Perindopril/indapamide 2/0.625 mg/day: a review of its place in the management of hypertension

The fixed low-dose combination of the ACE inhibitor perindopril and the non-thiazide diuretic indapamide has been evaluated in the management of patients with mild to moderate hypertension. Combination therapy aims to improve overall therapeutic efficacy while minimising adverse effects. In well-designed multicentre clinical trials, perindopril/indapamide at doses ranging from 2/0.625 to 8/2.5 mg/day was significantly more effective than placebo in achieving adequate blood pressure (BP) control. A similar reduction in supine BP was observed when combined perindopril/indapamide 2/0.625 mg/day was compared with losartan 50 mg/day or atenolol 50 mg/day. Similar reductions in 24-hour ambulatory BP were also seen with perindopril/indapamide 2/0.625 mg/day and irbesartan 150 mg/day. However, response and normalisation rates were significantly higher with combination therapy than with losartan or irbesartan monotherapy. Combined perindopril/indapamide 2/0.625 mg/day therapy effectively reduced BP in elderly patients aged 65 to 85 years to a significantly greater extent than either atenolol 50 mg/day or placebo. Supine BP was also normalised in approximately two-thirds of patients in a small noncomparative trial in patients with hypertension and renal impairment. Low-dose perindopril/indapamide 2/0.625 mg/day was well tolerated in clinical trials; the most common adverse events were headache and cough. Hypokalaemia, associated with the use of diuretics, occurred with a higher incidence with combined perindopril/indapamide 2/0.625 mg/day therapy than with either atenolol 50 mg/day or placebo. Perindopril/indapamide 2/0.625 mg/day has shown efficacy in well designed comparative trials with atenolol, losartan and irbesartan including elderly patients and patients with renal impairment. Studies comparing this dosage of perindopril/ indapamide with other combination therapies would be beneficial in allowing the place of perindopril/indapamide to be more accurately determined. The fixed-low dose combination of perindopril/indapamide provides a promising and well tolerated treatment option in the management of patients with mild to moderate hypertension.     

Efficacité comparée des trois stratégies antihypertensives recommandées en Europe

The latest European Guidelines for the treatment of hypertension recommend the use of low-dose combination therapies as the first line strategy.This paper presents the preliminary results of a recent study comparing the perindopril/indapamide combination treatment with sequential and step by step strategies. The 9-month randomised double-blind study included 533 patients.Patients were shown to have better blood pressure control without adverse effects following treatment with the perindopril/indapamide combination than with the sequential strategy of atenolol (50 mg) then losartan (50 mg) then amlodipine (5 mg) or with the step-by-step strategy of valsartan (40 mg then 80 mg, then 80 mg plus hydrochlorothiazide 12.5 mg). In addition, the perindopril/indapamide combination was shown to induce significantly greater control of systolic blood pressure levels with comparable effects on diastolic blood pressure.     

氯沙坦、培哚普利及联用吲哒帕胺治疗老年1、2级原发性高血压的疗效比较

目的 :评价氯沙坦、培哚普利及联用吲哒帕胺治疗老年 1、2级原发性高血压的临床疗效和安全性。方法 :77例老年 1、2级原发性高血压患者随机分为两组 :氯沙坦组 (n=3 8)用氯沙坦 5 0 mg/d;培哚普利组 (n=3 9)用培哚普利4mg/d,4周后未达目标血压 (<18.7/12 k Pa)者加用吲哒帕胺 2 .5 mg/d。结果 :经 8周治疗 ,两组药物均有显著的降压作用 (P<0 .0 1) ,氯沙坦组达标率 86.8% ,培哚普利组达标率 87.1% (P<0 .0 5 )。氯沙坦组和培哚普利组分别有 17例和 16例加用吲哒帕胺 (P>0 .0 5 )。两组不良反应发生率无显著性差别。结论 :氯沙坦和培哚普利治疗老年 1、2级高血压安全有效 ,与吲哒帕胺联用 ,能有效治疗氯沙坦或培哚普利单药治疗无效者     

Candesartan cilexetil plus hydrochlorothiazide combination: a review of its use in hypertension

The combination of candesartan cilexetil [an angiotensin II type 1 (AT(1)) receptor antagonist] plus hydrochlorothiazide (a thiazide diuretic), has been used in the treatment of patients with hypertension. The blood pressure (BP) lowering effect of various doses of this combination, administered orally once a day for 4 to 52 weeks, has been demonstrated in clinical trials. These studies showed that combinations of candesartan cilexetil 4 to 16 mg with hydrochlorothiazide 12.5 or 25 mg induced significant reductions reductions in systolic (S) BP and diastolic (D) BP from baseline in patients with mild to severe hypertension. Data from clinical trials indicated that reductions in BP induced by candesartan cilexetil 4 to 32 mg/hydrochlorothiazide 12.5 mg combinations were significantly greater than those observed after monotherapy with either drug. Treatment for 8 weeks with candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg or candesartan cilexetil 16 mg induced SBP/DBP reductions of 12.0/7.5 mm Hg and 7.5/5.5mm Hg, respectively (p < 0.05 both comparisons). Moreover, data from a randomised, double-blind, placebo-controlled, dose-finding study in 1038 patients with mild to moderate hypertension showed that the greatest reductions in SBP/DBP were achieved by candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg. Significant differences in BP reduction in favour of the combination were observed when hypertensive patients were given candesartan cilexetil 4 or 8 mg/hydrochlorothiazide 12.5 mg or hydrochlorothiazide monotherapy for 8 weeks. Additionally, greater efficacy of the combination compared to monotherapy with either drug was demonstrated by response rates to treatment. Moreover, a fixed combination of candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg demonstrated a greater antihypertensive effect than losartan 50 mg/hydrochlorothiazide 12.5 mg in two clinical trials. Candesartan cilexetil 8 mg/hydrochlorothiazide 12.5 mg showed a similar antihypertensive effect compared with that of combined lisinopril 10 mg/hydrochlorothiazide 12.5 mg. Candesartan cilexetil/hydrochlorothiazide combination was well tolerated in patients with hypertension. Combined data from placebo-controlled trials showed that most adverse events were uncommon and not serious. Patients receiving combination therapy exhibited, among other adverse events, headache (3.2 vs 5.5% for candesartan cilexetil/hydrochlorothiazide and placebo, respectively), back pain (3.0 vs 2.4%), dizziness (2.6 vs 1.2%) and respiratory infection (2.5 vs 1.4%). Moreover, 3.3 and 2.7% of patients receiving candesartan cilexetil/hydrochlorothiazide or placebo, respectively, discontinued treatment because of adverse events. CONCLUSION: The combination of candesartan cilexetil and hydrochlorothiazide (AT(1)-receptor antagonist and thiazide diuretic, respectively) is an effective treatment for patients with hypertension. Data from randomised, double-blind, placebo-controlled clinical trials showed that this combination is significantly more efficacious than either agent alone. Moreover, the combination of these two agents showed an excellent adverse event profile. Current data support the use of this combination as an alternative when monotherapy with either agent is not effective, and there are no compelling or specific indications for other drugs. However, data from large clinical trials, evaluating morbidity and mortality outcomes, are needed to determine the precise role of candesartan cilexetil/hydrochlorothiazide combination in the treatment of patients with hypertension.     

Evaluation of high dose of perindopril/indapamide fixed combination in reducing blood pressure and improving end-organ protection in hypertensive patients

ABSTRACT

Background: Despite the widespread notion that controlling hypertension is essential to improve cardiovascular outcome, uncontrolled hypertension rates remain high. Fixed-dose combinations are used routinely to reduce the impact of hypertension. Treatment with fixed-combination perindopril/indapamide, for example, at the currently approved doses (perindopril 2?mg/indapamide 0.625?mg [Per2/Ind0.625] and perindopril 4?mg/indapamide 1.25?mg [Per4/Ind1.25]), reduces blood pressure, end-organ damage, and cardiovascular morbidity and mortality in a wide range of hypertensive patients.

Aim and scope: This article reviews three published randomised trials that evaluated the efficacy and safety of the highest dose of perindopril/indapamide (perindopril 8?mg/indapamide 2.5?mg [Per8/Ind2.5]) in blood pressure lowering and end-organ protection studies.

Results: In the first (dose-finding) study, incremental reductions in SBP/DBP were observed with each dose doubling. After 8 weeks of treatment, decreases in supine SBP/DBP were statistically significant compared to placebo for all three doses, with incremental and progressive reductions with each dose doubling: ranging from SBP/DBP respectively ?14/?9?mmHg for Per2/Ind0.625 to ?23/?15?mmHg for Per8/Ind2.5 compared to ?5/?5?mmHg for placebo. In the PICXEL and PREMIER trials, SBP/DBP decreases of 16.3/8.1?mmHg (p?<?0.0001) and 2.5/2.6?mmHg, respectively, were noted when Per4/Ind1.25 was doubled to Per8/Ind2.5 (decreases from 167.7/101.7 to 151.4/93.6 in PICXEL and from 154.9/92.1 to 152.4/89.5 in PREMIER, respectively). As a consequence more patients had normalised blood pressure (22% and 17%), more patients responded to treatment (68% and 45%), and 29% and 10% of non-responders became responders, in PICXEL and PREMIER, respectively. Additional end-organ benefits were also noted with Per8/Ind2.5. In PICXEL, significant decreases from baseline in left ventricular mass were noted with all three doses, with a 17.5?g/m² decrease from baseline in patients whose maximum dose was Per8/Ind2.5 (from 148.5?g/m²?±?39.5 (mean?±?SD) to 131?g/m²; p?<?0.0001). In PREMIER, changes in albumin excretion rate were also noted with all three doses, with a 45% reduction from baseline in patients whose maximum dose was Per8/Ind2.5 (p?<?0.0001). When safety data, including potassium levels, were analysed, the increase in dose to Per8/Ind2.5 did not have a notable impact on the safety profile of perindopril/indapamide.

Conclusions: Based on data available from an evaluation of three randomised clinical trials, fixed-combination Per8/Ind2.5 provided a significant, incremental reduction in blood pressure as well as cardiac and renal end-organ protection while remaining safe and well-tolerated.     

Nouvelles stratégies pour le contrôle de l’hypertension: preuves supplémentaires en faveur des associations faiblement dosées

New Strategies for hypertension control. More evidence for low-dose combination therapyHypertension control remains inadequate around the world with many hypertensive people untreated and many treated patients remaining hypertensive. Normalisation of the systolic blood pressure presents the greatest challenge to the physician even though it is the dominant predictor of cardiovascular risk in hypertensive subjects. This is particularly true in people over the age of 50, reflecting the progressive “stiffening” of the arteries with advancing age.New strategies are needed to combat this challenge and the American, European and International guidelines in 2003 all recommend the use of more intensive therapy using combination therapy for the majority of patients. Furthermore, these guidelines all approve the use of fixed dose combinations, particularly fixed low-dose combinations, to improve compliance with therapy and blood pressure control, and to reduce costs. The American and European Guidelines approve the use of fixed low dose combinations to initiate the drug treatment of hypertension.The fixed low-dose combination of perindopril 2 mg and indapamide 0.625 mg, exemplifies all the benefits to be obtained with this strategy. Studies so far have confirmed the superior efficacy of this perindopril/indapamide combination in lowering blood pressure, particularly systolic blood pressure, and in slowing or reversing the progression of target organ damage, including left ventricular hypertrophy and albuminuria. These benefits appear to reflect actions on both large central arteries and on the microcirculation. Effective use of this fixed combination of perindopril and indapamide has the potential to reduce the growing burden of blood pressure related disease worldwide.     

ANGIOTENSIN-CONVERTING ENZYME INHIBITION AS FIRST-LINE TREATMENT FOR HYPERTENSION

1. Perindopril (4 mg) was compared with atenolol (50 mg), captopril (25 mg b. d.) or a diuretic (hydrochlorothiazide 50 mg and amiloride 5 mg) in three studies involving a total of 503 hypertensive patients with a diastolic blood pressure (DBP) of 95–125 mmHg.
2. A 4 week single-blind placebo period preceded 12 weeks of active treatment. Dose titration was at weeks 4 and 8 if supine DBP >90 mmHg. The dose was doubled and if necessary a diuretic was added in the atenolol or captopril comparisons, and atenolol was added in the diuretic study.
3. The fall in supine blood pressure (BP) was 27/17 mmHg with perindopril and 21/16 mmHg for atenolol. Monotherapy controlled 55% of patients on perindopril and 48% on atenolol, increasing to 78% and 58% with the addition of hydrochlorothiazide, respectively. Captopril caused a BP fall of 19/12 mmHg compared with 27/18 mmHg for perindopril, with 49% of both groups being controlled on monotherapy.
4. Diuretic addition produced a greater antihypertensive effect with perindopril (75%) compared with 57% for captopril in achieving control. Perindopril caused a comparable fall in supine BP to the diuretic combination 27/19 mmHg and 31/18 mmHg, but the fall in erect systolic BP was significantly greater for the diuretic. At 3 months, 85% of the diuretic group and 78% of the perindopril group achieved the target BP.
5. A multicentre trial of 856 patients treated with perindopril (690 patients treated for 1 year or more) has shown that BP control is maintained in the long term with a low incidence of side-effects (7.9%) causing withdrawal from treatment. These studies demonstrate that perindopril compares favourably with standard first-line therapy for mild to moderate hypertension.     

Dose-dependent prevention of fibrosis in aorta of salt-loaded stroke-prone spontaneously hypertensive rats by combined delapril and indapamide treatment

Combined treatment with the angiotensin-converting enzyme (ACE) inhibitor delapril and the diuretic indapamide prevented vascular damage in vital organs of salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp). Whether the changes occurring after long-term hypertension could also be modulated in large arteries was investigated. Two-month-old SHRsp were salt loaded and treated with the drug regimen until they reached 50% mortality or around midlife. In a first experiment, delapril (12 mg/kg) and indapamide (1 mg/kg) were administered daily separately or in combination. In the second dose-finding experiment, delapril (6, 3, 1.5 mg/kg) and indapamide (0.5, 0.25, 0.125 mg/kg) in decreasing dose combinations were analyzed. Ultrastructural, histomorphometric, and biochemical studies were performed on the thoracic aorta. When compared with delapril (12 mg/kg) or indapamide (1 mg/kg) administered individually for 5 months, the combination 12 + 1 mg/kg was able to prevent the increase in extracellular matrix deposition observed in other treatment groups, as assessed by histomorphometry or 4-OH-proline biochemical determination. In the second experiment, a half-dose (delapril 6 mg/kg + indapamide 0.5 mg/kg) combination was similarly effective in counteracting fibrosis, but the other doses progressively failed. In the first experiment, the combination had a stabilizing effect on hypertension and stimulated diuresis. In the second experiment, arterial blood pressure values and sodium balance were not consistently affected by the treatments that antagonized fibrosis (i.e., delapril 6 mg/kg + indapamide 0.5 mg/kg and, less efficiently, delapril 3 mg/kg + indapamide 0.25 mg/kg). These results suggest that indapamide interacts with ACE inhibitors to limit aortic fibrosis independent of any well-established mechanism.     

Protective effects of delapril combined with indapamide or hydrochlorothiazide in spontaneously hypertensive stroke-prone rats: a comparative dose-response analysis

In previous articles, we have shown that the combination of the angiotensin-converting enzyme (ACE) inhibitor delapril (12 mg/kg/day) and the diuretic indapamide (1 mg/kg/ day) was able to prolong the life span significantly in salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp). Because this finding was partly dependent on the antagonism of salt-loading effects by pharmacologic induction of diuresis, which prevented any increase in blood pressure values, we decided to evaluate whether lower doses of the combination could be equally protective without changing the progression of hypertension. Thus, we studied several treatments with progressively lower doses of delapril (6, 3, or 1.5 mg/kg/day) combined with indapamide (0.5, 0.25, or 0.125 mg/kg/day) or hydrochlorothiazide (2.5, 1.25, or 0.625 mg/kg/day) in salt-loaded SHRsp. Salt-loaded untreated animals were considered to be the control group. In agreement with previous experiments, control rats reached 50% mortality approximately 7 weeks after the beginning of salt loading. The combination of delapril and hydrochlorothiazide at the two lowest doses was not able to delay animal death significantly, whereas treatment with delapril and indapamide at the lowest dose was effective (50% survival rate, 15 weeks). The groups treated with the highest dose of delapril and hydrochlorothiazide or with the intermediate or highest dose of delapril and indapamide did not reach 50% mortality by the end of the experiment, at 44 weeks of treatment (i.e., when animals reached age 1 year). Only the highest delapril and indapamide doses were able to increase diuresis, but for a relatively short period. None of the treatments was able to lower or control blood pressure levels adequately. Therefore, blood pressure levels by themselves were not predictive of rat mortality. In contrast, the maximal value of proteinuria in the weeks preceding death was inversely correlated with the survival time. In conclusion, this study shows that low doses of an ACE inhibitor in combination with a diuretic can be effectively protective in a model of severe hypertension, independent of any change in blood pressure levels.     

What can be learned from the experience with the fixed low-dose combination of perindopril/indapamide in the treatment of hypertension?

The association of low doses of perindopril and indapamide in a single pill has been developed to meet the criteria required for a fixed-dose combination to be used as first-line therapy. The experience accumulated so far has demonstrated a greater antihypertensive efficacy of this preparation compared with various monotherapies, but not at the expense of a worsening of tolerability. The perindopril/indapamide combination is particularly effective in lowering systolic and pulse blood pressure. Starting treatment with this fixed-dose combination improves arterial stiffness and allows a better regression of cardiac hypertrophy than angiotensin-converting enzyme-inhibition or beta-adrenoceptor blockade alone. In hypertensive patients with Type 2 diabetes, a greater reduction of urinary albumin excretion can be obtained with the perindopril/indapamide association compared with an angiotensin-converting enzyme inhibitor administered as monotherapy. There is evidence that a first-line management of hypertension based on a low-dose perindopril/indapamide combination can provide a better efficacy/safety ratio than other well-established therapeutic strategies.     

What can be learned from the experience with the fixed low-dose combination of perindopril/indapamide in the treatment of hypertension?

The association of low doses of perindopril and indapamide in a single pill has been developed to meet the criteria required for a fixed-dose combination to be used as first-line therapy. The experience accumulated so far has demonstrated a greater antihypertensive efficacy of this preparation compared with various monotherapies, but not at the expense of a worsening of tolerability. The perindopril/indapamide combination is particularly effective in lowering systolic and pulse blood pressure. Starting treatment with this fixed-dose combination improves arterial stiffness and allows a better regression of cardiac hypertrophy than angiotensin-converting enzyme-inhibition or β-adrenoceptor blockade alone. In hypertensive patients with Type 2 diabetes, a greater reduction of urinary albumin excretion can be obtained with the perindopril/indapamide association compared with an angiotensin-converting enzyme inhibitor administered as monotherapy. There is evidence that a first-line management of hypertension based on a low-dose perindopril/indapamide combination can provide a better efficacy/safety ratio than other well-established therapeutic strategies.     

Efficacy and tolerability of the perindopril/indapamide combination therapy for hypertension: the PRIMUS study

BACKGROUND: Tight blood pressure (BP) control is required to reduce cardiovascular morbidity and mortality. OBJECTIVE: To evaluate the efficacy and tolerability of the first line combination perindopril/indapamide in hypertension in daily practice. DESIGN AND METHODS: In this prospective, open-label, observational trial, 1892 general practitioners in Germany recruited patients with hypertension (n = 8023; mean age 59.6 years, 48.1% males, body mass index 27.6 kg/m2, systolic BP >or= 140 mmHg and/or diastolic BP >or= 90 mmHg) between October 2002 and December 2004. Patients received perindopril 2 mg/indapamide 0.625 mg for 12 weeks. BP measured in the general practice setting, safety, and tolerability were evaluated after 4 and 12 weeks. RESULTS: At baseline, most patients had moderate to severe hypertension (78%); initial BP was 164.6/95.8 mmHg. At inclusion, 38% of the patients were newly diagnosed hypertensives (mean BP 166.1/97.2 mmHg) and 58% of patients had uncontrolled BP despite preexisting antihypertensive treatment (163.5/94.9 mmHg). Previous treatment consisted of beta-blockers (49.5%), ACE inhibitors (36.4%), calcium-antagonists (29.3%), diuretics (28.8%), AT-I receptor antagonists (7.1%), and other treatments (8.1%). In the entire study cohort, treatment with perindopril/indapamide significantly decreased systolic BP (27.9 mmHg), diastolic BP (13.7 mmHg), and pulse pressure (14.2 mmHg), compared with baseline (p < 0.0001); 96% of patients responded to treatment and in 50% of patients BP was normalized (< 140/90 mmHg). Treatment dose was doubled in 9.5% of patients. Similar results were found in various subgroup analyses (newly diagnosed patients, the elderly, and patients with isolated systolic hypertension, additional cardiovascular risk factors, associated diseases, or target organ damage). The most frequent adverse events (< 1% of patients) were dry cough and nausea. CONCLUSIONS: The open-label, observational study PRIMUS, extends the existing evidence that the first line combination treatment of hypertension with perindopril/indapamide is effective, safe, and well tolerated in a representative cross-section of patients with newly diagnosed or pretreated but uncontrolled hypertension in daily practice.     

The effect of perindopril and hydrochlorothiazide alone and in combination on blood pressure and on the renin-angiotensin system in hypertensive subjects

Summary The pharmacodynamic effects and acceptability of perindopril (4 mg daily) and hydrochlorothiazide (25 mg daily) given alone or in combination for 1 month were investigated in a double-blind, placebo controlled, parallel group study. The pharmacokinetics of perindopril and its active metabolite perindoprilat and the time course of angiotensin converting enzyme inhibition were studied for 72 h following the last dose of treatment in the two appropriate groups.Similar decreases in blood pressure were seen 24 h after the last dose of perindopril or hydrochlorothiazide (11/7 mm Hg supine) given alone at these doses. The effect of these drugs given together was additive on diastolic blood pressure and synergistic on systolic blood pressure (24.5/12.6 mm Hg supine) taking into account the placebo response. The significant increase in plasma renin activity produced by perindopril alone was potentiated by concurrent administration of hydrochlorothiazide.The formation of perindoprilat was slightly reduced in the group also receiving hydrochlorothiazide and there was a very small reduction in ACE inhibition in this group.Perindopril, whether given alone or in combination with hydrochlorothiazide, was well tolerated and produced no clinically significant change in routine haematology or serum biochemistry.The additive or synergistic effects of perindopril and hydrochlorothiazide on blood pressure must be due to their complementary physiological actions and not to a pharmacokinetic interaction.     

Valsartan/hydrochlorothiazide: a review of its pharmacology,therapeutic efficacy and place in the management of hypertension

The combination of valsartan [an angiotensin II type 1 (AT(1)) receptor blocker] and hydrochlorothiazide (a thiazide diuretic), administered once daily, has been evaluated in the treatment of patients with hypertension in clinical trials ranging in duration from 8 weeks to 3 years. These studies showed that combination treatment with valsartan 80 or 160mg and hydrochlorothiazide 12.5 or 25mg induced significant reductions from baseline in systolic blood pressure (SBP) and diastolic BP (DBP) in patients with mild to severe hypertension. Clinical trials have demonstrated that the combination of valsartan 80 or 160mg with hydrochlorothiazide 12.5 or 25mg is significantly more effective than either drug alone. Furthermore, valsartan plus hydrochlorothiazide was effective at reducing BP in patients unresponsive to monotherapy with either agent alone. Effective BP control with valsartan plus hydrochlorothiazide was maintained in long-term studies, with reductions observed after 3 months of treatment being similar to those seen after 1, 2 or 3 years. Fixed-dose valsartan/hydrochlorothiazide showed similar BP reductions to amlodipine and to valsartan plus benazepril. Valsartan/hydrochlorothiazide also provided effective 24-hour ambulatory SBP/DBP control. Headache, dizziness and fatigue were the most common adverse events occurring in clinical trials; the incidence of these events in valsartan plus hydrochlorothiazide recipients was not significantly different to that in placebo recipients. Hypokalaemia occurred in 4.5% of valsartan plus hydrochlorothiazide recipients; valsartan attenuated the hydrochlorothiazide-associated decrease in serum potassium concentrations. CONCLUSIONS: the combination of valsartan and hydrochlorothiazide is an effective treatment for patients with hypertension. Clinical trials have demonstrated that the combination is more effective than either drug alone, and is effective in patients not responding to monotherapy with either agent. Furthermore, the adverse event profile of valsartan/hydrochlorothiazide is similar to that of placebo. Unless there are compelling or specific indications for other drugs, current data support the use of valsartan/hydrochlorothiazide when patients are unresponsive to monotherapy with either agent. Results from clinical trials evaluating the effects of valsartan/hydrochlorothiazide on cardiovascular morbidity and mortality will help to further define the role of the combination in the management of hypertension.     

小剂量培哚普利吲达帕胺片治疗原发性高血压疗效观察

目的：探讨小剂量培哚普利吲达帕胺片治疗原发性高血压的疗效与安全性。方法：原发性轻中度高血压患者106例分为两组,观察组54例给予培哚普利吲哒帕胺片1片（培哚普利2 mg,吲哒帕胺0.625 mg）,qd,对照组52例给予培哚普利片4 mg,qd。治疗8周后,比较两组血压达标率、临床疗效,以及两组不良反应发生情况。结果：治疗后,观察组总有效率88.8%,对照组总有效率80.7%,两组比较差异无统计学意义（P〉0.05）。两组治疗后SBP和DSP均较治疗前明显下降（P〈0.05）,且观察组改善效果优于对照组（P〈0.05）。观察组不良反应发生率比较,明显低于对照组（P〈0.05）。结论：小剂量培哚普利吲达帕胺片治疗原发性高血压可提高血压达标率,降压效果较好,且不良反应少,值得临床推广应用。     

Valsartan/hydrochlorothiazide: a review of its use in the management of hypertension

Valsartan/hydrochlorothiazide is a fixed-dose (valsartan 80, 160 or 320mg plus hydrochlorothiazide 12.5 or 25mg) angiotensin II receptor blocker/diuretic drug combination indicated for the treatment of patients with essential hypertension not adequately controlled by monotherapy.There is ample evidence that valsartan/hydrochlorothiazide is an effective fixed-dose combination antihypertensive agent. However, efficacy and tolerability data pertaining to the 320mg dose of valsartan in the combination are currently relatively few. There is also some evidence of potential benefits associated with the relatively favourable tolerability profile of the combination, the low occurrence of new-onset diabetes mellitus versus amlodipine and the valsartan-associated improvements in cardiac and endothelial function.     

固定剂量的培哚普利和氨氯地平治疗原发性高血压的有效性和耐受性

目的观察固定剂量的培哚普利和氨氯地平联用治疗原发性高血压的有效性和耐受性。方法未经治疗的Ⅱ级高血压（BP≥160/100mm Hg）患者、单一药物或其他合并用药未能控制的高血压（BP≥140/90mm Hg）患者进行观察。患者每天服用固定剂量的培哚普利（4mg）和氨氯地平（5mg）共60d。给药前、给药15、30d以及60d分别测定患者血压。服药期间每周进行常规检查、随访不良事件及依从性。结果试验共纳入112名患者,其中有106名完成60d的治疗。治疗60d后所有患者平均收缩压和舒张压相对于治疗前显著降低（-41.9±8.5/-22.8±5.6）mm Hg,分别降低25.8%和22.9%。所有患者67.8%经治疗后血压达标。对亚组进行分析：未经治疗的高血压患者、单一药物没有控制的高血压患者以及其他合并用药没能控制血压的患者经治疗后血压达标62.8%、62.3%和58.8%。固定剂量的培哚普利和氨氯地平联用安全、耐受。结论固定剂量的培哚普利和氨氯地平联用为治疗原发性高血压安全、有效的治疗方法,并且临床依从性好。     

Efficacy and tolerability of the perindopril/indapamide combination therapy for hypertension: the PRIMUS study*

ABSTRACT

Background: Tight blood pressure (BP) control is required to reduce cardiovascular morbidity and mortality.

Objective: To evaluate the efficacy and tolerability of the first line combination perindopril/indapamide in hypertension in daily practice.

Design and methods: In this prospective, open-label, observational trial, 1892 general practitioners in Germany recruited patients with hypertension (?n = 8023; mean age 59.6 years, 48.1% males, body mass index 27.6?kg/m², systolic BP ≥ 140?mmHg and/or diastolic BP ≥ 90?mmHg) between October 2002 and December 2004. Patients received perindopril 2?mg/indapamide 0.625?mg for 12 weeks. BP measured in the general practice setting, safety, and tolerability were evaluated after 4 and 12 weeks.

Results: At baseline, most patients had moderate to severe hypertension (78%); initial BP was 164.6/95.8?mmHg. At inclusion, 38% of the patients were newly diagnosed hypertensives (mean BP 166.1/97.2?mmHg) and 58% of patients had uncontrolled BP despite preexisting antihypertensive treatment (163.5/94.9?mmHg). Previous treatment consisted of β‐blockers (49.5%), ACE inhibitors (36.4%), calcium-antagonists (29.3%), diuretics (28.8%), AT‐I receptor antagonists (7.1%), and other treatments (8.1%). In the entire study cohort, treatment with perindopril/indapamide significantly decreased systolic BP (27.9?mmHg), diastolic BP (13.7?mmHg), and pulse pressure (14.2?mmHg), compared with baseline (?p < 0.0001); 96% of patients responded to treatment and in 50% of patients BP was normalized (< 140/90?mmHg). Treatment dose was doubled in 9.5% of patients. Similar results were found in various subgroup analyses (newly diagnosed patients, the elderly, and patients with isolated systolic hypertension, additional cardiovascular risk factors, associated diseases, or target organ damage). The most frequent adverse events (< 1% of patients) were dry cough and nausea.

Conclusions: The open-label, observational study PRIMUS, extends the existing evidence that the first line combination treatment of hypertension with perindopril/indapamide is effective, safe, and well tolerated in a representative cross-section of patients with newly diagnosed or pretreated but uncontrolled hypertension in daily practice.     

Efficacy and tolerability of valsartan in combination with hydrochlorothiazide in essential hypertension

OBJECTIVE: This study compared the efficacy and tolerability of two combination regimens of valsartan and hydrochlorothiazide (HCTZ) with valsartan monotherapy in patients with essential hypertension inadequately controlled with valsartan 80mg once daily. PATIENTS AND METHODS: A total of 708 patients with inadequately controlled blood pressure after 4 weeks' treatment with valsartan 80mg once daily participated in this double-blind comparative trial. Patients were randomly allocated once-daily treatment with valsartan 80mg, valsartan 160mg, valsartan 80mg + HCTZ 12.5mg or valsartan 80mg + HCTZ 25mg for 8 weeks. RESULTS: Statistically significant decreases in mean sitting diastolic blood pressure (SDBP) and mean sitting systolic blood pressure (SSBP) from baseline were seen in all treatment groups (least squares mean change from baseline SDBP: -5.1mm Hg, -6.2mm Hg, -8.2mm Hg, -10.8mm Hg; SSBP: -3.9mm Hg, -6.5mm Hg, -9.8mm Hg, -16.0mm Hg for valsartan 80mg, valsartan 160mg, HCTZ 12.5mg combination, HCTZ 25mg combination, respectively). A significant difference for mean SDBP, SSBP and responder rates in favour of the combination regimens was observed compared with either valsartan monotherapy. All treatments were well tolerated with the percentage of patients reporting treatment-related adverse experiences at any time ranging from 9.9% (valsartan 160mg) to 21.0% (HCTZ 25mg combination). CONCLUSION: The study demonstrated that a combination of valsartan 80mg and HCTZ 12.5mg or 25mg provides an effective and well tolerated treatment in patients who need additional blood pressure control beyond valsartan monotherapy.     

Effects of a fixed-dose ACE inhibitor-diuretic combination on ambulatory blood pressure and arterial properties in isolated systolic hypertension

The ideal therapy for patients with isolated systolic hypertension remains unclear; diuretics, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors are all used in clinical practice. The aim of this study was to determine whether a fixed-dose ACE inhibitor/diuretic combination would reduce ambulatory blood pressures (BP) and arterial stiffness in isolated systolic hypertension more than antihypertensive monotherapy. In this randomized, double-blind study, 8 weeks of fosinopril/hydrochlorothiazide combination (10/12.5 mg titrated up to 20/12.5 mg) was compared with the calcium channel blocker (amlodipine, 5 mg titrated up to 10 mg) and diuretic (indapamide, 2.5 mg) monotherapy in 28 patients with isolated systolic hypertension. Each patient received all 3 therapies. Assessments included 24-hour ambulatory BP, clinic BP, and applanation tonometry-derived augmentation index. At 8 weeks, the fall in average 24-hour systolic BP and night time systolic BP were significantly greater in the fosinopril-hydrochlorothiazide group, compared to amlodipine and indapamide. The decrease in augmentation index and central aortic systolic BP was also greater in the fosinopril-hydrochlorothiazide group, compared to either amlodipine or indapamide. There was no difference between therapies in decrease in clinic systolic or diastolic BP, or diastolic ABP (average 24-h, diurnal, or nocturnal). Compared with either calcium channel blocker or diuretic therapy, a fixed-dose ACE inhibitor-diuretic combination induces greater reductions in systolic ABP, particularly at night, favorable effects that may be related to a decrease in the intensity of or delay in arterial wave reflections. ACE inhibitor-diuretic combination therapy is a useful approach to cardiovascular risk reduction in isolated systolic hypertension.