was apparent with blood pressure reductions that were significantly greater than that observed with placebo at doses of 2 mg lacidipine and above. In active control trials, diastolic blood pressure reductions of 10-15 mmHg were observed at the end of the monotreatment phases (> 6-8 weeks) with a final reduction of 15-20 mmHg with the efficacy of lacidipine being equivalent to that of the comparator drug. Comparable results were also achieved for the response rates to therapy which varied between 70 and 85% at the end of the monotreatment phase and 82-98 when combination with other antihypertensive agents was permitted. There was no evidence of cardio-acceleration in any of the trials where significant blood pressure reduction was detected. This retrospective analysis in a large population base confirms the documented antihypertensive efficacy of lacidipine and demonstrates the suitability of the drug as a first line antihypertensive agent.

Trough: peak ratio and smoothness index for antihypertensive agents.

There is a convincing volume of evidence to support the contention that optimal control of blood pressure should be based upon therapeutic strategies that consistently reduce blood pressure in a smooth and consistent fashion. Attention has, therefore, been focused on calculation of trough:peak ratios and, alternatively, the smoothing index as methodologies for defining the duration of action of an antihypertensive drug and for discriminating among alternative treatments. Acceptable accuracy and reproducibility for trough:peak ratio have been demonstrated in the controlled environment of a research unit. In contrast, trough:peak ratios from ambulatory blood pressure recordings exhibit wide inter-patient variability. With respect to clinical validity, unlike trough:peak ratio, the smoothing index has been shown to be correlated to the regression of left ventricular hypertrophy induced by treatment. Overall, neither index has been proven to offer definitive superiority and hence it is reasonable to suggest that the two are complementary.

Optimal dosing characteristics of the angiotensin II receptor antagonist telmisartan.

An optimal antihypertensive drug produces superior blood pressure-lowering effects at established dosages, with an acceptably low incidence of side effects, and at a dosage interval that is convenient for patients (ideally, once daily). The angiotensin II receptor antagonist, telmisartan, meets these criteria. At doses of > or = 40 mg, this once-daily drug produces a statistically significant reduction in blood pressure. Ambulatory blood pressure monitoring (ABPM) and high trough-peak ratios attest to the smooth, consistent blood pressure-lowering effect of telmisartan at 40- and 80-mg dosages. Telmisartan also demonstrates a statistically superior antihypertensive effect toward the end of the dosing interval compared with amlodipine and losartan, and it has a side-effect profile comparable to that of placebo. In summary, the evidence suggests that telmisartan at dosages of 40 and 80 mg once daily satisfies the 3 criteria of an ideal antihypertensive agent, producing an effective and sustained response with placebo-like tolerability.

Mortality amongst patients of the Glasgow Blood Pressure Clinic was high in the 1970s and 80s but has fallen since, why?

Established in 1968 the Glasgow Blood Pressure Clinic has over 11,000 patients on its computer record. Up to 1980, mortality from all-causes and from cardiovascular causes was high: relative risks compared with two local control populations were greater than 2.0. Since 1980, all-cause mortality has decreased to 1.31 (859 deaths, CI 1.23-1.39). Lower mortality from cardiovascular causes, particularly coronary heart disease, contributes to the decrease. Reasons for the decrease are under investigation currently. Referral of patients with slightly lower blood pressure contributes, as may better blood pressure control with newer antihypertensive drugs. ACE inhibitors and calcium channel blockers were introduced in 1980 and during the 16-year period to 1995, all-cause mortality has decreased most in patients taking ACE inhibitor. A decrease also occurred in patients taking antihypertensive drugs other than ACE inhibitor.

Is cancer related to hypertension or to its treatment?

Three questions related to cancer and blood pressure are discussed. (i) Is cancer related in some way to hypertension, or to blood pressure? Several studies show a relation of blood pressure and cancer in populations. However, our own experience, based on a cohort of 15,411 subjects with BP measured in the 1970s and with 1,392 fatal cancers since, shows no relation of cancer risk and diastolic pressure. Nor were cancer numbers (n=72) observed in the 1,078 untreated hypertensives of the Glasgow Blood Pressure Clinic different from those expected (n=71.2) in a control population matched for age, sex and smoking habit. (ii) Do antihypertensive drugs promote cancer? Atenolol and calcium channel blockers have been suspected of this, but evidence of larger studies, including two of our own, is negative: relative risk for cancer in our patients taking CCB was 1.02 (CI 0.82-1.27). (iii) Do antihypertensive drugs protect against cancer? A study of ours based on the Glasgow Clinic raises this possibility: relative risk for incident cancer amongst 1,559 patients taking ACE inhibitor was 0.72 (CI 0.55-0.92).

Lercanidipine: a novel lipophilic dihydropyridine calcium antagonist with long duration of action and high vascular selectivity.

Lercanidipine is a new 1,4-dihydropyridine derivative with potent, long-lasting and vascular-selective calcium entry blocking activity. Animal models of hypertension have shown lercanidipine to be potent, with a slow rate of onset and long lasting action and to have minimal or no effects on cardiac contractility. There was no evidence of tolerance after repeated oral treatment, and no effects were found on the autonomic nervous, central nervous, gastrointestinal or respiratory systems at antihypertensive doses. In man, lercanidipine is well absorbed after oral administration, with peak plasma levels occurring approximately 1.5 - 3 h after dosing. The drug is subject to extensive hepatic first pass metabolism with an elimination half-life of 2 - 5 h. With a more sensitive method, a mean terminal elimination half-life of 8 - 10 h was defined. Despite this short plasma half-life the drug has a long duration of action, most likely due to the high lipophilicity of lercanidipine and its partitioning in to the lipid bilayer of cell membranes, followed by diffusion to the receptor binding site. The efficacy of lercanidipine has been established in extensive clinical trials with comparison to both placebo and standard well-established antihypertensive therapies. These trials confirmed the efficacy of lercanidipine and its long duration of action which renders it suitable for once daily administration. Tolerability was good in all studies: the adverse event profile was comparable to that of placebo at lower doses, with a low incidence of palpitations and ankle oedema. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine calcium antagonist which is an effective antihypertensive drug with a slow onset and long duration of action; it is associated neither with reflex tachycardia nor cardio-depressant activity.

ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (enalaprilat) in humans.

BACKGROUND: We have investigated the possible effects of contrasting ACE (I/D) genotypes on the responses to the ACE inhibitor enalaprilat in normotensive men. METHODS AND RESULTS: Subjects with DD (n=12) and II (n=11) ACE genotypes received an intravenous infusion of enalaprilat or placebo. Pressor responses to stepwise, incremental doses of angiotensin I were measured at 1 and 10 hours after dosing. The dose required to raise mean blood pressure by 20 mm Hg (PD20) was calculated individually, and the ratio of PD20 during enalaprilat to that during placebo (dose ratio, DR) was used for assessment of the extent of ACE inhibition. The pressor response was significantly attenuated at 1 hour after enalaprilat in both groups, but significant attenuation was evident at 10 hours after dose only in the II subjects. The DRs at both 1 hour (median, 5.43 versus 2.82, P=0.0035) and 10 hours (2.06 versus 0.84, P=0.0008) after enalaprilat were significantly higher in II subjects than in DD subjects. CONCLUSIONS: The effect of enalaprilat was significantly greater and lasted longer in normotensive men homozygous for the II ACE genotype. By multivariate analysis, ACE (I/D) genotype and plasma angiotensin II levels were predictive of >50% of the variation in response to ACE inhibition.

Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer?

BACKGROUND: Previous studies have reported an increased risk of cancer with calcium-channel blockers in man. Other work in animals suggests that inhibitors of angiotensin-I-converting enzyme (ACE) protect against cancer. We aimed to assess the risk of cancer in hypertensive patients receiving ACE inhibitors or other antihypertensive drugs. METHODS: Our retrospective cohort study was based on the records of 5207 patients who attended the Glasgow Blood Pressure Clinic between Jan 1, 1980, and Dec 31, 1995. The patients' records are linked with the Registrar General Scotland and the West of Scotland Cancer Registry. FINDINGS: Compared with the West of Scotland controls, the relative risks of incident and fatal cancer among the 1559 patients receiving ACE inhibitors were 0.72 (95% CI 0.55-0.92) and 0.65 (0.44-0.93). Among the 3648 patients receiving antihypertensive drugs other than ACE inhibitors (calcium-channel blockers 1416, diuretics 2099, beta-blockers 2681), the corresponding relative risks were 110 (0.97-1.22) and 1.03 (0.87-1.20). The relative risk of cancer was lowest in women on ACE inhibitors: 0.63 (0.41-0.93) for incident cancer; 0.48 (0.23-0.88) for fatal cancer; and 0.37 (0.12-0.87) for female-specific cancers. The reduced relative risk of cancer in patients on ACE inhibitors was greatest with follow-up of longer than 3 years. Calcium-channel blockers, diuretics, and beta-blockers had no apparent effect on risk of cancer. INTERPRETATION: Long-term use of ACE inhibitors may protect against cancer. The status of this finding is more that of hypothesis generation than of hypothesis testing; randomised controlled trials are needed.

How to evaluate the duration of blood pressure control: the trough:peak ratio and 24-hour monitoring.

Recently published data provide confirming evidence to support existing epidemiologic data showing that treatment-induced changes in 24-h blood pressure are more closely correlated with treatment-induced changes in left ventricular mass index than corresponding changes in clinic blood pressure. This provides definitive support for the aim of achieving blood pressure control based on a smooth and consistent antihypertensive effect over a full 24-h period. With the plethora of agents now available for once-daily administration in the treatment of hypertension, it would be of value to have a validated index that defines duration of effect and that discriminates between alternative treatments and treatment regimens. The trough:peak ratio of blood pressure response has been proposed as such as index and has in part been validated in this role. Evidence suggests that many existing agents have suboptimal trough:peak ratios or, alternatively, that achieving a high ratio is dependent on utilizing inappropriately high doses of drug. Where a drug has a high trough:peak ratio that is associated with its intrinsic long duration of action and is independent of dose over the therapeutic range, the evidence indicates that the drug may offer the additional benefit of sustained blood pressure control after a missed dose. Finally, theoretic and experimental evidence supports the concept that rational drug combinations will produce enhanced trough:peak ratios compared to the individual drug components.