October 22, 2006
Efficacy and Tolerability of the Perindopril/Indapamide Combination Therapy for Hypertension: the PRIMUS Study*
By Holzgreve, Heinrich; Risler, Teut; Trenkwalder, Peter
Key words: Combination drug therapy - Hypertension - Indapamide - Perindopril - Risk factors
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/m^sup 2^, 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
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.
Various studies have demonstrated the close correlation between blood pressure during treatment and target organ damage or development of cardiovascular complications. Therefore current guidelines insist on strict blood pressure goals1,2. Target blood pressure for the general hypertensive patient is systolic blood pressure (SBP)
When a patient does not respond sufficiently to initial monotherapy, physicians have to increase treatment dose, switch the patient to another monotherapy, or add a second antihypertensive drug. Such scenarios are common in daily practice as studies have shown that only 25-60% of patients, depending on the grade of hypertension,, respond to monotherapies and that even after consecutive monotherapies, blood pressure is not always controlled4- 6. Not only does this search for optimal therapy increase the risk of side effects due to higher drug doses and problems with patient compliance and follow-up, but it also delays the normalization of blood pressure. These delays are not inconsequential; in a recent study, achieving blood pressure control within 6 months of treatment reduced cardiac events by 25%, stroke by 45%, myocardial infarction by 14%, and mortality by 21%7.
The use of a combination therapy as a first line treatment represents a more effective alternative to addon-therapy or sequential monotherapies. Indeed, several international studies have shown that combination therapies are more effective than monotherapies4,8,9, and that in order to normalize blood pressure many patients need to take combination therapies10-12. In the most recent guidelines of the European Society of Hypertension and the European Society of Cardiology (ESH/ESC)1, a low-dose combination therapy of two agents was described as an option for first line treatment of hypertension. If therapy has been initiated with a low- dose combination, a higher dose combination can subsequently be used or a third compound added1. An ACE inhibitor and a diuretic are available in a fixed dose combination of perindopril 2 mg/ indapamide 0.625 mg13.
Extensive clinical trials have shown that the first line combination perindopril/indapamide, at this low-dose, is effective in controlling essential hypertension in newly diagnosed patients and in patients with treated, but uncontrolled, hypertension14-23. Persistent blood pressure lowering effects have been observed19 in longterm trials lasting more than a year20. Eighty percent of patients included maintained their normalized blood pressure throughout the 1-year extension period20. These trials have also shown that the lowdose combination perindopril/indapamide is at least as well tolerated as either component administered as a monotherapy22. More patients taking combinations of perindopril/ indapamide (50% and 100% dose increases in patients with uncontrolled blood pressure), reached normal blood pressure without experiencing an adverse event than patients taking sequential monotherapies (atenolol, losartan, and amlodipine) or a single monotherapy at increasing doses (valsartan and, if necessary, in combination with a diuretic)16.
To evaluate the efficacy and tolerability of perindopril 2mg/ indapamide 0.625mg in daily practice, the prospective, open-label PRIMUS (acronym of the German PReterax* fix koMbiniert Und niedrig doSiert bei hypertonie von Anfang an) trial was conducted in a large cohort that included patients with different grades of hypertension, newly diagnosed patients, and patients with treated, but uncontrolled, hypertension.
Patients and methods
In this prospective, open-label, single-arm, German, multicenter, post-marketing trial, named PRIMUS, conducted between October 2002 and December 2004, general practitioners and internal medicine specialists enrolled patients with hypertension to be treated daily with a combination therapy of 2 mg of perindopril and 0.625mg of indapamide (Preterax, Servier International, Neuilly sur Seine, France)13 for 12 weeks. Physicians could titrate the dose to 4 mg of perindopril and 1.25 mg of indapamide (Bi Preterax, Servier International, Neuilly sur Seine, France)24.
In order to assess treatment under daily medical practice conditions, no special inclusion and exclusion criteria or treatment constraints, such as stopping previous antihypertensive medications, were specified. However, decisions concerning the choice of patients and treatment had to be made in accordance with the European Summary of Product Characteristics for Preterax and Bi Preterax13,24.
No approval by an institutional Ethical Committee is needed in Germany for observational trials. However, the study was conducted in accordance with ethical guidelines of the European Independent Ethics Committee.
Efficacy outcomes were calculated using patients with SBP and DBP data available at baseline and after 3 months of treatment (n = 7844). Office blood pressure (measured in the sitting position, in a general practice setting, upper arm) was assessed during ambulatory visits at week O (study entrance), 4 weeks (on average 5.5 weeks), and 12 weeks (on average 13.5 weeks). Responders were defined as patients for whom blood pressure was normalized (SBP/DBP
In addition to assessments in the entire cohort, efficacy was also evaluated in several pre-specified subgroups, for example newly diagnosed hypertensive patients, elderly patients, patients with isolated systolic hypertension, and patients with additional cardiovascular risk factors, end organ damage, or associated cardiovascular diseases. Elderly patients were defined as patients 65 years of age or older at baseline. Cardiovascular risk factors were defined as grade 3 hypertension (SBP/DBP ≥ 180/1 lOmmHg), isolated systolic hypertension (SBP ≥ 140/DBP 55 years for men and > 65 years for women, or excess body weight (body mass index ≥ 25kg/m^sup 2^). End or\gan damage was defined as left ventricular hypertrophy or microalbuminuria (20-200 mg/L). Associated cardiovascular diseases were defined as concomitant coronary heart disease or peripheral artery occlusive disease, or a history of myocardial infarction, aortocoronary bypass, transient ischemic attack, stroke, or heart failure. These definitions are in accordance with the German Hypertension League guidelines, which are based on the ESH/ESC guidelines1.
All patients were evaluated for safety and tolerability at every visit. Adverse events were recorded and classified by the physician according to severity (mild, moderate, or severe), and relation to study drug (none, unlikely, probable, definite, or unknown). Laboratory measurements (potassium, sodium, serum creatinine, glucose, triglycerides, total cholesterol, glycated hemoglobin [HbA^sub 1c^], and albuminurie) were performed at the physician's discretion. Tolerability was assessed by the investigator and categorized as poor, moderate, good, or very good.
A descriptive statistical analysis was performed. For nominal and ordinal data, absolute and relative frequencies were calculated. For interval data, statistical values, such as mean value and standard deviation, were calculated. When possible, explorative p-values and confidence intervals were calculated. Statistical significance was set as p ≤ 0.05. All statistical analyses were performed using SAS for Windows (Statistical Analysis System, SAS-Institute, Gary NC, USA).
In this study, 8023 patients with hypertension were treated with the low-dose combination perindopril 2 mg/indapamide 0.625 mg once daily for 12 weeks. At the baseline visit, the mean age was 60 years and the mean duration of hypertension since diagnosis was 4.2 years (Table 1). Most patients had moderate to severe hypertension (78%) and additional cardiovascular risk factors, end organ damage, or associated cardiovascular diseases (89%). At inclusion, the mean SBP was 164.6mmHg, mean DBP was 95.8mmHg, and mean pulse pressure (PP) was 68.8mmHg. Mean potassium was 4.4mmol/L, mean sodium was 139.9mmol/L, mean serum creatinine was 1 mg/dL, mean glucose was 107mg/dL, mean triglycerides was 187.6 mg/dL, mean total cholesterol was 220.4 mg/dL, mean albuminuria was 26.5mg/L, and mean HbA^sub 1C^ was 6.2%.
Hypertension was newly diagnosed in 38% of patients included in the trial (n = 3015); 58% of patients (n = 4618) had uncontrolled blood pressure (163.5/94.9mmHg) at inclusion despite preexisting antihypertensive treatment. Among the 4618 patients with treated, but uncontrolled hypertension, 2812 patients were taking one antihypertensive drug, 1034 patients were taking two antihypertensive drugs, 208 patients were taking three antihypertensive drugs, and 83 patients more than three antihypertensive drugs (missing data for 481 patients). Patients were prescribed 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 these patients, uncontrolled blood pressure with previous antihypertensive therapy was the reported reason for initiating treatment with the perindopril/indapamide combination. Additional reasons for initiating therapy with perindopril/indapamide included left ventricular hypertrophy (n = 2054), type 2 diabetes mellitus (n = 1788), albuminuria (n = 569), lack of compliance (n= 1717), and side effects (n = 950) with previous treatments.
During the course of the study, study treatment was titrated up to perindopril 4 mg/indapamide 1.25mg in 9.5% (n = 761) of patients. For most of these patients (n = 423), titration occurred during the first 10 weeks of the study.
Entire cohort of patients
At all visits during the study, treatment with perindopril/ indapamide significantly decreased mean SBP, DBP, and PP compared to baseline (p
Table 1. Baseline characteristics of penndoprit/indapamide treated patients enrolled in the large, observational PRIMUS trial
Patients with new diagnosis of hypertension
Among patients with a new diagnosis of hypertension (n = 3015, 38% of total patients, mean age 55 years), hypertension was mild, moderate, or severe in 17%, 58%, and 25% of cases, respectively. Initial blood pressure was 166.1/97.2mmHg (Table 2).
In newly diagnosed patients, treatment with perindopril/ indapamide significantly decreased mean SBP, DBP, and PP compared to baseline (p
Of the 2625 elderly patients, 368 patients were 80 years of age or older. Baseline blood pressure was 165.9/94.OmmHg (Table 2). Hypertension at baseline was mild, moderate, or severe in 21%, 55%, and 23% of elderly patients, respectively. Treatment with perindopril/indapamide significantly decreased SBP, DBP, and PP as early as 4 weeks after the start of treatment with reductions in SBP, DBP, and PP of 19.9 mmHg, 8.8 mmHg, and 11.1 mmHg, respectively (p
Figure 1. Blood pressure and responder rates in perindopril/ indapamide treated patients enrolled in the large observational PRIMUS trial
Table 2. Baseline blood pressure in subgroups of penndopril/ indapamide treated patients enrolled in the large, observational PRIMUS trial
Figure 2. Blood pressure and responder rates in newly diagnosed hypertensive patients treated with perindopnl/indapamide in the large observational PRIMUS trial
Patients with isolated systolic hypertension
Baseline blood pressure in patients with isolated systolic hypertension (n=1105) was 159.8/81.4mmHg (Table 2). Treatment with perindopril/indapamide significantly decreased SBP and PP as early as 4 weeks after the start of treatment, with reductions in SBP and PP of 17.1 mmHg and 15.4mmHg, respectively, while DBP decreased by 1.7 mmHg (p
Patients with additional cardiovascular risk factors, end organ damage, or associated cardiovascular diseases
Efficacy was also evaluated in patients with cardiovascular risk factors (1-2 risk factors; ≥ 3 risk factors, diabetes mellitus, or end organ damage; and associated cardiovascular diseases). Baseline blood pressure measurements are presented in Table 2. In each of these groups, treatment with perindopril/ indapamide significantly decreased SBP, DBP, and PP as early as 4 weeks after the start of treatment (p
Figure 3. Blood pressure and responder rates in additional subgroups of perindopril/indapamide treated patients in the large observational PRIMUS trial
Of the 8023 patients, 77 (
Table 3. Adverse events in penndopril/indapamide treated patients enrolled in the largeobservational PRIMUS trial
Three hundred and seventy-three patients discontinued treatment. Among these, 110 patients discontinued due to intolerance or an adverse event, 94 by choice, 78 due to non-compliance, and 91 for other reasons.
PRIMUS was a 12-week trial designed to evaluate the antihypertensive combination treatment perindopril/ indapamide in daily practice. Patients were either newly diagnosed hypertensives or treated but uncontrolled. Many of them were elderly, had multiple cardiovascular risk factors, associated cardiovascular conditions, isolated systolic hypertension, and/or type 2 diabetes mellitus. The results of PRIMUS confirm existing data14-23 that show that treatment with perindopril/indapamide, approved for first line combination therapy13,24, is effective and well tolerated in a large group of newly diagnosed and pretreated hypertensives.
Essential hypertension is a heterogeneous condition in which multiple pathways and feedback mechanisms interact to increase blood pressure. Antihypertensive monotherapies do not have a broad enough spectrum of action to inhibit all pathways. As a result, feedback mechanisms may be up-regulated thereby blunting the effect of the therapy. By contrast, appropriately chosen combination therapies target a broader range of pathways and interfere with the feedback mechanisms1,25. As a result, co-administration of drugs that lower blood pressure by different mechanisms substantially enhances the efficacy of antihypertensive treatments. Thus, the rationale for choosing a combination therapy is based on the potential for an enhancement of the antihypertensive efficacy of each individual agent, a reduction of the dose of each individual agent, a reduction in blood pressure greater than that of each component given alone at a higher dose, a reduction of the rate of adverse effects associated with high dose monotherapy, and better patient compliance.
Current European guidelines recommend fixed, low-dose combinations as a first line option for the treatment of hypertension1. In the present study, the data collected from newly diagnosed patients strongly support the use of perindopril/ indapamide as the first-line treatment of hypertension. Clinically significant reductions in blood pressure were noted as early as 4 weeks after the start of treatment; 98% of patients responded to treatment, and few adverse events were recorded.
Recently, the STRATHE study demonstrated that a first line strategy using the perindopril/indapamide combination results in the normalization of blood pressure in a significantly greater number of patients than conventional strategies (monotherapy with atenolol, losartan, or amlodipine, or a stepped care approach with valsartan and hydrochlorothiazide)16. Similar results were found in patients with stage II hypertension26. In the PRIMUS study, positive treatment effects were noted as early as 4 weeks after the start of treatment. In addition after 12 weeks, 50% of patients had normal blood pressure. The proportion of patients with moderate to severe hypertension had dropped from 78% at study entry to 5% at the final visit. Reduction of blood pressure, regardless of severity of hypertension, is noteworthy since early and persistent normalization of blood pressure implies a prevention of cardiovascular events7.
Sufficient evidence has accumulated to strongly suggest that high SBP is a major risk factor for cardiovascular disease. In individuals over 50 years of age especially, controlling SBP is essential17,18. Of particular note, in the STRATHE study, the effect of perindopril/indapamide on SBP was more marked than with the other strategies; and SBP reduction was greater in the subgroup of patients with stage II hypertension16'26. As expected, perindopril/ indapamide reduced SBP far more than DBP in PRIMUS.
Evaluation of target organ damage is important in stratifying the overall risk of cardiovascular events in hypertensive patients. In current guidelines, left ventricular hypertrophy, albuminuria/ microalbuminuria, and increased arterial stiffness are included in the description of hypertension-associated target organ damage127. Data from other trials suggest that the perindopril/indapamide combination has a beneficial effect on target organs and probably serious cardiovascular events14,15,21,23,28-30.
Furthermore, perindopril/indapamide treatment has been shown to decrease PP, an independent cardiovascular risk factor, as well as the aortic augmentation index and pulse wave velocity, which are both hemodynamic parameters related to an improvement in arterial stiffness (REASON study)21. In the present study, the recorded decrease in PP suggests improvements in large artery stiffness and wave reflections, which have, in turn, been related to an improvement in cardiovascular outcome. In addition, in patients with isolated systolic hypertension, a predictor of cardiovascular risk, perindopril/ indapamide significantly reduced SBP and PP, with only minor changes in DBP. This decrease in SBP and PP may account for changes in central blood pressure, a measure whose decrease has been potentially related to cardiovascular benefits31.
The good tolerability data presented here are consistent with the current understanding of side effects caused by antihypertensive drugs. Due to the low dosage and the synergistic mode of action of the components of the first line combination perindopril 2 mg/ indapamide 0.625 mg, good efficacy is accompanied by excellent tolerability. In comparative trials, perindopril/indapamide safety was comparable, or superior, to that of other common antihypertensive treatments14-16,19,21,22. Several other reasons might contribute to explaining the low incidence of side effects: (1) the majority of patients tolerated previous therapy; (2) in patients with adverse events, previous therapy was substituted by perindopril/indapamide; and (3) a low incidence of side effects is often seen in studies with spontaneous reporting of such events. As tolerability and ease of administration are key factors in determining patient compliance, fixed low-dose combination therapies may increase patient compliance. Further studies will be needed to confirm the impact of first line combination perindopril/indapamide therapy on compliance and patient satisfaction.
This study was an open-label observational study and, as such, was not placebo-controlled. Whereas newly diagnosed hypertensives received perindopril/ indapamide only, previously treated hypertensives (59%), at the discretion of the study physician, were prescribed perindopril/indapamide as an add-on treatment as a substitution to part or all previous antihypertensive agents. Concomitant antihypertensive medication use was not recorded. Therefore, it is important to note that the blood pressure reductions noted during the study may also be due to the combination of previous treatments with perindopril/ indapamide. However, this strategy corresponds to real world, daily practice situations rather than to controlled clinical trial situations.
Despite the limitations of an open-label, observational study, the patient cohort appears to be representative of the hypertensive population a physician may encounter. A similar distribution of patient characteristics (age, body mass index, baseline hypertension grade, cardiovascular risk factors) was recorded in another large, open-label trial32.
In conclusion, the data in this trial add to the growing evidence that treatment with the first line combination perindopril/ indapamide has significant beneficial effects on blood pressure in patients with a wide range of initial blood pressure values, concomitant organ damage, and additional risk factors14'18'20. In this observational, open-label trial designed to mimic daily practice, perindopril/indapamide was a highly effective and well- tolerated blood pressure lowering treatment. Early and persistent blood pressure control was achieved in newly diagnosed hypertensive patients and in patients with a history of uncontrolled hypertension, who may or may not have had additional cardiovascular risk factors and end organ damage. Since evidence-based data stress the importance of obtaining rapid and persistent blood pressure control to reduce cardiovascular end organ damage and events, early and successful blood pressure control with the first line combination perindopril/indapamide may ultimately improve cardiovascular outcomes31.
Declaration of interest: This study was supported by Sender.
The authors would like to thank all the investigators who participated in the study.
* This article was presented in abstract form at the European Society of Cardiology (ESC), Stockholm September 3-7, 2005 (Eur Heart J 2005;26:613), the German Congress of Geriatrics (13. Jahreskongress der Deutschen Gesellschaft fur Geria-trie) Fulda, November 3-5, 2005, and the German Congress of Hypertension (29. Wissenschaftliches Kongress Hypertonie Berlin), November 23-25, 2005
* Preterax and Bi Preterax are registered trade marks of Servier International, Neuilly sur Seine, France
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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-3499_3, Accepted for publication: 28 July 2006
Published Online: 22 August 2006
Heinrich Holzgreve(a), Teut Risler(b) and Peter Trenkwalder(c)
a Kardiologische Praxis, Munich, Germany
b University of Tubingen, Tubingen, Germany
c Klinikum Starnberg, Starnberg, Germany
Address for correspondence: Professor Heinrich Holzgreve, MD, Kardiologische Praxis, Burgstr. 7, DE 80331 Mnchen, Germany. Tel.: +49-89-2426-7530; Fax: +49-89-2426-7531; email: H.Holzgreve@t- online.de
Copyright Librapharm Sep 2006
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