http://informahealthcare.com/ceh ISSN: 1064-1963 (print), 1525-6006 (electronic) Clin Exp Hypertens, Early Online: 1–7 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10641963.2014.987395
Single-pill combination therapy in the initial treatment of marked hypertension: a propensity-matched analysis Emiliano Angeloni1, Angelo Vitaterna2, Paola Lombardo1, Michele Pirelli2, and Simone Refice1 Department of Cardiovascular Pathophysiology and Imaging, Sapienza, University of Rome, Rome, Italy and 2Department of Cardiology and Nutrition, Eurytmia Medical Center, Anagni (FR), Italy
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Abstract
Keywords
Background: Many drugs combinations are available and equally recommended for the initial treatment of patients with marked blood pressure (BP) elevation and high cardiovascular risk. Hypothesis: To investigate safety and efficacy of such combination therapies. Methods: Prospectively collected data were retrospectively reviewed, inclusion criteria were: initial singlepill combination therapy, availability of clinical and echocardiographic 6-month follow-up. Six treatment groups were identified: Enalapril 20 mg+ Hydrochlorothiazide 12.5 mg (E/H), E 20 mg + Lercanidipine 10 mg (E/L), Ramipril 2.5 mg+ H 12.5 mg (R/H), Perindopril 5 mg+ Amlodipine 5 mg (P/A), Olmesartan 40 mg+ H 12.5 mg (O/H) and Telmisartan 40 mg+ H 12.5 mg (T/H). To avoid selection bias a Propensity score (goodness of fit: c-statistic 0.78, p ¼ 0.0001) was used to select comparable cohorts of patients (n ¼ 142 each). Results: After 4 weeks of treatment BP goal was achieved by 624/852 (73.2%) patients, and adverse events were registered in 24/852 (2.8%) patients. After 6 months, 562/624 (90.1%) patients maintained the BP goal. Six-month responder rate was significantly higher in the E/L (69.0%) and P/A (68.3%) groups (p ¼ 0.05); especially among diabetics (52.0% and 51.0%, respectively; p ¼ 0.003). Patients receiving E/L (19.8 ± 3.2 mmHg) and P/A (19.9 ± 4.6 mmHg) showed greater reductions of diastolic BP (p ¼ 0.03); whereas reductions of systolic BP were similar between treatment groups (p ¼ 0.46). Echocardiographic follow-up revealed greater left ventricular reverse remodeling among patients receiving ACE-inhibitors (E/L, R/H, E/H and P/A), but this trend did not reach statistical significance. Conclusions: Single-pill fixed-dose combination therapies are highly effective and safe in the study settings. Best clinical and echocardiographic outcomes were noted among patients receiving E/L, R/H and P/A.
Blood pressure control, combination therapy, hypertension
Introduction High blood pressure (HBP) is the most common among cardiovascular risk factors. Recent literature reports nearly 80 million US adults having HBP, with a prevalence greater than 30%, increasing up to 70% among adults aged at least 65 years (1). Among hypertensive adults, 82% are aware of their condition and 75% are of using antihypertensive medication, but only 53% of those with documented hypertension have their condition controlled to target levels (1). HBP-related mortality ranges between 16% and 19% with an estimated direct and indirect cost of 51 billion US dollars (1,2). In every age or ethnicity subgroup, BP bears an independent continuous relationship with the incidence of several CV events (stroke, myocardial infarction, sudden death, heart failure and peripheral artery disease) and with the incidence of end-stage renal disease as well (3). As a consequence, hypertension control results in a 35% risk reduction of stroke, and in a 20% risk reduction of myocardial infarction (4). Correspondence: Emiliano Angeloni, M.D., Sapienza, Universita` di Roma, Policlinico Sant’Andrea, Via di Grottarossa 1035, 00189 Rome, Italy. Tel: +39 06 3377 5310. Fax: +39 06 3377 5483. E-mail: [email protected]
History Received 29 September 2014 Accepted 29 October 2014 Published online 11 December 2014
Current European guidelines (3) confirmed that diuretics, beta-blockers, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers are all suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in some combinations, with few different indications based on clinical characteristics. Furthermore, cited guidelines (3) recommend combination therapy for the initial treatment of marked HBP (systolic BP4160 mmHg, diastolic BP4100 mmHg) or in case of patients with high total cardiovascular risk (as based on clinical evaluation of risk factors, comorbidities and organ damage). The latter because monotherapy was found to be ineffective in achieving BP goal in the majority of patients, and particularly among high-risk patients who would need stricter BP control (3,5). In addition, it has been proven that single-pill combination therapies are more efficacious than the individual components and that improve patient adherence to therapy (5). With the exception of ACE inhibitor (ACEi) + angiotensin receptor blocker (ARB), all the other combinations of above mentioned drugs have been found to be effective in the control of HBP (5,6), although current guidelines (3) recognized the following as preferred combinations: ACEi + calcium channel
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blocker (CCB), ARB + thiazide diuretic (THZ), ACEi + THZ, ARB + CCB and THZ + CCB. Along with these, the ASCOTBPLA trial (6) founded a superiority of the combinations ACE inhibitor + calcium antagonist, and angiotensin receptor blocker + diuretic versus the association beta-blocker + diuretic; whereas the ACCOMPLISH trial (7), demonstrated the superiority of the ACE inhibitor + calcium antagonist in comparison with ACE inhibitor + thiazide diuretic. Aim of the present study was to investigate safety and efficacy of different single-pill combination therapies in the initial treatment of patients with marked hypertension and/or high cardiovascular risk.
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Methods This study, performed accordingly to the declaration of Helsinki, was reviewed and approved by local Institutional Review Board and a waiver of consent was granted. Patients and variables A total of 2762 patients with HBP were referred to our clinic (Eurytmia Medical Center, Anagni) between March 2013 and March 2014. Patients’ data were prospectively collected in an electronic database and were retrospectively reviewed for the purpose of the present study. Roughly half of such patients (n ¼ 1453 or 52.6%) met inclusion criteria: marked hypertension, high cardiovascular risk, initial single-pill combination therapy, availability of clinical and echocardiographic 6-months follow-up. Cardiovascular risk was assessed accordingly to current guidelines (8). Renal function was evaluated by means of glomerular filtration rate (GFR) calculated using the Modification of Diet in Renal Disease equation (9). Diagnosis of chronic kidney disease (CKD) was made because of previous renal replacement therapy or because of a GFR 560 ml/min/1.73 m2 (10).
Figure 1. Flow-Chart of the study. Pts, patients; 4w, Four weeks; BP, Blood pressure; AEs, Adverse effects.
Clin Exp Hypertens, Early Online: 1–7
Among these, six subgroups receiving different medications were identified: Enalapril 20 mg+ Lercanidipine 10 mg (E/L), Ramipril 2.5 mg+ Hydrochlorothiazide 12.5 mg (R/H), Enalapril 20 mg+ Hydrochlorothiazide 12.5 mg (E/H), Olmesartan 40 mg+ H 12.5 mg (O/H), Telmisartan 40 mg+ H 12.5 mg (T/H) and Perindopril 5 mg+ Amlodipine 5 mg (P/A). To avoid selection bias a Propensity score was used to perfectly match (1:1) comparable cohorts of patients (n ¼ 142 each for a total of 852 patients). After 4 weeks of treatment, patients were reviewed and those experiencing adverse effects and/or needing dose adjustment and/or other therapeutic variation were excluded from further analyses; a flowchart of the study is provided in Figure 1. During study visits, seated pulse and BP were measured using a standard manual cuff sphygmomanometer or other validated device and using a standardized procedure (seated trough cuff BP, with cuff size conforming with current guidelines). Measurements were performed on the same arm at all study visits. Study visit BP was recorded as the mean of three consecutive measurements, taken almost 2 min apart. Pulse rate was recorded during the 2-min interval between the second and third BP recording. Complete M-mode, bi-dimensional and Doppler transthoracic echocardiographic assessments by means of a MyLab Class C system (Esaote SPA, Genoa, Italy) were performed at first visit and 6 months thereafter. All echocardiographic studies were reviewed in core laboratory and independently reviewed by two echocardiologists. Left ventricular ejection fraction (LVEF) was calculated as the mean of two estimation using both the Teicholz and Simpson’s biplane methods. LV mass was calculated according to the EAE/ASE guidelines (11) and indexed to height 2.7 (indexed LV mass; LVMi). Relative wall thickness (RWT) was calculated with the formula ((diastolic posterior wall thickness + diastolic septal wall thickness)/left ventricular end-diastolic diameter) (11).
Combination therapies for marked hypertension
DOI: 10.3109/10641963.2014.987395
Endpoints
Results
Primary efficacy outcome investigated was BP goal (140/90 mmHg, 130/80 in high risk patients; accordingly to current guidelines (3,4)) achievement rate after 4 weeks and 6 months of treatment. As secondary outcomes, differences systolic and diastolic BP mean values, and differences in LV geometry as assessed by echocardiography, were investigated. Safety was evaluated by recording any adverse effect, notably: cough, rash, dizziness, headache, drowsiness, weakness, nausea, lower limbs or face oedema and hyperkalemia.
Efficacy and safety analyses
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Statistical analysis Statistical analysis was performed using the Statistical Package for the Social Sciences, version 11.0 (SPSS, Chicago, IL). Continuous data are expressed as the mean and standard deviation; categorical data are expressed as the percentage. To eliminate covariate differences that might lead to biased estimates, a propensity score matching was performed. Propensity score (12) was computed by means of a multivariable regression with the dependent variable being BP drugs combination and the independent variables (covariates) being age, gender, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes, smoking status, baseline left ventricular ejection fraction, baseline glomerular filtration rate, baseline body mass index, baseline systolic BP, baseline diastolic BP and baseline left ventricular mass; mixing continuous and binary variable to obtain a semisaturated model which showed acceptable goodness of fit (cstatistic 0.72; p ¼ 0.0001). Differences between the six subgroups of BP medications were firstly investigated by means of Levene’s Test for Equality of Variances. If the Levene test was positive (p50.05), the non-parametric Kruskal–Wallis test was used, if not ANOVA analysis of variance was performed.
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Propensity matching resulted in six fairly comparable groups of patients receiving different combination therapy for HBP, in fact baseline characteristics did not differ significantly as depicted in Table 1. After 4 weeks of treatment BP goal was overall achieved by 624/852 (73.2%) patients. Groups receiving P/A (107/142 or 75.3%) and E/L (106/142 or 74.7%) showed higher rates of BP goal achievement, although this trend did not reach statistical significance versus other groups: 102/142 (71.8%), 103/142 (72.5%), 102/142 (71.8%) and 104/142 (73.2%) for patients receiving respectively R/H, E/H, O/H and T/H (ANOVA p ¼ 0.28; Table 2). Adverse events were overall registered in 24/852 (2.8%) patients, with E/L group showing the lowest incidence (2/ 142 or 1.4%) although it was not statistically significant (ANOVA p ¼ 0.17) versus others: 6/142 (4.2%), 4 (2.8%), 3/142 (2.1%), 4 (2.8%) and 5/142 (3.5%) of patients receiving respectively R/H, E/H, O/H, T/H and P/A (Table 2). Because of adverse effects (n ¼ 24) and needing for dose adjustment or other therapeutic variation (n ¼ 204), 228/852 (26.9%) patients were excluded from further analyses (Figure 1). After 6 months of therapy, 562/624 (90.1%) patients maintained the BP goal. Again, groups receiving P/A (98/ 107 or 91.6%) and E/L (97/106 or 91.5%) showed higher rates of BP goal attainment, although this trend did not reach statistical significance versus other groups: 91/102 (89.2%), 92/103 (89.3%), 90/102 (88.2%) and 93/104 (89.4%) for patients receiving respectively R/H, E/H, O/H and T/H (ANOVA p ¼ 0.25; Table 2). Furthermore, investigating final responding to therapy after 6 months, P/ A and E/L showed higher rates of responders: 69.0% (98/ 142) and 68.3% (97/142), respectively, with a significant p ¼ 0.05 (Table 2).
Table 1. Baseline characteristics stratified for blood pressure treatment subgroups (n ¼ 142 each) after propensity matching.
Variables
Enalapril + Lercanidipine
Ramipril + HCT
Enalapril + HCT
Olmesartan + HCT
Telmisartan + HCT
Perindopril + Amlodipine
ANOVA p value
Age, years Male gender History of Smoking BMI430 kg/m2 Diabetes Dyslipidemia COPD Peripheral vascular disease GFR560 ml/min LVMi, g/m2 RWT, cm LVEF, % LVEDD, mm SBP, mmHg DBP, mmHg Heart rate, bpm
62.4 ± 5.9 102 (71.8) 66 (46.5) 30 (21.1) 50 (35.2) 47 (33.1) 14 (9.8) 8 (5.6) 10 (7) 53.1 ± 4.4 0.51 ± 0.07 57.2 ± 8.4 51.5 ± 7.7 157.1 ± 12.2 95.4 ± 3.2 75.7 ± 8.6
63.3 ± 4.8 100 (70.4) 68 (47.9) 28 (19.7) 47 (33.1) 50 (35.2) 16 (11.3) 8 (5.6) 9 (6.3) 53.5 ± 4.1 0.51 ± 0.05 57.5 ± 9.6 51.8 ± 5.1 156.9 ± 13.4 95.1 ± 2.9 76.3 ± 7.9
62.5 ± 6.1 103 (72.5) 69 (48.6) 28 (19.7) 48 (33.8) 51 (35.9) 14 (9.8) 9 (6.3) 8 (5.6) 52.3 ± 3.9 0.52 ± 0.08 56.9 ± 7.7 52.0 ± 4.4 157.2 ± 11.6 95.1 ± 3.4 75.8 ± 9.1
62.7 ± 5.5 100 (70.4) 69 (48.6) 27 (19) 49 (34.5) 48 (33.8) 15 (10.6) 8 (5.6) 7 (4.9) 52.7 ± 4.9 0.50 ± 0.1 57.5 ± 8.8 50.8 ± 5.6 157.1 ± 14.1 95.4 ± 2.7 76.6 ± 8.4
62.3 ± 6.4 100 (70.4) 65 (45.8) 28 (19.7) 47 (33.1) 50 (35.2) 16 (11.3) 8 (5.6) 8 (5.6) 52.9 ± 4.2 0.51 ± 0.09 58.1 ± 9.3 51.4 ± 6.2 156.9 ± 10.7 94.9 ± 3.4 75.5 ± 9.6
62.6 ± 5.8 101 (71.1) 67 (47.1) 29 (20.4) 51 (35.9) 48 (33.8) 14 (9.8) 7 (4.9) 9 (6.3) 53.1 ± 4.9 0.52 ± 0.07 57.7 ± 7.4 51.2 ± 5.8 157.8 ± 13.6 95.7 ± 3.2 76.2 ± 8.8
0.93 0.88 0.41 0.36 0.25 0.55 0.85 0.96 0.61 0.77 0.36 0.43 0.29 0.78 0.29 0.46
Continuous data are shown as mean ± standard deviation; categorical data as percentage and (absolute number). BMI, body mass index; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; LVMi, indexed left ventricular mass; RWT, relative wall thickness; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure; DBP, diastolic blood pressure.
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Table 2. Clinical and Echocardiographic end-points stratified for blood pressure treatment groups.
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Variables
Enalapril + Lercanidipine
4-week data n 142 Mean DBP, mmHg 80.1 ± 3.9 DBP reduction, mmHg 15.3 ± 4.0 Mean SBP, mmHg 129.4 ± 10.1 SBP reduction, mmHg 27.7 ± 6.8 Heart rate, bpm 72.4 ± 9.8 BP goal attainment, % 107 (74.7) Adverse Effects, % 2 (1.4) 6-month clinical data n 106 Mean DBP, mmHg 75.6 ± 2.8 DBP reduction, mmHg 19.8 ± 3.2 Mean SBP, mmHg 126.5 ± 10.8 SBP reduction, mmHg 30.6 ± 11.2 Heart rate, bpm 69.5 ± 5.4 BP goal attainment, % 97 (91.5) Total responders, % 97 (68.3) 6-month echocardiographic data LVEF, % 58.9 ± 9.6 Delta LVEF, % +1.7 ± 0.4 LVEDD, mm 47.9 ± 6.5 Delta LVEDD, mm 3.6 ± 0.9 RWT, cm 0.29 ± 0.03 Delta RWT, cm 0.22 ± 0.08 2 LVMi, g/m 42.2 ± 4.1 Delta LVMi, g/m2 10.9 ± 3.2
Ramipril + HCT
Enalapril + HCT
Olmesartan + HCT
Telmisartan + HCT
Perindopril + Amlodipine
p Value
142 83.5 ± 4.2 11.6 ± 4.4 130.1 ± 9.4 26.8 ± 8.5 73.8 ± 9.9 102 (71.8) 6 (4.2)
142 84.6 ± 4.4 10.5 ± 4.7 129.7 ± 9.6 27.5 ± 9.6 73.1 ± 10.1 103 (72.5) 4 (2.8)
142 86.1 ± 5.2 9.3 ± 3.6 129.5 ± 9.2 27.6 ± 8.8 72.6 ± 9.5 102 (71.8) 3 (2.1)
142 86.6 ± 3.7 8.3 ± 3.5 128.9 ± 8.3 28 ± 9.1 73.8 ± 10.6 104 (73.2) 4 (2.8)
142 81.2 ± 4.1 14.5 ± 4.6 128.1 ± 8.7 29.7 ± 7.7 72.2 ± 9.2 107 (75.3) 5 (3.5)
N/A 0.0001 0.001 0.001 0.08 0.51 0.28 0.17
102 79.8 ± 3.9 15.3 ± 7.4 127.7 ± 10.1 29.2 ± 14.7 70.8 ± 6.9 91 (89.2) 91 (64.1)
103 78.6 ± 4.2 16.5 ± 11.2 127.9 ± 11.4 29.3 ± 10.9 70.2 ± 8.2 92 (89.3) 92 (64.8)
102 80.2 ± 4.5 15.2 ± 9.6 126.9 ± 9.9 30.2 ± 10.6 71.1 ± 5.5 90 (88.2) 90 (63.4)
104 80.5 ± 4.6 14.4 ± 8.1 127.2 ± 10.3 29.7 ± 9.8 70.7 ± 6.6 93 (89.4) 93 (65.5)
107 75.8 ± 3.0 19.9 ± 4.6 126.4 ± 9.6 31.4 ± 10.8 69.3 ± 4.7 98 (91.6) 98 (69.0)
N/A 0.001 0.03 0.15 0.46 0.32 0.25 0.05
59.4 ± 8.8 +1.9 ± 0.6 48.4 ± 6.6 3.4 ± 0.9 0.27 ± 0.05 0.24 ± 0.09 42.4 ± 5.6 11.1 ± 6.4
59.1 ± 9.2 +2.2 ± 0.8 48.5 ± 7.2 3.5 ± 1.1 0.31 ± 0.04 0.21 ± 0.06 42.1 ± 5.8 10.2 ± 5.1
59.6 ± 9.3 +2.1 ± 0.5 47.9 ± 5.9 2.9 ± 0.6 0.35 ± 0.07 0.15 ± 0.04 43.6 ± 4.9 9.1 ± 2.2
59.4 ± 7.8 +1.3 ± 0.7 48.3 ± 6.3 3.1 ± 0.8 0.35 ± 0.05 0.16 ± 0.03 43.2 ± 3.6 9.7 ± 3.4
59.8 ± 9.5 +2.1 ± 0.5 47.7 ± 5.8 3.5 ± 0.9 0.31 ± 0.04 0.21 ± 0.07 42.8 ± 4.3 10.3 ± 4.5
0.77 0.82 0.64 0.88 0.16 0.07 0.23 0.11
Continuous data are shown as mean ± standard deviation; categorical data as percentage and (absolute number). HCT, hydrochlorothiazide; DBP, diastolic blood pressure; SBP, systolic blood pressure; Bpm, beats per minute; LVEF, left ventricular ejection fraction; LVEDD, left ventricular end-diastolic dimension; RWT, relative wall thickness; LVMi, indexed left ventricular mass.
Figure 2. Responders rate (%) stratified for treatment groups among diabetic patients. E/L, Enalapril + Lercanidipine; R/H, Ramipril + Hydrochlorothiazide; E/H, Enalapril + Hydrochlorothiazide, O/L, Olmesartan + Hydrochlorothiazide; T/H, Telmisartan + Hydrochlorothiazide; P/A, Perindopril + Amlodipine.
52.0%
46.8%
E/L R/H
47.9%
E/H O/H
49.0%
T/H 46.8%
P/A 51.0%
40.0%
In particular, among diabetic patients E/L and P/A configured as the treatments associated with significantly increased responder rate: 26/50 (52.0%) and 26/51 (51.0%), respectively; whereas responder rates of R/H, E/H, O/H and T/H were 22/47 (46.8%), 23/48 (47.9%), 24/49 (49.0%) and 22/47 (46.8%), respectively (p ¼ 0.003; Figure 2).
45.0%
50.0%
55.0%
Trends of diastolic BP After 4 weeks of treatment, greatest reductions of DBP were found among patients receiving E/L (15.3 ± 4.0 mmHg) and P/A (14.5 ± 4.6 mmHg), with respect to those administered with R/H (11.6 ± 4.4 mmHg), E/H (10.5 ± 4.7 mmHg),
DOI: 10.3109/10641963.2014.987395
Combination therapies for marked hypertension
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Figure 3. Trends of systolic and diastolic blood pressure (mmHg) stratified for treatment groups. SBP, Systolic blood pressure; DBP, Diastolic blood pressure; E/L, Enalapril + Lercanidipine; R/H, Ramipril + Hydrochlorothiazide; E/H, Enalapril + Hydrochlorothiazide, O/L, Olmesartan + Hydrochlorothiazide; T/H, Telmisartan + Hydrochlorothiazide; P/A, Perindopril + Amlodipine.
O/H (9.3 ± 3.6 mmHg) and T/H (8.3 ± 3.5 mmHg); with a statistically significant p ¼ 0.001. At 6-months control visit, DBP was still significantly reduced among patients receiving P/A (19.9 ± 4.6 mmHg), E/L (19.8 ± 3.2 mmHg), with respect to those receiving R/H (15.3 ± 7.4 mmHg), E/H (16.5 ± 11.2 mmHg), O/H (15.2 ± 9.6 mmHg) and T/H (14.4 ± 8.1 mmHg); p ¼ 0.03 (Table 2, Figure 3).
R/H, E/H and P/A), but this trend did not reach statistical significance (Table 2). In particular, greatest RWT reductions were 0.24 ± 0.09 cm in the group R/H, and 0.22 ± 0.08 cm in the group E/L in absence of statistical significance (p ¼ 0.07). Accordingly, greatest LVMi reductions were 11.1 ± 6.4 g/m2 in the group R/H, and 10.9 ± 3.2 cm in the group E/L in the absence of statistical significance (p ¼ 0.11).
Trends of systolic BP After 4 weeks of treatment, greatest reductions of SBP were found among patients receiving P/A (29.7 ± 7.7 mmHg) and T/H (28 ± 9.1 mmHg), with respect to those administered with E/L (27.7 ± 6.8 mmHg), R/H (26.8 ± 8.5 mmHg), E/H (27.5 ± 9.6 mmHg) and O/H (27.6 ± 8.8 mmHg); although this trend was not statistically significant (p ¼ 0.08). At 6months control visit, SBP was similarly reduced among each treatment group: P/A (31.4 ± 10.8 mmHg), E/L (30.6 ± 11.2 mmHg), R/H (29.2 ± 14.7 mmHg), E/H (29.3 ± 10.9 mmHg), O/H (30.2 ± 10.6 mmHg) and T/H (29.7 ± 9.8 mmHg); p ¼ 0.46 (Table 2, Figure 3). Echocardiographic outcomes Six-months echocardiography founded greater LV reverse remodeling among patients receiving ACE-inhibitors (E/L,
Discussion Main finding of the present study is that initial treatment of marked hypertension with single-pill fixed-dose therapies is safe and highly effective. Overall, excellent BP goal attainment rates were seen, especially with regards to patients administered with E/L and P/A, among whom were found significantly higher responders rate. Significant differences, always favoring E/L and P/A, were found in diastolic BP reduction, whilst reduction of systolic BP was similar between treatment groups. In addition, patients administered with E/L showed a very low incidence of adverse effects in comparison with other treatment groups, although this trend did not reach statistical significance. In addition, higher BP goal attainment rates with E/L and P/A were found among diabetic
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patients, which represented roughly one third of the study population. Summarizing, key finding of the present study is the superiority of the associations ACEi + CCB for the initial treatment of marked hypertension. Efficacy and safety of the associations ACEi + CCB was initially reported by different randomized trials (6,7,13), but the finding of its favorable metabolic effects, especially among diabetic patients, was demonstrated later on by other studies (14–16), according to the present results. Beside its effectiveness in achieving BP goal among diabetics, CCBs have also been advocate for many effects beyond BP control, such as anti-atherogenic effect (17), renoprotective effect (18) and metabolic modulation with positive variations of lipid profile and glucose tolerance (19). Each of the latter may be the reason explaining the higher effectiveness of ACEi + CCB in the settings of diabetes mellitus, in which cardiovascular and renal disease both show increased prevalence. In addition, high lipophilicity (enabling slower onset and longer duration of action) and its highly selective mechanism towards smooth muscle (20) are the key issue in determining the reduced rate of adverse events observed in patients administered with lercanidipine. Moreover, as stated in current guidelines (3), thiazide diuretics may decompensate glucose tolerance leading to hyperglycemia, reason limiting the usage of such agents. ACE inhibitors, instead, are well known agents which, reducing plasma levels of angiotensin II, determine peripheral vasodilatation and reduced vascular resistance resulting in decreased BP values. ACEis have also been found to be strongly associated with LV reverse remodeling (3), according to our results. From a theoretical point of view, the effectiveness of ACEi + CCB combinations is especially due to their complementary mechanisms; in fact whilst CCBs are potent vasodilators that induce reflex activation of the sympathetic system and renin–angiotensin–aldosterone system; ACEis can buffer this excessive activation. Furthermore, since CCBs promote a negative sodium balance and an increase of angiotensin II levels, this may reinforce the antihypertensive effect of ACEis (21), and reduces the incidence of adverse events such as peripheral oedema (22). As a matter of fact, development of lower extremity oedema during calcium entry blockade is due to an increase in intracapillary pressure (as a consequence of a selective diminution of the precapillary arteriolar tone). Hence, reduce lower extremity oedema observed when CCBs are administered along with ACEis, is most likely to the ability of ACEis to dilate both the arterial vascular bed and the venous capacitance vessels (21,23). In conclusion, in our study the usage of ACEi + CCB (either E/L and P/A) was associated with effective BP reduction, higher rates of BP control among diabetic patients, reduced rates of adverse effects and favorable LV reverse remodeling. Limitations Despite prospective data collection, a priori definition of the endpoints and propensity matching, the present remains an observational retrospective study. Because of the latter and
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given the lack of random allocation to treatment, results may not be generalizable. Further comparative prospective randomized trials are needed to confirm our findings.
Conclusion Single-pill fixed-dose combination therapies are associated with low incidence of side effects and optimal rates of BP control in the initial treatment of patients with marked hypertension and high cardiovascular risk; configuring themselves as a safe and effective strategy. Best clinical and echocardiographic outcomes were founded among patients receiving Perindopril + Amlodipine, and Enalapril + Lercanidipine. Latter combination therapy was also associated with the lowest rate of adverse events.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. EA is the recipient of a PhD Program from Sapienza, Universita` di Roma. Other authors have nothing to disclose.
References 1. Go AS, Mozaffarian D, Roger VL, et al. Heart Disease and Stroke Statistics – 2013 Update – a report from the American Heart Association. Circulation 2013;127:143–52. 2. Ford ES. Trends in mortality from all causes and cardiovascular disease among hypertensive and nonhypertensive adults in the United States. Circulation 2011;123:1737–44. 3. The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC): Mancia G, Fagard R, Narkiewicz K, et al. ESH/ESC guidelines for the management of arterial hypertension. J Hypertens 2013;31:1281–357. 4. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115:2761–88. 5. Salahuddin A, Mushtaq M, Materson BJ. Combination therapy for hypertension 2013: an update. J Am Soc Hyper 2013;7:401–7. 6. Dalhof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required vs. atenolol adding bendroflumethiazide as required in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOTBPLA) a multicentre randomised controlled trial. Lancet 2005;366:895–906. 7. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417–28. 8. Goff DC, Lloyd-Jones DM, Bennet G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2013. 2014;63:2935–59. 9. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure: definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204–12. 10. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473–83. 11. Lang RM, Bierig M, Devereux RB, et al. American Society of Echocardiography’s Nomenclature and Standards Committee; Task Force on Chamber Quantification; American College of Cardiology Echocardiography Committee; American Heart Association; European Association of Echocardiography, European Society of
Combination therapies for marked hypertension
DOI: 10.3109/10641963.2014.987395
12. 13.
14.
15.
16.
Clin Exp Hypertens Downloaded from informahealthcare.com by Selcuk Universitesi on 12/22/14 For personal use only.
17.
Cardiology. Recommendations for chamber quantification. Eur J Echocardiogr 2006;7:79–108. Blackstone EH. Comparing apples and oranges. J Thorac Cardiovasc Surg 2002;123:8–15. Collier DJ, Poulter NR, Dahlo¨f B, et al. Impact of amlodipine-based therapy among older and younger patients in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). J Hypertens 2011;29:583–91. Puig JG, Calvo C, Luurila O, et al. Lercanidipine, enalapril and their combination in the treatment of elderly hypertensive patients: placebo-controlled, randomized, crossover study with four ABPM. J Hum Hypertens 2007;21:917–24. Agrawal R, Marx A, Haller H. Efficacy and safety of lercanidipine versus hydrochlorothiazide as add-on to enalapril in diabetic populations with uncontrolled hypertension. J Hypertens 2006;24: 185–92. Cicero AF, Gerocarni B, Rosticci M, Borghi C. Blood pressure and metabolic effect of a combination of lercanidipine with different antihypertensive drugs in clinical practice. Clin Exp Hypertens 2012;34:113–17. Canavesi M, Baldini N, Leonardi A, et al. In vitro inhibitory effect of lercanidipine on cholesterol accumulation and matrix
18.
19. 20. 21.
22. 23.
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metalloproteinases secretion by macrophages. J Cardiovasc Pharmacol 2004;44:416–22. Barrios V, Escobar C, de la Figuera M, et al. High doses of lercanidipine are better tolerated than other dihydropyridines in hypertensive patients with metabolic syndrome: results from the TOLERANCE study. Int J Clin Pract 2008;62:723–8. Robles NR, Ocon J, Gomez CF, et al. Lercanidipine in patients with chronic renal failure: the ZAFRA study. Ren Fail 2005;27:73–80. Barrios V, Escobar C, Echarri R, et al. Fixed combinations in the management of hypertension: perspectives on lercanidipine – enalapril. Vasc Health Risk Manag 2008;4:847–53. Gojanovic B, Feihl F, Liaudet L, et al. 2008. Concomitant calcium entry blockade and inhibition of the renin-angiotensin system: a rational and effective means for treating hypertension. J Renin Angiotensin Aldosterone Syst 2008;9:1–9. Messerli FH. Vasodilatory edema: a common side effect of antihypertensive therapy. Curr Cardiol Reports 2002;4:479–82. Weir MR, Rosenberger C, Fink JC. Pilot study to evaluate a water displacement technique to compare effects of diuretics and ACE inhibitors to alleviate lower extremity edema due to dihydropyridine calcium antagonists. Am J Hypertens 2001;14: 963–8.
Single-pill combination therapy in the initial treatment of marked hypertension: a propensity-matched analysis Emiliano Angeloni1, Angelo Vitaterna2, Paola Lombardo1, Michele Pirelli2, and Simone Refice1 Department of Cardiovascular Pathophysiology and Imaging, Sapienza, University of Rome, Rome, Italy and 2Department of Cardiology and Nutrition, Eurytmia Medical Center, Anagni (FR), Italy
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Abstract
Keywords
Background: Many drugs combinations are available and equally recommended for the initial treatment of patients with marked blood pressure (BP) elevation and high cardiovascular risk. Hypothesis: To investigate safety and efficacy of such combination therapies. Methods: Prospectively collected data were retrospectively reviewed, inclusion criteria were: initial singlepill combination therapy, availability of clinical and echocardiographic 6-month follow-up. Six treatment groups were identified: Enalapril 20 mg+ Hydrochlorothiazide 12.5 mg (E/H), E 20 mg + Lercanidipine 10 mg (E/L), Ramipril 2.5 mg+ H 12.5 mg (R/H), Perindopril 5 mg+ Amlodipine 5 mg (P/A), Olmesartan 40 mg+ H 12.5 mg (O/H) and Telmisartan 40 mg+ H 12.5 mg (T/H). To avoid selection bias a Propensity score (goodness of fit: c-statistic 0.78, p ¼ 0.0001) was used to select comparable cohorts of patients (n ¼ 142 each). Results: After 4 weeks of treatment BP goal was achieved by 624/852 (73.2%) patients, and adverse events were registered in 24/852 (2.8%) patients. After 6 months, 562/624 (90.1%) patients maintained the BP goal. Six-month responder rate was significantly higher in the E/L (69.0%) and P/A (68.3%) groups (p ¼ 0.05); especially among diabetics (52.0% and 51.0%, respectively; p ¼ 0.003). Patients receiving E/L (19.8 ± 3.2 mmHg) and P/A (19.9 ± 4.6 mmHg) showed greater reductions of diastolic BP (p ¼ 0.03); whereas reductions of systolic BP were similar between treatment groups (p ¼ 0.46). Echocardiographic follow-up revealed greater left ventricular reverse remodeling among patients receiving ACE-inhibitors (E/L, R/H, E/H and P/A), but this trend did not reach statistical significance. Conclusions: Single-pill fixed-dose combination therapies are highly effective and safe in the study settings. Best clinical and echocardiographic outcomes were noted among patients receiving E/L, R/H and P/A.
Blood pressure control, combination therapy, hypertension
Introduction High blood pressure (HBP) is the most common among cardiovascular risk factors. Recent literature reports nearly 80 million US adults having HBP, with a prevalence greater than 30%, increasing up to 70% among adults aged at least 65 years (1). Among hypertensive adults, 82% are aware of their condition and 75% are of using antihypertensive medication, but only 53% of those with documented hypertension have their condition controlled to target levels (1). HBP-related mortality ranges between 16% and 19% with an estimated direct and indirect cost of 51 billion US dollars (1,2). In every age or ethnicity subgroup, BP bears an independent continuous relationship with the incidence of several CV events (stroke, myocardial infarction, sudden death, heart failure and peripheral artery disease) and with the incidence of end-stage renal disease as well (3). As a consequence, hypertension control results in a 35% risk reduction of stroke, and in a 20% risk reduction of myocardial infarction (4). Correspondence: Emiliano Angeloni, M.D., Sapienza, Universita` di Roma, Policlinico Sant’Andrea, Via di Grottarossa 1035, 00189 Rome, Italy. Tel: +39 06 3377 5310. Fax: +39 06 3377 5483. E-mail: [email protected]
History Received 29 September 2014 Accepted 29 October 2014 Published online 11 December 2014
Current European guidelines (3) confirmed that diuretics, beta-blockers, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers are all suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in some combinations, with few different indications based on clinical characteristics. Furthermore, cited guidelines (3) recommend combination therapy for the initial treatment of marked HBP (systolic BP4160 mmHg, diastolic BP4100 mmHg) or in case of patients with high total cardiovascular risk (as based on clinical evaluation of risk factors, comorbidities and organ damage). The latter because monotherapy was found to be ineffective in achieving BP goal in the majority of patients, and particularly among high-risk patients who would need stricter BP control (3,5). In addition, it has been proven that single-pill combination therapies are more efficacious than the individual components and that improve patient adherence to therapy (5). With the exception of ACE inhibitor (ACEi) + angiotensin receptor blocker (ARB), all the other combinations of above mentioned drugs have been found to be effective in the control of HBP (5,6), although current guidelines (3) recognized the following as preferred combinations: ACEi + calcium channel
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blocker (CCB), ARB + thiazide diuretic (THZ), ACEi + THZ, ARB + CCB and THZ + CCB. Along with these, the ASCOTBPLA trial (6) founded a superiority of the combinations ACE inhibitor + calcium antagonist, and angiotensin receptor blocker + diuretic versus the association beta-blocker + diuretic; whereas the ACCOMPLISH trial (7), demonstrated the superiority of the ACE inhibitor + calcium antagonist in comparison with ACE inhibitor + thiazide diuretic. Aim of the present study was to investigate safety and efficacy of different single-pill combination therapies in the initial treatment of patients with marked hypertension and/or high cardiovascular risk.
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Methods This study, performed accordingly to the declaration of Helsinki, was reviewed and approved by local Institutional Review Board and a waiver of consent was granted. Patients and variables A total of 2762 patients with HBP were referred to our clinic (Eurytmia Medical Center, Anagni) between March 2013 and March 2014. Patients’ data were prospectively collected in an electronic database and were retrospectively reviewed for the purpose of the present study. Roughly half of such patients (n ¼ 1453 or 52.6%) met inclusion criteria: marked hypertension, high cardiovascular risk, initial single-pill combination therapy, availability of clinical and echocardiographic 6-months follow-up. Cardiovascular risk was assessed accordingly to current guidelines (8). Renal function was evaluated by means of glomerular filtration rate (GFR) calculated using the Modification of Diet in Renal Disease equation (9). Diagnosis of chronic kidney disease (CKD) was made because of previous renal replacement therapy or because of a GFR 560 ml/min/1.73 m2 (10).
Figure 1. Flow-Chart of the study. Pts, patients; 4w, Four weeks; BP, Blood pressure; AEs, Adverse effects.
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Among these, six subgroups receiving different medications were identified: Enalapril 20 mg+ Lercanidipine 10 mg (E/L), Ramipril 2.5 mg+ Hydrochlorothiazide 12.5 mg (R/H), Enalapril 20 mg+ Hydrochlorothiazide 12.5 mg (E/H), Olmesartan 40 mg+ H 12.5 mg (O/H), Telmisartan 40 mg+ H 12.5 mg (T/H) and Perindopril 5 mg+ Amlodipine 5 mg (P/A). To avoid selection bias a Propensity score was used to perfectly match (1:1) comparable cohorts of patients (n ¼ 142 each for a total of 852 patients). After 4 weeks of treatment, patients were reviewed and those experiencing adverse effects and/or needing dose adjustment and/or other therapeutic variation were excluded from further analyses; a flowchart of the study is provided in Figure 1. During study visits, seated pulse and BP were measured using a standard manual cuff sphygmomanometer or other validated device and using a standardized procedure (seated trough cuff BP, with cuff size conforming with current guidelines). Measurements were performed on the same arm at all study visits. Study visit BP was recorded as the mean of three consecutive measurements, taken almost 2 min apart. Pulse rate was recorded during the 2-min interval between the second and third BP recording. Complete M-mode, bi-dimensional and Doppler transthoracic echocardiographic assessments by means of a MyLab Class C system (Esaote SPA, Genoa, Italy) were performed at first visit and 6 months thereafter. All echocardiographic studies were reviewed in core laboratory and independently reviewed by two echocardiologists. Left ventricular ejection fraction (LVEF) was calculated as the mean of two estimation using both the Teicholz and Simpson’s biplane methods. LV mass was calculated according to the EAE/ASE guidelines (11) and indexed to height 2.7 (indexed LV mass; LVMi). Relative wall thickness (RWT) was calculated with the formula ((diastolic posterior wall thickness + diastolic septal wall thickness)/left ventricular end-diastolic diameter) (11).
Combination therapies for marked hypertension
DOI: 10.3109/10641963.2014.987395
Endpoints
Results
Primary efficacy outcome investigated was BP goal (140/90 mmHg, 130/80 in high risk patients; accordingly to current guidelines (3,4)) achievement rate after 4 weeks and 6 months of treatment. As secondary outcomes, differences systolic and diastolic BP mean values, and differences in LV geometry as assessed by echocardiography, were investigated. Safety was evaluated by recording any adverse effect, notably: cough, rash, dizziness, headache, drowsiness, weakness, nausea, lower limbs or face oedema and hyperkalemia.
Efficacy and safety analyses
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Statistical analysis Statistical analysis was performed using the Statistical Package for the Social Sciences, version 11.0 (SPSS, Chicago, IL). Continuous data are expressed as the mean and standard deviation; categorical data are expressed as the percentage. To eliminate covariate differences that might lead to biased estimates, a propensity score matching was performed. Propensity score (12) was computed by means of a multivariable regression with the dependent variable being BP drugs combination and the independent variables (covariates) being age, gender, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes, smoking status, baseline left ventricular ejection fraction, baseline glomerular filtration rate, baseline body mass index, baseline systolic BP, baseline diastolic BP and baseline left ventricular mass; mixing continuous and binary variable to obtain a semisaturated model which showed acceptable goodness of fit (cstatistic 0.72; p ¼ 0.0001). Differences between the six subgroups of BP medications were firstly investigated by means of Levene’s Test for Equality of Variances. If the Levene test was positive (p50.05), the non-parametric Kruskal–Wallis test was used, if not ANOVA analysis of variance was performed.
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Propensity matching resulted in six fairly comparable groups of patients receiving different combination therapy for HBP, in fact baseline characteristics did not differ significantly as depicted in Table 1. After 4 weeks of treatment BP goal was overall achieved by 624/852 (73.2%) patients. Groups receiving P/A (107/142 or 75.3%) and E/L (106/142 or 74.7%) showed higher rates of BP goal achievement, although this trend did not reach statistical significance versus other groups: 102/142 (71.8%), 103/142 (72.5%), 102/142 (71.8%) and 104/142 (73.2%) for patients receiving respectively R/H, E/H, O/H and T/H (ANOVA p ¼ 0.28; Table 2). Adverse events were overall registered in 24/852 (2.8%) patients, with E/L group showing the lowest incidence (2/ 142 or 1.4%) although it was not statistically significant (ANOVA p ¼ 0.17) versus others: 6/142 (4.2%), 4 (2.8%), 3/142 (2.1%), 4 (2.8%) and 5/142 (3.5%) of patients receiving respectively R/H, E/H, O/H, T/H and P/A (Table 2). Because of adverse effects (n ¼ 24) and needing for dose adjustment or other therapeutic variation (n ¼ 204), 228/852 (26.9%) patients were excluded from further analyses (Figure 1). After 6 months of therapy, 562/624 (90.1%) patients maintained the BP goal. Again, groups receiving P/A (98/ 107 or 91.6%) and E/L (97/106 or 91.5%) showed higher rates of BP goal attainment, although this trend did not reach statistical significance versus other groups: 91/102 (89.2%), 92/103 (89.3%), 90/102 (88.2%) and 93/104 (89.4%) for patients receiving respectively R/H, E/H, O/H and T/H (ANOVA p ¼ 0.25; Table 2). Furthermore, investigating final responding to therapy after 6 months, P/ A and E/L showed higher rates of responders: 69.0% (98/ 142) and 68.3% (97/142), respectively, with a significant p ¼ 0.05 (Table 2).
Table 1. Baseline characteristics stratified for blood pressure treatment subgroups (n ¼ 142 each) after propensity matching.
Variables
Enalapril + Lercanidipine
Ramipril + HCT
Enalapril + HCT
Olmesartan + HCT
Telmisartan + HCT
Perindopril + Amlodipine
ANOVA p value
Age, years Male gender History of Smoking BMI430 kg/m2 Diabetes Dyslipidemia COPD Peripheral vascular disease GFR560 ml/min LVMi, g/m2 RWT, cm LVEF, % LVEDD, mm SBP, mmHg DBP, mmHg Heart rate, bpm
62.4 ± 5.9 102 (71.8) 66 (46.5) 30 (21.1) 50 (35.2) 47 (33.1) 14 (9.8) 8 (5.6) 10 (7) 53.1 ± 4.4 0.51 ± 0.07 57.2 ± 8.4 51.5 ± 7.7 157.1 ± 12.2 95.4 ± 3.2 75.7 ± 8.6
63.3 ± 4.8 100 (70.4) 68 (47.9) 28 (19.7) 47 (33.1) 50 (35.2) 16 (11.3) 8 (5.6) 9 (6.3) 53.5 ± 4.1 0.51 ± 0.05 57.5 ± 9.6 51.8 ± 5.1 156.9 ± 13.4 95.1 ± 2.9 76.3 ± 7.9
62.5 ± 6.1 103 (72.5) 69 (48.6) 28 (19.7) 48 (33.8) 51 (35.9) 14 (9.8) 9 (6.3) 8 (5.6) 52.3 ± 3.9 0.52 ± 0.08 56.9 ± 7.7 52.0 ± 4.4 157.2 ± 11.6 95.1 ± 3.4 75.8 ± 9.1
62.7 ± 5.5 100 (70.4) 69 (48.6) 27 (19) 49 (34.5) 48 (33.8) 15 (10.6) 8 (5.6) 7 (4.9) 52.7 ± 4.9 0.50 ± 0.1 57.5 ± 8.8 50.8 ± 5.6 157.1 ± 14.1 95.4 ± 2.7 76.6 ± 8.4
62.3 ± 6.4 100 (70.4) 65 (45.8) 28 (19.7) 47 (33.1) 50 (35.2) 16 (11.3) 8 (5.6) 8 (5.6) 52.9 ± 4.2 0.51 ± 0.09 58.1 ± 9.3 51.4 ± 6.2 156.9 ± 10.7 94.9 ± 3.4 75.5 ± 9.6
62.6 ± 5.8 101 (71.1) 67 (47.1) 29 (20.4) 51 (35.9) 48 (33.8) 14 (9.8) 7 (4.9) 9 (6.3) 53.1 ± 4.9 0.52 ± 0.07 57.7 ± 7.4 51.2 ± 5.8 157.8 ± 13.6 95.7 ± 3.2 76.2 ± 8.8
0.93 0.88 0.41 0.36 0.25 0.55 0.85 0.96 0.61 0.77 0.36 0.43 0.29 0.78 0.29 0.46
Continuous data are shown as mean ± standard deviation; categorical data as percentage and (absolute number). BMI, body mass index; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; LVMi, indexed left ventricular mass; RWT, relative wall thickness; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure; DBP, diastolic blood pressure.
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Table 2. Clinical and Echocardiographic end-points stratified for blood pressure treatment groups.
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Variables
Enalapril + Lercanidipine
4-week data n 142 Mean DBP, mmHg 80.1 ± 3.9 DBP reduction, mmHg 15.3 ± 4.0 Mean SBP, mmHg 129.4 ± 10.1 SBP reduction, mmHg 27.7 ± 6.8 Heart rate, bpm 72.4 ± 9.8 BP goal attainment, % 107 (74.7) Adverse Effects, % 2 (1.4) 6-month clinical data n 106 Mean DBP, mmHg 75.6 ± 2.8 DBP reduction, mmHg 19.8 ± 3.2 Mean SBP, mmHg 126.5 ± 10.8 SBP reduction, mmHg 30.6 ± 11.2 Heart rate, bpm 69.5 ± 5.4 BP goal attainment, % 97 (91.5) Total responders, % 97 (68.3) 6-month echocardiographic data LVEF, % 58.9 ± 9.6 Delta LVEF, % +1.7 ± 0.4 LVEDD, mm 47.9 ± 6.5 Delta LVEDD, mm 3.6 ± 0.9 RWT, cm 0.29 ± 0.03 Delta RWT, cm 0.22 ± 0.08 2 LVMi, g/m 42.2 ± 4.1 Delta LVMi, g/m2 10.9 ± 3.2
Ramipril + HCT
Enalapril + HCT
Olmesartan + HCT
Telmisartan + HCT
Perindopril + Amlodipine
p Value
142 83.5 ± 4.2 11.6 ± 4.4 130.1 ± 9.4 26.8 ± 8.5 73.8 ± 9.9 102 (71.8) 6 (4.2)
142 84.6 ± 4.4 10.5 ± 4.7 129.7 ± 9.6 27.5 ± 9.6 73.1 ± 10.1 103 (72.5) 4 (2.8)
142 86.1 ± 5.2 9.3 ± 3.6 129.5 ± 9.2 27.6 ± 8.8 72.6 ± 9.5 102 (71.8) 3 (2.1)
142 86.6 ± 3.7 8.3 ± 3.5 128.9 ± 8.3 28 ± 9.1 73.8 ± 10.6 104 (73.2) 4 (2.8)
142 81.2 ± 4.1 14.5 ± 4.6 128.1 ± 8.7 29.7 ± 7.7 72.2 ± 9.2 107 (75.3) 5 (3.5)
N/A 0.0001 0.001 0.001 0.08 0.51 0.28 0.17
102 79.8 ± 3.9 15.3 ± 7.4 127.7 ± 10.1 29.2 ± 14.7 70.8 ± 6.9 91 (89.2) 91 (64.1)
103 78.6 ± 4.2 16.5 ± 11.2 127.9 ± 11.4 29.3 ± 10.9 70.2 ± 8.2 92 (89.3) 92 (64.8)
102 80.2 ± 4.5 15.2 ± 9.6 126.9 ± 9.9 30.2 ± 10.6 71.1 ± 5.5 90 (88.2) 90 (63.4)
104 80.5 ± 4.6 14.4 ± 8.1 127.2 ± 10.3 29.7 ± 9.8 70.7 ± 6.6 93 (89.4) 93 (65.5)
107 75.8 ± 3.0 19.9 ± 4.6 126.4 ± 9.6 31.4 ± 10.8 69.3 ± 4.7 98 (91.6) 98 (69.0)
N/A 0.001 0.03 0.15 0.46 0.32 0.25 0.05
59.4 ± 8.8 +1.9 ± 0.6 48.4 ± 6.6 3.4 ± 0.9 0.27 ± 0.05 0.24 ± 0.09 42.4 ± 5.6 11.1 ± 6.4
59.1 ± 9.2 +2.2 ± 0.8 48.5 ± 7.2 3.5 ± 1.1 0.31 ± 0.04 0.21 ± 0.06 42.1 ± 5.8 10.2 ± 5.1
59.6 ± 9.3 +2.1 ± 0.5 47.9 ± 5.9 2.9 ± 0.6 0.35 ± 0.07 0.15 ± 0.04 43.6 ± 4.9 9.1 ± 2.2
59.4 ± 7.8 +1.3 ± 0.7 48.3 ± 6.3 3.1 ± 0.8 0.35 ± 0.05 0.16 ± 0.03 43.2 ± 3.6 9.7 ± 3.4
59.8 ± 9.5 +2.1 ± 0.5 47.7 ± 5.8 3.5 ± 0.9 0.31 ± 0.04 0.21 ± 0.07 42.8 ± 4.3 10.3 ± 4.5
0.77 0.82 0.64 0.88 0.16 0.07 0.23 0.11
Continuous data are shown as mean ± standard deviation; categorical data as percentage and (absolute number). HCT, hydrochlorothiazide; DBP, diastolic blood pressure; SBP, systolic blood pressure; Bpm, beats per minute; LVEF, left ventricular ejection fraction; LVEDD, left ventricular end-diastolic dimension; RWT, relative wall thickness; LVMi, indexed left ventricular mass.
Figure 2. Responders rate (%) stratified for treatment groups among diabetic patients. E/L, Enalapril + Lercanidipine; R/H, Ramipril + Hydrochlorothiazide; E/H, Enalapril + Hydrochlorothiazide, O/L, Olmesartan + Hydrochlorothiazide; T/H, Telmisartan + Hydrochlorothiazide; P/A, Perindopril + Amlodipine.
52.0%
46.8%
E/L R/H
47.9%
E/H O/H
49.0%
T/H 46.8%
P/A 51.0%
40.0%
In particular, among diabetic patients E/L and P/A configured as the treatments associated with significantly increased responder rate: 26/50 (52.0%) and 26/51 (51.0%), respectively; whereas responder rates of R/H, E/H, O/H and T/H were 22/47 (46.8%), 23/48 (47.9%), 24/49 (49.0%) and 22/47 (46.8%), respectively (p ¼ 0.003; Figure 2).
45.0%
50.0%
55.0%
Trends of diastolic BP After 4 weeks of treatment, greatest reductions of DBP were found among patients receiving E/L (15.3 ± 4.0 mmHg) and P/A (14.5 ± 4.6 mmHg), with respect to those administered with R/H (11.6 ± 4.4 mmHg), E/H (10.5 ± 4.7 mmHg),
DOI: 10.3109/10641963.2014.987395
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Figure 3. Trends of systolic and diastolic blood pressure (mmHg) stratified for treatment groups. SBP, Systolic blood pressure; DBP, Diastolic blood pressure; E/L, Enalapril + Lercanidipine; R/H, Ramipril + Hydrochlorothiazide; E/H, Enalapril + Hydrochlorothiazide, O/L, Olmesartan + Hydrochlorothiazide; T/H, Telmisartan + Hydrochlorothiazide; P/A, Perindopril + Amlodipine.
O/H (9.3 ± 3.6 mmHg) and T/H (8.3 ± 3.5 mmHg); with a statistically significant p ¼ 0.001. At 6-months control visit, DBP was still significantly reduced among patients receiving P/A (19.9 ± 4.6 mmHg), E/L (19.8 ± 3.2 mmHg), with respect to those receiving R/H (15.3 ± 7.4 mmHg), E/H (16.5 ± 11.2 mmHg), O/H (15.2 ± 9.6 mmHg) and T/H (14.4 ± 8.1 mmHg); p ¼ 0.03 (Table 2, Figure 3).
R/H, E/H and P/A), but this trend did not reach statistical significance (Table 2). In particular, greatest RWT reductions were 0.24 ± 0.09 cm in the group R/H, and 0.22 ± 0.08 cm in the group E/L in absence of statistical significance (p ¼ 0.07). Accordingly, greatest LVMi reductions were 11.1 ± 6.4 g/m2 in the group R/H, and 10.9 ± 3.2 cm in the group E/L in the absence of statistical significance (p ¼ 0.11).
Trends of systolic BP After 4 weeks of treatment, greatest reductions of SBP were found among patients receiving P/A (29.7 ± 7.7 mmHg) and T/H (28 ± 9.1 mmHg), with respect to those administered with E/L (27.7 ± 6.8 mmHg), R/H (26.8 ± 8.5 mmHg), E/H (27.5 ± 9.6 mmHg) and O/H (27.6 ± 8.8 mmHg); although this trend was not statistically significant (p ¼ 0.08). At 6months control visit, SBP was similarly reduced among each treatment group: P/A (31.4 ± 10.8 mmHg), E/L (30.6 ± 11.2 mmHg), R/H (29.2 ± 14.7 mmHg), E/H (29.3 ± 10.9 mmHg), O/H (30.2 ± 10.6 mmHg) and T/H (29.7 ± 9.8 mmHg); p ¼ 0.46 (Table 2, Figure 3). Echocardiographic outcomes Six-months echocardiography founded greater LV reverse remodeling among patients receiving ACE-inhibitors (E/L,
Discussion Main finding of the present study is that initial treatment of marked hypertension with single-pill fixed-dose therapies is safe and highly effective. Overall, excellent BP goal attainment rates were seen, especially with regards to patients administered with E/L and P/A, among whom were found significantly higher responders rate. Significant differences, always favoring E/L and P/A, were found in diastolic BP reduction, whilst reduction of systolic BP was similar between treatment groups. In addition, patients administered with E/L showed a very low incidence of adverse effects in comparison with other treatment groups, although this trend did not reach statistical significance. In addition, higher BP goal attainment rates with E/L and P/A were found among diabetic
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E. Angeloni et al.
patients, which represented roughly one third of the study population. Summarizing, key finding of the present study is the superiority of the associations ACEi + CCB for the initial treatment of marked hypertension. Efficacy and safety of the associations ACEi + CCB was initially reported by different randomized trials (6,7,13), but the finding of its favorable metabolic effects, especially among diabetic patients, was demonstrated later on by other studies (14–16), according to the present results. Beside its effectiveness in achieving BP goal among diabetics, CCBs have also been advocate for many effects beyond BP control, such as anti-atherogenic effect (17), renoprotective effect (18) and metabolic modulation with positive variations of lipid profile and glucose tolerance (19). Each of the latter may be the reason explaining the higher effectiveness of ACEi + CCB in the settings of diabetes mellitus, in which cardiovascular and renal disease both show increased prevalence. In addition, high lipophilicity (enabling slower onset and longer duration of action) and its highly selective mechanism towards smooth muscle (20) are the key issue in determining the reduced rate of adverse events observed in patients administered with lercanidipine. Moreover, as stated in current guidelines (3), thiazide diuretics may decompensate glucose tolerance leading to hyperglycemia, reason limiting the usage of such agents. ACE inhibitors, instead, are well known agents which, reducing plasma levels of angiotensin II, determine peripheral vasodilatation and reduced vascular resistance resulting in decreased BP values. ACEis have also been found to be strongly associated with LV reverse remodeling (3), according to our results. From a theoretical point of view, the effectiveness of ACEi + CCB combinations is especially due to their complementary mechanisms; in fact whilst CCBs are potent vasodilators that induce reflex activation of the sympathetic system and renin–angiotensin–aldosterone system; ACEis can buffer this excessive activation. Furthermore, since CCBs promote a negative sodium balance and an increase of angiotensin II levels, this may reinforce the antihypertensive effect of ACEis (21), and reduces the incidence of adverse events such as peripheral oedema (22). As a matter of fact, development of lower extremity oedema during calcium entry blockade is due to an increase in intracapillary pressure (as a consequence of a selective diminution of the precapillary arteriolar tone). Hence, reduce lower extremity oedema observed when CCBs are administered along with ACEis, is most likely to the ability of ACEis to dilate both the arterial vascular bed and the venous capacitance vessels (21,23). In conclusion, in our study the usage of ACEi + CCB (either E/L and P/A) was associated with effective BP reduction, higher rates of BP control among diabetic patients, reduced rates of adverse effects and favorable LV reverse remodeling. Limitations Despite prospective data collection, a priori definition of the endpoints and propensity matching, the present remains an observational retrospective study. Because of the latter and
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given the lack of random allocation to treatment, results may not be generalizable. Further comparative prospective randomized trials are needed to confirm our findings.
Conclusion Single-pill fixed-dose combination therapies are associated with low incidence of side effects and optimal rates of BP control in the initial treatment of patients with marked hypertension and high cardiovascular risk; configuring themselves as a safe and effective strategy. Best clinical and echocardiographic outcomes were founded among patients receiving Perindopril + Amlodipine, and Enalapril + Lercanidipine. Latter combination therapy was also associated with the lowest rate of adverse events.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. EA is the recipient of a PhD Program from Sapienza, Universita` di Roma. Other authors have nothing to disclose.
References 1. Go AS, Mozaffarian D, Roger VL, et al. Heart Disease and Stroke Statistics – 2013 Update – a report from the American Heart Association. Circulation 2013;127:143–52. 2. Ford ES. Trends in mortality from all causes and cardiovascular disease among hypertensive and nonhypertensive adults in the United States. Circulation 2011;123:1737–44. 3. The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC): Mancia G, Fagard R, Narkiewicz K, et al. ESH/ESC guidelines for the management of arterial hypertension. J Hypertens 2013;31:1281–357. 4. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115:2761–88. 5. Salahuddin A, Mushtaq M, Materson BJ. Combination therapy for hypertension 2013: an update. J Am Soc Hyper 2013;7:401–7. 6. Dalhof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required vs. atenolol adding bendroflumethiazide as required in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOTBPLA) a multicentre randomised controlled trial. Lancet 2005;366:895–906. 7. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417–28. 8. Goff DC, Lloyd-Jones DM, Bennet G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2013. 2014;63:2935–59. 9. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure: definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204–12. 10. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473–83. 11. Lang RM, Bierig M, Devereux RB, et al. American Society of Echocardiography’s Nomenclature and Standards Committee; Task Force on Chamber Quantification; American College of Cardiology Echocardiography Committee; American Heart Association; European Association of Echocardiography, European Society of
Combination therapies for marked hypertension
DOI: 10.3109/10641963.2014.987395
12. 13.
14.
15.
16.
Clin Exp Hypertens Downloaded from informahealthcare.com by Selcuk Universitesi on 12/22/14 For personal use only.
17.
Cardiology. Recommendations for chamber quantification. Eur J Echocardiogr 2006;7:79–108. Blackstone EH. Comparing apples and oranges. J Thorac Cardiovasc Surg 2002;123:8–15. Collier DJ, Poulter NR, Dahlo¨f B, et al. Impact of amlodipine-based therapy among older and younger patients in the AngloScandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). J Hypertens 2011;29:583–91. Puig JG, Calvo C, Luurila O, et al. Lercanidipine, enalapril and their combination in the treatment of elderly hypertensive patients: placebo-controlled, randomized, crossover study with four ABPM. J Hum Hypertens 2007;21:917–24. Agrawal R, Marx A, Haller H. Efficacy and safety of lercanidipine versus hydrochlorothiazide as add-on to enalapril in diabetic populations with uncontrolled hypertension. J Hypertens 2006;24: 185–92. Cicero AF, Gerocarni B, Rosticci M, Borghi C. Blood pressure and metabolic effect of a combination of lercanidipine with different antihypertensive drugs in clinical practice. Clin Exp Hypertens 2012;34:113–17. Canavesi M, Baldini N, Leonardi A, et al. In vitro inhibitory effect of lercanidipine on cholesterol accumulation and matrix
18.
19. 20. 21.
22. 23.
7
metalloproteinases secretion by macrophages. J Cardiovasc Pharmacol 2004;44:416–22. Barrios V, Escobar C, de la Figuera M, et al. High doses of lercanidipine are better tolerated than other dihydropyridines in hypertensive patients with metabolic syndrome: results from the TOLERANCE study. Int J Clin Pract 2008;62:723–8. Robles NR, Ocon J, Gomez CF, et al. Lercanidipine in patients with chronic renal failure: the ZAFRA study. Ren Fail 2005;27:73–80. Barrios V, Escobar C, Echarri R, et al. Fixed combinations in the management of hypertension: perspectives on lercanidipine – enalapril. Vasc Health Risk Manag 2008;4:847–53. Gojanovic B, Feihl F, Liaudet L, et al. 2008. Concomitant calcium entry blockade and inhibition of the renin-angiotensin system: a rational and effective means for treating hypertension. J Renin Angiotensin Aldosterone Syst 2008;9:1–9. Messerli FH. Vasodilatory edema: a common side effect of antihypertensive therapy. Curr Cardiol Reports 2002;4:479–82. Weir MR, Rosenberger C, Fink JC. Pilot study to evaluate a water displacement technique to compare effects of diuretics and ACE inhibitors to alleviate lower extremity edema due to dihydropyridine calcium antagonists. Am J Hypertens 2001;14: 963–8.
