Efficacy of candesartan cilexetil as add-on therapy in hypertensive patients uncontrolled on background therapy: a clinical experience trial

A large-scale, 8-week, open-label, clinical experience trial evaluated the efficacy of the angiotensin II receptor (AT₁ subtype) blocker candesartan cilexetil (16 to 32 mg once daily) either alone or as add-on therapy in 6465 hypertensive patients. The study population was 52% female and 16% African American with a mean age of 58 years. It included 5446 patients who had essential hypertension (HBP) and 1014 patients who had isolated systolic hypertension (ISH). These patients had either untreated or uncontrolled hypertension (systolic blood pressure [SBP] 140 to 179 mm Hg or diastolic blood pressure [DBP] 90 to 109 mm Hg inclusive at baseline) despite a variety of antihypertensive medications including diuretics, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and α- or β-blockers, either singly or in combination. The mean baseline blood pressure for the HBP group was 156/97 mm Hg. Candesartan cilexetil as monotherapy (in 51% of HBP patients) reduced mean SBP/DBP by 18.7/13.1 mm Hg. As add-on therapy (in 49% of HBP patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.8/11.3 mm Hg), calcium antagonists (16.6/11.2 mm Hg), β-blockers (16.5/10.4 mm Hg), ACE inhibitors (15.3/10.0 mm Hg), α-blockers (16.4/10.4 mm Hg). The mean baseline blood pressure for the ISH group was 158/81 mm Hg. Candesartan cilexetil, as monotherapy (in 34% of ISH patients), reduced SBP/DBP by 17.0/4.4 mm Hg. As add-on therapy (in 66% of ISH patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.4/5.1 mm Hg), calcium antagonists (15.6/3.6 mm Hg), β-blockers (14.0/4.8 mm Hg), ACE inhibitors (13.4/4.3 mm Hg), and α-blockers (11.6/4.5 mm Hg). The further blood pressure lowering effects of candesartan cilexetil as add-on therapy were seen regardless of age, sex, and race. Overall, 6.8% of the 6465 patients withdrew because of adverse events, most commonly headache (6.3%) and dizziness (5.0%). Orthostatic hypotension was infrequent; 0.2% with candesartan cilexetil alone, and 0.8% with candesartan cilexetil as add-on therapy. Thus, candesartan cilexetil either alone or as add-on therapy was highly effective for the control of systolic or diastolic hypertension regardless of demographic background when used in typical clinical practice settings.     

Hypertension in older people: part 2

There is overwhelming evidence that pharmacologic treatment of isolated systolic hypertension (ISH) (systolic blood pressure >or=140 mm Hg and diastolic blood pressure <90 mm Hg) reduces cardiovascular events and extends longevity in the elderly; in the very old (80 years or older), the evidence supports decreased incident stroke and heart failure, but is less convincing in terms of longevity. Thus, the inherent increased risk for ISH vascular events highlights the importance of its control. Importantly, ISH in the elderly, primarily related to large artery stiffness, remains more difficult to control than diastolic hypertension in the young, which is primarily related to increased peripheral vascular resistance. Appropriate lifestyle and pharmacologic intervention is indicated in individuals with systolic blood pressure >or=140 mm Hg in general and >or=130 mm Hg in persons with diabetes or chronic kidney disease. Lifestyle intervention may reduce the need for extensive antihypertensive therapy and minimize associated cardiovascular risk factors. To date, only a small percentage of older ISH patients are being treated to goal. Reaching target systolic blood pressure levels most often requires the use of polypharmacy that includes a diuretic and perhaps specific agents that target arterial stiffness and early wave reflection.     

The effects of losartan compared to atenolol on stroke in patients with isolated systolic hypertension and left ventricular hypertrophy. The LIFE study

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study reported that a losartan-based antihypertensive regimen reduced cardiovascular morbidity and mortality (composite of cardiovascular death, stroke, and myocardial infarction) more than therapy based on atenolol in patients with left ventricular hypertrophy and isolated systolic hypertension (ISH). Patients aged 55-80 years with blood pressures 160-200/<90 mm Hg were followed for a mean of 4.7 years. Blood pressure was similarly reduced in the losartan (n=660) and atenolol (n=666) ISH groups. There were 88 (6.6%) patients who experienced a stroke, 18 of which were fatal. Of patients experiencing strokes, 72.7% had an ischemic stroke. ISH patients in LIFE compared to the non-ISH group had a higher incidence of any stroke and embolic stroke, and similar incidences of fatal, atherosclerotic, and hemorrhagic/other strokes. The incidence of any stroke (40% risk reduction [RR], p=0.02), fatal stroke (70% RR, p=0.035), and atherothrombotic stroke (45% RR, p=0.022) was significantly lower in losartan-treated compared to the atenolol-treated patients. The 36% RR for embolic strokes in the losartan group was not statistically significantly (p=0.33) different from the atenolol group. These data suggest that losartan-based treatment is more effective than an atenolol-based treatment for patients with ISH and a high risk for stroke.     

The role of diastolic blood pressure when treating isolated systolic hypertension.

OBJECTIVE: To assess the role of treated diastolic blood pressure (DBP) level in stroke, coronary heart disease (CHD), and cardiovascular disease (CVD) in patients with isolated systolic hypertension (ISH). DESIGN: An analysis of the 4736 participants in the Systolic Hypertension in the Elderly Program (SHEP) was undertaken. The SHEP was a randomized multicenter double-blind outpatient clinical trial of the impact of treating ISH in men and women aged 60 years and older. MAIN OUTCOME MEASURES: Cox proportional hazards regression analysis, with DBP and systolic blood pressure (SBP) as time-dependent covariables. RESULTS: After adjustment for the baseline risk factors of race (black vs other), sex, use of antihypertensive medication before the study, a composite variable (diabetes, previous heart attack, or stroke), age, and smoking history (ever vs never) and adjustment for the SBP as a time-dependent variable, we found, for the active treatment group only, that a decrease of 5 mm Hg in DBP increased the risk for stroke (relative risk, [RR], 1.14; 95% confidence interval [CI], 1.05-1.22), for CHD (RR, 1.08; 95% CI, 1.00-1.16), and for CVD (RR, 1.11; 95% CI, 1.05-1.16). CONCLUSIONS: Some patients with ISH may be treated to a level that uncovers subclinical disease, and some may be overtreated. Further studies need to determine whether excessively low DBP can be prevented by more careful titration of antihypertensive therapy while maintaining SBP control. It is reassuring that patients receiving treatment for ISH never perform worse than patients receiving placebo in terms of CVD events.     

Prevalence of isolated systolic and isolated diastolic hypertension subtypes in China

BACKGROUND: Isolated systolic hypertension (ISH), more so than any other hypertension subtype, increases the risk for stroke and coronary heart disease. The prevalence of ISH versus other hypertension subtypes in the general Chinese adult population is not known. METHODS: The prevalence of isolated systolic and isolated diastolic hypertension (IDH) was examined in a representative national sample of 15,540 Chinese adults aged 35 to 74 years. Three seated blood pressure (BP) measurements taken after 5 min of rest were averaged and hypertension subtypes were defined among individuals not receiving antihypertensive therapy as follows: ISH as systolic BP >/=140 mm Hg and diastolic BP <90 mm Hg; IDH as systolic BP <140 mm Hg and diastolic BP >/=90 mm Hg; and combined systolic/diastolic hypertension (SDH) as a systolic BP >/=140 mm Hg and diastolic BP >/=90 mm Hg. RESULTS: Overall, 7.6% of the Chinese adult population had ISH, 7.4% had SDH, and 4.4% had IDH. The prevalence of ISH increased with age and was more common in older women than in older men. Stage 1 hypertension was much more prevalent than stage 2 hypertension among all hypertension subtypes. The prevalence of SDH, IDH, and ISH (women, only) were higher in northern China than southern. The prevalence of ISH and SDH (women, only) were higher among rural residents versus urban residents. CONCLUSIONS: These data document high rates of ISH in China. Given the risk of cardiovascular disease associated with ISH, our findings underscore the critical need for enhanced hypertension screening and treatment programs in China.     

valsartan in elderly isolated systolic hypertension (VALISH) study: rationale and design.

Although antihypertensive therapy has been proven to reduce cardiovascular morbidity and mortality, it is unclear how much blood pressure should be decreased in elderly patients with hypertension. The Valsartan in Elderly Isolated Systolic Hypertension (VALISH) study is a multicenter parallel-group study comparing the incidence of cardiovascular events between two target systolic blood pressure levels, below 140 mmHg and below 150 mmHg, under treatment with valsartan, an angiotensin II receptor blocker, as an initial antihypertensive drug in elderly patients with isolated systolic hypertension. The number of patients to be recruited is 3,000 and the duration of follow-up is at least 2 years. This 3,000-patient trial was designed with a two-sided alpha level of 0.05 and 80% power to detect the difference in incidence of cardiovascular events between the target blood pressure levels based on estimation of the cardiovascular events ratio as 21.5/1,000 patient-years and 29.1/1,000 patient-years for the two blood pressure levels. The VALISH study, a large-scale investigator-initiated trial in Japan, will determine whether age should be considered in setting target blood pressure in treatment of isolated systolic hypertension in elderly patients.     

Comparison of the efficacy and safety of azilsartan with that of candesartan cilexetil in Japanese patients with grade I-II essential hypertension: a randomized, double-blind clinical study

Azilsartan is a novel angiotensin receptor blocker being developed for hypertension treatment. This 16-week, multicenter, randomized, double-blind study compared the efficacy and safety of azilsartan (20-40 mg once daily by forced titration) and its ability to provide 24-h blood pressure (BP) control, with that of candesartan cilexetil (candesartan; 8-12 mg once daily by forced titration) in 622 Japanese patients with grade I-II essential hypertension. Efficacy was evaluated by clinic-measured sitting BP, and by ambulatory BP monitoring (ABPM) at week 14. Participants (mean age: 57 years, 61% males) had a mean baseline sitting BP of 159.8/100.4 mm Hg. The mean change from baseline in sitting diastolic BP at week 16 (primary endpoint) was -12.4 mm Hg in the azilsartan group and -9.8 mm Hg in the candesartan group, demonstrating a statistically significant greater reduction with azilsartan vs. candesartan (difference: -2.6 mm Hg, 95% confidence interval (CI): -4.08 to -1.22 mm Hg, P=0.0003). The week 16 (secondary endpoint) mean change from baseline in sitting systolic BP was -21.8 mm Hg and -17.5 mm Hg, respectively, a significant decrease with azilsartan vs. candesartan (difference: -4.4 mm Hg, 95% CI: -6.53 to -2.20 mm Hg, P<0.0001). On ABPM, the week 14 mean changes from baseline in diastolic and systolic BP were also significantly greater with azilsartan over a 24-h period, and during the daytime, night-time and early morning. Safety and tolerability were similar among the two groups. These data demonstrate that once-daily azilsartan provides a more potent 24-h sustained antihypertensive effect than that of candesartan but with equivalent safety.     

Design of the omapatrilat in persons with enhanced risk of atherosclerotic events (OPERA) trial

The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial is a large clinical trial of omapatrilat, a vasopeptidase inhibitor, in patients with stage 1 isolated systolic hypertension (ISH). OPERA is the first study to examine whether effective antihypertensive treatment can provide survival and clinical end point benefits in older persons with this common condition. This 5-year multinational, randomized, double-blind, parallel-group, placebo-controlled, forced-titration study will be conducted in approximately 12,600 subjects randomized by approximately 1100 study centers worldwide over a recruitment period of approximately 2 years. The primary objective of OPERA is to determine whether treatment with once-daily omapatrilat (target dose 40 mg) will reduce cardiovascular (CV) morbidity and mortality in older (≥65 years) men and women with enhanced risk for atherosclerotic events due to stage 1 ISH plus other risk factors for which currently there is no evidence-based requirement for treatment. Blood pressure inclusion criteria are systolic blood pressure (SBP) 140 to 159 mm Hg (SBP 125 to 139 mm Hg in diabetic individuals) and diastolic blood pressure (DBP) <90 mm Hg.The primary end point is defined as the composite of fatal/nonfatal stroke, fatal/nonfatal myocardial infarction, fatal/nonfatal heart failure, and other CV mortality. Secondary end points include the individual components of the primary end point, CV mortality, and major cardiovascular end points, as well as effects on cognitive function and initiation of treatment for diabetes. Additional analyses will be conducted in men and women, in diabetic patients, in different risk classes and according to prior evidence of vascular disease.     

Prothrombotic factors, endothelial function and left ventricular hypertrophy in isolated systolic hypertension compared with systolic-diastolic hypertension.

BACKGROUND: Individuals with systolic-diastolic hypertension (SDH, systolic blood pressure (SBP) >160 mm Hg and diastolic blood pressure (DBP) >90 mm Hg) are at increased risk of thrombotic complications, such as stroke and heart attacks, which may be related to a hypercoagulable state. Individuals with only isolated systolic hypertension (ISH; i.e. SBP >160 mm Hg but DBP <90 mm Hg) are also at significant cardiovascular risk. We hypothesized that patients with ISH would exhibit a prothrombotic state similar to that seen in SDH. A secondary hypothesis was that individuals with ISH had similar echocardiographic parameters to those seen in SDH. METHODS: We measured indices of haemorheology, endothelial dysfunction, thrombogenesis and platelet activation in 23 individuals with ISH (mean blood pressure 193/82 mm Hg), who were compared with 51 matched patients with SDH (mean blood pressure 198/112 mm Hg) and 34 age- and sex- matched normotensive healthy control individuals (mean blood pressure 130/78 mm Hg). Echocardiographic parameters in patients with ISH were compared to those from patients with SDH. RESULTS: Mean plasma viscosity (an index of blood rheology, ANOVA, P = 0.001), von Willebrand factor (an index of endothelial damage, P = 0.013), plasminogen activator inhibitor-1 and lipoprotein (a) (both markers of thrombogenesis; Kruskal-Wallis test, both P<0.001) were all significantly raised in ISH and SDH relative to controls. Individuals with SDH also had high mean plasma fibrinogen (P = 0.018) and haematocrit (P = 0.010) levels compared with control individuals. There were no significant differences in levels of fibrin D-dimer or the platelet activation marker soluble P-selectin in the hypertensive patients (i.e. ISH and SDH) compared with control individuals. Patients with ISH had similar M-mode and Doppler echocardiographic parameters compared to patients with SDH. CONCLUSIONS: We conclude that individuals with ISH have abnormalities in plasma prothrombotic factors and markers of endothelial dysfunction, and echocardiographic parameters, broadly similar to that seen in SDH. This is consistent with the increased risk of thrombotic events (strokes and heart attacks) in patients with ISH.     

Factors influencing the systolic blood pressure response to drug therapy

In the early stage of hypertension, diastolic blood pressure has greater prognostic importance, but in the elderly, systolic blood pressure is the most important marker of cardiovascular complications. Therefore, the need for more strict control of this component of blood pressure must be reconsidered. The benefit obtained in different studies in the elderly suggests that the treatment of isolated systolic hypertension is associated with a reduction in overall cardiovascular mortality of 22%, in coronary heart disease mortality of 26%, and in stroke mortality of 33%. However, a higher percentage of patients (73%) attain the diastolic goal of <90 mm Hg, while only 34% have systolic pressure reduced to <140 mm Hg. In a review of randomized trials comparing at least four different antihypertensive drugs, significant differences in systolic blood pressure reduction have not been demonstrated, except in black populations, in whom calcium channel blockers and diuretics seem to be more effective. In patients with isolated systolic hypertension, data are inconclusive, but calcium channel blockers and diuretics appear to lower blood pressure to a greater degree than do other antihypertensive drugs. Two main predictors of difficulty in controlling systolic blood pressure are the baseline blood pressure and the presence of diabetes. Other predictors are the duration of arterial hypertension, older age, the presence of target organ damage and associated clinical conditions (myocardial infarction, stroke, chronic renal failure), and an elevated serum uric acid level. It appears that the profile of patients with a poorer therapeutic response includes a greater severity of hypertension and/or the presence of cardiovascular disease.     

A Meta-analysis of antihypertensive effect of telmisartan versus candesartan in patients with essential hypertension

Objective: The comparison of antihypertensive effects between telmisartan and candesartan in patients with essential hypertension has been investigated in several small studies. The results were not consistent. We performed this meta-analysis determining the antihypertensive effect of telmisartan versus candesartan in these patients. Methods: We searched Pubmed, Web of Science, and Cochrane Central for all published studies comparing the antihypertensive effects between telmisartan and candesartan in patients with essential hypertension. Results: The antihypertensive effects were assessed in 302 patients included in 4 trials with a mean follow-up of 10 ± 4 weeks. There were no significant differences between telmisartan and candesartan in reduction of systolic blood pressure (SBP) and diastolic BP (DBP) in patients with essential hypertension (weighted mean differences (WMD) for SBP 1.98 mm Hg (95% confidence interval (CI), ?0.53, 4.49), p > 0.05; WMD for DBP 0.26 mm Hg (95% CI, ?1.65, 2.16), p > 0.05), respectively. In a sub-analysis including 2 randomized studies, there was not a significant difference for the reduction of SBP (WMD 0.90 (95% CI, ?2.88, 4.68) mm Hg, p > 0.05) or DBP (WMD ?0.80 (95% CI, ?3.40, 1.81) mm Hg, p > 0.05) treated with telmisartan or candesartan. Conclusions: This meta-analysis provides the evidence that the antihypertensive effects of telmisartan and candesartan are similar on SBP and DBP reduction in patients with essential hypertension, suggesting that strict designed randomized controlled trial would be helpful to compare antihypertensive effects of angiotensin II receptor blockers (ARBs) and improve the choice of ARBs in antihypertensive therapy.     

Stroke risk in systolic and combined systolic and diastolic hypertension determined using ambulatory blood pressure. The Ohasama study

BACKGROUND: To investigate the risk of stroke in subjects with isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and combined systolic and diastolic hypertension (SDH) in a Japanese general population, we used 24-h ambulatory blood pressure (ABP) and casual-screening blood-pressure (CBP) readings. METHODS: Subtypes of hypertension were defined based on systolic blood pressure (SBP) >135 mm Hg or diastolic blood pressure (DBP) >80 mm Hg for 24-h ABP, and SBP >140 mm Hg or DBP >90 mm Hg for CBP. We obtained 24-h ABP and CBP data for 1271 (40% male) subjects aged > or =40 years (mean age, 61 years) without a history of symptomatic stroke; their stroke-free survival was then determined. The prognostic significance of each subtype of hypertension was determined by Cox proportional hazard analysis. RESULTS: There were 113 symptomatic strokes during follow-up (mean time, 11 years). Compared with normotension, among the hypertension subtypes determined by 24-h ABP, the adjusted relative hazards (RHs) of stroke were 2.24 for ISH (P = .002) and 2.39 for SDH (P = .0004). The association was less marked among subtypes determined by CBP (RH = 1.40 and P = .13 for ISH; RH = 2.07 and P = .017 for SDH). The IDH group was excluded from the Cox analysis because both the prevalence and the number of events were low in this group. CONCLUSIONS: Isolated systolic hypertension, as determined by 24-h ABP measurements, was associated with a high risk of stroke, similar to that found in SDH subjects; this suggests that the prognosis of hypertensive patients would be improved by focusing treatment on 24-h systolic ABP.     

Treatment of isolated systolic hypertension

Isolated systolic hypertension (ISH) is the dominant form of hypertension in the elderly. It is associated with increased arterial pulse pressure, to which an early-returning and magnified pulse-wave reflection makes an important contribution. Treatment of ISH with diuretics, calcium channel blockers (CCBs), and angiotensin II inhibitors is effective in reducing systolic blood pressure, preventing cardiovascular morbid events, and lowering mortality; these agents may have to be used in combination to achieve the systolic blood pressure goal of < 140 mm Hg. Treatment with β-blockers appears to be less effective. The relative efficacy of various classes of antihypertensive drugs for lowering pulse pressure and systolic blood pressure is determined in part by their differing abilities to reduce pulse-wave reflection. In patients with ISH that is refractory to dual or triple therapy, measurement of the reflected wave by applanation tonometry may be useful in determining which additional antihypertensive agent to use.     

Comparison of the AT1-receptor blocker, candesartan cilexetil, and the ACE inhibitor, lisinopril, in fixed combination with low dose hydrochlorothiazide in hypertensive patients

AIM: To compare candesartan cilexetil and lisinopril in fixed combination with hydrochlorothiazide with respect to antihypertensive efficacy and tolerability. METHODS: This was a double-blind (double-dummy), randomised, parallel group comparison in patients with a mean sitting diastolic blood pressure 95-115 mm Hg on prior antihypertensive monotherapy. Treatments were candesartan cilexetil/hydrochlorothiazide 8/12.5 mg once daily (n = 237) and lisinopril/hydrochlorothiazide 10/12.5 mg once daily (n = 116) for 26 weeks. The primary efficacy variable was change in trough sitting diastolic blood pressure. RESULTS: Changes in mean sitting diastolic blood pressure did not differ significantly between the groups (mean difference 0.5 mm Hg; 95% confidence interval -1.6, 2.7, P = 0.20). No significant differences between the groups was found for other haemodynamic variables (sitting systolic blood pressure, standing blood pressure, sitting/erect heart rate, and proportion of responders and controlled patients). Both drugs were well tolerated but the proportion of patients with at least one adverse event was significantly greater in the lisinopril group (80% vs 69%, P = 0.020). The proportion of patients spontaneously reporting cough (23.1% vs 4.6%) and discontinuing therapy due to adverse events (12.0% vs 5.9%) was also higher in the lisinopril group compared with the candesartan cilexetil group. CONCLUSIONS: The fixed combinations of candesartan cilexetil and hydrochlorothiazide 8/12.5 mg and lisinopril and hydrochlorothiazide 10/12.5 mg once daily are equally effective as antihypertensive agents. The fixed combination containing candesartan cilexetil is better tolerated than that containing lisinopril.     

Combination angiotensin-receptor blocker (ARB)/calcium channel blocker with HCTZ vs the maximal recommended dose of an ARB with HCTZ in patients with stage 2 hypertension: the exforge as compared to losartan treatment in stage 2 systolic hypertension (EXALT) study

This study compared the efficacy and safety of combination angiotensin-receptor blocker (ARB)/calcium-channel blocker (CCB) with hydrochlorothiazide (valsartan/amlodipine/HCTZ 160/5/2mg) vs maximal available combination doses of an ARB with HCTZ (losartan/HCTZ 100/25 mg) in the management of stage 2 hypertension. After 1 to 2 weeks of antihypertensive drug washout, patients with a mean sitting systolic blood pressure (MSSBP) of ≥ 160 mm Hg and <200 mm Hg were randomized to valsartan/amlodipine 160/5 mg (n = 241) or losartan 100 mg (n = 247). At week 3, HCTZ 25 mg was added to both treatments. The primary end point, reduction in MSSBP from baseline to week 6, was significantly greater in the valsartan/amlodipine group than in the losartan group (least-squares [LS] mean change, -31.8 mm Hg vs -26.4 mm Hg; P<.001). Additional reductions occurred after titrating to 320/10/25 mg at week 6 in the valsartan/amlodipine group and switching from losartan/HCTZ to valsartan/amlodipine/HCTZ (week 6, 160/5/25 mg; week 9, 320/10/25 mg) in the losartan group. Achievement of blood pressure <140/90 mm Hg also favored the valsartan/amlodipine group. Dizziness was the only adverse event reported in >5% of patients (5.4% valsartan/amlodipine group, 3.6% losartan group). Moderate doses of an ARB/CCB combination with HCTZ reduced blood pressure more effectively than the maximal dose of an ARB with HCTZ.     

Clinical efficacy and tolerability of candesartan cilexetil. Candesartan Study Groups in Japan

Clinical trials of candesartan cilexetil conducted in Japan are reviewed. Candesartan cilexetil inhibited the pressor response to intravenous angiotensin II in healthy volunteers, with peak effects observed at 4 or 8 h after oral dosing; suppressing effects persisted up to 24 h. In 14 multicentre studies with 928 hypertensive patients treated for 8 to 12 weeks, candesartan cilexetil had an efficacy rate (reduction of systolic/diastolic blood pressure > or = 20/10 mm Hg and/or mean blood pressure > or = 13 mm Hg) of 72% and 63%, and an adverse effect rate of 9.9% and 7.3%, in patients with mild-to-moderate essential hypertension and those with impaired renal function, respectively. When data for elderly patients were analysed, there was no difference in efficacy and tolerability compared to non-elderly patients. In a double-blind comparative study, candesartan cilexetil was superior to enalapril in hypertensive patients: efficacy rate, 74% vs 66% (NS); adverse symptom rate, 10.4% vs 27.3% (P < 0.01); incidence of cough, 1.5% vs 14.8% (P < 0.01). Treatment with 2-8 mg of candesartan cilexetil once daily for 8 to 12 weeks reduced the left ventricular mass index without deterioration of cardiac function. In conclusion, 4-12 mg of candesartan cilexetil once daily is effective and well tolerated in patients with essential hypertension, including elderly patients, those with severe hypertension, and hypertensive patients with renal insufficiency. Its improved tolerability profile over angiotensin-converting enzyme inhibitors, as well as its end-organ protective effects, suggest that candesartan cilexetil is useful as a first-line antihypertensive drug.     

老年单纯收缩期高血压的治疗进展

单纯收缩期高血压是心血管疾病的重要危险因素。大量研究显示,积极控制单纯收缩期高血压可以显著降低不良心血管事件危险性。我国高血压防治指南建议将老年单纯收缩期高血压患者收缩压降低至150 mm Hg以下。生活方式干预是治疗老年单纯收缩期高血压的基石,但多数患者需要降压药物治疗才能使血压达标。对于没有明确并发症的老年单纯收缩期高血压患者,可首选利尿剂、长效钙通道阻滞剂或血管紧张素受体拮抗剂,但对于已经发生靶器官损害者则应根据药物的强制性适应证确定治疗方案。     

Arterial hypertension difficult to control in the elderly patient. The significance of the "white coat effect"]

OBJECTIVE: Previous studies have revealed a high prevalence of white coat effect among treated hypertensive patients. The difference between clinic and ambulatory blood pressure seems to be more pronounced in older patients. This abnormal rise in blood pressure BP in treated hypertensive patients can lead to a misdiagnosis of refractory hypertension. Clinicians may increase the dosage of antihypertensive drugs or add further medication, increasing costs and producing harmful secondary effects. Our aim was to evaluate the discrepancy between clinic and ambulatory blood pressure in hypertensive patients on adequate antihypertensive treatment and to analyse the magnitude of the white coat effect and its relationship with age, gender, clinic blood pressure and cardiovascular or cerebrovascular events. POPULATION AND METHODS: We included 50 consecutive moderate/severe hypertensive patients, 58% female, mean age 68 +/- 10 years (48-88), clinic blood pressure (3 visits) > 160/90 mm Hg, on antihypertensive adequate treatment > 2 months with good compliance and without pseudohypertension. The patients were submitted to clinical evaluation (risk score), clinic blood pressure and heart rate, electrocardiogram and ambulatory blood pressure monitoring (Spacelabs 90,207). Systolic and diastolic 24 hour, daytime, night-time blood pressure and heart rate were recorded. We considered elderly patients above 60 years of age (80%). We defined white coat effect as the difference between systolic clinic blood pressure and daytime systolic blood pressure BP > 20 mm Hg or the difference between diastolic clinic blood pressure and daytime diastolic blood pressure > 10 mm Hg and severe white coat effect as systolic clinic blood pressure--daytime systolic blood pressure > 40 mm Hg or diastolic clinic blood pressure--daytime diastolic blood pressure > 20 mm Hg. The patients were asked to take blood pressure measurements out of hospital (at home or by a nurse). The majority of them performed an echocardiogram examination. RESULTS: Clinic blood pressure was significantly different from daytime ambulatory blood pressure (189 +/- 19/96 +/- 13 vs 139 +/- 18/78 +/- 10 mm Hg, p < 0.005). The magnitude of white coat effect was 50 +/- 17 (8-84) mm Hg for systolic blood pressure and 18 +/- 11 (-9 +/- 41) mm Hg for diastolic blood pressure. A marked white coat effect (> 40 mm Hg) was observed in 78% of our hypertensive patients. In elderly people (> 60 years), this difference was greater (50 +/- 15 vs 45 +/- 21 mm Hg) though not significantly. We did not find significant differences between sexes (males 54 +/- 16 mm Hg vs 48 +/- 17 mm Hg). In 66% of these patients, ambulatory blood pressure monitoring showed daytime blood pressure values < 140/90 mm Hg, therefore refractory hypertension was excluded. In 8 patients (18%) there was a previous history of ischemic cardiovascular or cerebrovascular disease and all of them had a marked difference between systolic clinic and daytime blood pressure (> 40 mm Hg). Blood pressure measurements performed out of hospital did not help clinicians to identify this phenomena as only 16% were similar (+/- 5 mm Hg) to ambulatory daytime values. CONCLUSIONS: Some hypertensive patients, on adequate antihypertensive treatment, have a significant difference between clinic blood pressure and ambulatory blood pressure measurements. This difference (White Coat Effect) is greater in elderly patients and in men (NS). Although clinic blood pressure values were significantly increased, the majority of these patients have controlled blood pressure on ambulatory monitoring. In this population, ambulatory blood pressure monitoring was of great value to identify a misdiagnosis of refractory hypertension, which could lead to improper decisions in the therapeutic management of elderly patients (increasing treatment) and compromise cerebrovascular or coronary circulation.     

The use of olmesartan medoxomil as monotherapy or in combination with other antihypertensive agents in elderly hypertensive patients in Japan

The efficacy and safety of the angiotensin receptor blocker olmesartan medoxomil (OLM) was assessed in 550 elderly Japanese hypertensive patients who were followed for 24 weeks in daily clinical practice. Patients were given OLM alone or in combination with other antihypertensive drugs at the discretion of the investigators. After 24 weeks of treatment, systolic and diastolic blood pressure (BP) significantly decreased from baseline (P<.0001). When patients were classified as either young-old (65-74 years) or older-old (75 years and older), with either isolated systolic hypertension (ISH) or systolic-diastolic hypertension (SDH), the reduction of diastolic BP in ISH patients was significantly smaller than that in SDH patients (5.0 vs 15.2 mm Hg; P<.0001), indicating that OLM did not cause excessive reduction of diastolic BP in ISH patients. Treatment was well tolerated in all groups. In conclusion, the medication was safe and effective in reducing BP levels in ISH patients aged 75 years and older, as well as in other elderly hypertensive patients.     

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in African-American patients with hypertension

African-American patients with hypertension are less responsive to blockers of the renin-angiotensin system than white patients. The relative efficacy of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and the extent of cross-resistance to these agents has not been studied. Fifty-one African-American patients with stage 1-2 hypertension were randomly assigned to enalapril or candesartan cilexetil for 8 weeks and then crossed over to the other treatment. Nonresponders to enalapril and candesartan used a combination of the two. Of the 51 patients randomized (average age 61.2+/-9 years, blood pressure 148/100 mm Hg, heart rate 74 bpm, and body weight 92.8 kg), 44 completed the study. At Week 8, systolic blood pressure (SBP) was reduced by 4.8 mm Hg with enalapril and by 4.7 mm Hg with candesartan (p=NS), and diastolic blood pressure (DBP) was reduced by 4.4 mm Hg and 5.6 mm Hg, respectively (p<0.04). Of these 44 patients, 11 (25%) responded to enalapril by SBP criteria and 19 (43%) by DBP criteria. Seven patients (16%) responded by both SBP and DBP criteria, and 21 patients (48%) were nonresponders. With candesartan, 13 patients (29%) responded by SBP criteria, 20 (45%) by DBP criteria and 12 (27%) by both SBP and DBP criteria (p<0.04, compared with enalapril). Only six patients (14%) responded to both enalapril and candesartan by both SBP and DBP criteria. Of the 18 nonresponders to either enalapril or candesartan, the combination of the two had minimal additional effect. Significant changes in plasma-renin activity and angiotensin II levels were noted only with the high dose of each drug. In this small group of patients, treatment with candesartan resulted in slightly higher response and control rates than enalapril, more than 40% of patients who responded to enalapril did not respond to candesartan and vice versa, and in nonresponders, a combination of candesartan and enalapril offered little additional antihypertensive effect.