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Control of blood pressure in hypertensive patients on combination therapy
Med Clin (Barc). 2015;144(4):145–150
www.elsevier.es/medicinaclinica
Original article
Control of blood pressure in hypertensive patients on combination therapy夽 Alejandro de la Sierra a,∗ , Anna Oliveras b , Pedro Armario c , Silvia Lucas d , on behalf of the investigators of the COMBICONTROL study♦ a
Servicio de Medicina Interna, Hospital Mutua Terrassa, Universidad de Barcelona, Barcelona, Spain Servicio de Nefrología, Hospital del Mar, Barcelona, Spain c Área de Enfermedades Cardiovasculares, Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain d Departamento Médico, Menarini, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 21 June 2013 Accepted 26 September 2013 Available online 21 October 2015 Keywords: Hypertension Blood pressure control Microalbuminuria Drug combinations
a b s t r a c t Background and aim: The impact of antihypertensive treatment on blood pressure (BP) control is fairly unknown. The aim of the study was to evaluate the degree of BP control and its relationship with treatment-related factors in hypertensive patients treated with two or three agents and attended in referral units. Patients and methods: We studied 1337 hypertensive subjects (41% women) with a mean age (SD) of 63 (12) years, who were receiving two or three antihypertensive drugs. The degree of BP control was estimated in a single visit by the proportion of patients with BP below 140/90 mmHg. Results: BP was controlled in 767 patients (57%). Lack of BP control was related to older age (12% risk for each 10-year increase) and the presence of microalbuminuria (64% risk increase). In those treated with two agents, BP control was 61%, without differences between those treated with fixed-drug or free combinations. BP control in those treated with three agents was 55%, higher in those receiving three agents in a fixed-drug combination (68%) compared with those on three agents administered separately (52%; p = 0.025). Drug classes used in combinations did not influence the degree of BP control. Conclusions: The degree of BP control in patients treated with two or three agents is 57%. Microalbuminuria is related to a lack of BP control. In those receiving three agents, the use of fixed-drug combinations is associated with better BP control. ˜ S.L.U. All rights reserved. © 2013 Elsevier Espana,
Control de la presión arterial en pacientes en tratamiento con terapia combinada r e s u m e n Palabras clave: Hipertensión arterial Control de la presión arterial Oligoalbuminuria Asociaciones farmacológicas
Fundamento y objetivo: El impacto del tratamiento antihipertensivo sobre el control de la presión arterial (PA) es poco conocido. El objetivo del estudio ha sido examinar el grado de control de la PA y su relación con aspectos derivados del tratamiento en hipertensos tratados con 2 o 3 fármacos y atendidos en unidades hospitalarias. Pacientes y método: Se han estudiado 1.337 hipertensos (41% mujeres) con una edad media (DE) de 63 ˜ (12) anos, en tratamiento con 2 o 3 fármacos antihipertensivos. El grado de control se ha estimado en una única visita, calculando la proporción de pacientes con cifras inferiores a 140/90 mmHg. Resultados: Un total de 767 pacientes (57%) tenían las cifras de PA controladas. El riesgo de mal control ˜ tensional se incrementaba con la edad (12% para cada 10 anos) y con la presencia de oligoalbuminuria (64% de incremento). En los tratados con 2 fármacos, el grado de control fue del 61%, sin diferencias entre combinaciones fijas o libres. Los tratados con 3 fármacos presentaban tasas de control del 55%, mayores en
夽 Please cite this article as: de la Sierra A, Oliveras A, Armario P, Lucas S, en representación de los investigadores del estudio COMBICONTROL. Control de la presión arterial en pacientes en tratamiento con terapia combinada. Med Clin (Barc). 2015;144:145–150. ∗ Corresponding author. ♦
E-mail address: [email protected] (A. de la Sierra). The names of the study COMBICONTROL investigators can be found in Annex 1.
˜ S.L.U. All rights reserved. 2387-0206/© 2013 Elsevier Espana,
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los que recibían una asociación fija de los 3 antihipertensivos (68%) frente a los 3 fármacos por separado (52%; p = 0,025). Los principios farmacológicos utilizados en las combinaciones no influyeron en el grado de control. Conclusiones: El 57% de los pacientes en tratamiento con 2 o 3 antihipertensivos tiene sus cifras de presión controladas. La presencia de oligoalbuminuria se asocia al mal control. En los tratados con 3 fármacos, la utilización de asociaciones fijas se asocia con mayor control. ˜ S.L.U. Todos los derechos reservados. © 2013 Elsevier Espana,
Introduction The main problem in the treatment of high blood pressure (HBP) is that a significant part of the treated population does not manage to keep their blood pressure (BP) figures below therapeutic objectives, frequently set at values lower than 140/90 mmHg.1 Though cooperative data is scarce, heterogeneous, and not always contemporary, global figures seem to set BP control below 50%.2 In Spain, data on the progression of control is somewhat contradictory. Thus, studies conducted on both the general population randomly selected from the census3–5 and patients from primary care consults,6–9 seem to show some improvement regarding control rates, which would exceed 50%. However, studies conducted in reference units, where strict BP measurement is apparently more homogeneous, show certain stagnation, with 2 similar studies conducted 8 years apart that demonstrate a prevalence of 42% in both instances.10,11 This tendency towards stagnation would match an independent review of most of the studies published in the last decade, which included hypertensive Spanish patients, but with heterogeneous characteristics.12 Some studies that have assessed BP control in the treated hypertensive population have outlined patient characteristics associated with poor BP control. Female sex, obesity, and the co-existence of other risk factors, such as smoking, dyslipidaemia or diabetes, are all factors associated with a greater resistance to treatment.11,13 On the other hand, there is practically no evidence on the impact that treatment (in particular, the drugs used and their possible combinations) has on the control of BP figures. Though it is believed that inadequate therapeutic adherence, clinical inertia, and the poor use of pharmacological combinations may affect the lack of control,14 there is no data as to whether the use of fixed or free combinations, as well as the kinds of drugs used in those combinations, may or may not have an impact on attaining control figures. In that regard, various international guidelines support the use of combinations that are considered preferential, though the heterogeneity of said recommendations is evident.1,15–17 In this study, we assessed the degree of control in a cohort of patients selected because they received an antihypertensive pharmacological treatment with 2 or 3 combined drugs. Our objectives were especially focused on the characteristics of said treatment (fixed or free combinations, as well as the kind of drugs used) and its impact on control. Likewise, we analysed the patient characteristics that correlated with the lack of blood pressure control. Patients and method Patient selection This study involved 1,337 hypertensive male and female patients over the age of 18 who were selected consecutively in 2012 from 36 high blood pressure/vascular risk hospital units located in 12 autonomous communities in Spain. The inclusion criteria were the presence of HBP (defined by at least 3 separate measurements with figures equal to or higher than 140 and/or 90 mmHg), a minimum follow-up of 6 months conducted by the investigator or the pertinent unit and an antihypertensive pharmacological treatment
consisting of 2 or 3 antihypertensive drugs in a fixed or free combination during a minimum of 3 months before data collection. Design and method The study was authorised by the clinical research ethics committees of the participating centres. Once informed consent was obtained, the patients’ clinical data was collected from their previous medical history or by means of a direct questionnaire and clinical examination. The variables collected were age, gender, length of HBP, family history of premature cardiovascular disease, weight, size and body mass index calculation (obesity defined by a body mass index ≥30 kg/m2 ), waist perimeter (abdominal obesity defined by values over 102 cm in male patients and 88 cm in female patients), smoking (active consumption of cigarettes or other tobacco products) and history of diabetes (blood sugar levels >125 mg/dL or treatment with antidiabetic drugs) or cardiovascular disease (coronary disease, cerebrovascular disease, heart failure, peripheral arterial disease and progressed retinopathy). BP was determined by means of a mercury sphygmomanometer or a validated electronic oscillometric device, according to the Spanish Society of Hypertension1 recommendations. We also recorded antihypertensive treatment (number of drugs) as well as the pharmacological substances used and combination type (fixed or free, in patients with a 2-drug treatment; fixed, free or mixed, the latter being defined as a 2-drug fixed combination and a third separate drug, in patients with a 3-drug treatment). Basic blood test data was collected and the presence of renal disease was assessed by serum creatinine, urinary excretion of albumin in a random urine sample corrected by creatinine, creatinine clearance calculated based on the Cockroft and Gault formula18 and glomerular filtrate estimated by means of the simplified Modification of Diet in Renal Disease formula.19 All data should have been no older than 6 months. Statistical analysis Data are expressed by means (standard deviation [SD]) for normally distributed continuous variables, by median (interquartile range) for continuous variables with non-Gaussian distribution, or by frequencies and percentages for categorical variables. Differences among controlled or non-controlled patients were analysed by means of bilateral hypothesis tests with the t-Student test, the Mann–Whitney non-parametric test, or chi-square test, as appropriate. The analysis of 3 groups used the Cochran–Armitage statistic (tendency test). A logistic regression analysis (stepwise forward method) was conducted with the variables that showed a significant or nearly significant difference (p < 0.1) in the simple analysis. Results Degree of blood pressure control The study involved a total of 1,337 patients, 785 male patients and 552 female patients (41.3%), with a mean age of 63 (12) years. Clinical characteristics are shown in Table 1.
A. de la Sierra et al. / Med Clin (Barc). 2015;144(4):145–150 Table 1 General characteristics of the series. Age, years Sex M/F Weight, kg BMI, kg/m2 Waist perimeter, cm Male patients Female patients SBP, mmHg DBP, mmHg Length of HBP, years Family history of early CVD Smokers Dyslipidaemia Diabetes Coronary disease Cerebrovascular disease Heart failure Peripheral arteriopathy Progressed retinopathya Blood sugar levels, mg/dL Creatinine, mg/dL Creatinine clearance, ml/minb eGF, ml/min/1.73 m2 c eGF <60 ml/min/1.73 m2 Total cholesterol, mg/dL Triglycerides, mg/dL Urinary excretion of albumin, mg/g Oligoalbuminuria/Urine protein
63.2 (12.0) 785 (58.7%)/552 (41.3%) 81.3 (14.7) 30.0 (4.7) 105.0 (10.4) 98.8 (11.5) 137.2 (17.1) 78.9 (10.6) 11 [6–19] 231 (17.3%) 158 (11.8%) 925 (69.2%) 473 (35.4%) 191 (14.3%) 170 (12.7%) 62 (4.6%) 149 (11.1%) 38 (2.8%) 113 (33) 1.07 (0.43) 82 [60–108] 76 [59–93] 355 (26.8%) 186 (36) 130 (79) 13 [5–45] 293 (23.9%)/110 (9%)
CVD: cardiovascular disease; eGF: estimated glomerular filtrate; HBP: high blood pressure; BMI: body mass index; DBP: diastolic blood pressure; SBP: systolic blood pressure; F: female patient; M: male patient. Values expressed by means of their mean (standard deviation), median (interquartile range) or frequency (%). a Grades III or IV of the Keith-Wagener classification. b Calculated by means of the Cockroft-Gault formula.18 c Calculated by means of the simplified formula of Modification of Diet in Renal Disease.19
A total of 767 patients (57.4%) had BP figures below 140/90 mmHg and could be considered controlled. When BP control was analysed with stricter criteria, lower control rates were observed. Thus, the grade of control expressed in figures lower than 140/90 mmHg, except for patients with diabetes or chronic renal disease (figures lower than 130/80 mmHg), was 45% (597 patients). If figures lower than 130/80 mmHg were also applied to
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patients with established cardiovascular disease (criterion in force when the study was designed16 ), the degree of control was 40.5% (538 patients). Differences among patients with controlled or non-controlled blood pressure Table 2 shows the clinical differences among patients who presented figures lower than 140/90 mmHg (controlled patients), or equal to or higher than said values (non-controlled patients). Patients who did not achieve BP control were older (64.3 vs 62.4 years; p = 0.005) and had a greater prevalence of obesity (49.1 vs 41.5%; p = 0.006) and diabetes (39.6 compared to 32.2%; p = 0.005). Regarding organic lesions, though no significant differences were observed regarding creatinine figures or renal function estimators (creatinine clearance and estimated glomerular filtration rate), urinary excretion of albumin was significantly higher (medians of 20 compared to 11 mg/g; p < 0.001) as was the prevalence of oligoalbuminuria (figures above 22 mg/g in male patients and 31 mg/g in female patients), which led to 40.5% in non-controlled patients, compared to 29.2% in controlled patients (p < 0.001). In a logistic regression analysis which included independent variables whose difference was below 0.1 (age, obesity, abdominal obesity, diabetes, dyslipidaemia and oligoalbuminuria), only age (multivariate odds ratio [OR] every 10 years 1.12; 95% confidence interval [95% CI] 1.02–1.22; p = 0.0172) and the presence of oligoalbuminuria (multivariate OR 1.64; 95% CI 1.29–2.09; p < 0.001) were associated with the lack of blood pressure control. Correlation between antihypertensive treatment and blood pressure control A total of 531 patients (39.7%) received antihypertensive treatment with 2 drugs, while 806 patients (60.3%) were treated with 3 antihypertensive drugs. Table 3 shows the pharmacological groups used. As can be observed, the angiotensin receptor antagonists (69.8%), diuretics (67.5%) and calcium antagonists (62.5%) were, by far, the most commonly used pharmacological groups. As for molecules, hydrochlorothiazide accounted for 63.8% of all diuretics, amlodipine represented 63.2% of all calcium antagonists and enalapril accounted for 56% of angiotensin-converting enzyme (ACE) inhibitors. The most commonly used beta-blocker was
Table 2 Clinical differences among patients with controlled blood pressure figures (<140/90 mmHg) and non-controlled patients. Parameter
Controlled (No. = 767)
Non-controlled (No. = 570)
p
Age, years Sex, female patients % BMI, kg/m2 Obesity, % Abdominal obesity, % Length, years Early FHCVD, % Smokers, % Diabetes, % Dyslipidaemia, % Blood sugar levels, mg/dL Creatinine, mg/dL Creatinine clearance, ml/min eGF, ml/min/1.73 m2 eGF <60 ml/min/1.73 m2 Total cholesterol, mg/dL Triglycerides, mg/dL UEA, mg/g Oligoalbuminuria, % CVD, %
62.4 ± 12 40.5 29.8 ± 4.8 41.5 59.7 13.1 ± 9.1 17.1 11.7 32.2 67.3 111 ± 33 1.06 ± 0.4 87.3 ± 38.1 76.8 ± 26.1 25.6 184 ± 37 127 ± 88 11 [4.1–33] 29.2 31.9
64.3 ± 12 42.3 30.3 ± 4.5 49.1 69.3 13.7 ± 9.2 17.5 11.9 39.6 71.8 116 ± 34 1.08 ± 0.5 86.6 ± 39.4 76.4 ± 33.1 28.5 189 ± 35 134 ± 66 19.8 [6–56] 40.5 31.1
0.005 0.524 0.005 0.006 0.081 0.285 0.409 0.830 0.005 0.079 0.014 0.585 0.596 0.332 0.241 0.010 0.022 <0.001 <0.001 0.729
FHCVD: family history of cardiovascular disease; CVD: cardiovascular disease; UEA: urinary excretion of albumin; eGF: estimated glomerular filtrate; BMI: body mass index. Values expressed by means of their mean ± standard deviation or median (interquartile range).
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Table 3 Most commonly used antihypertensive drug groups. Group
Number of patients
% of patients
ARA-2 Diuretics Calcium antagonists Beta blockers ACE inhibitors Alpha blockers Renin inhibitors Other drugs
933 903 835 328 298 121 25 6
69.8 67.5 62.5 24.5 22.3 9.1 1.9 0.5
ARA-2: angiotensin receptor antagonists 2; ACEI: angiotensin converting enzyme inhibitors.
bisoprolol (44.9%), while the most commonly used angiotensin receptor antagonists (ARA-2) were olmesartan and valsartan (29.8% and 25.6%, respectively). In patients treated with 2 drugs, the combination type was free in 54.6% of cases and fixed in 45.4% of cases. The most frequent combinations were ARA-2 and calcium antagonists (31.8%), ARA-2 and diuretics (28.4%), ACE inhibitors and diuretics (9.8%) and ACE inhibitors and calcium antagonists (7.7%). In patients treated with 3 drugs, only 8.4% received a fixed combination of the 3 drugs; 53.7% took 2 drugs in fixed combination and a third drug in a free fashion, and 37.8% received 3 separate drugs. The most frequent combinations were ARA-2, calcium antagonists and diuretics (41.7%), ACE inhibitors, calcium antagonists and diuretics (10%) and ARA-2, betablockers and diuretics (9.2%). 60.8% of patients with dual treatment and 55.1% of patients treated with 3 drugs had controlled BP figures. In patients with 2 drugs, there were no significant differences regarding the degree of control among patients receiving a fixed (59.3%) or free combination (62.1%; p = 0.521). Meanwhile, in patients treated with 3 drugs the control probability showed an upward tendency from patients receiving 3 separate drugs (51.5%) to those receiving 2 in a fixed combination and a third separate drug (55.7%) and, finally, to those receiving 3 drugs in a fixed combination (67.7%; p for tendency = 0.025) (Fig. 1). In patient groups treated with 3 drugs, the influence of the combination components on BP control was also assessed. Thus, upon comparing patients who received a combination of angiotensin renin system blockers (ACE inhibitors, ARA-2 or renin inhibitors), calcium antagonists, and diuretics with those who received other kinds of combinations, no differences were seen in degree of BP control (55.7% compared to 54.5%; p = 0.730). Discussion This study, conducted in specialised centres, shows that BP control in patients treated with combinations of 2 or 3 antihypertensive drugs is 57%, using 140/90 mmHg as a cut point. Lack of BP control was associated with older patients, presence of other concomitant risk factors (such as obesity and diabetes) and oligoalbuminuria. The latter was the most relevant factor and was associated with lack of control even in a multivariate adjustment. Regarding the specific aspects arising from the treatment, the use of fixed or free combinations does not modify the control rate in patients treated with 2 drugs, although it does have an effect in those treated with 3 drugs. Thus, the tendency towards better control correlated with fixed doses of the 3 components. The pharmacological groups used did not have a significant impact on the degree of control. The lack of control of BP figures is the main problem for attaining the expected benefits related to antihypertensive treatment. The results of this study seem to show improvements over other previously published studies, although the cohort is limited to patients treated with 2 or 3 drugs. Therefore, the exclusion of a patient group
treated with more than 3 drugs, usually with very low control rates, or of patients with monotherapy, among whom there may be a greater therapeutic inertia, may have led to overestimated control rate results. However, it seems logical to think that there has been a growing awareness of the need for control over time and, therefore, a growing therapeutic effort. That would be in line with the results obtained for the general population3–5 or for primary care patients,6–9 where there has actually been an improvement during the last decade. This study focused on the factors associated with the lack of control, including those related to patients and those specifically related to the treatment. As to the first, older age and related risk factors (obesity, diabetes and lipid profile changes) are all associated with a lower probability of attaining control. However, the most relevant factor that minimises the effect of all the other factors is the presence of oligoalbuminuria, which increases the risk of poor control by 64%. This is an innovative discovery, which had not been described up to now. In previous studies, there was no report of oligoalbuminuria or, upon determining it only in a small subgroup of patients, it was not included in multivariate analyses. Therefore, the latest study conducted on primary care patients8 showed a greater prevalence of oligoalbuminuria (24% compared to 16%), determined by means of the urinary excretion of albumin within 24 h in non-controlled patients. The fact that said determination was present in less than 25% of all the included patients made it impossible to adjust other factors. Similarly, in a study conducted in hospital units,11 there was greater urinary excretion of albumin in non-controlled patients. The lack of said determination in an equally high proportion of patients also made it impossible to adjust other variables. On the other hand, the main characteristic of this work is that the albumin–creatinine ratio was determined in 1,225 out of 1,337 included patients, thus allowing the inclusion of said variable in the logistic regression analysis and, therefore, making an appropriate adjustment for the remaining related variables. The results of that analysis showed that, apart from age, it was the only parameter independently associated with poor control. The importance of oligoalbuminuria as a progress marker of the effect of the treatment arises from previous studies that demonstrated its association with truly resistant HBP,20 as well as an increase in both night21 and aortic22 BP. The other aspect of this study that has not been previously analysed is the effect of the kind of treatment used and its influence on the control of BP figures. Thus, it has been said that the scarce use of antihypertensive combinations could be one of the described causes of low control rates. In this sense, an analysis of the national health surveys conducted during the last decade in the U.S.A. showed a relation between the use of combinations and the higher probability of control.23 This relation had also been demonstrated in Spain by the investigators participating in the PRESCAP study.9 In the present study, which was limited to patients already treated with combinations, we have analysed the effect of the use of fixed-dose associations, as well as the kinds of combinations used. Regarding the first aspect, the results did not show any difference in patients treated with 2 drugs, where the control rates among those with fixed or free associations were very similar. On the other hand, among patients treated with 3 drugs, control rates were higher in those receiving 3 drugs in only one tablet than in patients receiving separate drugs. Patients with a mixed regimen of 2 fixed components and a third separate drug were located in the middle position. These results were significant in a chi-square test and upon using the Cochran–Armitage statistic, which analyses the tendency in organised categories. It is clear that the essential advantage of fixed-dose associations stems from a foreseeably greater therapeutic compliance. In this sense, a recent prospective study demonstrated that, among patients starting an antihypertensive treatment with monotherapy or associations, the latter have a
A. de la Sierra et al. / Med Clin (Barc). 2015;144(4):145–150
80 Control %
62.1
59.3
60 40
Control %
80 70 60 50 40 30
149
67.7 55.7 51.5
20
20
10 0
0 C. free
C. fixed
C. free
C. mixed (2+1)
C. fixed
Fig. 1. Percentage of patients with blood pressure figures controlled based on the kind of combination used (fixed, mixed or free). Panel A: patients treated with a combination of 2 drugs. Panel B: patients treated with a combination of 3 antihypertensive drugs.
greater probability of control after one year and, among those, said control is higher in patients receiving fixed-dose associations.24 Based on our results, it seems that such effect is not as significant when a 2-drug combination is used, though it is relevant when that figure is exceeded. However, it is necessary to outline that the study was conducted on a cohort of patients treated in highly specialised and monographic units, where it is possible that the closer physician–patient relationship may lead to better compliance and better results.25 The other analysed aspect arising from the treatment was the effect of the various components used in the combinations. In the group of patients treated with 2 drugs, there were many kinds of combinations, which did not allow the performance of a comparative analysis. In the group of patients treated with 3 drugs, a paper from the European Society of Hypertension26 suggested that the most logical combination regarding the complementarity of action mechanisms would be that of an angiotensin renin system blocker, with a calcium antagonist and a diuretic. In our patients, the comparison between those who received this kind of combination and the rest of the patients showed a very similar proportion of controlled patients in both groups. This study has the limitations inherent to studies that examine the grade of control and reflect only one visit. Besides, the cohort is limited to patients with a 2 or 3 antihypertensive drug treatment, so results cannot be extrapolated to populations with more hypertensive patients. Finally, the comparative analysis among ways of treatment does not take into account the previous situations that may have led to the selection of one treatment or the other. In conclusion, the grade of control of the hypertensive population treated with a combination of 2 or 3 antihypertensive drugs in specialised units is 57%. The presence of oligoalbuminuria is the patient-related factor that is most closely related to the difficulty of reaching BP control. The use of fixed or free combinations has no impact on the grade of control of patients treated with 2 drugs, but it does affect those treated with 3 antihypertensive drugs. The use of a fixed 3 drug or, at least, 2 drug combination should be favourable.
Annex 1. Investigators of the COMBINCONTROL study Jaume Almirall; Hospital Parc Taulí (Sabadell, Barcelona). Pedro Armario; Hospital Moisés Broggi (Sant Joan Despí, Barcelona). Jesús Arteaga; Hospital de Navarra (Pamplona). José M. Bonet; Hospital Germans Trías i Pujol (Badalona, Barcelona). Francesca Calero; Fundación Puigvert (Barcelona). Carlos Calvo; Hospital ˜ General de Santiago (Santiago de Compostela, A Coruna). Josep Closas; Hospital de Viladecans (Viladecans, Barcelona). Antonio Coca; Hospital Clínico (Barcelona). Alejandro de la Sierra; Hospital Mutua Terrassa (Terrassa, Barcelona). Eugenia Espinel; Hospital Vall d’Hebrón (Barcelona). Vicente Esteve; Hospital de Terrassa (Terrassa, Barcelona). Ángela Felip; Hospital de Mataró (Mataró, Barcelona). Francisco Fernández-Vega; Hospital Central de Asturias (Oviedo). Jacinto Fernández; Hospital Reina Sofía (Murcia). Josep María Galcerán; Fundación Altahia (Manresa, Barcelona). Juan García-Puig; Hospital de la Paz (Madrid). Olga González-Albarrán; Hospital Ramón y Cajal (Madrid). Manuel Gorostidi; Hospital Central de Asturias (Oviedo). José L. Górriz; Hospital Doctor Peset (Valencia). Antonio Grillo; Hospital de Valme (Sevilla). Pedro Horcajo; Hospital de Guadalajara (Guadalajara). Antonio Liébana; Hospital Ciudad de Jaén (Jaén). Manuel López; Hospital de Móstoles (Móstoles, Madrid). Jesús Martín; Hospital Nuestra Sra. de Sonsoles (Ávila). Francisco Martínez-Debén; Hospital A. Marcide ˜ Isabel Martínez; Hospital Galdakano (Bilbao). (El Ferrol, A Coruna). Juan D. Mediavilla; Hospital Virgen de las Nieves (Granada). Pedro Morillas; Hospital San Juan (Alicante). Javier Nieto; Hospital de Ciudad Real (Ciudad Real). Josefina Oliván; Hospital Virgen de la Macarena (Sevilla). Anna Oliveras; Hospital del Mar (Barcelona). José María Pascual; Hospital de Sagunto (Sagunto, Valencia). Alejandro Roca-Cusachs; Hospital de Sant Pau (Barcelona). Jose C. Rodríguez; Hospital Dr. Negrín (Gran Canaria). Julián Segura; Hospital 12 de Octubre (Madrid). Javier Sobrino; Hospital del Espíritu Santo (Santa Coloma de Gramanet, Barcelona). Carmen Suárez; Hospital de la Princesa (Madrid). Gerard Torres; Hospital de Santa María (Lleida). Luis Vigil; Hospital de Móstoles (Madrid).
References Funding ˜ S.A. The COMBICONTROL study was funded by Menarini Espana
Conflict of interest Alejandro de la Sierra, Anna Oliveras and Pedro Armario declare that they have received fees from Menarini S.A. for the study design and coordination, statistical plan and document writing. Silvia Lucas is an employee of Menarini S.A.
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6. Llisterri JL, Rodríguez GC, Alonso FJ, Lou S, Divisón JA, Santos JA, et al. Control ˜ atendida en atención de la presión arterial en la población hipertensa espanola primaria. Estudio PRESCAP 2002. Med Clin (Barc). 2004;122:165–71. 7. Llisterri JL, Rodríguez-Roca GC, Alonso FJ, Banegas JR, González-Sedura D, Lou S, ˜ atendida et al. Control de la presión arterial en la población hipertensa espanola en atención primaria. Estudio PRESCAP 2006. Med Clin (Barc). 2008;130:681–7. 8. Llisterri JL, Rodríguez-Roca G, Alonso FJ, Prieto MA, Banegas JR, GonzálezSegura D, et al. Control de la presión arterial en la población hipertensa ˜ asistida en Atención Primaria. Estudio PRESCAP 2010. Med Clin (Barc). espanola 2012;139:653–61. 9. Llisterri JH, Rodríguez-Roca GC, Escobar C, Alonso-Moreno FJ, Prieto MA, Barrios V, et al. Treatment and blood pressure control in Spain during 2002–2010. J Hypertens. 2012;30:2425–31. 10. Banegas JR, Segura J, Ruilope LM, Luque M, García-Robles R, Campo C, et al. Blood pressure control and physician management of hypertension in hospital hypertension units in Spain. Hypertension. 2004;43:1338–44. 11. De la Sierra A, Barrios V, González-Segura D. Control de la presión arte˜ rial en unidades hospitalarias de referencia en Espana. Med Clin (Barc). 2013;141:47–52. 12. Catala-Lopez F, Sanfelix-Gimeno G, Garcia-Torres C, Ridao M, Peiro S. Control of arterial hypertension in Spain: a systematic review and meta-analysis of 76 epidemiological studies on 341632 participants. J Hypertens. 2012;30:168–76. 13. De la Sierra A, Banegas JR, Oliveras A, Gorostidi M, Segura J, de la Cruz JJ, et al. Clinical differences between resistant hypertensives and patients treated and controlled with three or les drugs. J Hypertens. 2012;30:1211–6. 14. De la Sierra A. Blood pressure control in the hypertensive population. What else the doctor can do? J Hypertens. 2010;28:1129–30. 15. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003;289:2560–72. 16. Mancia G, de Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of
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Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105–87. National Institute for Health and Clinical Excellence (NICE). Hypertension. The clinical management of primary hypertension in adults. Clinical Guideline 127; 2011. Available from: www.nice.org.uk/guidance/CG127 [accessed 15.05.13]. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–70. Oliveras A, Armario P, Hernández-del Rey R, Arroyo JA, Poch E, Larrousse M, et al. Urinary albumin excretion is associated with true resistant hypertension. J Hum Hypertens. 2010;24:27–33. Oliveras A, Armario P, Martell-Clarós N, Ruilope LM, de la Sierra A. Urinary albumin excretion is associated with nocturnal systolic blood pressure in resistant hypertensives. Hypertension. 2011;57:556–60. Oliveras A, García-Ortiz L, Segura J, Banegas JR, Martell-Claros N, Vigil L, et al. Association between urinary albumin excretion and both central and peripheral blood pressure in subjects with insulin resistance. J Hypertens. 2012;31:103–8. Gu Q, Burt VL, Dillon CF, Yoon S. Trends in antihypertensive medication use and blood pressure control among United States adults with hypertension: the National Health and Nutrition Examination Survey, 2001 to 2010. Circulation. 2012;126:2105–14. Egan BM, Bandyopadhyay D, Shaftman SR, Wagner CS, Zhao Y, Yu-Isenberg KS. Initial monotherapy and combination therapy and hypertension control the first year. Hypertension. 2012;59:1124–31. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51:1403–19. Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121–58.
www.elsevier.es/medicinaclinica
Original article
Control of blood pressure in hypertensive patients on combination therapy夽 Alejandro de la Sierra a,∗ , Anna Oliveras b , Pedro Armario c , Silvia Lucas d , on behalf of the investigators of the COMBICONTROL study♦ a
Servicio de Medicina Interna, Hospital Mutua Terrassa, Universidad de Barcelona, Barcelona, Spain Servicio de Nefrología, Hospital del Mar, Barcelona, Spain c Área de Enfermedades Cardiovasculares, Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain d Departamento Médico, Menarini, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 21 June 2013 Accepted 26 September 2013 Available online 21 October 2015 Keywords: Hypertension Blood pressure control Microalbuminuria Drug combinations
a b s t r a c t Background and aim: The impact of antihypertensive treatment on blood pressure (BP) control is fairly unknown. The aim of the study was to evaluate the degree of BP control and its relationship with treatment-related factors in hypertensive patients treated with two or three agents and attended in referral units. Patients and methods: We studied 1337 hypertensive subjects (41% women) with a mean age (SD) of 63 (12) years, who were receiving two or three antihypertensive drugs. The degree of BP control was estimated in a single visit by the proportion of patients with BP below 140/90 mmHg. Results: BP was controlled in 767 patients (57%). Lack of BP control was related to older age (12% risk for each 10-year increase) and the presence of microalbuminuria (64% risk increase). In those treated with two agents, BP control was 61%, without differences between those treated with fixed-drug or free combinations. BP control in those treated with three agents was 55%, higher in those receiving three agents in a fixed-drug combination (68%) compared with those on three agents administered separately (52%; p = 0.025). Drug classes used in combinations did not influence the degree of BP control. Conclusions: The degree of BP control in patients treated with two or three agents is 57%. Microalbuminuria is related to a lack of BP control. In those receiving three agents, the use of fixed-drug combinations is associated with better BP control. ˜ S.L.U. All rights reserved. © 2013 Elsevier Espana,
Control de la presión arterial en pacientes en tratamiento con terapia combinada r e s u m e n Palabras clave: Hipertensión arterial Control de la presión arterial Oligoalbuminuria Asociaciones farmacológicas
Fundamento y objetivo: El impacto del tratamiento antihipertensivo sobre el control de la presión arterial (PA) es poco conocido. El objetivo del estudio ha sido examinar el grado de control de la PA y su relación con aspectos derivados del tratamiento en hipertensos tratados con 2 o 3 fármacos y atendidos en unidades hospitalarias. Pacientes y método: Se han estudiado 1.337 hipertensos (41% mujeres) con una edad media (DE) de 63 ˜ (12) anos, en tratamiento con 2 o 3 fármacos antihipertensivos. El grado de control se ha estimado en una única visita, calculando la proporción de pacientes con cifras inferiores a 140/90 mmHg. Resultados: Un total de 767 pacientes (57%) tenían las cifras de PA controladas. El riesgo de mal control ˜ tensional se incrementaba con la edad (12% para cada 10 anos) y con la presencia de oligoalbuminuria (64% de incremento). En los tratados con 2 fármacos, el grado de control fue del 61%, sin diferencias entre combinaciones fijas o libres. Los tratados con 3 fármacos presentaban tasas de control del 55%, mayores en
夽 Please cite this article as: de la Sierra A, Oliveras A, Armario P, Lucas S, en representación de los investigadores del estudio COMBICONTROL. Control de la presión arterial en pacientes en tratamiento con terapia combinada. Med Clin (Barc). 2015;144:145–150. ∗ Corresponding author. ♦
E-mail address: [email protected] (A. de la Sierra). The names of the study COMBICONTROL investigators can be found in Annex 1.
˜ S.L.U. All rights reserved. 2387-0206/© 2013 Elsevier Espana,
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los que recibían una asociación fija de los 3 antihipertensivos (68%) frente a los 3 fármacos por separado (52%; p = 0,025). Los principios farmacológicos utilizados en las combinaciones no influyeron en el grado de control. Conclusiones: El 57% de los pacientes en tratamiento con 2 o 3 antihipertensivos tiene sus cifras de presión controladas. La presencia de oligoalbuminuria se asocia al mal control. En los tratados con 3 fármacos, la utilización de asociaciones fijas se asocia con mayor control. ˜ S.L.U. Todos los derechos reservados. © 2013 Elsevier Espana,
Introduction The main problem in the treatment of high blood pressure (HBP) is that a significant part of the treated population does not manage to keep their blood pressure (BP) figures below therapeutic objectives, frequently set at values lower than 140/90 mmHg.1 Though cooperative data is scarce, heterogeneous, and not always contemporary, global figures seem to set BP control below 50%.2 In Spain, data on the progression of control is somewhat contradictory. Thus, studies conducted on both the general population randomly selected from the census3–5 and patients from primary care consults,6–9 seem to show some improvement regarding control rates, which would exceed 50%. However, studies conducted in reference units, where strict BP measurement is apparently more homogeneous, show certain stagnation, with 2 similar studies conducted 8 years apart that demonstrate a prevalence of 42% in both instances.10,11 This tendency towards stagnation would match an independent review of most of the studies published in the last decade, which included hypertensive Spanish patients, but with heterogeneous characteristics.12 Some studies that have assessed BP control in the treated hypertensive population have outlined patient characteristics associated with poor BP control. Female sex, obesity, and the co-existence of other risk factors, such as smoking, dyslipidaemia or diabetes, are all factors associated with a greater resistance to treatment.11,13 On the other hand, there is practically no evidence on the impact that treatment (in particular, the drugs used and their possible combinations) has on the control of BP figures. Though it is believed that inadequate therapeutic adherence, clinical inertia, and the poor use of pharmacological combinations may affect the lack of control,14 there is no data as to whether the use of fixed or free combinations, as well as the kinds of drugs used in those combinations, may or may not have an impact on attaining control figures. In that regard, various international guidelines support the use of combinations that are considered preferential, though the heterogeneity of said recommendations is evident.1,15–17 In this study, we assessed the degree of control in a cohort of patients selected because they received an antihypertensive pharmacological treatment with 2 or 3 combined drugs. Our objectives were especially focused on the characteristics of said treatment (fixed or free combinations, as well as the kind of drugs used) and its impact on control. Likewise, we analysed the patient characteristics that correlated with the lack of blood pressure control. Patients and method Patient selection This study involved 1,337 hypertensive male and female patients over the age of 18 who were selected consecutively in 2012 from 36 high blood pressure/vascular risk hospital units located in 12 autonomous communities in Spain. The inclusion criteria were the presence of HBP (defined by at least 3 separate measurements with figures equal to or higher than 140 and/or 90 mmHg), a minimum follow-up of 6 months conducted by the investigator or the pertinent unit and an antihypertensive pharmacological treatment
consisting of 2 or 3 antihypertensive drugs in a fixed or free combination during a minimum of 3 months before data collection. Design and method The study was authorised by the clinical research ethics committees of the participating centres. Once informed consent was obtained, the patients’ clinical data was collected from their previous medical history or by means of a direct questionnaire and clinical examination. The variables collected were age, gender, length of HBP, family history of premature cardiovascular disease, weight, size and body mass index calculation (obesity defined by a body mass index ≥30 kg/m2 ), waist perimeter (abdominal obesity defined by values over 102 cm in male patients and 88 cm in female patients), smoking (active consumption of cigarettes or other tobacco products) and history of diabetes (blood sugar levels >125 mg/dL or treatment with antidiabetic drugs) or cardiovascular disease (coronary disease, cerebrovascular disease, heart failure, peripheral arterial disease and progressed retinopathy). BP was determined by means of a mercury sphygmomanometer or a validated electronic oscillometric device, according to the Spanish Society of Hypertension1 recommendations. We also recorded antihypertensive treatment (number of drugs) as well as the pharmacological substances used and combination type (fixed or free, in patients with a 2-drug treatment; fixed, free or mixed, the latter being defined as a 2-drug fixed combination and a third separate drug, in patients with a 3-drug treatment). Basic blood test data was collected and the presence of renal disease was assessed by serum creatinine, urinary excretion of albumin in a random urine sample corrected by creatinine, creatinine clearance calculated based on the Cockroft and Gault formula18 and glomerular filtrate estimated by means of the simplified Modification of Diet in Renal Disease formula.19 All data should have been no older than 6 months. Statistical analysis Data are expressed by means (standard deviation [SD]) for normally distributed continuous variables, by median (interquartile range) for continuous variables with non-Gaussian distribution, or by frequencies and percentages for categorical variables. Differences among controlled or non-controlled patients were analysed by means of bilateral hypothesis tests with the t-Student test, the Mann–Whitney non-parametric test, or chi-square test, as appropriate. The analysis of 3 groups used the Cochran–Armitage statistic (tendency test). A logistic regression analysis (stepwise forward method) was conducted with the variables that showed a significant or nearly significant difference (p < 0.1) in the simple analysis. Results Degree of blood pressure control The study involved a total of 1,337 patients, 785 male patients and 552 female patients (41.3%), with a mean age of 63 (12) years. Clinical characteristics are shown in Table 1.
A. de la Sierra et al. / Med Clin (Barc). 2015;144(4):145–150 Table 1 General characteristics of the series. Age, years Sex M/F Weight, kg BMI, kg/m2 Waist perimeter, cm Male patients Female patients SBP, mmHg DBP, mmHg Length of HBP, years Family history of early CVD Smokers Dyslipidaemia Diabetes Coronary disease Cerebrovascular disease Heart failure Peripheral arteriopathy Progressed retinopathya Blood sugar levels, mg/dL Creatinine, mg/dL Creatinine clearance, ml/minb eGF, ml/min/1.73 m2 c eGF <60 ml/min/1.73 m2 Total cholesterol, mg/dL Triglycerides, mg/dL Urinary excretion of albumin, mg/g Oligoalbuminuria/Urine protein
63.2 (12.0) 785 (58.7%)/552 (41.3%) 81.3 (14.7) 30.0 (4.7) 105.0 (10.4) 98.8 (11.5) 137.2 (17.1) 78.9 (10.6) 11 [6–19] 231 (17.3%) 158 (11.8%) 925 (69.2%) 473 (35.4%) 191 (14.3%) 170 (12.7%) 62 (4.6%) 149 (11.1%) 38 (2.8%) 113 (33) 1.07 (0.43) 82 [60–108] 76 [59–93] 355 (26.8%) 186 (36) 130 (79) 13 [5–45] 293 (23.9%)/110 (9%)
CVD: cardiovascular disease; eGF: estimated glomerular filtrate; HBP: high blood pressure; BMI: body mass index; DBP: diastolic blood pressure; SBP: systolic blood pressure; F: female patient; M: male patient. Values expressed by means of their mean (standard deviation), median (interquartile range) or frequency (%). a Grades III or IV of the Keith-Wagener classification. b Calculated by means of the Cockroft-Gault formula.18 c Calculated by means of the simplified formula of Modification of Diet in Renal Disease.19
A total of 767 patients (57.4%) had BP figures below 140/90 mmHg and could be considered controlled. When BP control was analysed with stricter criteria, lower control rates were observed. Thus, the grade of control expressed in figures lower than 140/90 mmHg, except for patients with diabetes or chronic renal disease (figures lower than 130/80 mmHg), was 45% (597 patients). If figures lower than 130/80 mmHg were also applied to
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patients with established cardiovascular disease (criterion in force when the study was designed16 ), the degree of control was 40.5% (538 patients). Differences among patients with controlled or non-controlled blood pressure Table 2 shows the clinical differences among patients who presented figures lower than 140/90 mmHg (controlled patients), or equal to or higher than said values (non-controlled patients). Patients who did not achieve BP control were older (64.3 vs 62.4 years; p = 0.005) and had a greater prevalence of obesity (49.1 vs 41.5%; p = 0.006) and diabetes (39.6 compared to 32.2%; p = 0.005). Regarding organic lesions, though no significant differences were observed regarding creatinine figures or renal function estimators (creatinine clearance and estimated glomerular filtration rate), urinary excretion of albumin was significantly higher (medians of 20 compared to 11 mg/g; p < 0.001) as was the prevalence of oligoalbuminuria (figures above 22 mg/g in male patients and 31 mg/g in female patients), which led to 40.5% in non-controlled patients, compared to 29.2% in controlled patients (p < 0.001). In a logistic regression analysis which included independent variables whose difference was below 0.1 (age, obesity, abdominal obesity, diabetes, dyslipidaemia and oligoalbuminuria), only age (multivariate odds ratio [OR] every 10 years 1.12; 95% confidence interval [95% CI] 1.02–1.22; p = 0.0172) and the presence of oligoalbuminuria (multivariate OR 1.64; 95% CI 1.29–2.09; p < 0.001) were associated with the lack of blood pressure control. Correlation between antihypertensive treatment and blood pressure control A total of 531 patients (39.7%) received antihypertensive treatment with 2 drugs, while 806 patients (60.3%) were treated with 3 antihypertensive drugs. Table 3 shows the pharmacological groups used. As can be observed, the angiotensin receptor antagonists (69.8%), diuretics (67.5%) and calcium antagonists (62.5%) were, by far, the most commonly used pharmacological groups. As for molecules, hydrochlorothiazide accounted for 63.8% of all diuretics, amlodipine represented 63.2% of all calcium antagonists and enalapril accounted for 56% of angiotensin-converting enzyme (ACE) inhibitors. The most commonly used beta-blocker was
Table 2 Clinical differences among patients with controlled blood pressure figures (<140/90 mmHg) and non-controlled patients. Parameter
Controlled (No. = 767)
Non-controlled (No. = 570)
p
Age, years Sex, female patients % BMI, kg/m2 Obesity, % Abdominal obesity, % Length, years Early FHCVD, % Smokers, % Diabetes, % Dyslipidaemia, % Blood sugar levels, mg/dL Creatinine, mg/dL Creatinine clearance, ml/min eGF, ml/min/1.73 m2 eGF <60 ml/min/1.73 m2 Total cholesterol, mg/dL Triglycerides, mg/dL UEA, mg/g Oligoalbuminuria, % CVD, %
62.4 ± 12 40.5 29.8 ± 4.8 41.5 59.7 13.1 ± 9.1 17.1 11.7 32.2 67.3 111 ± 33 1.06 ± 0.4 87.3 ± 38.1 76.8 ± 26.1 25.6 184 ± 37 127 ± 88 11 [4.1–33] 29.2 31.9
64.3 ± 12 42.3 30.3 ± 4.5 49.1 69.3 13.7 ± 9.2 17.5 11.9 39.6 71.8 116 ± 34 1.08 ± 0.5 86.6 ± 39.4 76.4 ± 33.1 28.5 189 ± 35 134 ± 66 19.8 [6–56] 40.5 31.1
0.005 0.524 0.005 0.006 0.081 0.285 0.409 0.830 0.005 0.079 0.014 0.585 0.596 0.332 0.241 0.010 0.022 <0.001 <0.001 0.729
FHCVD: family history of cardiovascular disease; CVD: cardiovascular disease; UEA: urinary excretion of albumin; eGF: estimated glomerular filtrate; BMI: body mass index. Values expressed by means of their mean ± standard deviation or median (interquartile range).
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Table 3 Most commonly used antihypertensive drug groups. Group
Number of patients
% of patients
ARA-2 Diuretics Calcium antagonists Beta blockers ACE inhibitors Alpha blockers Renin inhibitors Other drugs
933 903 835 328 298 121 25 6
69.8 67.5 62.5 24.5 22.3 9.1 1.9 0.5
ARA-2: angiotensin receptor antagonists 2; ACEI: angiotensin converting enzyme inhibitors.
bisoprolol (44.9%), while the most commonly used angiotensin receptor antagonists (ARA-2) were olmesartan and valsartan (29.8% and 25.6%, respectively). In patients treated with 2 drugs, the combination type was free in 54.6% of cases and fixed in 45.4% of cases. The most frequent combinations were ARA-2 and calcium antagonists (31.8%), ARA-2 and diuretics (28.4%), ACE inhibitors and diuretics (9.8%) and ACE inhibitors and calcium antagonists (7.7%). In patients treated with 3 drugs, only 8.4% received a fixed combination of the 3 drugs; 53.7% took 2 drugs in fixed combination and a third drug in a free fashion, and 37.8% received 3 separate drugs. The most frequent combinations were ARA-2, calcium antagonists and diuretics (41.7%), ACE inhibitors, calcium antagonists and diuretics (10%) and ARA-2, betablockers and diuretics (9.2%). 60.8% of patients with dual treatment and 55.1% of patients treated with 3 drugs had controlled BP figures. In patients with 2 drugs, there were no significant differences regarding the degree of control among patients receiving a fixed (59.3%) or free combination (62.1%; p = 0.521). Meanwhile, in patients treated with 3 drugs the control probability showed an upward tendency from patients receiving 3 separate drugs (51.5%) to those receiving 2 in a fixed combination and a third separate drug (55.7%) and, finally, to those receiving 3 drugs in a fixed combination (67.7%; p for tendency = 0.025) (Fig. 1). In patient groups treated with 3 drugs, the influence of the combination components on BP control was also assessed. Thus, upon comparing patients who received a combination of angiotensin renin system blockers (ACE inhibitors, ARA-2 or renin inhibitors), calcium antagonists, and diuretics with those who received other kinds of combinations, no differences were seen in degree of BP control (55.7% compared to 54.5%; p = 0.730). Discussion This study, conducted in specialised centres, shows that BP control in patients treated with combinations of 2 or 3 antihypertensive drugs is 57%, using 140/90 mmHg as a cut point. Lack of BP control was associated with older patients, presence of other concomitant risk factors (such as obesity and diabetes) and oligoalbuminuria. The latter was the most relevant factor and was associated with lack of control even in a multivariate adjustment. Regarding the specific aspects arising from the treatment, the use of fixed or free combinations does not modify the control rate in patients treated with 2 drugs, although it does have an effect in those treated with 3 drugs. Thus, the tendency towards better control correlated with fixed doses of the 3 components. The pharmacological groups used did not have a significant impact on the degree of control. The lack of control of BP figures is the main problem for attaining the expected benefits related to antihypertensive treatment. The results of this study seem to show improvements over other previously published studies, although the cohort is limited to patients treated with 2 or 3 drugs. Therefore, the exclusion of a patient group
treated with more than 3 drugs, usually with very low control rates, or of patients with monotherapy, among whom there may be a greater therapeutic inertia, may have led to overestimated control rate results. However, it seems logical to think that there has been a growing awareness of the need for control over time and, therefore, a growing therapeutic effort. That would be in line with the results obtained for the general population3–5 or for primary care patients,6–9 where there has actually been an improvement during the last decade. This study focused on the factors associated with the lack of control, including those related to patients and those specifically related to the treatment. As to the first, older age and related risk factors (obesity, diabetes and lipid profile changes) are all associated with a lower probability of attaining control. However, the most relevant factor that minimises the effect of all the other factors is the presence of oligoalbuminuria, which increases the risk of poor control by 64%. This is an innovative discovery, which had not been described up to now. In previous studies, there was no report of oligoalbuminuria or, upon determining it only in a small subgroup of patients, it was not included in multivariate analyses. Therefore, the latest study conducted on primary care patients8 showed a greater prevalence of oligoalbuminuria (24% compared to 16%), determined by means of the urinary excretion of albumin within 24 h in non-controlled patients. The fact that said determination was present in less than 25% of all the included patients made it impossible to adjust other factors. Similarly, in a study conducted in hospital units,11 there was greater urinary excretion of albumin in non-controlled patients. The lack of said determination in an equally high proportion of patients also made it impossible to adjust other variables. On the other hand, the main characteristic of this work is that the albumin–creatinine ratio was determined in 1,225 out of 1,337 included patients, thus allowing the inclusion of said variable in the logistic regression analysis and, therefore, making an appropriate adjustment for the remaining related variables. The results of that analysis showed that, apart from age, it was the only parameter independently associated with poor control. The importance of oligoalbuminuria as a progress marker of the effect of the treatment arises from previous studies that demonstrated its association with truly resistant HBP,20 as well as an increase in both night21 and aortic22 BP. The other aspect of this study that has not been previously analysed is the effect of the kind of treatment used and its influence on the control of BP figures. Thus, it has been said that the scarce use of antihypertensive combinations could be one of the described causes of low control rates. In this sense, an analysis of the national health surveys conducted during the last decade in the U.S.A. showed a relation between the use of combinations and the higher probability of control.23 This relation had also been demonstrated in Spain by the investigators participating in the PRESCAP study.9 In the present study, which was limited to patients already treated with combinations, we have analysed the effect of the use of fixed-dose associations, as well as the kinds of combinations used. Regarding the first aspect, the results did not show any difference in patients treated with 2 drugs, where the control rates among those with fixed or free associations were very similar. On the other hand, among patients treated with 3 drugs, control rates were higher in those receiving 3 drugs in only one tablet than in patients receiving separate drugs. Patients with a mixed regimen of 2 fixed components and a third separate drug were located in the middle position. These results were significant in a chi-square test and upon using the Cochran–Armitage statistic, which analyses the tendency in organised categories. It is clear that the essential advantage of fixed-dose associations stems from a foreseeably greater therapeutic compliance. In this sense, a recent prospective study demonstrated that, among patients starting an antihypertensive treatment with monotherapy or associations, the latter have a
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80 Control %
62.1
59.3
60 40
Control %
80 70 60 50 40 30
149
67.7 55.7 51.5
20
20
10 0
0 C. free
C. fixed
C. free
C. mixed (2+1)
C. fixed
Fig. 1. Percentage of patients with blood pressure figures controlled based on the kind of combination used (fixed, mixed or free). Panel A: patients treated with a combination of 2 drugs. Panel B: patients treated with a combination of 3 antihypertensive drugs.
greater probability of control after one year and, among those, said control is higher in patients receiving fixed-dose associations.24 Based on our results, it seems that such effect is not as significant when a 2-drug combination is used, though it is relevant when that figure is exceeded. However, it is necessary to outline that the study was conducted on a cohort of patients treated in highly specialised and monographic units, where it is possible that the closer physician–patient relationship may lead to better compliance and better results.25 The other analysed aspect arising from the treatment was the effect of the various components used in the combinations. In the group of patients treated with 2 drugs, there were many kinds of combinations, which did not allow the performance of a comparative analysis. In the group of patients treated with 3 drugs, a paper from the European Society of Hypertension26 suggested that the most logical combination regarding the complementarity of action mechanisms would be that of an angiotensin renin system blocker, with a calcium antagonist and a diuretic. In our patients, the comparison between those who received this kind of combination and the rest of the patients showed a very similar proportion of controlled patients in both groups. This study has the limitations inherent to studies that examine the grade of control and reflect only one visit. Besides, the cohort is limited to patients with a 2 or 3 antihypertensive drug treatment, so results cannot be extrapolated to populations with more hypertensive patients. Finally, the comparative analysis among ways of treatment does not take into account the previous situations that may have led to the selection of one treatment or the other. In conclusion, the grade of control of the hypertensive population treated with a combination of 2 or 3 antihypertensive drugs in specialised units is 57%. The presence of oligoalbuminuria is the patient-related factor that is most closely related to the difficulty of reaching BP control. The use of fixed or free combinations has no impact on the grade of control of patients treated with 2 drugs, but it does affect those treated with 3 antihypertensive drugs. The use of a fixed 3 drug or, at least, 2 drug combination should be favourable.
Annex 1. Investigators of the COMBINCONTROL study Jaume Almirall; Hospital Parc Taulí (Sabadell, Barcelona). Pedro Armario; Hospital Moisés Broggi (Sant Joan Despí, Barcelona). Jesús Arteaga; Hospital de Navarra (Pamplona). José M. Bonet; Hospital Germans Trías i Pujol (Badalona, Barcelona). Francesca Calero; Fundación Puigvert (Barcelona). Carlos Calvo; Hospital ˜ General de Santiago (Santiago de Compostela, A Coruna). Josep Closas; Hospital de Viladecans (Viladecans, Barcelona). Antonio Coca; Hospital Clínico (Barcelona). Alejandro de la Sierra; Hospital Mutua Terrassa (Terrassa, Barcelona). Eugenia Espinel; Hospital Vall d’Hebrón (Barcelona). Vicente Esteve; Hospital de Terrassa (Terrassa, Barcelona). Ángela Felip; Hospital de Mataró (Mataró, Barcelona). Francisco Fernández-Vega; Hospital Central de Asturias (Oviedo). Jacinto Fernández; Hospital Reina Sofía (Murcia). Josep María Galcerán; Fundación Altahia (Manresa, Barcelona). Juan García-Puig; Hospital de la Paz (Madrid). Olga González-Albarrán; Hospital Ramón y Cajal (Madrid). Manuel Gorostidi; Hospital Central de Asturias (Oviedo). José L. Górriz; Hospital Doctor Peset (Valencia). Antonio Grillo; Hospital de Valme (Sevilla). Pedro Horcajo; Hospital de Guadalajara (Guadalajara). Antonio Liébana; Hospital Ciudad de Jaén (Jaén). Manuel López; Hospital de Móstoles (Móstoles, Madrid). Jesús Martín; Hospital Nuestra Sra. de Sonsoles (Ávila). Francisco Martínez-Debén; Hospital A. Marcide ˜ Isabel Martínez; Hospital Galdakano (Bilbao). (El Ferrol, A Coruna). Juan D. Mediavilla; Hospital Virgen de las Nieves (Granada). Pedro Morillas; Hospital San Juan (Alicante). Javier Nieto; Hospital de Ciudad Real (Ciudad Real). Josefina Oliván; Hospital Virgen de la Macarena (Sevilla). Anna Oliveras; Hospital del Mar (Barcelona). José María Pascual; Hospital de Sagunto (Sagunto, Valencia). Alejandro Roca-Cusachs; Hospital de Sant Pau (Barcelona). Jose C. Rodríguez; Hospital Dr. Negrín (Gran Canaria). Julián Segura; Hospital 12 de Octubre (Madrid). Javier Sobrino; Hospital del Espíritu Santo (Santa Coloma de Gramanet, Barcelona). Carmen Suárez; Hospital de la Princesa (Madrid). Gerard Torres; Hospital de Santa María (Lleida). Luis Vigil; Hospital de Móstoles (Madrid).
References Funding ˜ S.A. The COMBICONTROL study was funded by Menarini Espana
Conflict of interest Alejandro de la Sierra, Anna Oliveras and Pedro Armario declare that they have received fees from Menarini S.A. for the study design and coordination, statistical plan and document writing. Silvia Lucas is an employee of Menarini S.A.
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