Gastrointestinal Therapeutic System Research Articles

Seasonal variation in ambulatory blood pressure control in patients on clinic blood pressure-guided antihypertensive treatment.

We investigated seasonal variation in ambulatory blood pressure control in hypertensive patients on clinic blood pressure-guided antihypertensive treatment. The study participants were hypertensive patients enrolled in an 8-week therapeutic study. Antihypertensive treatment was initiated with long-acting dihydropyridine calcium channel blockers amlodipine 5 mg/day or the gastrointestinal therapeutic system (GITS) formulation of nifedipine 30 mg/day, with the possible up-titration to amlodipine 10 mg/day or nifedipine-GITS 60 mg/day at 4 weeks of follow-up. The proportion of up-titration to higher dosages of antihypertensive drugs at 4 weeks of follow-up was higher in patients who commenced treatment in autumn/winter ( n = 302) than those who commenced treatment in spring/summer ( n = 199, 24.5 vs. 12.0%, P < 0.001). The control rate of clinic blood pressure, however, was lower in autumn/winter than in spring/summer at 4 (56.7 vs. 70.7%, P = 0.003) and 8 weeks of follow-up (52.5 vs. 74.9%, P < 0.001). At 8 weeks, patients who commenced treatment in autumn/winter, compared with those who commenced treatment in spring/summer, had a significantly ( P ≤0.03) smaller daytime (mean between-season difference -3.2/-2.8 mmHg) but greater nighttime SBP/DBP reduction (3.6/1.6 mmHg). Accordingly, at 8 weeks, the prevalence of nondippers was significantly ( P < 0.001) higher in spring/summer than in autumn/winter for both SBP (54.8 vs. 30.0%) and DBP (53.4 vs. 28.8%). Clinic blood pressure-guided antihypertensive treatment requires a higher dosage of medication in cold than warm seasons, which may have led to over- and under-treatment of nighttime blood pressure, respectively.

PS-P07-3: EFFICACY AND SAFETY OF NIFEDIPINE GASTROINTESTINAL THERAPEUTIC SYSTEM VERSUS RAMIPRIL IN CHINESE AND EUROPEAN PATIENTS WITH HYPERTENSION

Objective: In a post-hoc analysis of a multinational, randomized trial, we investigated whether the efficacy and safety of nifedipine gastrointestinal therapeutic system (GITS) and ramipril differed between Chinese and European patients with hypertension. Method: Previously treated (2-week washout) and untreated patients with hypertension were randomly assigned to treatment with nifedipine GITS 30 mg or ramipril 10 mg for 12 months, if they had elevated clinic (≧ 140/90 mmHg) and daytime (≧ 135/85 mmHg) ambulatory systolic/diastolic blood pressure (BP) and standard deviation of home (&gt; 7 mmHg) and daytime systolic BP (&gt; 12 mmHg). BP was measured at each of the clinic visits at baseline and during follow-up. Ambulatory and 7-day home BP monitoring were performed at baseline and 10 weeks and 12 months of follow-up. Results: The 67 Chinese and 101 European patients significantly differed in age (50.9 vs. 54.6 years), body mass index (24.5 vs. 27.0 kg/m2), clinic diastolic BP (87.9 vs. 92.5 mmHg), clinic heart rate (75.0 vs. 70.8 beats/minute) and nighttime diastolic BP (79.3 vs. 75.9 mmHg). However, within each ethnicity, patients were comparable between the nifedipine GITS and ramipril groups (P≧ 0.05). In both Chinese and European patients, BP was similarly reduced in the nifedipine GITS and ramipril groups, except that daytime systolic/diastolic BP reductions were 7.4/4.1 mmHg greater in the ramipril than nifedipine GITS group in Chinese (P = 0.02). The safety profile significantly (P for drug*ethnicity interaction ≦ 0.046) differed between the Chinese and European patients for the incidence of all adverse events (lower on nifedipine GITS in Chinese), ankle edema (higher on nifedipine GITS in Europeans) and dry cough (higher on ramipril in Chinese). Conclusion: In the Chinese and European patients with hypertension, nifedipine GITS and ramipril had similar BP lowering efficacy, but different safety profile and tolerability.

Role of α1-blockers in the current management of hypertension.

There is emerging evidence that α1‐blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood pressure control. However, there are several special indications. Benign prostatic hyperplasia is a compelling indication of α1‐blockers, because of the dual treatment effect on both high blood pressure and lower urinary tract symptoms. Many patients with resistant hypertension would require α1‐blockers as add‐on therapy. Primary aldosteronism screen is a rapidly increasing clinical demand in the management of hypertension, where α1‐blockers are useful for blood pressure control in the preparation for the measurement of plasma aldosterone and renin. Nonetheless, α1‐blockers have to be used under several considerations. Among the currently available agents, only long‐acting α1‐blockers, such as doxazosin gastrointestinal therapeutic system 4–8 mg daily and terazosin 2–4 mg daily, should be chosen. Orthostatic hypotension is a concern with the use of α1‐blockers especially in the elderly, and requires careful initial bedtime dosing and avoiding overdosing. Fluid retention is potentially also a concern, which may be overcome by combining an α1‐blocker with a diuretic.

Nicardia® XL (Nifedipine Extended Release): Technologically Advanced GITS Formulation Ensures Robust Efficacy and Assured Safety

Nifedipine is a classical dihydropyridine calcium channel blocker (CCB) indicated for the management of hypertension, vasospastic angina and chronic stable angina. Prestigious regulatory bodies like USFDA, EMA, CDSCO and TGA have approved long-acting Nifedipine for the management of hypertension and angina. Nifedipine was 1st introduced in United States as Adalat® (Bayer) in 1981 and in India as Nicardia® (J. B. Chemicals &amp; Pharmaceuticals) in 1985.&#x0D; Conventional Nifedipine shows the rapid onset and short duration of action which results in prompt and marked hypotensive effect but exhibits reflex SNS activation leading to flushing, tachycardia, worsening myocardial ischemia, and cerebrovascular ischemia. Nifedipine gastrointestinal therapeutic system (GITS) formulation addresses many of the concerns surrounding the older formulations of Nifedipine. Nifedipine GITS is a gold standard once-daily formulation of Nifedipine which allows relatively constant plasma drug concentrations over 24 hours. Nifedipine GITS provides a controlled release and gradual onset of action of Nifedipine, avoiding the reflex SNS activation resulting in improved tolerability and compliance.&#x0D; Clinical studies suggest that long-acting formulations of Nifedipine have slightly greater antihypertensive actions than Amlodipine. Nifedipine was also found to be more efficient than other CCBs like Amlodipine, Nicardipine, and Isradipine in resistant hypertensive patients. The addition of Nifedipine GITS to the conventional treatment of angina pectoris is safe and reduces the need for coronary angiography and interventions.&#x0D; Several landmark trials have demonstrated that long-acting Nifedipine improves endothelial function and arterial stiffness and reduces albuminuria, LV hypertrophy, atherosclerotic plaques and cardiovascular and cerebrovascular complications.&#x0D; This comprehensive review focuses on the superiority of the Nifedipine GITS formulation over the conventional Nifedipine and elaborates on the role of long-acting Nifedipine as a CCB of choice for the management of hypertension, resistant hypertension, angina pectoris and coronary artery disease.&#x0D; Keywords – Calcium Channel Blockers, Nifedipine, Long-Acting Nifedipine, Nifedipine GITS, Nifedipine Extended Release, Nicardia XL.

BLOOD PRESSURE VARIABILITY ASSESSED WITH OFFICE, HOME AND AMBULATORY MEASUREMENTS BEFORE AND AFTER ANTIHYPERTENSIVE DRUG TREATMENT: THE REVERENT TRIAL

Objective: Blood pressure (BP) variability (BPV) can be assessed using office (OBP), home (HBP) and ambulatory BP (ABP) measurements. In this analysis BPV indices derived using all the three methods were compared before and after 10 weeks of antihypertensive drug treatment. Design and method: Untreated hypertensives (or treated after washout period) with elevated BPV (systolic HBP standard deviation [SD] &gt; 7 mmHg and/or systolic daytime ABP SD &gt; 12 mmHg), were nalysedd to ramipril 10 mg or nifedipine gastrointestinal therapeutic system (GITS) 30 mg once daily, in the context of a multicenter 10-week, prospective, nalysedd, open-label, blinded-end point study. BPV was assessed using SD and coefficient of variation (CV) [weighted SD (wSD) and weighted CV (wCV) for 24h-ABP variability) of individual measurements. Results: Data from 146 participants from three research centers (Athens, Milan, Shanghai) were nalysed (mean age 53 ± 10 [SD] years, males 60%, baseline systolic OBP, HBP and 24h-ABP 143 ± 10, 138 ± 10, and 143 ± 10 mmHg, respectively). Systolic CV assessed by HBP was decreased with treatment, by OBP was unchanged and by ABP increased (p &lt; 0.05). HBP and ABP (not OBP) variability indices presented weak to moderate correlation, which was consistent before and after treatment (Table). HBP and ABP (not OBP) variability indices presented slight to fair agreement in detecting participants with high systolic BPV (top quartile of respective distribution) both before and after treatment (kappa statistic range 0.12–0.27). Conclusions: These data showed a moderate association between out-of-office (but not office) BPV indices both before and after administering BP lowering treatment, with reasonable agreement in detecting individuals with high BPV. Out-of-office BP measurements provide more similar BPV information than office measurements, both before and after administering antihypertensive drug treatment.

EFFICACY AND SAFETY OF NIFEDIPINE GASTROINTESTINAL THERAPEUTIC SYSTEM VERSUS RAMIPRIL IN CHINESE AND EUROPEAN PATIENTS WITH HYPERTENSION

Objective: In a post-hoc analysis of a multinational, randomized trial, we investigated whether the efficacy and safety of ramipril and nifedipine gastrointestinal therapeutic system (GITS) differed between the Chinese and European patients with hypertension. Design and method: Previously treated and untreated (2 weeks washout) male and females patients aged 35–75 years with a clinic systolic/diastolic blood pressure (BP) over 140/90 mmHg and a daytime ambulatory systolic/diastolic BP over 135/85 mmHg were randomly assigned to ramipril 10 mg or nifedipine GITS 30 mg for 10 weeks in monotherapy (main study) and for an extension to 12 months with the possible up-titration of the monotherapy and combination with a diuretic or an alpha-blocker (extension study). BP lowering efficacy was evaluated for clinic, ambulatory and home BP at 10 weeks and 12 months follow-up. Results: The 67 Chinese and 101 European patients significantly (P &lt; 0.01) differed in several major characteristics such as age (50.9 vs. 54.6 years), body-mass index (24.5 vs. 27.0 kg/m2), heart rate (75.0 vs. 70.8 beats/minute) and clinic (87.9 vs. 92.5 mmHg) and nighttime diastolic BP (79.3 vs. 75.9 mmHg), but did not differ in any characteristic between the ramipril and nifedipine GITS groups within each ethnicity (P&gt; 0.05). BP was similarly reduced in the two treatment groups in both Chinese and European patients, except for a significantly greater daytime systolic/diastolic BP reduction in the ramipril than nifedipine-GITS group in the Chinese patients (+7.4/ + 4.1 mmHg, P = 0.02). The Chinese, compared with European patients, had a higher incidence rate of all adverse events (13 [38.2%] vs. 14 [28.6%], P = 0.48) and dry cough in the ramipril group (11 [32.4%] vs. 3 [6.1%], P = 0.003) but lower incidence rate of all adverse events in the nifedipine GITS group (4 [12.1%] vs. 18 [34.6%], P = 0.02). Conclusions: In the Chinese and European patients with hypertension, ramipril and nifedipine GITS had similar BP lowering efficacy, but different incidence rate of adverse events.

IDENTIFICATION OF HYPERTENSIVE PATIENTS WITH INCREASED BLOOD PRESSURE VARIABILITY USING DIFFERENT MEASUREMENT METHODS BEFORE AND AFTER TREATMENT: THE REVERENT TRIAL

Objective: Blood pressure (BP) variability (BPV) can be assessed with office (OBP), home (HBP), and ambulatory BP (ABP) measurements. In this analysis, BPV indices assessed using all the three methods were compared before and 10 weeks after administering antihypertensive drug treatment. Design and method: Untreated hypertensives (or treated after washout period) with elevated BPV (systolic HBP standard deviation [SD] &gt; 7 mmHg and/or systolic daytime ABP SD &gt; 12 mmHg), were nalysedd to ramipril 10 mg or nifedipine gastrointestinal therapeutic system (GITS) 30 mg once daily, in the context of a multicenter 10-week, prospective, nalysedd, open-label, blinded-end point study. BPV was assessed using SD and coefficient of variation (CV) [weighted SD (wSD) and weighted CV (wCV) for 24h-ABP variability) of individual measurements. Results: Data from 146 participants from three research centers (Athens, Milan, Shanghai) were nalysed (mean age 53 ± 10 [SD] years, males 60%, baseline systolic OBP, HBP and 24h-ABP 143 ± 10, 138 ± 10, and 143 ± 10 mmHg, respectively). All BPV indices (except for diastolic OBP) presented significant correlations in terms of pre- vs post- treatment, with ABP indices (especially diastolic) achieving the strongest correlations (Table). Moreover, out-of-office BPV indices (especially ABP) presented fair to moderate agreement in detecting participants with high BPV (top quartile of respective distribution) pre- vs post- treatment. Conclusions: Untreated hypertensives with high out-of-office BPV retain this classification even after BP lowering therapy, which suggests that BPV is an intrinsic feature of the individuals’ BP.

Dosing Time Matters? Nighttime vs. Daytime Administration of Nifedipine Gastrointestinal Therapeutic System (GITS) or Amlodipine on Non-dipper Hypertension: A Randomized Controlled Trial of NARRAS.

Background: Non-dipper hypertension is often characterized by a blunted decrease of nocturnal blood pressure (BP) and is associated with increased risk of target organ damage and cardiovascular (CV) events, while the optimal treatment strategy is yet to be established. This trial was designed to evaluate whether nocturnal BP reduction and arterial stiffness improvement differ from antihypertensive agents and time of administration.Methods: Young and middle-aged adults (18–65 years) with non-dipper hypertension were randomly assigned to nifedipine GITS (gastrointestinal therapeutic system) 30 mg or amlodipine besylate 5 mg once daily for 8 weeks, either taken in the morning or at night. Dose was doubled at 4-week if BP is not at goal. Twenty-four hour ambulatory BP monitoring (ABPM) and arterial stiffness were evaluated before and after 8 weeks of pharmacotherapy. The primary efficacy measure was the average nighttime systolic BP reduction.Results: A total of 98 non-dipper hypertensive patients (mean age 46.3 years) were randomized during Dec, 2016 and Dec, 2020, of whom 72 (73%) patients completed all ABPM and follow-up evaluations. Nighttime systolic BP significantly reduced at 8 weeks vs. baseline with nifedipine GITS or amlodipine, irrespective of dosing at nighttime (−9.9 vs −9.9 mmHg, P > 0.05) or daytime (−11.5 vs. −10.9 mmHg, P > 0.05). No difference was seen between these two agents, when combining the data of nighttime and daytime dosing together (−10.8 vs. −10.5 mmHg, respectively, P = 0.898). Daytime, 24-h systolic BP, diastolic BP at different time and pulse wave velocity reduced significantly and comparably, and recovery of dipping rhythm were similar among groups.Conclusion: Nighttime dosing of long-acting antihypertensive preparations, nifedipine GITS or amlodipine demonstrated similar effects on nocturnal BP reduction, dipping rhythm restoration and arterial elasticity improvement in younger subjects with non-dipper hypertension. These effects were comparable with morning dosing.

Serum uric acid change in relation to antihypertensive therapy with the dihydropyridine calcium channel blockers

Purpose We investigated serum uric acid changes in relation to the achieved clinic and ambulatory blood pressure after 8 weeks of antihypertensive therapy with two dihydropyridine calcium channel blockers. Materials and methods The study participants were patients with clinic and ambulatory hypertension, enrolled in a randomised controlled trial that compared amlodipine (5–10 mg, n = 215) and nifedipine gastrointestinal therapeutic system (GITS, 30–60 mg, n = 203). Hyperuricaemia was defined as a serum uric acid concentration of ≥420 µmol/L in men and ≥360 µmol/L in women. Analysis of covariance and multiple regression analyses were performed to study the associations between serum uric acid changes and the achieved clinic and ambulatory blood pressure during follow-up. Results At baseline, 67 (16.0%) of the 418 patients had hyperuricaemia. Antihypertensive treatment reduced clinic and 24-h daytime and night-time systolic/diastolic blood pressure by a mean (±standard error [SE]) change of −17.4 ± 0.6/−8.6 ± 0.4 mm Hg and −13.7 ± 0.5/−8.3 ± 0.3 mm Hg, −13.8 ± 0.6/−8.4 ± 0.4 mm Hg, and −12.7 ± 0.7/−8.0 ± 0.4 mm Hg, respectively. Antihypertensive treatment reduced serum uric acid by a mean (±SE) change of −9.3 ± 2.8 μmol/L. The serum uric acid changes differed according to the achieved clinic and ambulatory blood pressure, and were statistically significant (mean ± SE −20.6 ± 6.6 to −10.7 ± 2.9 μmol/L, p ≤ 0.04) at the systolic/diastolic ranges of 130–139/≥90 mm Hg in clinic pressure, and <130/75–84 mm Hg, <145/80–84 mm Hg and <120/65–69 mm Hg in 24-h, daytime and night-time ambulatory pressure. Conclusion Our study showed that antihypertensive therapy with a dihydropyridine calcium channel blocker was associated with reduced serum uric acid, especially when 24-h ambulatory systolic blood pressure was controlled.

Effectiveness and Tolerability of Nifedipine GITS in Patients with Chronic Kidney Disease and Uncontrolled Hypertension: A Prospective, Multicenter, Observational Study (ADRENAL).

IntroductionAchieving target blood pressure (BP) goals in patients with chronic kidney disease (CKD) and uncontrolled hypertension is a challenge. Various studies have shown the efficacy of nifedipine gastrointestinal therapeutic system (GITS) 60 mg in patients with hypertension. However, there is a paucity of clinical studies in patients with CKD. Hence, we conducted this study to evaluate the effectiveness and tolerability of nifedipine GITS 60 mg in Chinese patients with CKD and uncontrolled hypertension in real-world clinical settings.MethodsIn a prospective, multicenter, observational study, Chinese patients with CKD and uncontrolled hypertension were given nifedipine GITS 60 mg with a primary endpoint of change in office systolic BP (SBP) at 12 weeks. The secondary endpoints included changes at 12 weeks in office diastolic BP (DBP), office SBP and DBP in SBP subgroups (140–160 mmHg and ≥ 160 mmHg) and CKD stages subgroups, SBP and DBP control rate, and the adverse events (AEs). Statistical analysis was performed using SAS® version 9.4.ResultsIn total, 871 and 622 patients were included in the safety analysis set and efficacy analysis set respectively. The mean office SBP and DBP at baseline were 162.9 and 97.3 mmHg, respectively. At week 12, the mean change in SBP was − 24.0 mmHg (95% confidence interval [CI] − 25.32, − 22.65 mmHg); after missing data were accounted for, it was − 23.9 mmHg (95% CI − 25.25, − 22.60 mmHg). Marked decreases in DBP, and office SBP and DBP in baseline SBP subgroups as well as CKD stages were observed at week 12. The BP control rate at week 12 was 50.0%. Twenty-three (2.6%) patients reported at least one drug-related AEs. No event of hypotension or death occurred during the study.ConclusionNifedipine GITS 60 mg showed effectiveness and tolerability in reducing office SBP and DBP in Chinese patients with CKD and uncontrolled hypertension.Trial RegistrationClinicalTrials.gov identifier NCT03194633.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01850-3.

Preoperative Amlodipine Is Efficacious in Preventing Intraoperative HDI in Pheochromocytoma: Pilot RCT.

Preoperative blockade with α-blockers is recommended in patients with pheochromocytoma/paraganglioma (PPGL). The data on calcium channel blockade (CCB) in PPGL are scarce. We aimed to compare the efficacy of CCB and α-blockers on intraoperative hemodynamic instability (HDI) in PPGL. In the interim analysis of this monocentric, pilot, open-label, randomized controlled trial, patients with solitary, secretory, and nonmetastatic PPGL were randomized to oral prazosin gastrointestinal therapeutic system (GITS) (maximum 30 mg, n = 9) or amlodipine (maximum 20 mg, n = 11). The primary outcomes were the episodes and duration of hypertension (systolic blood pressure ≥ 160 mmHg) and hypotension (mean arterial pressure < 60 mmHg) and duration of HDI (hypertension and/or hypotension) as a percentage of total surgical time (from induction of anesthesia to skin closure). The median (IQR) episodes (2 [1-3] vs 0 [0-1]; P = 0.002) and duration of hypertension (19 [14-42] vs 0 [0-3] minutes; P = 0.001) and intraoperative HDI duration (22.85 ± 18.4% vs 2.44 ± 2.4%; CI, 8.68-32.14%; P 0.002) were significantly higher in the prazosin GITS arm than the amlodipine arm, whereas episodes and duration of hypotension did not differ between the 2 groups. There was no perioperative mortality. One patient had intraoperative ST depression on the electrocardiogram. The drug-related adverse effects were pedal edema (1 in amlodipine), dizziness (1 in prazosin GITS), and tachycardia (6 in prazosin GITS and 3 in amlodipine). Preoperative blockade with amlodipine is an efficacious alternative to prazosin GITS in preventing intraoperative HDI in PPGL. Larger studies that compare preoperative blockade by amlodipine with other α-blockers like phenoxybenzamine and/or doxazosin in PPGL patients are warranted.

Effects of the valsartan/amlodipine combination and nifedipine gastrointestinal therapeutic system monotherapy on brachial pulse pressure and radial augmentation index in hypertensive patients.

In a substudy of a randomized controlled trial, we investigated the effects of the valsartan/amlodipine single-pill combination and nifedipine gastrointestinal therapeutic system (GITS) monotherapy on brachial pulse pressure (bPP) and radial augmentation index (rAI) in patients with previously uncontrolled hypertension. We performed measurements of clinic blood pressure (BP) and pulse rate and rAI (n = 63) and ambulatory BP monitoring (n = 42) at baseline and 12-week of follow-up. Analysis of covariance was performed to calculate the least square mean change from baseline and between-group differences [95% confidence interval (CI)]. Correlation analysis was performed to study the interrelationship between the changes in bPP and rAI and in pulse rate. After 12-week treatment, clinic and ambulatory SBP/DBP and pulse rate were not differently changed between the valsartan/amlodipine (n = 29) and nifedipine GITS groups (n = 34, P ≥ 0.06) except daytime SBP (P = 0.01). The reductions in 24-h and daytime ambulatory bPP were significantly greater in the former than the latter group (P ≤ 0.04). rAI increased slightly by 3.5% (P = 0.20) and 5.2% (P = 0.06) in the valsartan/amlodipine and nifedipine groups, respectively, with a between-group difference of -1.7% (95% CI -9.6 to 6.1%, P = 0.66). In the two groups combined, the changes in clinic and ambulatory bPP were not or weakly associated with that in clinic or ambulatory pulse rate (r = -0.14 to 0.36, P = 0.02-0.95), while the changes in rAI were more strongly or significantly associated with that in clinic or ambulatory pulse rate (r = -0.39 to -0.23, P = 0.02-0.16). Antihypertensive drug-induced changes in rAI but not bPP were dependent on pulse rate.

A comparative study for the effects of nifedipine GITS and amlodipine besylate administrated in daytime or at nighttime on recovery of blood pressure rhythm and arterial stiffness in the young and middle-aged subjects with non-dipper hypertension (NARRAS): Design and rationale.

Hypertensive patients with a blunted or absent nocturnal blood pressure (BP) drop (non-dipper) are associated with arterial stiffening and additional cardiovascular risk. Non-dipper hypertension is prevalent in young and middle-aged adults; but the optimal antihypertensive strategy remains unclear. There is a need to explore the effects of different antihypertensive agents and time of administration on recovery of dipper rhythm and arterial stiffness in this population. NARRAS is a randomised controlled trial (RCT), designed to evaluate the effects of long-acting antihypertensive agents administrated in daytime or at nighttime on BP rhythm restoration and arterial stiffness in young and middle-aged non-dipper hypertensive patients. Participants will be randomly assigned to nifedipine GITS (gastrointestinal therapeutic system) 30mg or amlodipine besylate 5mg once daily, either taken in the morning or at night. Subjects will be divided into the following groups: group A. nifedipine administrated in the morning (N-M); B. nifedipine at night (N-N); C. amlodipine in the morning (A-M); D. amlodipine at night (A-N). If BP is not at goal during 4week's visit, dosage of antihypertensive agents will be doubled. BP is measured via 24-hour ambulatory BP monitoring (ABPM) and arterial stiffness is examined before and after 8weeks of pharmaceutical intervention. The primary endpoint is the difference of average nighttime systolic BP reduction between nifedipine GITS and amlodipine. The second endpoint is the percentage of restoration of a dipper rhythm at 8weeks. The potential of nighttime dosing on arterial stiffness is also investigated. A sample size of 120 will have 80% power to detect a 3mmHg nighttime systolic BP difference between 2 drugs determined with ABPM. NARRAS study is the first RCT to evaluate the effects of nifedipine GITS and amlodipine besylate on restoration of dipping rhythm and arterial elasticity, either administrated in the morning or evening, in younger non-dipper hypertensive subjects. The findings of NARRAS are likely to be potential to facilitate new therapeutic strategies for this condition. NARRAS was registered in clinicaltrials.gov, NCT02940548.

Investigation of bioequivalence, safety, and tolerability of a fixed-dose combination of nifedipine GITS and candesartan compared with the corresponding loose-dose combination under fed conditions .

To investigate the bioequivalence, safety, and tolerability of single-dose nifedipine gastrointestinal therapeutic system (GITS) and candesartan as a fixed-dose combination (FDC) relative to the loose combination in healthy males under fed conditions. A total of 48 subjects received nifedipine GITS 60 mg and candesartan 32 mg as an FDC or loose combination in an open-label, 2-way crossover, 2-treatment sequence design, with a washout of at least 5 days between treatments. Study medications were administered following an overnight fast of at least 10 hours, and 30 minutes after ingestion of a high-fat test meal. Plasma samples were collected at intervals over a 48-hour period post-dosing. Safety and tolerability parameters were documented throughout the study. For nifedipine, 90% confidence intervals (CIs) for the ratios of FDC/loose combination were within acceptance limits of bioequivalence (i.e., 80 - 125%) for both AUC0-tlast (91.36%; 111.5%) and Cmax (87.93%; 100.5%). For candesartan, 90% CIs for the ratios of FDC/loose combination were within acceptance limits for AUC0-tlast (112.8%; 124.4%), but not for Cmax (120.5%; 137.8%). There were no serious adverse events (AEs) or AEs leading to treatment discontinuation and no clinically relevant changes in vital signs or laboratory parameters. A single dose of the FDC-containing nifedipine GITS 60 mg and candesartan 32 mg, when compared to the corresponding loose combination under fed conditions, met the criterion for bioequivalence based on AUC0-tlast, while the slightly higher Cmax for candesartan is not considered clinically relevant. The FDC displayed safety and tolerability profiles similar to the loose combination.

A randomized controlled trial on the blood pressure-lowering effect of amlodipine and nifedipine-GITS in sustained hypertension.

In a multicenter, randomized trial, we investigated whether the long half-time dihydropyridine calcium channel blocker amlodipine was more efficacious than the gastrointestinal therapeutic system (GITS) formulation of nifedipine in lowering ambulatory blood pressure (BP) in sustained hypertension (clinic systolic/diastolic BP 140-179/90-109mmHg and 24-hour systolic/diastolic BP≥130/80mmHg). Eligible patients were randomly assigned to amlodipine 5-10mg/day or nifedipine-GITS 30-60mg/day. Ambulatory BP monitoring was performed for 24hours at baseline and 4-week treatment and for 48hours at 8-week treatment with a dose of medication missed on the second day. After 8-week treatment, BP was similarly reduced in the amlodipine (n=257) and nifedipine-GITS groups (n=248) for both clinic and ambulatory (24-hour systolic/diastolic BP10.3/6.5 vs 10.9/6.3mmHg, P≥0.24) measurements. However, after missing a dose of medication, ambulatory BP reductions were greater in the amlodipine than nifedipine-GITS group, with a significant (P≤0.04) between-group difference in 24-hour (-1.2mmHg) and daytime diastolic BP (-1.5mmHg). In conclusion, amlodipine and nifedipine-GITS were efficacious in reducing 24-hour BP. When a dose of medication was missed, amlodipine became more efficacious than nifedipine-GITS.

PP.02.03] EFFICACY AND TOLERABILITY OF NIFEDIPINE GASTROINTESTINAL THERAPEUTIC SYTEM 60MG IN CHINESE PATIENTS WITH UNCONTROLLED HYPERTENSION

Objective: Efficacy and tolerability of nifedipine gastrointestinal therapeutic system (GITS) 60 mg once daily (QD) in uncontrolled blood pressure (BP) is not completely explored in China. Therefore, we studied the efficacy and tolerability of nifedipine GITS 60 mg in Chinese hypertensive patients inadequately controlled with prior monotherapy. Design and method: This single-arm phase-4 study (NCT02413515) enrolled 278 hypertensive adults from 13 centers in China, in whom BP was uncontrolled after 4-weeks of antihypertensive monotherapy. The patients received oral nifedipine GITS 60 mg QD for 8-consecutive weeks. Primary endpoint was mean sitting systolic BP control rate (MSSBP; <130 mmHg for subjects with diabetes (DM) and <140 mmHg for others) at 8-weeks. Secondary endpoints included change in MSSBP and mean sitting diastolic BP (MSDBP), 24-h SBP and DBP reduction measured by 24 hour ABPM, and safety of nifedipine GITS 60 mg. Results: A total of 269 patients (mean age 55 ± 8.21 years, 62.8% males, 28.3% with DM) were included for efficacy and 278 for safety analysis. At week 8, overall MSSBP control rate was 64.7%. From baseline to 8-weeks, decrease in MSSBP and MSDBP was −15.2 ± 11.37 mmHg (147.9 ± 6.87 mmHg to 132.7 ± 11.82 mmHg) and −6.4 ± 7.87 mmHg (89.1 ± 7.13 mmHg to 82.7 ± 8.04), respectively (Table 1). The control rate was lower in patients with DM From baseline to 8-weeks, mean 24-h SBP was decreased from 138.5 ± 12.78 mmHg to 131.6 ± 12.29 mmHg (diff. −6.9 ± 11.30 mmHg, 95% CI −8.29, −5.56) and mean 24-h DBP was decreased from 86.4 ± 9.32 mmHg to 82.5 ± 9.12 mmHg (diff. −3.9 ± 7.63 mmHg, 95% CI −9.47, −6.42). Fifty (18%) cases of adverse events (AEs) and 25 (9%) cases of peripheral edema were reported. No drug related serious AEs and deaths occurred during the study.Conclusions: Nifedipine GITS 60 mg QD further improved control rate of MSSBP and MSDBP and was well tolerated in Chinese patients previously treated with standard dosage of antihypertensive monotherapy.

Clinical Utility of Amlodipine/Valsartan Fixed-Dose Combination in the Management of Hypertension in Chinese Patients

Amlodipine/valsartan (Aml/Val) single-pill combination (SPC) therapy has been widely used and studied in clinical practice in recent years. This article reviews the Chinese and English literature on the clinical use of Aml/Val SPC therapy in Chinese hypertensive patients. According to five studies concerning the efficacy and safety of this treatment, Aml/Val SPC therapy was more efficacious than monotherapy with valsartan, amlodipine, or the nifedipine gastrointestinal therapeutic system. This treatment showed greater blood pressure-lowering effects, a higher blood pressure control rate, and a higher response rate. Aml/Val SPC treatment was well tolerated, with adverse event rates similar to those of monotherapy with valsartan or amlodipine and significantly rarer adverse events compared with the nifedipine gastrointestinal therapeutic system. Aml/Val SPC is a highly efficacious and well-tolerated antihypertensive treatment in Chinese hypertensive patients.

OP.4C.10] CLINICALLY IMPORTANT DIFFERENCES IN SYSTOLIC AMBULATORY BLOOD PRESSURE IN PATIENTS SWITCHED BETWEEN ALTERNATE NIFEDIPINE OSMOTIC DELIVERY FORMULATIONS

Objective: Anecdotal evidence suggested clinically important systolic blood pressure (SBP) differences occurred in our patients whose nifedipine was being switched by pharmacies between AdN (Adalat XL – a formulation providing zero order release from the GastroIntestinal Therapeutic System - GITS) and MyN (Mylan-nifedipine ER - a formulation providing a delayed first-order release from the Osmotic Release Oral System - OROS). In vitro dissolution studies showed greater lag time to initial release from MyN and declining release at end of dosing interval. The objective of this study was to use Ambulatory Blood Pressure Monitoring (ABPM) to examine whether differences in overall effectiveness and duration of action exist between these two nifedipine formulations. Design and method: A randomized cross-over trial studied 20 patients receiving daily morning AdN vs. MyN 60 mg. After each 2-week period, 24-h ABPM was done. SBP data for 24 h and last 8 h (22:00 - 06:00 h) were examined using a Generalized Additive Mixed Model (GAMM). The software (R) used 2560 data points to model SBP population curves and compare them statistically. Results: GAMM of SBP over time showed MyN mean ± SE SBP was 2.59 ± 1.09 mmHg higher for 24 h (p = 0.0173) and 4.18 ± 1.6 mmHg higher for last 8 h (p = 0.0098). Mean 24-h SBP was > = 2 mmHg higher, while taking MyN in 50% of patients while SBP for last 8 h ranged as high as 18 mmHg higher while taking MyN.Conclusions: Clinically meaningful differences in SBP were seen in a cohort of patients when taking MyN compared to when they were taking AdN. This was likely based on differences in release profiles. For nifedipine, a potent vasodilator with a steep dose-response relationship and a 2-hour half-life, differences in timing and/or extent of delivery over as little as 6 h could allow clinically important changes in SBP. These data support the conclusion that formulations using differing release technologies are not suitable for bioequivalence testing. Undisclosed switching of nifedipine formulations by pharmacies can lead to an undesirable increase in variability in BP control.

Evidence for Using Doxazosin in the Treatment of Posttraumatic Stress Disorder.

There is evidence that doxazosin is effective in the treatment of posttraumatic stress disorder (PTSD). Doxazosin is a "me-too" drug of prazosin. Doxazosin has an improved absorption profile and this likely minimizes the risk for unintended adverse hypotensive effects. The availability of doxazosin in the gastrointestinal therapeutic system (GITS) form permits a higher initial daily dose (4 mg/day) while avoiding significant first-dose side effects. The treatment of PTSD with prazosin has several disadvantages due to its short duration of action (6-8 hours), which results in multiple doses being required. Prazosin may wear off and this may lead to nightmares in the latter half of the sleep. Doxazosin has significant advantages over prazosin in clinical practice because it has a long half-life and requires only once-daily dosing. This may lead to better adherence and greater effectiveness in the treatment of PTSD.

PP.26.12] EFFICACY OF NIFEDIPINE GASTROINTESTINAL SYSTEM ON ARTERIAL STIFFNESS AND STRUCTURAL VASCULAR LESIONS IN MILD HYPERTENSIVE CHINESE PATIENTS WITH INCREASED PULSE WAVE VELOCITY

Objective: Limited data are available on the effects of nifedipine gastrointestinal therapeutic system (GITS) on arterial stiffness in hypertensive Chinese patients. This study evaluated the efficacy of nifedipine GITS on arterial stiffness and structural vascular lesions in mild hypertensive Chinese patients with increased pulse wave velocity (PWV). Design and method: This single-center, single-group, open-label, prospective, phase IV study recruited patients with mild hypertension and increased PWV from December 2013 to December 2014 (N = 138; age, 18–75 years; systolic blood pressure (SBP),>140 mmHg,<160 mmHg; diastolic BP (DBP),>90 mmHg,<100 mmHg; increased brachial-ankle PWV [baPWV,12 ms1]). Nifedipine GITS (30 mg/d) was administered for 24 weeks to achieve target BP of <140/90 mmHg. The dose was up-titrated of 60 mg/d in case of unsatisfactory BP reduction after 4 weeks. Primary study end point was the change in baPWV after nifedipine GITS treatment. Hemodynamic parameters (office BP, 24-h ambulatory BP monitoring (ABPM), heart rate (HR) and baPWV) were evaluated at baseline and followed-up at 2, 4, 8, 12, 18 and 24 weeks. Results: A majority of the patients (n = 117; 84.8%) completed the study. baPWV decreased significantly at 4 weeks compared with baseline (1598.87 ± 239.82 cm/s vs. 1500.89 ± 241.15 cm/s,P < .001) and remained stable at 12 weeks (1482.24 ± 215.14 cm/s,P < .001) and maintained steadily up to 24 weeks (1472.58 ± 205.01 cm/s,P < .001). Office BP reduced from baseline to week 4 (154/95 mmHg vs 136/85 mmHg) and maintained until 24 weeks. Nifedipine GITS significantly decreased 24-h ABPM (P < .001) after 24 weeks from baseline. Mean arterial pressure (MAP) and pulse pressure were lowered significantly after 4, 12 and 24 weeks treatment (P < .001). HR did not change significantly at any time point compared with baseline (P > .05). Multiple linear regression analysis revealed that baPWV were significantly correlated with changes in SBP, DBP, and MAP (P < .05), but not with changes in pulse pressure (P > .05). Conclusions: baPWV was significantly decreased after the administration of nifedipine GITS in patients with mild hypertension and increased PWV. Improvement in arterial stiffness was seen after 4 weeks, reflecting the BP-lowering effects of nifedipine GITS.