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Isradipine Versus Placebo in Early Parkinson Disease: A Randomized Trial.
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Annals of internal medicine. 2020;(9):591-598
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Abstract
BACKGROUND Studies suggest that dihydropyridine calcium-channel blockers may be associated with reduced risk for Parkinson disease (PD). OBJECTIVE To assess the effect of isradipine, a dihydropyridine calcium-channel blocker, on the rate of clinical progression of PD. DESIGN Multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT02168842). SETTING 57 Parkinson Study Group sites in North America. PARTICIPANTS Patients with early-stage PD (duration <3 years) who were not taking dopaminergic medications at enrollment. INTERVENTION 5 mg of immediate-release isradipine twice daily or placebo for 36 months. MEASUREMENTS The primary outcome was change in the Unified Parkinson's Disease Rating Scale (UPDRS) parts I to III score measured in the antiparkinson medication "ON" state between baseline and 36 months. Secondary outcomes included time to initiation and use of antiparkinson medications, time to onset of motor complications, change in nonmotor disability, and quality-of-life measures. RESULTS 336 patients were randomly assigned (mean age, 62 years [SD, 9]; 68% men; disease duration, 0.9 year [SD, 0.7]; mean UPDRS part I to III score, 23.1 [SD, 8.6]); 95% of patients completed the study. Adjusted least-squares mean changes in total UPDRS score in the antiparkinson medication ON state over 36 months for isradipine and placebo recipients were 2.99 (95% CI, 0.95 to 5.03) points versus 3.26 (CI, 1.25 to 5.26) points, respectively, with a treatment effect of -0.27 (CI, -3.02 to 2.48) point (P = 0.85). Statistical adjustment for antiparkinson medication use did not change the findings. Secondary outcomes showed no effect of isradipine treatment. The most common adverse effects of isradipine were edema and dizziness. LIMITATION The isradipine dose may have been insufficient to engage the target calcium channels associated with neuroprotective effects. CONCLUSION Long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage PD. PRIMARY FUNDING SOURCE National Institute of Neurological Disorders and Stroke.
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Beta blockers versus calcium channel blockers for provocation of vasospastic angina after drug-eluting stent implantation: a multicentre prospective randomised trial.
Sawano, M, Katsuki, T, Kitai, T, Tamita, K, Obunai, K, Ikegami, Y, Yamane, T, Ueda, I, Endo, A, Maekawa, Y, et al
Open heart. 2020;(2)
Abstract
BACKGROUND Drug-eluting stent-induced vasospastic angina (DES-VSA) has emerged as a novel complication in the modern era of percutaneous coronary intervention (PCI). Although beta blockers (BBs) are generally recommended for coronary heart disease, they may promote incidence of DES-VSA. This study aimed to compare the effects of calcium channel blockers (CCBs) perceived to be protective against DES-VSA and BBs on subsequent coronary events after second-generation drug-eluting stent implantation. METHODS In this multicentre prospective, randomised study, 52 patients with coronary artery disease who underwent PCI for a single-vessel lesion with everolimus-eluting stent placement were randomised into post-stenting BB (N=26) and CCB (N=26) groups and followed for 24 months to detect any major cardiovascular events (MACE). A positive result on acetylcholine provocation testing during diagnostic coronary angiography (CAG) at 9 months was the primary endpoint for equivalence. MACE included all-cause death, non-fatal myocardial infarction, unstable angina, cerebrovascular disease or coronary revascularisation for stable coronary artery disease after index PCI. RESULTS At 9 months, 42 patients (80.8%) underwent diagnostic coronary angiography and acetylcholine provocation testing. Among them, seven patients in each group were diagnosed with definite vasospasm (intention-to-treat analysis 26.9% vs 26.9%, risk difference 0 (-0.241, 0.241)). Meanwhile, the secondary endpoint, 24-month MACE, was higher in the CCB group (19.2%) than in the BB group (3.8%) (p=0.01). In detail, coronary revascularisation for stable coronary artery disease was the predominant endpoint that contributed to the greater proportion of MACE in the CCB group (CCB (19.2%) vs BB (3.8%), p=0.03). CONCLUSIONS The incidence of acetylcholine-induced coronary artery spasms did not differ between patients receiving BBs or CCBs at 9 months after PCI. However, a higher incidence of 2-year MACE was observed in the CCB group, suggesting the importance of BB administration. TRIAL REGISTRATION NUMBER This study was registered at the Japanese University Hospital Medical Information Network (UMIN) Clinical Trial Registry (The Prospective Randomized Trial for Optimizing Medical Therapy After Stenting: Calcium-Beta Trial; UMIN000008321, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009536).
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A Prospective Noninterventional, Observational Study to Describe the Effectiveness and Safety of Trandolapril and Verapamil Single-Pill Combination in the Management of Patients with Hypertension and Type 2 Diabetes Mellitus: A Harvest TR Study.
Atalar, E, Eskin, F, Tugtekin, HB, Karabulut, A, Kanyilmaz, S, Kirbiyik, H, Ozyildiz, AG
BioMed research international. 2020;:2123601
Abstract
Maintaining regular blood pressure control usually requires multidrug regimens rather than monotherapy. The objective of this study was to describe the effectiveness and safety of an angiotensin-converting enzyme inhibitor and a nondihydropyridine calcium channel blocker in a single-tablet combination in patients with hypertension, a heart rate higher than 70 beats/min, and type 2 diabetes mellitus (T2DM). This study was conducted in Turkey as a prospective, noninterventional, observational study. At 22 clinical sites, the data of 200 patients with hypertension were used for efficacy analysis; however, 262 patients received at least one dose of trandolapril/verapamil fixed-dose combination at two dose strengths. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, PR interval, glycated haemoglobin (HbA1c), and albumin/creatinine ratios were recorded during 8 weeks of treatment. With treatment, the mean (±SD) SBP that was recorded as 162.8 (±14.642) mm Hg at baseline was reduced to 131.7 ± 11.1 mm Hg at week 8 (p < 0.05). Similarly, the mean DBP was reduced from 93.76 ± 9.16 mm Hg to 77.6 ± 7.6 mm Hg (p < 0.001). Following 8 weeks of treatment, SBP and DBP values were reduced below 140 mm Hg and 90 mm Hg in most patients (81.5%), respectively. The mean heart rate as evaluated using electrocardiography measurements was reduced to 78.25 beats/min at week 8 as compared with baseline during trandolapril/verapamil single-pill combination treatment (p < 0.001). Treatment with trandolapril and verapamil was well tolerated over 8 weeks with no unexpected safety signals. In conclusion, the single-pill combination of trandolapril and verapamil was considered effective in reducing and controlling blood pressure in patients with hypertension and T2DM. There was a significant improvement in HbA1c and ACR levels in a smaller subgroup of the patient cohort. The trandolapril/verapamil combination was evaluated as being safe and well-tolerated following a treatment period of 8 weeks. This trial was registered with NCT02298556.
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Reaching blood pressure guideline targets with the CNIC polypill in patients with a previous cardiovascular event in Mexico: a post hoc analysis of the SORS study.
Gómez-Álvarez, E, Verdejo, J, Ocampo, S, Ruiz, E, Martinez-Rios, MA
Future cardiology. 2020;(1):53-60
Abstract
Aim: To determine the effectiveness of Centro Nacional de Investigaciones Cardiovasculares (CNIC)-polypill (acetylsalicylic acid 100 mg, ramipril 5/10 mg, simvastatin 40 mg) in achieving blood pressure (BP) goals. Patients & methods: A multicenter, observational, one cohort, prospective study. BP targets were analyzed in patients with cardiovascular disease after 12-months treatment with the CNIC polypill. Results: A total of 572 patients (59.4 ± 13.9 years, 57.3% men) were analyzed. At baseline, BP was 147.1 ± 18.1/88.3 ± 10.6 mmHg, 97.1% of patients were taken renin-angiotensin system inhibitors, 5.4% calcium antagonists, 1.9% diuretics and 13.1% β-blockers. The proportion of patients who achieved BP targets increased from 20.1 to 55.4% (p < 0.001). Conclusion: In routine practice, switching from usual care to the CNIC-polypill in patients with cardiovascular disease could facilitate achieving BP goals.
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Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease.
de Jong, DLK, de Heus, RAA, Rijpma, A, Donders, R, Olde Rikkert, MGM, Günther, M, Lawlor, BA, van Osch, MJP, Claassen, JAHR
Hypertension (Dallas, Tex. : 1979). 2019;(2):413-420
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Cerebrovascular changes, including reduced cerebral blood flow (CBF), occur early in the development of Alzheimer disease and may accelerate disease progression. This randomized, double-blind, placebo-controlled study investigated how 6 months of treatment with the calcium antagonist nilvadipine would affect CBF in patients with mild-to-moderate Alzheimer disease. CBF was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in a priori defined regions of interest including the hippocampus. Fifty-eight patients were randomly assigned (29 in each group), of whom 22 in both groups had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean age was 72.8±6.2 years, mean mini-mental state examination was 20.4±3.4. Nilvadipine treatment lowered systolic blood pressure (Δ=-11.5 [95% CI, -19.7 to -3.2] mm Hg; P<0.01), while whole-brain gray-matter CBF remained stable (Δ=5.4 [95% CI, -6.4 to 17.2] mL/100 g per minute; P=0.36). CBF in the hippocampus increased (left: Δ=24.4 [95% CI, 4.3-44.5] mL/100 g per minute; P=0.02; right: Δ=20.1 [95% CI, -0.6 to 40.8] mL/100 g per minute; P=0.06). There was no significant change in CBF in the posterior cingulate cortex (Δ=5.2 [95% CI, -16.5 to 27.0] mL/100 g per minute; P=0.63) or other regions of interest. In conclusion, nilvadipine reduced blood pressure and increased CBF in the hippocampus, whereas other regions showed stable or small nonsignificant increases in CBF. These findings not only indicate preserved cerebral autoregulation in Alzheimer disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02017340.
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A randomized controlled trial on the blood pressure-lowering effect of amlodipine and nifedipine-GITS in sustained hypertension.
Huang, QF, Sheng, CS, Li, Y, Dou, Y, Zheng, MS, Zhu, ZM, Wang, JG, ,
Journal of clinical hypertension (Greenwich, Conn.). 2019;(5):648-657
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Abstract
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 140-179/90-109 mm Hg and 24-hour systolic/diastolic BP ≥ 130/80 mm Hg). Eligible patients were randomly assigned to amlodipine 5-10 mg/day or nifedipine-GITS 30-60 mg/day. Ambulatory BP monitoring was performed for 24 hours at baseline and 4-week treatment and for 48 hours 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 BP 10.3/6.5 vs 10.9/6.3 mm Hg, 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 (-1.2 mm Hg) and daytime diastolic BP (-1.5 mm Hg). 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.
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The effect of an L/N-type calcium channel blocker on intradialytic blood pressure in intradialytic hypertensive patients.
Ito, T, Fujimoto, N, Ishikawa, E, Dohi, K, Fujimoto, M, Murata, T, Kiyohara, M, Takeuchi, H, Koyabu, S, Nishimura, H, et al
Clinical and experimental hypertension (New York, N.Y. : 1993). 2019;(1):92-99
Abstract
BACKGROUND Intradialytic hypertension (HTN), which is one of the poor prognostic markers in patients undergoing hemodialysis, may be associated with sympathetic overactivity. The L/N-type calcium channel blocker, cilnidipine, has been reported to suppress sympathetic nerves activity in vivo. Therefore, we hypothesized that cilnidipine could attenuate intradialytic systolic blood pressure (SBP) elevation. METHODS Fifty-one patients on chronic hemodialysis who had intradialytic-HTN (SBP elevation ≥10 mmHg during hemodialysis) and no fluid overload were prospectively randomized into two groups: control and cilnidipine groups. Cilnidipine group patients took cilnidipine (10 mg/day) for 12 weeks. The primary endpoint was the change in the intradialytic SBP elevation before and after the 12-week intervention. RESULTS Before the intervention, no differences were observed in age, sex or pre-dialytic SBP (148.5 ± 12.9 vs. 148.3 ± 19.3 mmHg) between the two groups. Intradialytic SBP elevation was unchanged in the control group. Cilnidipine significantly lowered the post-dialytic SBP with an attenuation of the intradialytic SBP elevation from 12.0 ± 15.4 mmHg to 4.8 ± 10.1 mmHg. However, the observed difference in the intradialytic SBP elevation by cilnidipine did not reach statistical significance (group×time interaction effect p = 0.25). Cathecolamine levels were unaffected by the intervention in both groups. CONCLUSION Cilnidipine lowers both the pre- and post-dialytic SBP and might attenuate intradialytic SBP elevation. Therefore, cilnidipine may be effective in lowering SBP during HD in patients with intradialytic-HTN.
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Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.
Lawlor, B, Segurado, R, Kennelly, S, Olde Rikkert, MGM, Howard, R, Pasquier, F, Börjesson-Hanson, A, Tsolaki, M, Lucca, U, Molloy, DW, et al
PLoS medicine. 2018;(9):e1002660
Abstract
BACKGROUND This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.
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Impact of Intensive Versus Standard Blood Pressure Management by Tertiles of Blood Pressure in SPRINT (Systolic Blood Pressure Intervention Trial).
Shapiro, BP, Ambrosius, WT, Blackshear, JL, Cushman, WC, Whelton, PK, Oparil, S, Beddhu, S, Dwyer, JP, Gren, LH, Kostis, WJ, et al
Hypertension (Dallas, Tex. : 1979). 2018;(6):1064-1074
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Intensive systolic blood pressure (SBP) control improved outcomes in SPRINT (Systolic Blood Pressure Intervention Trial). Our objective was to expand on reported findings by analysis of baseline characteristics, primary outcomes, adverse events, follow-up blood pressure, and medication use differences by baseline SBP (tertile 1 [T1], <132; tertile 2 [T2], 132-145; and tertile 3 [T3], >145 mm Hg). Participants with higher baseline SBP tertile were more often women and older, had higher cardiovascular risk, and lower utilization of antihypertensive medications, statins, and aspirin. Achieved SBP in both treatment arms was slightly higher in T2 and T3 compared with T1 and fewer in the T3 groups achieved SBP targets compared with T1 and T2 groups. The primary composite outcome with intensive versus standard SBP treatment was reduced by 30% in T1, 23% in T2, and 17% in T3 with no evidence of an interaction (P=0.77). Event rates were lower in the intensive arm, and there was no evidence that this benefit differed by SBP tertile. There was no difference in the hazard for serious adverse events in any of the 3 tertiles. Medication utilization differed across the SBP tertiles at baseline with a lesser percentage of diuretics and angiotensin-converting enzyme inhibitors/angiotensin receptor blocker drugs in the higher tertiles-a finding that reversed during the trial. The beneficial effects of intensive SBP lowering were not modified by the level of baseline SBP. Within the parameters of this population, these findings add support for clinicians to treat blood pressure to goal irrespective of baseline SBP.
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Comparison of amlodipine versus other calcium channel blockers on blood pressure variability in hypertensive patients in China: a retrospective propensity score-matched analysis.
Zhang, L, Yang, J, Li, L, Liu, D, Xie, X, Dong, P, Lin, Y
Journal of comparative effectiveness research. 2018;(7):651-660
Abstract
AIM: Reducing the fluctuation of blood pressure has recently been recognized as a potential target for improving management of hypertension to prevent cardiovascular events, particularly for strokes. Some randomized controlled trials demonstrated that amlodipine can effectively reduce blood pressure as a well-established, long-acting calcium channel blocker (CCB). However, few data are available for amlodipine on blood pressure variability (BPV) in China in a real-world setting. This study aimed to assess the effect of amlodipine versus other CCB antihypertensive agents on BPV. MATERIALS & METHODS A retrospective propensity score-matched analysis was conducted, which retrieved the encounter data from 5582 hypertensive inpatients (with a median age of 69, female percentage of 48%, diastolic blood pressure ≥40 and <150 mmHg; systolic blood pressure (SBP) ≥70 mmHg and <260 mmHg), who had taken at least one antihypertensive agent and completed at least three SBP measurements during the visit. International Classification of Diseases was used to identify the hypertensive patients. BPV was calculated with standard deviation (SD) and coefficient of variation (CV) of SBP during a single inpatient visit. The Propensity Score Matching was used to balance the cohort of patients prescribed amlodipine or other CCBs. A series of appropriate statistical tests were applied to the propensity score-matched samples to examine the different effects on BPV. Additionally, the hypertensive patients with comorbidity such as coronary artery disease, diabetes mellitus, myocardial infarction, heart failure and chronic kidney disease were analyzed. RESULTS For the hypertensive patients (n = 1756, for each cohort), patients prescribed amlodipine showed lower BPV than patients prescribed other CCBs (12.90 vs 13.76 mmHg, p < 0.05 [SD] and 9.47 vs 10.06, p < 0.05 [CV]). For the hypertensive patients with comorbidity (n = 1080, for each cohort), patients prescribed amlodipine had lower BPV than patients prescribed other CCBs as well (13.24 vs 14.23 mmHg, p < 0.05 [SD] and 9.66 vs 10.28, p < 0.05 [CV]). CONCLUSION amlodipine was associated with lower BPV than other CCBs for both hypertensive patients and hypertensive patients with comorbidity.