[show abstract][hide abstract] ABSTRACT: Blood pressure (BP) control is frequently difficult to achieve in patients with predominantly elevated systolic BP. Consequently, these patients frequently require combination therapy including a thiazide diuretic such as hydrochlorothiazide (HCTZ) and an agent blocking the renin-angiotensin-aldosterone system. Current clinical practice usually limits the daily dose of HCTZ to 25 mg. This often leads to the necessity of using additional antihypertensive agents to control BP in a high proportion of patients.
To compare the efficacy of two doses of losartan (LOS)⁄HCTZ combinations in patients with uncontrolled ambulatory systolic hypertension after six weeks of treatment with LOS 100 mg⁄HCTZ 25 mg (LOS100⁄HCTZ25).
Following a two- to four-week washout period, subjects with a mean clinic sitting systolic BP of 160 mmHg or higher and a mean ambulatory daytime systolic BP (MDSBP) of 135 mmHg or higher on LOS100⁄HCTZ25 (n=105; 33 women and 72 men) were randomly assigned to receive LOS 150 mg⁄HCTZ 25 mg (group 1; n=53) or LOS 150 mg⁄HCTZ 37.5 mg (LOS150⁄HCTZ37.5, group 2; n=52). The primary end point was the difference in MDSBP reductions.
At the end of the six-week treatment period, the respective additional decreases in MDSBP were 1.2 mmHg (P=0.335) on LOS 150 mg⁄HCTZ 25 mg and 5.6 mmHg (P<0.0001) on LOS150⁄HCTZ37.5 (difference of 4.4 mmHg; P=0.011). Daytime systolic ambulatory BP goal (lower than 130 mmHg) achievement tended to be higher (25% versus 17%; P=0.313) with LOS150⁄HCTZ37.5, while it was significantly higher (65% versus 43%; P=0.024) for mean daytime diastolic BP (lower than 80 mmHg). No deleterious metabolic changes were observed.
In patients with uncontrolled systolic ambulatory hypertension receiving LOS100⁄HCTZ25, increasing both HCTZ and LOS dosages simultaneously to LOS150⁄HCTZ37.5 may be an effective strategy that does not affect metabolic parameters.
The Canadian journal of cardiology 10/2010; 26(8):313-9. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Stress dipyridamole technetium-99(m) sestamibi single photon emission computed tomographic imaging was used to study myocardial perfusion in 1116 hypertensive patients without known coronary artery disease (CAD). The test confirmed the presence of CAD in 28.9% of patients. As expected, patients with diabetes mellitus (DM) had a significantly higher prevalence of myocardial perfusion abnormalities (35.9% vs 23.9%; odds ratio, 1.79; 95% confidence interval [CI], 1.38-2.33; P<.0001) and high-risk myocardial imaging (16.4% vs 10.6%; odds ratio, 1.67; 95% CI, 1.18-2.37; P=.004) than those without DM. Odd ratios further increased, again as expected, with dyslipidemia (2.19; 95% CI, 1.54-3.12; P<.0001), peripheral arterial disease (2.61; 95% CI, 1.77-3.85; P<.0001), microalbuminuria (3.03; 95% CI, 1.91-4.82; P<.0001), and abnormal electrocardiographic findings (3.06; 1.68; 95% CI, 2.08-4.48; P<.0001). This large cohort study showed that more than 1 of 4 treated hypertensive patients have subclinical CAD. These study data should be clinically helpful in selecting hypertensive patients who are the most suitable candidates to screen for the presence of CAD.
Journal of Clinical Hypertension 12/2007; 9(12):921-8. · 2.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: * The variability in drug metabolism has been recognized as an important factor in the occurrence of adverse effects or lack of therapeutic efficacy. * The metabolism of the third-generation beta(1)-receptor antagonist nebivolol has been shown to be highly dependent on cytochrome P450 2D6 enzymatic activity in preclinical studies.
* This paper assesses the role of a cytochrome P450 2D6 gene defect on the antihypertensive response to nebivolol in a clinical setting. * Despite significant differences in drug disposition, the chronic administration of nebivolol produced similar efficacy and tolerability in hypertensive patients either characterized as poor or extensive metabolizers of the drug. * The study offers insight into the relative contribution of nebivolol enantiomers in systemic blood pressure control.
Nebivolol is a beta(1)-adrenergic receptor antagonist with vasodilating properties used in the treatment of hypertension. It is administered as a racemic mixture (D- and L-nebivolol) and is highly metabolized by the cytochrome P-450 2D6 (CYP2D6). The purpose of this study was to determine the role of CYP2D6 phenotypes on the efficacy and tolerability of nebivolol during chronic administration to patients with essential hypertension.
Two hundred and eighteen patients were genotyped and phenotyped for CYP2D6 activity, allowing to find and match 14 poor metabolizers (PMs) with 23 extensive metabolizers (EMs). Patients took rac-nebivolol 5 mg daily for 12 weeks. Blood pressure (BP), heart rate, adverse events, plasma levels of the two enantiomers D- and L-nebivolol and their corresponding hydroxymetabolites were assessed.
The metabolic disposition of nebivolol was enantioselective and highly influenced by CYP2D6 phenotypes. Mean steady-state plasma concentrations of D- and L-nebivolol were 10- and 15-fold greater in PMs than in EMs, respectively (P < 0.0001). Despite these differences in the pharmacokinetics of nebivolol, EMs and PMs displayed similar BP responses. Mean reductions in sitting systolic and diastolic BPs were -11/-10 +/- 9/4 mmHg in EMs and -11/-9 +/- 10/5 mmHg in PMs. Side-effects were mild to moderate and not different between groups.
Polymorphisms in the gene encoding CYP2D6 significantly influenced the metabolism of nebivolol, but not its antihypertensive efficacy and tolerability. The similar clinical response between EMs and PMs could be explained by the contribution of active hydroxylated metabolites of nebivolol to its antihypertensive actions in EMs.
British Journal of Clinical Pharmacology 06/2007; 63(5):575-82. · 3.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: The present study investigated whether initiating therapy with a combination of losartan (L) and hydrochlorothiazide (HCTZ) allows for faster blood pressure (BP) control and fewer medications than the usual stepped-care approach in patients with stage 2 or 3 hypertension and ambulatory systolic hypertension.
Patients with a mean daytime systolic ambulatory BP (ABP) of 135 mmHg or higher were randomly assigned to receive L 50 mg plus HCTZ 12.5 mg titrated to L 100 mg plus HCTZ 25 mg versus HCTZ 12.5 mg plus atenolol 50 mg. Amlodipine 5 mg was then added, if needed, to achieve a BP goal of less than 130 mmHg. Treatment titration was based on ABP.
Significantly more patients randomly assigned to L/HCTZ (63.5%) than stepped-care (37.5%; P=0.008) achieved the primary end point (daytime systolic BP of less than 130 mmHg). Initial L/HCTZ induced significantly greater decreases in ABP during each 24 h period after six weeks of therapy. Although reductions in systolic and diastolic ABP were not statistically different at the end of the study, ABP reduction was significantly greater (P<0.001) with the L/HCTZ-based regimen. Twice as many patients in the L/HCTZ group achieved the goal ABP with no more than two drugs (30.0% versus 14.7%; P=0.03). Moreover, tolerability was significantly better (P=0.006) in the L/HCTZ group, with a 40.0% incidence of adverse events, versus 65.6% in the stepped-care group.
Initiating antihypertensive therapy with the combination of L/HCTZ in patients with stage 2 or 3 hypertension and ambulatory systolic hypertension reaches a target BP faster in a higher proportion of patients, with fewer adverse events and less need for a third drug regimen than the conventional stepped-care approach.
The Canadian journal of cardiology 05/2007; 23(5):377-82. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Coronary artery disease (CAD) is the leading cause of morbidity and mortality in hypertensive and diabetic patients. Early diagnosis of CAD and identification of high-risk subgroups, followed by appropriate therapy, may therefore enhance survival.
To prospectively establish the prevalence of silent CAD in asymptomatic patients with essential hypertension (EH), and to establish to what extent type 2 diabetes mellitus (DM) modifies the prevalence and severity of silent CAD in these patients.
The study population consisted of 543 patients 45 years of age and older with EH (n=321) or EH with type 2 DM (n=222), without typical angina or known CAD, selected according to criteria defined by the American Diabetes Association. All patients underwent dipyridamole stress and rest 99mtechnetium sestamibi myocardial single-photon emission computed tomography imaging. The stress and rest myocardial images were divided into 20 segments and blindly scored by two experienced observers. The summed stress score and summed rest score were obtained by adding the scores of the 20 segments of the stress and rest sestamibi images, respectively. The difference between the summed stress score and the summed rest score was defined as the summed difference score, representing reversible ischemia.
There was a significant difference (P=0.001) between the percentage of EH patients with (41.4%) and without (27.7%) DM, with regard to abnormal summed stress scores. Moreover, hypertensive, diabetic patients had a significantly greater incidence of moderate to severe ischemia (P=0.011). In addition, a significantly greater proportion of hypertensive patients with DM showed reversible ischemia compared with EH patients without DM (39.6% versus 24.6%; P<0.0001). Proteinuria and dyspnea were significant predictors of silent ischemia in EH patients with DM.
In this high-risk population screened according to the American Diabetes Association criteria with dipyridamole sestamibi myocardial single-photon emission computed tomography imaging, the prevalence of silent ischemia was 28% in EH patients. It is noteworthy that the prevalence (41%) and severity of silent ischemia were significantly greater in EH patients with DM.
The Canadian journal of cardiology 02/2006; 22 Suppl A:16A-21A. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Am J Hypertens (2005) 18, 66A–67A; doi:10.1016/j.amjhyper.2005.03.183
P-165: Comparative effects of lercanidipine, amlodipine and hydrochlorothiazide on 24-hour ambulatory blood pressure and leg edema in confirmed ambulatory hypertensive patients
Jean Lefebvre1, Luc Poirier1 and Yves Lacourcière11Hypertension Research Unit, Centre Hospitalier Universitaire de Québec, Ste-Foy, QC, Canada.
American Journal of Hypertension 04/2005; · 3.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: More than one drug is often needed in treating patients with the systolic form of hypertension. The efficacy of 2 types of antihypertensive combination therapy on 24-hour blood pressure profile was compared in patients who have elevated systolic blood pressure (SBP) both in clinic (>150mmHg) and during daytime ambulatory monitoring (>135mmHg). Eligible patients (n=121; 40F/81M) were randomized to received a once daily morning regimen with either Losartan (L) 50 mg plus hydrochlorothiazide (H) 12.5 mg (Group 1; n=60) or H 12.5 mg (Group 2; n=61). If the target SBP (mean daytime ambulatory ≤ 135 mm Hg) was not achieved after 6 weeks of treatment, drug regimens were titrated up to L 100 mg plus H 25 mg or to H 12,5 mg plus Atenolol 50 mg for an additional 6-week period. Amlodipine 5 mg was then added as a third drug in combination for a further 6 weeks in non responders of each group. Clinic and ambulatory BP were measured after 6, 12 and 18 weeks. Daytime ambulatory systolic/diastolic BP were comparable in Group 1 (152.6/87.0 mmHg) and Group 2 (154.3/89.0 mmHg) at baseline. Average decreases were −9.8/−4.4, −16.0/−8.0 and −22.3/−11.3 mmHg in Group 1 and −2.2/−0.1, −12.3/−8.1 and −20.1/−12.0 mmHg in Group 2, after 6, 12 and 18 weeks, respectively. All reductions were significant (p
American Journal of Hypertension - AMER J HYPERTENS. 01/2005; 18(5).
[show abstract][hide abstract] ABSTRACT: To review and comment on methods used to assess the duration of action of antihypertensive drugs.
A MEDLINE search (1966-June 2000) using key terms such as trough-to-peak ratio and ambulatory blood pressure monitoring was conducted.
An article was considered for this review if it pertained to the assessment of the duration of action of antihypertensive drugs. Special attention was given to articles dealing with methodologic aspects.
Antihypertensive drugs with a long duration of action are thought to provide better therapeutic coverage against hypertensive complications compared with that of short-acting agents. Measuring blood pressure at the end of the dosing interval may be a way to assess the duration of action of a drug. However, the use of high doses of a short-acting agent to obtain sufficient effect when at trough concentrations can potentially cause dose-related adverse effects at the peak time, contributing to nonadherence to therapy and thus to adverse outcomes. To alleviate this problem, the US Food and Drug Administration (FDA) has conceptualized the trough-to-peak (T:P) ratio. Although this arithmetic index has since been widely used to characterize the duration and safety of blood pressure control achieved by antihypertensive agents, several methodologic flaws limit its interpretation in the clinic. Ambulatory blood pressure monitoring (ABPM) is a more reliable approach to assess the duration of action and outcome of antihypertensive therapy.
Different methodologic approaches exist to evaluate the duration of action of antihypertensive drugs. Although the T:P ratio has been suggested by the FDA, it is difficult to establish a fair comparison among various antihypertensive agents based solely on this index. Treatment evaluation based on ABPM may be preferable to those guided by T:P because ABPM is more reproducible and is now established as a predictor of cardiovascular risk.
Annals of Pharmacotherapy 06/2002; 36(5):874-81. · 2.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ambulatory blood pressure (ABP) monitoring has contributed significantly to the diagnosis, prognosis and treatment of hypertension. However, most of the published reviews have not focused on the 24 h efficacy of conventional and new antihypertensive agents as measured by ABP monitoring.
To discuss the importance of 24 h blood pressure control, and to review the antihypertensive efficacy of conventional antihypertensive agents and of angiotensin II type I receptor (AT1R) blockers as assessed by ABP monitoring.
The 24 h antihypertensive efficacy of the different classes of agents was reviewed based on clinical, randomized, double-blind trials published in peer review journals. These trials were mainly performed in the authors' research unit but were performed in other centres as well.
Most antihypertensive agents provided 24 h ABP control. However, in the authors' experience, hydrochlorothiazide, some angiotensin converting enzyme inhibitors and low dosages of the calcium antagonist diltiazem did not permit satisfactory blood pressure reduction as assessed by ABP monitoring in truly hypertensive patients. AT1R blockers and especially those of the new generation characterized by tight and long lasting AT1-receptor binding produced adequate 24 h ABP control and continued effectiveness during the high risk early morning hours.
The Canadian journal of cardiology 10/2000; 16(9):1155-66. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is increasing evidence that polymorphism of ACE gene is associated with diabetic nephropathy (GENEDIABStudy). Since hypertension plays important and independant role in the development of diabetic complications, it is worth measuring the occurrence of ACE polymorphism in hypertensives with type 2 diabetes.Objective: To evaluate the association of ACE Insertion/Deletion (I/D) polymorphism with ambulatory hypertension in patients with or without type 2 diabetes mellitus (DM).Methods: The genomic DNA was isolated from peripheral leukocytes in hypertensive sujects (clinic DBP 90–115 mmHg plus mean daytime ambulatory BP ≥135/85 mmHg), with or without DM, and in normotensive patients without DM (mean daytime ambulatory BP
American Journal of Hypertension - AMER J HYPERTENS. 01/2000; 13(4).
[show abstract][hide abstract] ABSTRACT: Objectives: To evaluate the efficacy of Nebivolol (N), a beta-blocking agent, in hypertensive patients classified as extensive metabolizers (EM) or non-extensive metabolizers (non-EM) based on phenotype for cytochrome 2D6.Methods: Approximately 400 hypertensive patients (clinic DBP ≥ 95 mm Hg) were phenotyped for P-450 2D6 polymorphism. Each screened patient was instructed to take dextrometorphan 30 mg at bedtime and to collect urine overnight. Based on metabolic ratio (MR) (dextrometorphan/dextrorphan), patients were classified as EM (MR 0.30). A total of 37 patients (18 EM and 19 non-EM) were enrolled in the study and matched for age and sex. After a 2–4 week placebo period, patients received N 5 mg o.d. for 12 weeks. Clinic sitting BP was measured at baseline and after 12 weeks of treatment at trough and at peak, 2 hours after drug intake.Results: N induced significant (p < 0.0001) and non-statistically different systolic/diastolic BP decrements at trough after 12 weeks of treatment in the EM group (−9.0/−10.3 mm Hg) and in the non-EM group (−12.3/−9.5 mm Hg). Heart rate was significantly (p < 0.0001) and similarly decreased in both EM and non-EM (−8.7; −6.6 beats/min, respectively) treatment groups. BP measured at peak revealed that N induced additional trough to peak systolic/diastolic BP decrements in the EM group (−5.2/−4.6 mm Hg) and in the non-EM group (−11.4/−7.9 mm Hg). However, non-significant additional heart rate decreases were produced by N at peak in both EM and non-EM groups (−4.2; −3.3 beats/min, respectively). Treatment with N was well tolerated in both EM and non-EM groups with a similar incidence of side effects.Conclusion: N induced significant and similar reductions in clinic BP and heart rate in both groups. Our results do not support the hypothesis that patients identified as non-EM and treated with N will experience more pronounced antihypertensive effects and a different tolerability profile than EM patients.
American Journal of Hypertension - AMER J HYPERTENS. 01/2000; 13(4).
[show abstract][hide abstract] ABSTRACT: Objectives: Recent studies have demonstrated the importance of not only decreasing systolic and diastolic blood pressures (BP) but also pulse pressure (PP). This parameter, defined as the difference between systolic and diastolic BP, has been described as a good marker of arterial compliance and is identified as an independant cardiovascular risk factor. The effects of candesartan (C) and losartan (L) on PP were assessed in patients with confirmed ambulatory hypertension.Methods: This randomized, double-blind, force titrated study regrouped 268 patients (20–80 years) with a clinic diastolic BP between 95–110 mm Hg and a mean daytime ambulatory diastolic BP above 85 mm Hg. Patients were randomly treated with either C 8 mg, L 50 mg or a placebo for 4 weeks. Doses were then doubled to C 16 mg, L 100 mg or a placebo for an additional 4-week treatment period. On the day of ambulatory monitoring, patients took their medication but skipped the next morning dose administration. Ambulatory BP monitoring was performed during 36 hours after 4 (low dose) and 8 (high dose) weeks of active treatment. Clinic BP was measured 48 hours after the last medication intake with an automatic sphygmomanometer (Omron).Results: Clinic PP was reduced by both drugs but more significantly by C 16 mg than by L 100 mg, 24 hours (p = 0.022) and 48 hours (p = 0.036) after drug intake. Pulse pressure derived from ambulatory monitoring were significantly decreased by both treatments during all the 24-hour interval. However, C at doses of 8 and 16 mg was significantly more effective than L 50 mg and 100 mg in decreasing ambulatory PP. Ambulatory BPs measured during the 24–36 hour period demonstrated that C was superior to L after 4 (p = 0.005) and 8 (p = 0.003) weeks of treatment.Conclusions: Treatment with candesartan was associated with a significantly greater reduction in both clinic and ambulatory PP than losartan.
American Journal of Hypertension - AMER J HYPERTENS. 01/2000; 13(4).
[show abstract][hide abstract] ABSTRACT: Objectives: To compare the antihypertensive efficacy of Irbesartan, an angiotensin receptor antagonist, and Enalapril, an angiotensin-converting enzyme inhibitor, in patients aged 65 years and over with grade I and II essential hypertension.Methods: This randomized, double-blind study enrolled 150 elderly patients (≥65 years) with a diastolic BP between 95 and 110 mm Hg. After a 4-week placebo run-in period, patients were randomly treated with either Irbesartan 150 mg (n = 70) or Enalapril 10 mg (n = 71) administered once daily for 8 weeks. If diastolic BP was not adequately controlled (≤90 mm Hg) after 4 weeks of active treatment, doses were increased to Irbesartan 300 mg od or Enalapril 20 mg od.Results: Intent-to-treat analysis demonstrated significant and similar (p = 0.93) reductions in clinic seated diastolic BPs after 8 weeks of treatment with Irbesartan (−9.6 mm Hg) and Enalapril (−9.8 mm Hg). The percentages of patients experiencing normalized BP (diastolic BP < 90 mmHg) at week 8 revealed to be similar in both treatment groups (Irbesartan 52.9% vs Enalapril 54.9%; p = 0.81). Both drugs were associated with a similar incidence of adverse events as well as drop-out rate. However, Irbesartan demonstrated a lower incidence of cough in comparison with Enalapril (4.3% vs 15.5%; p = 0.046, respectively).Conclusion: Both treatments induced significant and similar reductions in clinic BP. The incidence of cough was lower in the Irbesartan group. Thus, the results of this study suggest that angiotensin II receptor antagonists may represent a valuable alternative in elderly patients with essential hypertension.
American Journal of Hypertension - AMER J HYPERTENS. 01/2000; 13(4).