Trials using a crossover design and ambulatory blood pressure recordings to determine the efficacy of antihypertensive agents in individual patients.

The antihypertensive effects of the beta-blocking agent betaxolol and the calcium entry blocker verapamil were compared in a crossover single-blind trial. Seventeen patients with uncomplicated essential hypertension took either betaxolol or a slow-release formulation of verapamil for two consecutive 6-week periods. The sequence of treatment phases was randomly allocated and a 2-week washout period preceded each treatment. The antihypertensive effect of the test drugs was assessed both at the physician's office and during everyday activities using a portable blood pressure recorder. The crossover design of the trial made it possible to evaluate the antihypertensive efficacy of betaxolol and verapamil both in the group as a whole and in the individual patient. The individual patient response to one of these agents was not a reliable indicator of the same patient's response to the alternative agent. Betaxolol brought both office and ambulatory recorded blood pressures under control in a larger fraction of patients than verapamil, although the magnitude of the blood pressure fall in the responders was equal for each drug. These observations stress the need for an individualized approach to the evaluation of antihypertensive therapy. The present results also demonstrate that optimal antihypertensive therapy is still a matter of trial and error. The precise methodology that ought to characterize crossover trials may make it possible to improve the therapeutic approach to hypertensive patients.

Aminopeptidase A inhibitors as potential central antihypertensive agents

Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental models, such as spontaneously hypertensive rats and transgenic mice expressing both human renin and human angiotensinogen transgenes. We recently reported that, in the murine brain, angiotensin II (AngII) is converted to angiotensin III (AngIII) by aminopeptidase A (APA), whereas AngIII is inactivated by aminopeptidase N (APN). If injected into cerebral ventricles (ICV), AngII and AngIII cause similar pressor responses. Because AngII is metabolized in vivo into AngIII, the exact nature of the active peptide is not precisely determined. Here we report that, in rats, ICV injection of the selective APA inhibitor EC33 [(S)-3-amino-4-mercaptobutyl sulfonic acid] blocked the pressor response of exogenous AngII, suggesting that the conversion of AngII to AngIII is required to increase blood pressure (BP). Furthermore, ICV injection, but not i.v. injection, of EC33 alone caused a dose-dependent decrease in BP by blocking the formation of brain but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol), administered alone via the ICV route, increases BP. This pressor response was blocked by prior treatment with the angiotensin type 1 (AT1) receptor antagonist, losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in BP increase, through interaction with AT1 receptors. These data demonstrate that AngIII is a major effector peptide of the brain RAS, exerting tonic stimulatory control over BP. Thus, APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors as central antihypertensive agents.

Modulation of osteoclastogenesis by antihypertensive drugs

Despite its rigid structure, bone is a dynamic tissue that is in constant remodeling. This process requires the action of the bone-resorbing osteoclasts and the bone-synthesing osteoblasts. One of the adverse effects attributed to some antihypertensive agents is the ability to alter normal bone metabolism. However, their effective actions on human bone cells remain to be clarified. In this work, the effects of five calcium channel blockers, a class of antihypertensive drugs (AHDs), were investigated on osteoclastic differentiation. Osteoclastic cell cultures were established from precursor cells isolated from human peripheral blood, and were maintained in the absence (control) or in the presence of 10-8-10-4 M of different AHDs (amlodipine, felodipine, diltiazem, lercanidipine and nifedipine). Cell cultures were characterized throughout a 21 day period for tartrate-resistant acid phosphatase (TRAP) activity, number of TRAP+ multinucleated cells, presence of cells with actin rings and expressing vitronectin and calcitonin receptors, and apoptosis rate. Also, the involvement of several signaling pathways on the cellular response was addressed. It was observed that the tested AHDs had the ability to differentially affect osteoclastogenesis. At low doses, amlodipine and felodipine caused an increase on osteoclastic differentiation, while the other drugs inhibited it. At higher doses, all the molecules caused a decrease on the process. The tested AHDs also showed different effects on the analysed signaling pathways. In conclusion, AHDs appeared to have a direct effect on human osteoclast precursor cells, affecting their differentiation. Interestingly, some of them increased while others inhibited the process. Unraveling the mechanisms beneath these observations might help to explain the adverse effects on bone tissue described for this drug class.

Ambulatory blood pressure measurement and antihypertensive therapy.

The traditional basis for assessing the effect of antihypertensive therapy is the blood pressure reading taken by a physician. However, several recent trials have been designed to evaluate the blood pressure lowering effect of various therapeutic agents during the patients' normal daytime activities, using a portable, semi-automatic blood pressure recorder. The results have shown that in a given patient, blood pressure measured at the physician's office often differs greatly from that prevailing during the rest of the day. This is true both in treated and untreated hypertensive patients. The difference between office and ambulatory recorded pressures cannot be predicted from blood pressure levels measured by the physician. Therefore, a prospective study was carried out in patients with diastolic blood pressures that were uncontrolled at the physician's office despite antihypertensive therapy. The purpose was to evaluate the response of recorded ambulatory blood pressure to treatment adjustments aimed at reducing office blood pressure below a pre-set target level. Only patients with high ambulatory blood pressures at the outset appeared to benefit from further changes in therapy. Thus, ambulatory blood pressure monitoring can be used to identify those patients who remain hypertensive only when facing the physician, despite antihypertensive therapy. Ambulatory monitoring could thus help to evaluate the efficacy of antihypertensive therapy and allow individual treatment.

Improved blood pressure control by monitoring compliance with antihypertensive therapy.

Compliance with antihypertensive therapy was monitored for three months using an electronic medication dispenser in 35 patients remaining hypertensive despite the once-daily administration of a blood pressure lowering drug (either as monotherapy or as fixed-dose combination therapy). During the monitoring of compliance, the treatment was unchanged but blood pressure decreased significantly (p < 0.001) from 167.9/100.4 +/- 16.3/7.2 mmHg (mean +/- SD) to 152.5/90.9 +/- 20.9/11.5 mmHg. The percentage of days with one opening per day was 80.8 +/- 20.5. Thus, discussing with the patient about compliance with the prescribed drug regimen and monitoring compliance for a few months allows better control of blood pressure. This most likely reflects increased compliance with antihypertensive drug therapy.

Les combinaisons fixes de medicaments antihypertenseurs. [Fixed antihypertensive drug combinations]

Arterial hypertension is a highly heterogeneous condition. It is therefore not surprising that blood pressure lowering agents acting via a given mechanism allow a normalization of blood pressure in a fraction of hypertensive subjects only. The combination of drugs with different mechanisms of action on the cardiovascular system results in a considerably higher antihypertensive efficacy, not only with regard to the absolute blood pressure reduction but also in the number of responders. This effect is not achieved at the expenses of tolerance, because usually lower doses of the combined agents are sufficient to achieve the target blood pressure. The administration of antihypertensive agents in fixed combination has the advantage of its simplicity for both the physician as well as the patient. This aspect also explains the increasing popularity of fixed combinations as a valuable option in the initial treatment of the hypertensive patient.

The return of increased blood pressure after discontinuation of antihypertensive treatment is associated with an impaired post-ischemic skin blood flow response.

OBJECTIVE: To assess the post-ischemic skin blood flow response after withdrawal of antihypertensive therapy in hypertensive patients with normal blood pressure during treatment. DESIGN AND METHODS: Twenty hypertensive patients (group A) with a normal clinic blood pressure (<140/ 90 mmHg) receiving antihypertensive treatment (any monotherapy; one pill per day for at least 6 months) had their treatment discontinued. Before medication withdrawal and 2, 4, 12 and 24 weeks thereafter, the following measurements were made: clinic blood pressure, home blood pressure (three times per week, morning and evening) and skin blood flow response to a 5 min forearm arterial occlusion (using laser Doppler flowmetry). The patients were asked to perform an ambulatory blood pressure recording at any time if home blood pressure was > or =160/95 mmHg on two consecutive days, and treatment was initiated again, after determination of the skin hyperemic response, if daytime ambulatory blood pressure was > or =140/90 mmHg. The same studies were performed in 20 additional hypertensive individuals in whom antihypertensive treatment was not withdrawn (group B). The allocation of patients to groups A and B was random. RESULTS: The data fom 18 patients in group A who adhered strictly to the procedure were available for analysis. Seven of them had to start treatment again within the first 4 weeks of follow-up; four additional patients started treatment again during the next 8 weeks (group A1). The seven other patients remained untreated (group A2). The skin hyperemic response decreased significantly in patients in group A1 and returned to baseline values at the end of the study, when there were again receiving antihypertensive treatment. In patients in group A2 a significant attenuation of the hyperemic response was also observed. This impaired response was present even at the end of the 6 month follow-up, at which time the patients were still untreated but exhibited a significantly greater blood pressure than before drug discontinuation. The hyperemic response of patients who did not stop treatment (group B) did not change during the course of the study. CONCLUSIONS: Our findings show a decrease in the postischemic skin blood flow response after withdrawal of antihypertensive treatment in hypertensive patients. This impaired response may be due to the development of endothelial dysfunction, vascular remodeling, or both, and might contribute to the return of blood pressure to hypertensive values after withdrawal of antihypertensive therapy.

Hypertension. Effets du traitement antihypertenseur sur les fonctions cognitives [Hypertension. Effects of antihypertensive therapy on cognitive functions].

A cause and effect relationship between arterial hypertension and decline of cognitive function has long been suspected. In middle-age subjects indeed, an abnormally high blood pressure is a risk factor for the long-term development of dementia. Presently, it seems crucial to treat hypertensive patients in order to better protect them against cognitive decline. However, in the elderly patients the risk of mental deterioration may also be enhanced when diastolic pressure becomes too low, for example below 70 mmHg. Further studies are required to better define the antihypertensive drug regimen and target blood pressure which would be optimal for the prevention of cerebral small vessel disease.

Angiotensin II antagonists: a new class of antihypertensive agent

Losartan is an orally active angiotensin II antangonist that selectively blocks effects mediated by the stimulation of the AT1 subtype of the angiotensin II receptor. This agent, at doses of 50-150mg/day, is as effective at lowering blood pressure as chronic angiotensin converting enzyme (ACE) inhibitors. Losartan is generally well tolerated and has an incidence of adverse effects very similar, in double-blind controlled trials, to that of placebo. It does not cause coughing, the most common side-effect of the ACE inhibitors, most probably because angiotensin II antagonism has no impact on ACE, an enzyme known to process bradykinin and other cough-inducing peptides. Losartan is a promising antihypertensive agent with the potential to become a first-line option for the treatment of patients with high blood pressure.

How quickly should we titrate antihypertensive medication? Systematic review modelling blood pressure response from trial data.

Context There are no evidence syntheses available to guide clinicians on when to titrate antihypertensive medication after initiation. Objective To model the blood pressure (BP) response after initiating antihypertensive medication. Data sources electronic databases including Medline, Embase, Cochrane Register and reference lists up to December 2009. Study selection Trials that initiated antihypertensive medication as single therapy in hypertensive patients who were either drug naive or had a placebo washout from previous drugs. Data extraction Office BP measurements at a minimum of two weekly intervals for a minimum of 4 weeks. An asymptotic approach model of BP response was assumed and non-linear mixed effects modelling used to calculate model parameters. Results and conclusions Eighteen trials that recruited 4168 patients met inclusion criteria. The time to reach 50% of the maximum estimated BP lowering effect was 1 week (systolic 0.91 weeks, 95% CI 0.74 to 1.10; diastolic 0.95, 0.75 to 1.15). Models incorporating drug class as a source of variability did not improve fit of the data. Incorporating the presence of a titration schedule improved model fit for both systolic and diastolic pressure. Titration increased both the predicted maximum effect and the time taken to reach 50% of the maximum (systolic 1.2 vs 0.7 weeks; diastolic 1.4 vs 0.7 weeks). Conclusions Estimates of the maximum efficacy of antihypertensive agents can be made early after starting therapy. This knowledge will guide clinicians in deciding when a newly started antihypertensive agent is likely to be effective or not at controlling BP.

Evaluation par des médecins installés de l'efficacité antihypertensive de la débrisoquine, de la méthyldopa et du propranolol [Evaluation by practicing physicians of the antihypertensive efficacy of debrisoquin, methyldopa and propranolol]

The antihypertensive effect of debrisoquine (20 mg/day), methyldopa (100 mg/day) and propranolol (160 mg/day) was compared to that obtained with a placebo in a controlled trial carried out by a group of 14 internists. Forty-eight patients with uncomplicated essential hypertension were included. Mefruside (25 mg/day) was first given alone for 6 weeks ("open phase" of the trial) and to this diuretic was then added in double-blind fashion and randomized sequence a placebo or an active drug. Each of the 4 blind phases lasted 4 weeks. At the end of the "open phase", blood pressure in seated position averaged 168/111 +/- 19.6/13.5 mm Hg (mean +/- SD). A significant blood pressure decrease was observed after 4 weeks of treatment with the placebo as well as with the investigated compounds. With the placebo blood pressure was reduced to 158/102 +/- 19.6/13.5 mm Hg (p less than 0.001). The magnitude of the additional blood pressure decrease induced by the active drugs was relatively small and varied from 4 (debrisoquine) to 10 mm Hg (methyldopa, p less than 0.01) for the systolic and from 3 (debrisoquine, p less than 0.05) to 5 mm Hg (propranolol, p less than 0.05) for the diastolic. The percentage of patients with systolic pressure of less than or equal to 140 mm Hg and with diastolic pressure of less than 90 mm Hg during administration of either drug was not greater than 40 to 20% respectively. Propranolol appeared to be better tolerated than the other antihypertensive agents. These rather disappointing blood pressure results suggest that the efficacy of antihypertensive agents in private practice cannot be extrapolated from studies carried out in specialized hypertension clinics.