Safety and Effectiveness of Candesartan and Candesartan/
HCT Fixed Dose Combination in Patients with Hypertension
Arini Setiawati
1,2, Taufik Pohan
31 Clinical Study Unit, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia. 2 Department of Pharmacology and Therapeutics, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia. 3 Department of Cardiology, Pondok Indah Hospital, Jakarta, Indonesia.
Correspondence mail:
Clinical Study Unit, Faculty of Medicine Universitas Indonesia. Jl Salemba 6, Jakarta 10430, Indonesia.
email: [email protected].
ABSTRAK
Tujuan: untuk menilai keamanan dan efektifitas candesartan dan kombinasi tetap (KT) candesartan/HCT pada pasien hipertensi dalam praktek klinik sehari-hari. Metode: suatu studi terbuka observasional dengan masa pengobatan selama 12 minggu. Tablet candesartan 4 mg, 8 mg, atau 16 mg, atau candesartan/HCT 16/12,5 mg diresepkan untuk pasien hipertensi dewasa, yang belum pernah diobati (naïve) dan sudah diobati sebelumnya tetapi tidak terkontrol, tergantung pada dokter yang merawat berdasarkan penilaiannya pada kondisi klinik pasien yang bersangkutan. Hasil: dari total 112 pasien naïve dan 381 pasien yang sudah diobati sebelumnya, yang memenuhi syarat untuk analisis keamanan, hanya ada 3 pasien dengan kejadian tidak diinginkan, dan 2 di antaranya diperkirakan mungkin disebabkan oleh candesartan (0,41%) dan tidak ada kejadian tidak diinginkan yang serius. Kedua pasien tersebut sudah diobati sebelumnya, satu pasien mengalami nausea, dan pasien yang lain mengalami parestesia. Candesartan dan candesartan/HCT efektif dalam menurunkan TDS dan TDD dari baseline pada minggu 4, 8 dan 12, pada kedua kelompok, dengan penurunan TDS sebesar 26–27 mm Hg pada minggu 12 dan cenderung lebih besar pada pasien naïve dibandingkan pada pasien yang sudah diobati sebelumnya, meskipun tidak berbeda bermakna. Akan tetapi, pencapaian TD <140/90 mm Hg antar kelompok berbeda bermakna pada minggu 8 (56% v.s. 40%; p=0,003) dan minggu 12 (69% v.s. 53%; p=0,004).
Candesartan dan candesartan/HCT juga efektif untuk pasien hipertensi yang tidak terkontrol dengan terapi antihipertensi sebelumnya selama >4 tahun (>50% di antaranya menjadi terkontrol). Kesimpulan: hasil studi terbuka observasional ini menunjukkan bahwa candesartan dan candesartan/HCT ditoleransi dengan baik dan efektif pada pasien hipertensi yang belum pernah diobati maupun pada pasien hipertensi yang sebelumnya sudah diobati tetapi tidak terkontrol.
Kata kunci: candesartan, kombinasi tetap candesartan/HCT, hipertensi.
ABSTRACT
Aim: to assess the safety and effectiveness of candesartan and candesartan/HCT fixed-dose combination (FDC) in patients with hypertension in daily clinical practice. Methods: an open observational study with a 12-week period of treatment. Candesartan tablets of 4 mg, 8 mg, or 16 mg, or candesartan/HCT FDC tablets (16/12.5 mg) were prescribed to adult hypertensive subjects, both treatment-naïve patients and previously treated but uncontrolled patients, depending on the physicians’ discretion based on his/her judgment on the clinical condition. Results: from a total of 112 treatment-naïve patients and 381 previously treated patients eligible for safety analysis, there were only 3 patients with adverse events, and 2 of which were considered possibly related to candesartan (0.41%) and there were no serious adverse events. Both patients were previously
treated patients, one patient experienced nausea and the other patient experienced paresthesia. Candesartan and candesartan/HCT were effective in lowering systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline at weeks 4, 8, and 12, in both groups, with 26-27 mm Hg decreases in SBP at week 12 and a trend toward a larger reduction in treatment-naïve patients than in previously treated patients, although not statistically significant. However, in terms of patients achieving a BP of <140/90 mm Hg between groups were significantly superior in treatment-naïve patients than in previously treated patients at week 8 (56% vs 40%; p = 0.003) and week 12 (69% vs 53%; p=0.004). Candesartan and candesartan/HCT were also effective for patients with long-standing (>4 years) uncontrolled hypertension with previous antihypertensive therapy, which was most commonly calcium channel blockers (became controlled in >50% of all uncontrolled patients).
Conclusion: results of this open observational study showed that candesartan and candesartan/HCT were well tolerated and effective in both treatment-naïve patients and uncontrolled hypertensive patients with previous antihypertensive treatment.
Key words: candesartan, candesartan/HCT fixed, hypertension.
INTRODUCTION
Hypertension is a major risk factor for cardiovascular diseases, and the purpose of antihypertensive treatment is to reduce morbidity and mortality of cardiovascular disease resulted from hypertension. With increasing age, diastolic blood pressure (DBP) increases until about the age of 60, while systolic blood pressure (SBP) continues to rise.1 Blood pressure (BP) reductions of 10 mm Hg systolic or 5 mm Hg diastolic are associated with a 33 to 48%
reduction in stroke and a 17 to 27% reduction in CHD events.2
The renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure and the development of hypertension, atherosclerosis, heart failure, type 2 diabetes mellitus, and renal disease. ACE- inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) decrease BP, and improve heart failure. Both ACEIs and ARBs generally have the same indications, contraindications, precautions, and adverse events, except for the incidence of dry cough, which is very high for ACEIs and very low for ARBs.3 In JNC-6, 19974, ARBs were used only for patients intolerant of ACEIs due to dry cough.
In JNC-7, 20035, ARBs have become one of the five first-line drugs for hypertension. It was also mentioned that when BP is more than 20/10 mm Hg above goal, consideration should be given to initiating therapy with two drugs, either as separate prescriptions or as fixed dose
combinations.
The present study assessed the use of candesartan and candesartan/HCT FDC for hypertensive patients in daily clinical practice.
The primary objective of this study was to assess the safety of candesartan (Blopress®) and candesartan/HCT FDC (Blopress Plus®) in patients with hypertension in daily practice.
The secondary objective was to evaluate the effectiveness of candesartan and candesartan/
HCT FDC in patients with the same condition.
METHODS
The plan was to recruit 1000 patients from 200 participating physicians in from several big cities in Indonesia.
Men and women, age >18 years, with uncomplicated essential hypertension, sitting diastolic BP (sDBP) >90 mm Hg and/or sitting systolic BP (sSBP) >140 mm Hg were recruited for this study. They were (i) newly diagnosed hypertensive patients not previously treated (treatment-naïve patients), (ii) hypertensive patients previously treated but uncontrolled, (iii) patients previously treated with candesartan at a lower dose but now requiring either a higher dose of candesartan or candesartan/HCT FDC, or (iv) hypertensive patients previously treated but intolerant of the side effects (for these latter patients there were no limits for sDBP or sSBP).
The decision to enter a patient into this study was purely based on clinical consideration of the physician. Excluded from the study were patients
who were hypersensitive to any component of the study drugs; pregnant or nursing women;
and patients with cholestasis or severe renal or hepatic impairment, refractory hypokalemia or hypercalcemia, gout, or any condition that in the opinion of the physician would jeopardize the safety of the patients and/or effectiveness of the study drugs.
Study Design and Procedure
This was an open observational, multi- centre study with a 12-week treatment period.
The study protocol was approved by the Ethics Committee of the Faculty of Medicine, Universitas Indonesia.
Safety and tolerability were observed throughout the study period, particularly during recommended visits (visit 2, 3, and 4, at week 4, 8, and 12, respectively).
Blood pressure measurements were performed at visit 1, 2, 3, and 4 at the participating physician’s office or clinic.
The recommended initial dose for treatment- naïve patients was 4 mg (1/2 tablet of candesartan 8 mg) taken orally once daily, and the dose could be uptitrated at every follow up visit (visit 2, 3 and 4). However, the physician could also determine proper initial dose depending on patient’s condition. Different schedules of uptitration from the recommended protocol could be applied by the physician based on medical consideration during the study period whenever the target BP was not yet achieved.
For patients who were not yet controlled with previous antihypertensives, the initial dose was at the physician’s discretion.
The study drugs were candesartan 8 mg tablets, candesartan 16 mg tablets and candesartan/HCT 16/12.5 mg tablets. These medications were given once daily for 12 weeks.
The medications were recommended to be taken preferentially in the morning independent of mealtime.
Concomitant medications for non- hypertensive therapy could be given at the discretion of the physician, and these medications were recorded in the case report form (CRF).
Every patient had the right to discontinue his/her participation in the study at any time without giving the reason. All data generated
up to the time of discontinuation from the study were recorded and analyzed, including reasons for the discontinuation (if it could be obtained).
At baseline, patients were selected based on the inclusion and exclusion criteria, and then the following data were collected: patient’s age, gender, and physical examination findings.
Included in the medical history were the onset date of hypertension and all antihypertensive drugs taken in the last 3 months. The blood pressure was measured in sitting position after 5 minutes rest with a mercury sphygmomanometer.
Two measurements were minimally performed at each visit and the average value was recorded.
The physician recorded all adverse events/side effects reported by patients in the CRF.
At visits 2, 3 and 4 (weeks 4, 8, and 12), the investigators assessed the following related to safety/tolerability and effectiveness of the study drugs and recorded in the CRF:
blood pressure, concomitant drugs, safety and tolerability. The physician recorded all adverse events/side effects, either new or continuing, reported by patients into the CRF. If an adverse event occurred, either serious or nonserious, the physician also had to complete the available CIOM form (according to the SOP of Takeda).
Safety Assessment
Safety assessment consisted of monitoring and recording adverse events (AEs), including serious adverse events (SAEs). Information of all AEs, either volunteered by the patient, questioned by the physician, or detected through physical examination, laboratory tests or other means, were collected and recorded in the CRF.
An adverse event (AE) means any adverse medical event which occurs in a patient or clinical trial subject who receives a pharmaceutical product irrespective of causal relationship with the product given. Therefore, an adverse event may be a sign (including abnormal laboratory test), symptom, or unexpected or untoward disease which occurs during the use of a drug, irrespective of its relationship with the drug.
A previous medical condition before starting the study drug is only considered as an AE when the condition worsens after starting the study drug. An abnormal laboratory result or other test result is considered as an AE only
when the laboratory value worsens or induces clinical sign or symptom, which is clinically significant, requiring therapy, or results in study discontinuation of the patient; and this data is recorded in the CRF based on the related sign, symptom or diagnosis.
Pregnancy, overdose, or drug abuse that occur during study participation must also be reported.
An SAE means any untoward medical occurrence, irrespective of its relation to the study drug or the dose administered, that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in permanent or significant disability or incapacity, results in a congenital anomaly/birth defect, or requires intervention to prevent one of the above events or may endanger the patient although the occurrence is not life-threatening or fatal or does not result in inpatient hospitalization, and written in “List of Medically Significant Side Effect Takeda” (According to the relevant SOP of Takeda).
Efficacy Analysis
Patients were classified into two groups, i.e. (a) treatment-naïve patients and (b) patients
already treated with antihypertensive drugs but not yet controlled (including candesartan and non-candesartan regimens).
Changes in sSBP and sDBP from baseline at visit 2 (week 4), visit 3 (week 8) and visit 4 (week 12) were analyzed in each group using Wilcoxon test, and the differences between groups were also analyzed using Mann-Whitney test.
The percentages of patients achieving target BP of <140/90 mm Hg at each visit were compared between groups using chi-square test.
RESULTS
Starting in September 2009 and ending in July 2011, a total of 493 patients were recruited, and 461 patients were eligible for efficacy analysis. Fourteen patients had BP of <140/90 mm Hg after repeated measurements and 18 patients had gouty arthritis, which excluded them from this study. Therefore 493 patients were the safety population and 461 patients were the efficacy population.
From a total safety population of 493 patients, consisting of 112 treatment-naïve patients and 381 patients with previous antihypertensive drugs, adverse events occurred in only 3 patients
493 patients recruited
32 were excluded:
14 had BP < 140/90 mm Hg 18 had gouty arthritis 461 were eligible for efficacy analysis
351 previously -treated 110 treatment -naive
18 discontinued:
12 uncontrolled BP 1 move to other city 1 visit another physician 2 patient’s request 2 expensive drug 12 discontinued:
7 uncontrolled BP 3 move to other city 1 visit another physician 1 repeated chest pain
351 analyzed for efficacy 110 analyzed for efficacy
Figure 1. Disposition of patients
(0.61%) and there was no serious adverse event found. Nausea and paresthesia, possibly/
probably related to candesartan (according to the investigators), each occurred in one patient with previous antihypertensive drugs. Repeated chest pain with a normal ECG occurred in one naïve patient, it was considered by the investigator as not related to candesartan.
From the total efficacy population of 461 patients, 110 (24%) were recently diagnosed with hypertension and had not received any antihypertensive drug (treatment-naïve patients), while 351 (76%) were already on antihypertensive treatment but either the blood pressure had not yet controlled (>140/90 mm Hg) or the current antihypertensive therapy caused disturbing adverse drug reactions.
Male patients were only slightly more prevalent than female patients (52.7% versus 47.1%), mean age was 54.5 years, and mean weight was 66.2 kg. Patients with previous antihypertensives were older than naïve patients, with similar weight and BMI. There were 18.7% elderly patients, and 8.2% overweight and obese patients. Patients with previous antihypertensives had been diagnosed for a mean duration of 4.4 years but the BP had not yet controlled.
On physical examination, 426 patients (92.4%) had normal findings. The abnormalities in 35 patients (7.6%) were as follows: post-stroke with hemiparesis in 10 patients (1 naïve patient and 9 patients with previous antihypertensive drugs), followed by signs of heart disease in 9 patients (1 naïve and 8 patients with previous antihypertensive drugs), obesity in 3 patients
(all with previous antihypertensive drugs), and other findings in 13 patients (5 naïve and 8 with previous antihypertensive drugs).
A total of 30 patients discontinued from the study, 12 patients from the treatment-naïve group and 18 patients from the previously treated group. The most frequent reason for discontinuation was uncontrolled hypertension, 7 patients from treatment naïve group and 12 patients from previously treated group.
Eligible patients received a prescription of candesartan tablets (4 mg, 8 mg, 16 mg) or candesartan/HCT (16/12.5 mg) once daily in the morning, depending on physician’s discretion based on his/her clinical judgement on the clinical condition of the patient. Uptitration was done every 4 weeks (as required) until 12 weeks (final visit) or until goal BP was achieved (<140/90 mmHg. Since this was an observational study, there was no intervention from the investigator.
Among 351 patients with previous antihypertensive drugs, calcium channel blockers were the predominant drugs (47.0%), followed by ACE inhibitors (28.5%) and angiotensin receptor blockers (24.2%).
Concomitant antihypertensive drugs were listed in Table 2, and concomitant drugs other than antihypertensives in Table 3.
Table 1. Demographics and baseline characteristics Total
(N = 461) Treatment-naive patients (n = 110)
Patients with previous antihypertensive treatment
(n = 351)
Males: n (%) 243 (52.7) 58 (52.7) 185 (52.7)
Age (yr): mean (SD) 54.5 (11.20) 52.2 (10.79) 55.2 (11.24)
Weight (kg): mean (SD) 66.2 (11.67) 65.7 (12.19) 66.3 (11.53)
BMI (kg/m2): mean (SD) 25.0 (3.54) 24.5 (3.52) 25.1 (3.53)
Diagnosis (yr): mean (SD) 3.7 (5.40) 1.2 (3.82) 4.4 (5.58)
Diabetes : n (%) 42 (9.11) 6 (5.5) 36 (10.3)
Table 2. Concomitant antihypertensives (n = 87/461) Antihypertensives n (%) Calcium channel blockers 48 (10.4)
ACE inhibitors 16 (3.5)
b-blockers 12 (2.6)
Diuretics 11 (2.4)
When using or after switching to candesartan or candesartan/HCT, less than 20% of patients required concomitant antihypertensives, and a majority of these patients were on calcium channel blockers.
Effects of candesartan on blood pressure in treatment-naïve and in previously treated patients can be seen in Table 4 and Figures 2 and 3.
The decreases in SBP and DBP were similar between treatment-naïve patients and patients with previous antihypertensive drugs, at 4 weeks, 8 weeks, and 12 weeks. However, a greater percentage of treatment-naïve patients were brought to a BP <140/90 than previously- treated patients at week 8 and week 12.
For all patients in the present study, the effects of candesartan on blood pressure based on doses at week 12 are shown in Table 5, and the majority of patients ended up on a dose of 8 mg candesartan monotherapy.
DISCUSSION
This study was an open observational study to assess the safety (primary objective) and effectiveness (secondary objective) of candesartan and candesartan/HCT FDC for the treatment of hypertensive patients in clinical daily practice in Indonesia.
Table 3. Concomitant drugs other than antihypertensives (N = 461)
Concomitant drugs N (%)
Oral antidiabetics 51 (11.1)
Lipid lowering drugs 45 (9.8)
Antiplatelet drugs 25 (5.4)
Hypnotic sedatives and other CNS drugs 20 (4.3)
Vitamins & Minerals 19 (4.1)
Gastrointestinal drugs 14 (3.1)
NSAIDs 12 (2.6)
Analgesics 8 (1.7)
Antiasthmatic drugs 5 (1.1)
Cardiac drugs 4 (0.9)
Others 42 (9.1)
The concomitant drugs other than antihypertensives were dominated by oral antidiabetics, followed by lipid lowering drugs and antiplatelet drugs.
Table 4. Effects of candesartan on BP in treatment-naïve and previously treated patients (mm Hg) Treatment-naïve pts
(n=110) Pts with previous antihypertensive medications (n=351)
Between group comparison (between differences from
baseline)
Week SBP DBP SBP DBP Mann-Whitney test
Week 0 (mean) 157.4 96.6 160.3 96.7
SBP: Z=1.57 (NS) DBP: Z=1.37 (NS)
Week 4 (mean) 140.5 88.0 145.7 88.7
Diff. from week 0 (mean) -16.9 - -14.6 -
- -8.6 - -8.0
Wilcoxon test (Z) -8.27 -7.95 -15.06 -13.64
p-value <0.001 <0.001 <0.001 <0.001
BP <140/90 33 (30%) 82 (23%) X2=1.63; p=0.2 (NS)
Week 8 (mean) 134.4 84.8 139.4 85.4
SBP: Z=1.60 (NS) DPB: Z=0.89 (NS)
Diff. from week 0 (mean) -23.0 - -20.9 -
Wilcoxon test (Z) -8.77 -8.54 -15.28 -14.38
p-value <0.001 <0.001 <0.001 <0.001
BP <140/90 62 (56%) 140 (40%) X2=8.58; p=0.003
Week 12 (mean) 129.8 82.3 134.1 83.9
SBP: Z=1.13 (NS) DBP: Z=1.61 (NS)
Diff. from week 0 (mean) -27.6 - -26.2 -
- -14.3 - -12.8
Wilcoxon test (Z) -8.91 -8.95 -15.80 -14.61
p-value <0.001 <0.001 <0.001 <0.001
BP <140/90 76 (69%) 186 (53%) X2=8.58; p=0.004
tract. Candesartan is one of the ARBs that has competitive binding with angiotensin II to the AT1 receptor with high affinity. The affinity of candesartan for the AT1 receptor is 80 times that of losartan.6 Candesartan has four binding sites on the AT1 receptor, while losartan has only two binding sites.7 The dissociation half-life from the AT1 receptor is 152 minutes for candesartan and 5 minutes for losartan.8 Candesartan’s tight binding to and slow dissociation from AT1 receptor provides insurmountable antagonism and inverse agonism9, producing more potent inhibition of AT1 receptors.10
A total of 1000 patients from 200 physicians were planned (5 patients per physician), but only 493 patients were recruited and 461 patients were eligible for efficacy analysis.
From a total of 112 treatment-naïve patients and 381 previously treated patients eligible for safety analysis, there were only 2 patients with adverse events (0.41%), one patient experienced nausea and the other patient experienced paresthesia. Both patients were previously treated patients and both adverse events were considered possibly related to candesartan.
This was consistent with ARBs in general: well tolerated and comparable to placebo.10
Twelve among 110 naïve patients (10.9%) and 18 among 351 previously treated patients (5.1%) discontinued from the study, mostly due to uncontrolled hypertension (7 naïve and 12
Figure 2. Effects of candesartan on BP in treatment-naïve and previously treated patients at weeks 4, 8, and 12
Figure 3. BP <140/90 mm Hg) in treatment-naïve and previously treated patients at weeks 4, 8, and 12
Table 5. Effects of candesartan on BP (mm Hg) based on doses at week 12
Doses at week 12 4 mg (n=25) 8 mg (n=279) 16 mg (n=104) Cand/HCT (16/12.5 mg) (n=49) SBP (mm Hg)
Wk 0 (mean) 158.7 156.9 164.7 164.2
Wk 12 (mean) 128.4 132.1 136.1 134.4
Diff. from wk 0 (mean) -30.3 -24.8 -28.6 -29.8
Wilcoxon test (Z) -4.373 -14.110 -8.631 - 5.828
p value <0.001 <0.001 <0.001 <0.001
DBP (mm Hg)
Wk 0 (mean) 95.8 95.9 98.9 97.4
Wk 12 (mean) 79.6 83.4 85.0 83.5
Diff. from wk 0 (mean) -16.2 -12.5 -13.9 -13.9
Wilcoxon test (Z) -3.948 -13.424 -8.336 -5.336
p value <0.001 <0.001 <0.001 <0.001
Target BP <140/90 18 (72%) 164 (59%) 53 (51%) 26 (53%)
From the total of 461 patients, 4 patients did not have the drug doses at week 12 recorded
In this 12-week study, the patients either used, or switched to, candesartan or candesartan/ HCT.
Candesartan cilexetil is converted to candesartan during absorption from the gastrointestinal
previously treated patients).
In a meta-analysis including 13 trials between 1980 and 2008, candesartan was shown to be more effective than losartan.11 Candesartan was also shown to have similar or even greater efficacy compared with enalapril or HCT12, and a similar efficacy to amlodipine13,14 with less side-effects. Candesartan/HCT was known to be more effective than candesartan alone15,16, and that this dual antihypertensive therapy has additive action, producing high efficacy, similar to amlodipine17, and was effective in treating severe hypertension18, while being well tolerated.
Data from 72 Swedish primary care centers involving adult hypertensives without CVD where patients received candesartan or losartan as antihypertensives and were followed for up to 9 years, were analysed with two different study objectives by a same group of investigators.19,20 Both studies compared the effects of candesartan vs losartan as the primary treatment of hypertension;one study investigated the various cardiovascular events19, while the other study investigated the various subgroups of patients.20 There was no difference in BP reduction in these studies; but compared with losartan, candesartan produced lower hazard ratio for total CVD, heart failure, and peripheral artery disease.19 Furthermore, compared with losartan, candesartan also reduced the risk of all CVDs (primary composite endpoint), irrespective of sex, age, previous antihypertensive treatment, baseline blood pressure, and presence of diabetes.20 These reductions in hazard ratios by candesartan might be attributed to the tight binding of candesartan to the AT1 receptor, leading to more potent inhibition of this receptor by candesartan.19,20 This clinical efficacy was in line with the preclinical data and clinical profile mentioned previously.6-10
In the present observational study, within the treatment-naïve group and the previously treated group, the majority of patients ended up on a dose of 8 mg candesartan; and overall, candesartan or candesartan/HCT was effective in lowering the BP from baseline (p<0.001 for both SBP and DBP) at 4-, 8- and 12-week visits (Table 4 and Figure 2). However, comparing
between these 2 groups, the SBP and DBP reductions from baseline were not significantly different (Table 4).
It should be noted, however, that many patients in both groups apparently remained uncontrolled with sub-maximal therapy at 12 weeks, as only 69% and 53% of naïve and previously treated patients, respectively, had BP
<140/90 mm Hg; and only 49 patients (10.6%) were on candesartan/HCT at the end of the observation period. While this might be because 12 weeks is not enough time for titration-to- target, or the concern of the physicians that many patients may not tolerate a higher level of therapy; it seems simply to reflect the real-world interest of physicians in escalating therapy.
Nevertheless, this showed the effectiveness of candesartan in actual clinical practice in Indonesia.
There were four additional points that should be noted from these study results. First, although the mean BP reductions were not significantly different between the two groups, the percent of patients achieving BP of <140/90 mm Hg was higher in the treatment-naïve group than in the previously treated group at weeks 8 and 12. Second, the diagnosis of previously treated patients was an average of 4.4 years, and yet their BPs were still uncontrolled. In more than 50%
of these patients, BP could now be controlled with candesartan or candesartan/HCT at week 12 (Table 4). Third, almost half of the previous antihypertensives were CCBs, and about half were ACEIs and ARBs, all of these patients had not reached the BP of <140/90 mm Hg, and more than 50% of these patients reached that BP after receiving candesartan or candesartan/
HCT at week 12. These latter two points show that candesartan can be more effective than the previous antihypertensives, and this is consistent with the findings by Hasegawa et al.,21 who switched other ARBs to candesartan on morning hypertension. Finally, the BP reductions were more dramatic over the first four weeks, than over the following weeks (weeks 8 and 12) for both groups (Table 4 and Figure 2). This last point, however, seems to be a common phenomenon for other antihypertensives as well.
CONCLUSION
Our study showed that candesartan and candesartan/HCT in clinical daily practice were well tolerated and effective for treatment- naïve patients and for long-standing (>4 years) hypertensive patients uncontrolled with other antihypertensive medications, including calcium- channel blockers.
CONFLICT OF INTEREST
The authors received research grant support from PT. Takeda Indonesia.
ACKNOWLEDGMENTS
We acknowledge PT. Takeda Indonesia for the financial support for this study. We appreciate Dr. T. Tanaka from Takeda for reviewing this manuscript. We thank all physicians who participated in this study for their contribution in patient recruitment and data collection.
REFERENCES
1. Vasan RS, Beiser A, Seshadri S, et al. Residual life time risk for developing hypertension in middle-aged women and men: the Framingham Heart Study. JAMA.
2002;287:1003-10.
2. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomized trials in the context of expectations from prospective epidemiological studies. BMJ. 2009:338:b1665.
3. Brunton LL, Chabner BA, Knollmann BC, eds.
Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. Ch 26. New York: McGraw-Hill;
2011. p. 721.
4. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:
2413-45.
5. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 2003;289:2560-72.
6. Nishikawa K, Nata T, Chatani F, et al. Candesartan cilexetil: a review of its preclinical pharmacology.
J.Hum Hypertens. 1997;11(Suppl 2):S9-S17.
7. Bhuiyan MA, Ishiguro M, Hossain M, et al. Binding sites of valsartan, candesartan and losartan with angiotensin II receptor 1 subtype by molecular modeling. Life Sci. 2009;85:136-40.
8. Vanderheyden PM, Fierens FL, De Bacher J, et al. Reversible and syntopic interaction between angiotensin receptor antagonists on chinese hamster
ovary cells expressing human angiotensin II type 1 receptors. Biochem Pharmacol. 2000;59:927-35.
9. Van Liefde J, Vauquelin G. Sartan-AT1 receptor interactions: in vitro evidence for insurmountable antagonism and inverse agonism. Moll Cell Endocrinol.
2009;302:237-43.
10. Cernes R, Mashavi M, Zimlichman R. Differential clinical profile of candesartan compared to other angiotensin receptor blockers. Vasc Health and Risk Manag. 2011;7:749-59.
11. Meredith PA, Murray LS, McInnes GT. Comparison of the efficacy of candesartan and losartan: a meta- analysis of trials in the treatment of hypertension. J Hum Hypertens. 2010;24:525-31.
12. Joost A, Schunkert H, Radke PW. Candesartan cilexetil: an update. Expert Opin Pharmacother. 2011;
12(11):1769-80.
13. Ogihara T, Nakao K, Fukui T, et al. Effect of candesartan compared with amlodipine in hypertensive patients with high cardiovascular risks. Hypertension.
2008;51:1- 6.
14. Kloner RA, Weinberger M, Pool JL, et al. for the comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators. Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Am J Cardiol. 2001;87:727-31.
15. Borner G. Antihypertensive efficacy and tolerability of candesartan-HCT in patients not optimally controlled with candesartan monotherapy. Blood Press. 2008;
17(Suppl 2):22-30.
16. MacGregor G, Viskopfer J, Antonios T, et al. (UK and Israel Candesartan Investigators): Efficacy of candesartan cilexetil alone or in combination with amlodipine and HCT in moderate-to-severe hypertension. Hypertension. 2000;36:454.
17. Fogari R, Mugellini A, Derosa G. CANDA (Candesartan and diuretic vs amlodipine in hypertensive patients) Study Group: efficacy and tolerability of candesartan cilexetil / HCT and amlodipine in patients with poorly controlled mild-to-moderate essential hypertension. J Renin Angiotensin Aldosterone Syst. 2007;8(3):139-44.
18. Oparil S. Candesartan cilexetil in combination with low-dose HCT is effective in severe hypertension.
Am J Cardiol. 1997;15(6):S9-S12.
19. Kjeldsen SE, Stälhammer J, Hasvold P, et al. Effects of losartan vs candesartan in reducing cardiovascular events in the primary treatment of hypertension. J Hum Hypertens. 2010;24:263-73.
20. Russell D, Stälhammer J, Bodegard J, et al.
Cardiovascular events in subgroups of patients during primary treatment of hypertension with candesartan or losartan. J Clin Hypertens. 2011;13:189-97.
21. Hasegawa H, Takano H, Kameda Y, et al. Effect of switching from telmisartan, valsartan, olmesartan, or losartan to candesartan on morning hypertension. Clin Exper Hypertens. 2012;34:86-91.
