Abstract
The aim of the PICASSO study was to evaluate the efficacy and safety of fixed-dose perindopril 10 mg/indapamide 2.5 mg in everyday medical practice. In this 3-month, open-label, observational study, outpatients with primary hypertension who did not reach the blood pressure goal (< 140/90 mmHg) with antihypertensive treatment were enrolled if their treating physician had planned, as part of their ongoing therapy, to switch them to fixed-dose perindopril 10 mg/indapamide 2.5 mg. Blood pressure, heart rate, and metabolic parameters and – optionally – ambulatory blood pressure were measured. Data from 9257 patients were evaluated. Over the course of 3 months, mean blood pressure decreased from 159/93 mmHg to 132/80 mmHg (p < 0.001) and heart rate decreased from 79 to 73 beats/min (p < 0.001). The target blood pressure was reached by 72.7% of patients. Reductions in total cholesterol, low-density lipoprotein-cholesterol (LDL-c), triglycerides, fasting glucose and uric acid levels were clinically significant. Blood levels of high-density lipoprotein-cholesterol (HDL-c), sodium and potassium remained unchanged. Beneficial changes in metabolic parameters were primarily attributed to the reduction in therapy with drugs with unfavourable metabolic profiles (thiazides and beta-blockers). Perindopril/indapamide is an effective and safe antihypertensive treatment in everyday medical practice.
Introduction
According to World Health Organization estimates, Eastern European countries have the highest worldwide rates of cardiovascular mortality (Citation1), and Hungary ranks in the top four countries, with almost 50% of all deaths being attributable to cardiovascular disease (Citation1).
Hypertension is not only a major cardiovascular risk factor, it is also a significant a target in the prevention of cardiovascular disease. European and Hungarian hypertension guidelines recommend lowering blood pressure to < 140/90 mmHg (Citation2,Citation3). However, despite the availability of many different treatment options, these targets are often difficult to reach and maintain (Citation4). As results from many large-scale studies have shown that two or more blood pressure lowering agents are often necessary to control blood pressure (Citation4), use of combination therapies, preferably – if available – fixed-dose combination therapies, is suggested for initiation as well as long-term treatment of hypertension.
The choice of a combination treatment is generally based on the complementary mechanisms of action of specific antihypertensive drug classes, which improve risk factors, accompanying diseases and prevent target organ damage. Inhibitors of the renin–angiotensin–aldosterone system (RAAS), such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers have specifically been recommended for hypertensive patients at high risk (Citation2,Citation5). They have been successfully combined with thiazides and thiazide-like diuretics. In particular, the beneficial effects of the combination of the ACE inhibitor perindopril with the metabolically neutral, thiazide-like, indapamide is supported by several large international studies (PROGRESS, ADVANCE, HYVET, PREMIER, PIXCEL and STRATHE) (Citation6–11). The synergistic effects observed in these trials have underscored the robust, metabolically neutral, organ protective effect of this blood pressure lowering combination. It is this well documented efficacy and tolerability profile, combined with availability of the single-tablet formulation, which has been shown to improve compliance and reduce medication errors (Citation12), that prompted us to evaluate the fixed-dose combination of perindopril/indapamide in the routine management of large hypertensive patient populations in Hungary. We chose the highest available dosage based on evidence that it leads to greater drops in blood pressure with minimal impact on tolerability (Citation13–16).
Materials and methods
The Perindopril Plus Indapamide Combination Blood Pressure Reduction (PICASSO) study was a prospective, multicentre, 3-month, non-interventional, observational, open-label study. Inclusion criteria included age > 18 years and female patients using a safe contraceptive method or being postmenopausal for at least 1 year. Treated outpatients with primary hypertension, who had grade 1 or 2 hypertension (blood pressure of 140–179/90–109 mmHg), had fluctuating blood pressure, or had experienced side-effects while on previously administered drugs, were enrolled if their physician had planned to switch their therapy to the fixed-dose combination of perindopril 10 mg + indapamide 2.5 mg (Coverex AS® Komb Forte, EGIS Pharmaceuticals Plc, Budapest, Hungary) (Citation17). Patients with contraindications to these drugs were excluded. If necessary, previous antihypertensive medications could be preserved or additional antihypertensive treatments could be added.
The study was conducted in accordance with the European Guidelines for Good Clinical Practice/ICH guidelines and the ethical standards put forth in the Helsinki Declaration (1975, 1983). The protocol was approved by the Ethics Committee of the Hungarian Medical Research Council (TUKEB). The ethical committee registration number is 8-348/2009 1018EKU (866/PI/09). Patients provided written informed consent.
Measurements
Patients only underwent diagnostic and monitoring procedures that were warranted by clinical practice. Blood pressure and heart rate were measured at baseline, 1 month and 3 months. Office blood pressure was measured using a mercury sphygmomanometer according to the European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines (Citation18). For ambulatory blood pressure monitoring (ABPM), Meditech ABPM monitors (Meditech Ltd, Budapest, Hungary) were used. Metabolic parameters (fasting plasma glucose, serum total cholesterol, high-density lipoprotein-cholesterol [HDL-c], low-density lipoprotein- cholesterol [LDL-c], triglycerides, sodium, potassium, creatinine, gamma-glutamyl transpeptidase [gamma-GT] and uric acid) were measured by routine laboratory methods at baseline and 3 months. Adverse events, laboratory abnormalities and drug discontinuations were recorded at 1 and 3 months in official patient medical records. Patient general condition (well-being) was rated by the physicians at 1 and 3 months as excellent, improved, appropriate or worse compared with baseline.
Statistics
Data were collected and analysed in accordance with the European Guidelines for Good Clinical Practice/ICH guidelines. Data were analysed by an independent statistics company (WEB2 Research Kft., Budapest, Hungary).
The primary objective was to evaluate the antihypertensive effect of perindopril 10 mg/indapamide 2.5 mg. The secondary objective was to evaluate changes in metabolic parameters and in ABPM values and to assess tolerability of the treatment. Treatments were defined as successful if patients reached the target blood pressure value (< 140/90 mmHg) as defined in ESH/ESC and Hungarian therapeutic guidelines (Citation2,Citation3).
The main analysis cohort included patients for whom all three visits were completed and for whom blood pressure measurements had been recorded. For subjective well-being, only patients with well-being data at 1 and 3 months were included in the analysis. For metabolic parameters, the analysis cohort included only patients with data (per parameter and time point). Post hoc analyses were performed in subgroups of patients based on their baseline systolic blood pressure (SBP)/diastolic blood pressure (DBP) and previous antihypertensive treatment. All the data were analysed and presented using descriptive statistical methods. The consistency of the different frequency distributions was tested with a chi-square test. The level of significance was set at 5%.
Results
The trial was conducted between 27 January 2010 and 31 August 2010, and was carried out at 800 locations in Hungary with the participation of general practitioners, internal medicine specialists and cardiologists. Of the 11,571 patients whose data were collected, 1888 patients were excluded due to administrative deficiencies, missing data or loss to follow up. Of the 9683 patients included in the study, another 426 patients were excluded from the main analysis because they did not have blood pressure data at every visit. The final analysis population included 9257 patients. The most frequent reasons for enrolment in the study were blood pressure values above target levels (67.7%), fluctuating blood pressure (35.9%) and side-effects of previous treatment (6.0%).
Demographic and baseline information are presented in . Among the 9683 patients enrolled, hypertension was previously known and/or treated in 8969 patients (92.6%) and newly diagnosed in 714 patients (7.4%). The mean duration of hypertension for previously diagnosed patients was 10.2 ± 7.8 years. At baseline, most patients (n = 5457; 56.4%) were being treated with one or two hypertensive medications; 1353 (15.1%) were given more than two antihypertensive drugs, while 2159 (22.3%) were receiving no antihypertensive medication.
Table I. Baseline characteristics in the enrolled population: PICASSO study.
During the study, in addition to the fixed-dose combination of perindopril 10 mg/indapamide 2.5 mg, 4539 (46.9%), 3469 (35.8%), 1469 (15.2%), 192 (2.0%) and 14 (0.1%) patients were treated with none, one, two, three or four additional antihypertensive drugs, respectively. Use of antihypertensive agents with known unfavourable metabolic effects (beta-blockers, hydrochlorothiazide) decreased significantly with the switch to perindopril 10 mg/indapamide 2.5 mg: use of previous RAAS inhibitors/hydrochlorothiazide decreased from 9% to 0%, use of hydrochlorothiazide alone decreased from 9% to 1% and use of metoprolol and/or atenolol decreased from 18% to 13%. Prescriptions for medications to treat comorbidities (lipid or uric acid lowering or anti-diabetic drugs) did not change significantly (data not shown).
Changes in blood pressure and heart rate
Average office blood pressure between the baseline and 3-month visits decreased significantly from 158.9 ± 14.3/93.0 ± 9.4 to 131.5 ± 9.5/79.9 ± 6.2 mmHg (SBP/DBP± standard deviation, SD); with changes from baseline of − 27.4 ± 14.6/ − 13.0 ± 9.8 mmHg; p < 0.001 (). After 3 months of treatment, 72.7% of patients reached blood pressure target (SBP/DBP < 140/90 mmHg). Mean heart rate decreased significantly from 79.0 ± 9.6 to 73.4 ± 6.4 beats/min (p < 0.001).
Figure 1. Office blood pressure after treatment with perindopril/indapamide: PICASSO study. Patients (n = 9257) were treated with fixed-dose combination perindopril 10 mg/indapamide 2.5 mg. Baseline values represent blood pressure prior to the switch to perindopril/indapamide. Data are expressed as means ± standard deviation (SD).
When changes in blood pressure were analysed according to baseline measurements, statistically significant decreases in SBP were noted regardless of the severity of the baseline hypertension. Mean decreases in SBP/DBP of − 4.6 ± 10.1/ − 1.6 ± 7.5 mmHg, − 19.5 ± 9.5/− 9.3 ± 7.8 mmHg, − 29.9 ± 10.8/− 14.3 ± 8.6 mmHg and − 45.1 ± 15.6/ − 21.2 ± 11.5 mmHg were observed in patients with a baseline SBP/DBP of 130–139/85–89 mmHg (n = 207), 140–159/90–99 mmHg (n = 3205), 160–179/100–109 mmHg (n = 4550) and > 180/110 mmHg (n = 1204), respectively (p < 0.001 vs baseline; ). Data for patients with a SBP/DBP < 130/85 mmHg are not available (n = 91). In another subgroup analysis, mean office SBP/DBP decreased by 27.7 ± 16.1/13.1 ± 10.9 mmHg from 159.0 ± 15.1/92.8 ± 10.7 to 131.3 ± 9.6/79.7 ± 5.9 mmHg in patients previously treated with a fixed dose ACE inhibitor/hydrochlorothiazide combination (n = 729; p < 0.001 vs baseline).
Figure 2. Statistically significant changes in systolic and diastolic blood pressure according to baseline severity. Patients were treated with fixed-dose combination perindopril 10 mg/indapamide 2.5 mg for 3 months. *All changes from baseline were statistically significant (p < 0.001). Data are expressed as means ± SD. DBP, diastolic blood pressure; SBP systolic blood pressure; SD, standard deviation.
Ambulatory blood pressure was monitored in 349 patients. Mean daytime, night-time and 24-h blood pressure values and pulse pressure decreased significantly over the course of the 3 months of treatment ().
Table II. Ambulatory blood pressure monitoring during treatment with perindopril/indapamide: PICASSO study (n = 349).
Changes in metabolic parameters
Between baseline and 3 months, total cholesterol levels decreased from 5.7 ± 1.1 to 5.2 ± 0.9 mmol/l, LDL-c from 3.2 ± 1.0 to 3.0 ± 0.9 mmol/l, triglycerides from 2.2 ± 1.2 to 2.0 ± 0.9 mmol/l, fasting blood glucose from 6.1 ± 1.6 to 5.8 ± 1.3 mmol/l and serum uric acid from 322.2 ± 84.5 to 308.2 ± 77.2 μmol/l (p < 0.001 for each variable; ). Creatinine levels did not change significantly. Changes in HDL-c and serum potassium () and in gamma-GT and sodium were statistically significant, but clinically irrelevant (data not shown).
Figure 3. Metabolic parameters after treatment with perindopril/indapamide: PICASSO study. Patients were treated with fixed-dose combination perindopril 10 mg/indapamide 2.5 mg. Measurement of metabolic markers was optional and was prescribed only if deemed necessary. Data are expressed as means ± SD. Differences between baseline and 3 months were statistically significant for all parameters, but need to be considered in light of their clinical relevance. *p ≤ 0.001. HDL-c, high-density lipoprotein-cholesterol; LDL-c, low density lipoprotein-cholesterol; SD, standard deviation.
Patient well-being
After 3 months of therapy, patient well-being (n = 9185) was rated as “excellent” in 4792 patients (52.2%), “improved” in 3278 patients (35.7%), “appropriate” in 1095 patients (11.9%) and “worse” in 20 patients (0.2%) compared with baseline ().
Figure 4. Subjective well-being after treatment with perindopril/indapamide: PICASSO study. Patient general condition (well-being) was rated by the physicians at 1 month and 3 months as excellent, improved, appropriate, or worse compared with baseline (n = 9185).
Safety
During the study, 138 patients experienced side-effects or adverse reactions. Adverse events, none of which was serious, were presumed by treating physicians as drug related in 103 patients. The most common drug-related adverse events were dizziness (n = 21; 0.2%), cough (n = 20; 0.2%), hypotension (n = 15; 0.2%), leg oedema (n = 15; 0.2%) and headache (n = 12; 0.1%). Twenty-one patients discontinued treatment due to a drug-related adverse event, among them the most frequent reason being cough (n = 10).
Discussion
In this 3-month, open-label, hypertension study performed in Hungary, mean blood pressure decreased significantly and most of patients reached the blood pressure target after switching previous treatment to fixed-dose perindopril 10 mg/indapamide 2.5 mg. It is important to note that these patients were previously uncontrolled as their SBP/DBP was 140–179/90–109 mmHg. Changes in blood pressure were accompanied by decreases in heart rate, favourable changes in the metabolic parameters and improvements in patient well-being. Treatment was well tolerated throughout the study; this is the most probable reason for improvement in patient well-being.
To mimic real life clinical practice as much as possible, the decision to prescribe perindopril/indapamide was largely independent from the decision to include a patient in the study. Patients were only enrolled if treatment with perindopril/indapamide had been part of the therapeutic plan. Patients only underwent diagnostic and monitoring procedures that were required by normal clinical practice. The data and information derived from the PICASSO study should thus be considered to reflect the therapeutic practice of the Hungarian physicians taking part in the study.
Results of the ABPM sub-study are consistent with the office blood pressure measurements and with ABPM data from other perindopril/indapamide trials (Citation10,Citation19). The fact that 24-h, daytime and night-time SBP/DBP, mean arterial pressure, and pulse pressure decreased significantly after 3 months of therapy suggests a smooth and consistent 24-h antihypertensive effect with perindopril 10 mg/ indapamide 2.5 mg treatment.
Indapamide in monotherapy and in combination with perindopril has been shown in a wide range of populations and in many studies to be metabolically neutral and to have little effect on potassium, creatinine, and lipid and glucose profiles (Citation8,Citation16,Citation20,Citation21). In this study, in which 2.5 mg of indapamide was prescribed, mean changes in potassium were not clinically significant and no laboratory abnormalities were reported. The improvements in metabolic parameters that were observed are likely to be due to the combination of the effect of perindopril/indapamide treatment, the decreased use of antihypertensives with unfavourable metabolic effects (hydrochlorothiazide, RAAS inhibitor + hydrochlorothiazide fixed-dose combinations, metoprolol, and/or atenolol) and the lack of change in prescription of concomitant medications likely to affect metabolic parameters (anti-diabetic, lipid or uric acid lowering drugs). Similar observations were made in the STAR-LET study, where replacing the RAAS inhibitor/hydrochlorothiazide regimen with the metabolically neutral combination of a RAAS inhibitor/verapamil was associated with an improvement in the 2-h oral glucose tolerance test (Citation22). Similarly, hydrochlorothiazide use tended to increase the risk of diabetes in the INVEST study (Citation23). Furthermore, a switch from a hydrochlorothiazide combination to perindopril/indapamide is in line with the recent NICE Guidelines (Citation24), which recommend that if diuretic treatment is to be initiated or changed, indapamide or chlorthalidone should be preferred over hydrochlorothiazide. Indeed, metabolic neutrality of perindopril/indapamide in type 2 diabetics was confirmed in the ADVANCE study (Citation11).
Safety data presented in PICASSO are consistent with the fact that by 3 months, 88% of patients in the trial reported feeling better or excellent. Very few adverse events were reported (< 1.4% of patients) and only 0.1% of patients discontinued treatment due to an adverse event. Thus, these data suggest that at this 10-mg/2.5-mg dose, which is higher than the dose used in the initial dosing studies and pivotal trials (Citation13–15), the safety and tolerability profile of perindopril/indapamide was maintained.
Study duration was not long enough to evaluate long-term outcomes. A wealth of data, however, supports the prediction that with a longer treatment period, cardiovascular outcomes would be expected to decrease, as in the general hypertensive population, and incremental decreases in blood pressure have been shown to improve cardiovascular outcomes (Citation25). More specifically in perindopril/indapamide trials, improvements in long-term outcomes have been observed. Significant reductions in cerebrovascular and cardiovascular events (43% and 40% risk reduction, respectively) after perindopril/indapamide treatment were noted in the PROGRESS trial in patients with a history of cerebrovascular disease (Citation7). Significant reductions in left ventricular hypertrophy and microalbuminuria were recorded in the PICXEL and PREMIER studies (Citation9,Citation10). Lastly, in the ADVANCE and the HYVET studies, treatment of hypertensive patients with perindopril/indapamide lead to a concomitant and significant mortality reduction (Citation8,Citation11).
Study limitations
As with any open-label, phase IV trial, the data presented herein were not compared with a placebo group and any placebo effect due to enrolment in the study cannot be evaluated. The fact that several changes in metabolic parameters were statistically yet not clinically significant, underscores the fact that this trial was not powered to measure metabolic parameters. As with all statistical analyses, interpretation of data should always be anchored in clinical practice. As such, we estimated that the absence in change in HDL-c and the small decreases in potassium and gamma-GT were not clinically significant. Furthermore, we noted a large drop in the number of metabolic measurements between baseline and 3 months. As the measurement of metabolic parameters was optional and subject to the physician's discretion, we hypothesize that these data reflect the fact that in everyday practice a patient who had normal results at baseline would probably not be tested again after 3 months. If this hypothesis is correct, then we would expect that baseline means calculated in patients who had a 3-month measurement would be less “good” and therefore the improvements with the switch to a metabolically neutral treatment even more pronounced.
Conclusions
In the PICASSO study, switching patients with uncontrolled hypertension to the fixed-dose combination perindopril 10 mg/indapamide 2.5 mg allowed a large percentage of patients to reach the target blood pressure value. These data, thus, provide the first evidence from a large group of patients that the high dose of the fixed-dose combination of perindopril 10 mg/indapamide 2.5 mg can reduce blood pressure in a large number of patients, including difficult-to-treat diabetic patients, while remaining metabolically improved, safe and well tolerated.
Acknowledgements
We would like to thank Hélène Dassule, PhD for her editorial support. In addition to Professor Farsang (principal investigator), the PICASSO investigator group included Bela Malomvolgyi, MD (medical advisor) and Norbert Habony, MD (coordinator).
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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