Fimasartan versus perindopril with and without diuretics in the treatment of elderly patients with essential hypertension (Fimasartan in the Senior Subjects (FITNESS)): study protocol for a randomized controlled trial.
ABSTRACT: BACKGROUND:Hypertension is an important risk factor for cardiovascular disease, even in the elderly. Fimasartan is a new non-peptide angiotensin II receptor blocker with a selective type I receptor blocking effect. The objective of this study is to confirm the safety and the non-inferiority of the blood pressure-lowering effect of fimasartan compared with those of perindopril, which has been proven safe and effective in elderly patients with hypertension. METHODS:This is a randomized, double-blind, active-controlled, two-parallel group, optional-titration, multicenter, phase 3 study comparing the efficacy and safety of fimasartan and perindopril arginine. The study population consists of individuals 70?years old or older with essential hypertension. The primary outcome will be a change in sitting systolic blood pressure from baseline after the administration of the investigational product for 8?weeks. The secondary outcomes will be a change in sitting diastolic blood pressure from baseline and changes in sitting systolic blood pressure and diastolic blood pressure from baseline after the administration of the investigational product for 4, 16, and 24?weeks. The sample size will be 119 subjects for each group to confer enough power to test for the primary outcome. DISCUSSION:Research to confirm the efficacy and safety of a new medicine compared with those of previously proven anti-hypertensive drugs is beneficial to guide physicians in the selection of therapeutic agents. If it is confirmed that the new drug is not inferior to the existing drug, the drug will be considered as an option in the treatment of hypertension in elderly patients. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03246555 , registered on July 25, 2017.
Project description:The study reported here compared the blood pressure (BP)-lowering efficacy of fimasartan alone with that of fimasartan/hydrochlorothiazide (HCTZ) combination in patients whose BP goal was not achieved after 4 weeks of treatment with once-daily fimasartan 60 mg.Patients with sitting diastolic blood pressure (siDBP) ?90 mmHg with 4 weeks of once-daily fimasartan 60 mg were randomly assigned to receive either once-daily fimasartan 60 mg/HCTZ 12.5 mg or fimasartan 60 mg for 4 weeks. After 4 weeks, the dose was increased from fimasartan 60 mg/HCTZ 12.5 mg to fimasartan 120 mg/HCTZ 12.5 mg or from fimasartan 60 mg to fimasartan 120 mg if siDBP was ?90 mmHg.Of the 263 randomized patients, 256 patients who had available efficacy data were analyzed. The fimasartan/HCTZ treatment group showed a greater reduction of siDBP compared to the fimasartan treatment group at Week 4 (6.88±8.10 mmHg vs 3.38±7.33, P=0.0008), and the effect persisted at Week 8 (8.67±9.39 mmHg vs 5.02±8.27 mmHg, P=0.0023). Reduction of sitting systolic BP in the fimasartan/HCTZ treatment group was also greater than that in the fimasartan treatment group (at Week 4, 10.50±13.76 mmHg vs 5.75±12.18 mmHg, P=0.0069 and, at Week 8, 13.45±15.15 mmHg vs 6.84±13.57 mmHg, P=0.0007). The proportion of patients who achieved a reduction of siDBP ?10 mmHg from baseline and/or a mean siDBP <90 mmHg after 4 weeks of treatment was higher in the fimasartan/HCTZ treatment group than in the fimasartan treatment group (53.6% vs 39.8%, P=0.0359). The overall incidence of adverse drug reaction was 11.79% with no significant difference between the treatment groups.The combination treatment of fimasartan and HCTZ achieved better BP control than fimasartan monotherapy, and had comparable safety and tolerance to fimasartan monotherapy.
Project description:<h4>Background</h4>Angiotensin II receptor blockers (ARBs) are recommended for treating patients with hypertension. However, comparative safety and efficacy of ARB use in elderly patients have not been well established. This study was designed to determine the efficacy of fimasartan, an ARB, in hypertensive elderly patients by measuring clinic and home blood pressures (BPs) and evaluating safety compared to nonelderly patients.<h4>Method</h4>In the K-MetS study, a nationwide prospective observational study of hypertensive patients on fimasartan, elderly patients (60 years and older) who were treated for 1 year with fimasartan were recruited. BP was evaluated in clinic and at home.<h4>Results</h4>Of the 6 399 enrolled patients, 2 363 were elderly (46.9% males, mean age 67.3 ± 5.7 years). Fimasartan reduced systolic and diastolic BP (SBP and DBP) in clinic from 144.1 ± 17.3 to 127.7 ± 12.9 mmHg and from 85.1 ± 10.4 to 76.8 ± 8.4 mmHg, respectively, (all p<0.0001) in 1 year. Similar results were found in home BPs. These BP changes were consistent with those in nonelderly patients. However, pulse pressure, a better predictor of cardiovascular events in the elderly, decreased more in elderly than in nonelderly patients by -8.2 ± 0.3 in elderly and -7.0 ± 0.2 mmHg (p<0.0001), respectively, after adjustment for confounding factors. Adverse events were reported in 1.6% of elderly hypertensives, independent of dose, which was consistent with results in nonelderly patients.<h4>Conclusions</h4>Fimasartan resulted in better pulse pressure reduction with similar BP reduction efficacy and safety in hypertensive elderly patients compared with nonelderly patients.
Project description:<h4>Background</h4>Angiotensin II receptor blockers (ARBs) play a key role in hypertension therapy. Recently, fimasartan, the ninth ARB, was developed, but its safety and efficacy have not been well established.<h4>Objective</h4>The objective of this study was to determine whether age, sex, concomitant disease, and current antihypertensive medications affect the safety and efficacy of fimasartan in patients with arterial hypertension.<h4>Methods</h4>This was a large-scale, open-label observational study to determine the safety and efficacy of fimasartan in patients with hypertension. Patients who were treated for more than 2 months with fimasartan (60 or 120 mg, once daily) were recruited, and the data were systematically collected using electronic case report forms. Written informed consent forms were obtained from all patients.<h4>Results</h4>A total of 14,151 patients (50.7 % males; mean age 59 ± 12 years) were evaluated, of whom 37.9 % were never treated with fimasartan, 53.5 % were switched to fimasartan, and 8.5 % had fimasartan added to their treatment. Overall, fimasartan reduced systolic blood pressure (SBP) from 145.4 ± 18.1 to 126.8 ± 12.6 mmHg and diastolic blood pressure (DBP) from 88.7 ± 11.8 to 79.0 ± 8.7 mmHg (all p < 0.001). The pulse rate decreased from 74.4 ± 10.3 to 71.9 ± 9.2 beats/min in comparison with before treatment (p < 0.001). The reductions were similar between sexes, age groups, and patients with and without co-morbidities, and were not dependent on prior or concomitant treatment with other antihypertensive drugs. Adverse events were reported in 3.31 % (treatment-emergent) and 2.35 % (drug-related) of patients; there were no dose differences for adverse events. The most frequent adverse events were dizziness (1.55 %) and headache (0.52 %); other adverse events were rare. The responder rate (DBP to <90 mmHg or a reduction of ≥10 mmHg) and the goal rate (combined SBP/DBP <140/90 mmHg) were 85.0 and 75.6 %, respectively. Global drug compliance was rated as excellent, very good, good, and poor in 68.1, 26.9, 3.4, and 1.7 % of patients, respectively.<h4>Conclusion</h4>The safety, efficacy, and compliance of fimasartan were found to be excellent in a large patient population that included patients potentially at higher risk for adverse events.
Project description:The safety and efficacy of fimasartan have been evaluated through post-marketing surveillance in real world clinical practice. The multi-center, prospective, open-label and non-interventional study. A total of 3,945 patients (3,729 patients for safety assessment and 3,473 patients for efficacy assessment) were screened in patients with essential hypertension in 89 study centers from 9 September 2010 through 8 September 2016. Among the total patients, 2,893 patients (77.6%) were administered fimasartan for 24 weeks or longer and were classified as 'patients with long-term follow-up', and the additional safety and efficacy analysis were performed. The improvement was defined as systolic blood pressure (SBP) controlled to ? 140 mmHg or decreased SBP differences ? 20 mmHg after treatment or diastolic blood pressure (DBP) controlled to ? 90 mmHg or decreased DBP differences ? 10 mmHg after treatment. Adverse drug reactions (ADRs) were reported in 3.8% patients; dizziness, and hypotension were the most frequently reported ADRs in total patients. The results of patients with long-term follow-up were comparable with total patients. The overall improvement rate in all efficacy assessment at the last visit was 87.1% (3,025/3,473 patients). The overall improvement rate of the patients with long-term follow-up was 88.9%. Fimasartan was well tolerated, with no new safety concerns identified and an effective treatment in the real world clinical practice for Korean patients with hypertension.
Project description:BACKGROUND:Hypertension and dyslipidemia are major risk factors of cardiovascular disease (CVD) events. The objective of this study was to evaluate the efficacy and safety of the co-administration of fimasartan and rosuvastatin in patients with hypertension and hypercholesterolemia. METHODS:We conducted a randomized double-blind and parallel-group trial. Patients who met eligible criteria after 4 weeks of therapeutic life change were randomly assigned to the following groups. 1) co-administration of fimasartan 120 mg/rosuvastatin 20 mg (FMS/RSV), 2) fimasartan 120 mg (FMS) alone 3) rosuvastatin 20 mg (RSV) alone. Drugs were administered once daily for 8 weeks. RESULTS:Of 140 randomized patients, 135 for whom efficacy data were available were analyzed. After 8 weeks of treatment, the FMS/RSV treatment group showed greater reductions in sitting systolic (siSBP) and diastolic (siDBP) blood pressures than those in the group receiving RSV alone (both p?<?0.001). Reductions in siSBP and siDBP were not significantly different between the FMS/RSV and FMS alone groups (p?=?0.500 and p?=?0.734, respectively). After 8 weeks of treatment, FMS/RSV treatment showed greater efficacy in percentage reduction of low-density lipoprotein cholesterol (LDL-C) level from baseline than that shown by FMS alone treatment (p?<?0.001). The response rates of siSBP with FMS/RSV, FMS alone, and RSV alone treatments were 65.22, 55.56, and 34.09%, respectively (FMS/RSV vs. RSV, p?=?0.006). The LDL-C goal attainment rates with FMS/RSV, RSV alone, and FMS alone treatments were 80.43%, 81.82%, and 15.56%, respectively (FMS/RSV vs. FMS, p?<?0.001). Incidence of adverse drug reactions with FMS/RSV treatment was 8.33%, which was similar to those associated with FMS and RSV alone treatments. CONCLUSION:This study demonstrated that the co-administration of fimasartan and rosuvastatin to patients with both hypertension and hypercholesterolemia was efficacious and safe. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02166814 . 16 June 2014.
Project description:<h4>Background and purpose</h4>Blood pressure (BP) control is strongly recommended, but BP control rate has not been well studied in patients with stroke. We evaluated the BP control rate with fimasartan-based antihypertensive therapy initiated in patients with recent cerebral ischemia.<h4>Methods</h4>This multicenter, prospective, single-arm trial involved 27 centers in South Korea. Key inclusion criteria were recent cerebral ischemia within 90 days and high BP [systolic blood pressure (SBP) >140 mm Hg or diastolic blood pressure (DBP) >90 mm Hg]. BP lowering was initiated with fimasartan. BP management during the follow-up was at the discretion of the responsible investigators. The primary endpoint was the target BP goal achievement rate (<140/90 mm Hg) at 24 weeks. Key secondary endpoints included achieved BP and BP changes at each visit, and clinical events (ClinicalTrials.gov Identifier: NCT03231293).<h4>Results</h4>Of 1,035 patients enrolled, 1,026 were included in the safety analysis, and 951 in the efficacy analysis. Their mean age was 64.1 years, 33% were female, the median time interval from onset to enrollment was 10 days, and the baseline SBP and DBP were 162.3±16.0 and 92.2±12.4 mm Hg (mean±SD). During the study period, 55.5% of patients were maintained on fimasartan monotherapy, and 44.5% received antihypertensive therapies other than fimasartan monotherapy at at least one visit. The target BP goal achievement rate at 24-week was 67.3% (48.6% at 4-week and 61.4% at 12-week). The mean BP was 139.0/81.8±18.3/11.7, 133.8/79.2±16.4/11.0, and 132.8/78.5±15.6/10.9 mm Hg at 4-, 12-, and 24-week. The treatment-emergent adverse event rate was 5.4%, including one serious adverse event.<h4>Conclusions</h4>Fimasartan-based BP lowering achieved the target BP in two-thirds of patients at 24 weeks, and was generally well tolerated.
Project description:As hypercholesterolemia is often accompanied by hypertension, statins are usually prescribed with angiotensin receptor blockers in clinical practice. This study was performed to evaluate the pharmacokinetics and safety of fimasartan and rosuvastatin when coadministered or administered alone as a single dose or as multiple doses to healthy Caucasians.Thirty-six subjects were enrolled into an open-labeled, randomized, 6-sequence, 3-period, 3-way crossover study, and randomly received fimasartan (120 mg), rosuvastatin (20 mg) or both. Blood samples for pharmacokinetics were collected up to 48 hours for fimasartan and 72 hours for rosuvastatin after the last dosing and plasma concentrations of study drugs were determined by liquid chromatography-tandem mass spectrometry. Maximum plasma concentration (Cmax), area under the concentration-time curve (AUC) from 0 to the last measurable time (AUClast), maximum plasma concentration at steady state (Cmax,ss) and AUC to the end of the dosing period at steady state (AUC?,ss) were estimated using a non-compartmental method. Safety and tolerability were evaluated throughout the study.Thirty subjects completed the study. After single dose administration, the geometric mean ratio (GMR) and 90% confidence intervals (CIs) of fimasartan with or without rosuvastatin were 0.95 (0.80-1.14) and 0.98 (0.91-1.07) for Cmax and AUClast, respectively. The corresponding values for rosuvastatin with or without fimasartan were 1.32 (1.16-1.50) and 0.97 (0.89-1.05), respectively. After administration of multiple doses, the GMRs (90% CIs) for Cmax,ss and AUC?,ss of fimasartan with or without rosuvastatin were 0.94 (0.74-1.20) and 1.07 (0.90-1.16), respectively. The corresponding values for rosuvastatin with or without fimasartan were 1.16 (1.02-1.32) and 0.86 (0.79-0.94), respectively. A total of 74 adverse events (AEs) were reported and incidences of AEs did not increase significantly with co-administration.Co-administration of fimasartan and rosuvastatin did not result in clinically relevant changes in the systemic exposure of fimasartan or rosuvastatin after single and multiple administrations, and they were well tolerated.
Project description:Introduction:Major cardiovascular risk factors, including hypertension and dyslipidemia, are often comorbidities, frequently leading to concurrent prescription of angiotensin receptor blockers and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). The study's objective was to evaluate the effect of coadministration of fimasartan and atorvastatin on their pharmacokinetics (PKs). Subjects and methods:In a randomized, open-label, three-period, six-sequence, crossover, multiple-dose study, 36 healthy subjects received 120 mg fimasartan, 40 mg atorvastatin, or both (based on their assigned sequence) once daily for 7 days in each period, with a 7-day washout between periods. Blood samples for the PK analysis of fimasartan, atorvastatin, and the 2-hydroxy atorvastatin metabolite were collected up to 48 h after the last dose. Results:The coadministration of fimasartan and atorvastatin was well tolerated and led to an increase in the peak concentration and area under the concentration-time curve at steady state of fimasartan by 2.18-fold (95% confidence interval [CI], 1.79-2.65) and 1.35-fold (95% CI, 1.26-1.43) and those of atorvastatin increased by 1.82-fold (95% CI, 1.51-2.18) and 1.12-fold (95% CI, 1.04-1.22), respectively. Conclusion:Coadministration increased the systemic exposures of fimasartan and atorvastatin, but the clinical significance of this finding needs to be evaluated with respect to exposure responses and clinical outcomes.
Project description:BACKGROUND/AIMS:Angiotensin II in the failing heart initially helps to maintain cardiac output and blood pressure, but ultimately accelerates its deterioration. In this study, we established a model of arrhythmia-induced heart failure (HF) in zebrafish and investigated the role of renin-angiotensin-aldosterone system (RAAS) modulation by using an angiotensin II type 1 receptor blocker, fimasartan, through the assessment of cellular and physiologic responses, morbidity, and mortality. METHODS:HF was induced in zebrafish larvae by exposure to 20 ?M terfenadine. Morphologic, physiologic, and functional parameters were assessed in the presence or absence of fimasartan treatment. RESULTS:Zebrafish exposed to terfenadine showed marked dilatation of the ventricle and reduced systolic function. Treatment with terfenadine was associated with 10-fold higher expression of atrial natriuretic peptide (p < 0.001 vs. vehicle), increased p53 mRNA expression, and chromatin fragmentation in the TUNEL assay, all of which were significantly reduced by fimasartan treatment. Moreover, fimasartan improved fractional shortening (terfenadine + fimasartan 16.9% ± 3.1% vs. terfenadine + vehicle 11.4% ± 5.6%, p < 0.05) and blood flow (terfenadine + fimasartan 479.1 ± 124.1 nL/sec vs. terfenadine + vehicle 273.0 ± 109.0 nL/sec, p < 0.05). Finally, treatment with fimasartan remarkably reduced mortality (terfenadine + fimasartan 36.0% vs. terfenadine + vehicle 96.0%, p < 0.001). CONCLUSION:Fimasartan effectively protected against the progression of HF in zebrafish by improving hemodynamic indices, which improved survival. A reduction in apoptotic cell death and an improvement in hemodynamics may be the mechanisms behind these effects. Further human studies are warranted to evaluate the possible role of fimasartan in the treatment of HF.
Project description:Objective:Fimasartan, an angiotensin II type 1 receptor blocker, and linagliptin, a dipeptidyl-peptidase-4 inhibitor, are frequently coadministered to treat patients with hypertension and diabetes, respectively. This study sought to evaluate the pharmacokinetic interactions between fimasartan and linagliptin after co-administration in healthy Korean subjects. Methods:The overall study was divided into two separate parts, with each part designed as an open-label, multiple-dose, two-period, and single-sequence study. In Part A, to investigate the effect of linagliptin on fimasartan, 25 subjects received 120 mg fimasartan alone once daily for seven days during Period I, and 120 mg fimasartan with 20 mg linagliptin for seven days during Period II. In Part B, to examine the effect of fimasartan on linagliptin, 12 subjects received only linagliptin once daily for seven days during Period I, followed by concomitant administration of fimasartan for seven days during Period II, at the same doses used in Part A. Serial blood samples were collected at scheduled intervals for up to 24 h after the last dose to determine the steady-state pharmacokinetics of both drugs. Results:Thirty-six subjects completed the study. The geometric mean ratio and 90% confidence intervals for maximum plasma concentration at steady state (Cmax,ss) and area under the concentration-time curve at steady state (AUC?,ss) of fimasartan with or without linagliptin were 1.2633 (0.9175-1.7396) and 1.1740 (1.0499-1.3126), respectively. The corresponding values for Cmax,ss and AUC?,ss of linagliptin with or without fimasartan were 0.9804 (0.8480-1.1336) and 0.9950 (0.9322-1.0619), respectively. A total of eight adverse events (AEs) were reported and the incidence of AEs did not increase significantly with co-administration of the drugs. Conclusion:Our results suggest that there are no clinically significant pharmacokinetic interactions between fimasartan and linagliptin when co-administered. Treatments were well tolerated during the study, with no serious adverse effects. Clinical Trial Registry:http://clinicaltrials.gov, NCT03250052.