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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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Pharmacogenomic association of nonsynonymous SNPs in SIGLEC12, A1BG, and the selectin region and cardiovascular outcomes.
McDonough, CW, Gong, Y, Padmanabhan, S, Burkley, B, Langaee, TY, Melander, O, Pepine, CJ, Dominiczak, AF, Cooper-Dehoff, RM, Johnson, JA
Hypertension (Dallas, Tex. : 1979). 2013;(1):48-54
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Abstract
We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR-Trandolapril STudy (INVEST), where participants were randomized to a β-blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)×treatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study. SIGLEC12 rs16982743 and A1BG rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (INVEST whites and Hispanics combined interaction P=0.0038 and 0.0036, respectively). A genetic risk score, including rs16982743, rs893184, and rs4525 in F5, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the INVEST study and in the Nordic Diltiazem study (meta-analysis interaction P=2.39×10(-5)). In patients with a genetic risk score of 0 or 1, calcium channel blocker treatment was associated with lower risk (odds ratio [95% confidence interval]=0.60 [0.42-0.86]), and in those with a genetic risk score of 2 to 3, calcium channel blocker treatment was associated with higher risk (odds ratio [95% confidence interval]=1.31 [1.08-1.59]). These results suggest that cardiovascular outcomes may differ based on SIGLEC12, A1BG, F5 genotypes, and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection.
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Identifying iatrogenic depression using confirmatory factor analysis of the Center for Epidemiologic Studies Depression Scale in patients prescribed a verapamil-sustained-release-led or atenolol-led hypertension treatment strategy.
Wilson, DL, Ried, LD
Research in social & administrative pharmacy : RSAP. 2012;(4):309-20
Abstract
BACKGROUND β-blockers and calcium channel blockers are highly effective medications indicated for treatment and prevention of hypertension. However, the literature regarding the potential depressive effects of β-blockers and calcium channel blockers is equivocal regarding whether one or both are associated with depression. OBJECTIVES To determine whether self-reported depressive symptoms of older persons with hypertension and coronary artery disease and who were randomly assigned to a verapamil-sustained-release-led (Ve-led) or atenolol-led (At-led) hypertension treatment strategy were similar using confirmatory factor analytical models of the Center for Epidemiologic Studies Depression Scale (CES-D). METHODS This study used a mail survey of patients enrolled in a substudy of an international randomized controlled clinical trial. Complete data on the CES-D after 1 year of treatment were obtained from 1019 study subjects. Multiple group confirmatory factor analysis (CFA) procedures were used to test for differences in the fit of the data to the initial 4-factor CES-D model among patients assigned to the 2 treatment groups after 12 months of therapy. A test of configural invariance was conducted by sequentially constraining various matrices to be equal across groups. The convergent validity of the model was tested by examining the standard errors of the lambda-X parameter estimates of the configural model. The factor loadings for like items were investigated across the 2 groups using a test of strong factorial invariance. Finally, the 2 treatment groups were compared on the 4 factors to detect differences in the model's parameters. RESULTS Overall, the data fit the CFA models across the 2 treatment groups based on the 4-factor model. However, 3 items differed slightly, including appetite, depressed, and crying. The data suggested significant differences across groups on the positive affect, interpersonal relations, and somatic and retarded activity latent variables. CONCLUSIONS The domains indicating less happiness and more depressive symptoms were most likely to be unfavorably impacted by the At-led treatment strategy. Given a choice between these equally effective high blood pressure treatment strategies, it may be prudent to use the Ve-led strategy. This is especially true if the risk of the occurrence of a mood-related side effect of the β-blocker outweighs its other benefits in comparison.
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Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial.
Ruggenenti, P, Fassi, A, Ilieva, A, Iliev, IP, Chiurchiu, C, Rubis, N, Gherardi, G, Ene-Iordache, B, Gaspari, F, Perna, A, et al
Journal of hypertension. 2011;(2):207-16
Abstract
OBJECTIVES To address whether nondihydropyridine calcium-channel blocker added-on angiotensin-converting-enzyme inhibitor therapy ameliorates albuminuria and cardiovascular outcomes in type 2 diabetes patients. DESIGN The Bergamo Nephrologic Diabetes Complications Trial-B was a multicentre, prospective, double-blind, parallel-group trial comparing renal and cardiovascular outcomes in 281 hypertensive type 2 diabetes patients with microalbuminuria randomized to at least 2-year VeraTran (verapamil/trandolapril 180 mg/2 mg daily) or trandolapril (2 mg daily, identical image) treatment. Main outcome was persistent macroalbuminuria (albuminuria >200 µg/min in two consecutive visits). Treatment targets were SBP/DBP less than 120/80 mmHg and HbA1C less than 7%. RESULTS Over a median follow-up of 4.5 years, 18 patients (13%) on VeraTran vs. 15 (10.5%) on trandolapril [unadjusted hazard ratio (95% confidence interval [CI]) 1.07 (0.54-2.12), P = 0.852] progressed to macroalbuminuria, respectively; 62 (44.9%) vs. 71 (49.7%) [0.80 (0.57-1.12), P = 0.198] regressed to normoalbuminuria (urinary albumin excretion <20 µg/min), and 20 (14.5%) vs. 21 (14.7%) [hazard ratio 0.93 (0.50-1.72), P = 0.816] had major cardiovascular events. BP and metabolic control were similar between groups. Patients with cardiovascular events were significantly less [13 (9.8%) vs. 28 (18.9%), hazard ratio: 0.37 (0.19-0.71), P = 0.003] among those regressing to normoalbuminuria than those without regression. Difference was independent of treatment allocation and was significant also after adjusting for baseline characteristics [0.40 (0.20-0.79), P = 0.009], follow-up SBP [0.40 (0.20-0.80), P = 0.010] or DBP [0.36 (0.18-0.73), P = 0.004] BP or HbA1C [0.43 (0.21-0.88), P = 0.021]. CONCLUSION In hypertensive type 2 diabetes patients with microalbuminuria, verapamil added-on trandolapril did not improve renal or cardiovascular outcomes. Independent of verapamil, trandolapril normalized albuminuria in half of patients and this translated into significant cardioprotection.
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Therapeutic window for calcium-channel blockers in the management of dilated cardiomyopathy: a prospective, two-centre study on non-advanced disease.
Wojnicz, R, Nowak, J, Lekston, A, Wilczewski, P, Nowalany-Kozielska, E, Streb, W, Wojciechowska, C, Stolarz, W, Helewski, K, Szyguła-Jurkiewicz, B, et al
Cardiology. 2010;(2):148-54
Abstract
OBJECTIVE This study aimed to investigate the usefulness of the calcium-channel blocker verapamil in non-advanced dilated cardiomyopathy (DCM). METHODS This was a randomised trial of 70 DCM patients treated with carvedilol (36 patients) and verapamil (instead of β-blocker; 34 patients) for 12 months. The remaining heart failure (HF) therapy was constant in both groups. The primary outcomes were to determine selected echocardiography parameters and functional status of patients. The secondary outcome included death, heart transplantation and re-hospitalisation due to HF progression. RESULTS Of the primary outcomes, only the mean ratio of early to late transmitral flow velocities increased significantly in the verapamil-treated patients as compared with the carvedilol-based therapy (1.1 ± 0.3 vs. 0.7 ± 0.2; 95% CI -0.6 to -0.1; p = 0.015). Simultaneously, the Minnesota Quality of Life improved significantly in the verapamil group (95% CI 5.2-19.9; p = 0.002). It was accompanied by the favourable effect of verapamil therapy on exercise capacity in the 6-min walk test (95% CI 21.3-110.7; p = 0.005). CONCLUSION The addition of verapamil to angiotensin-converting enzyme and aldosterone inhibitors in non-advanced DCM patients has been shown to have a neutral or even positive effect in a few patients.
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Factors influencing blood pressure response to trandolapril add-on therapy in patients taking verapamil SR (from the International Verapamil SR/Trandolapril [INVEST] Study).
Brunner, M, Cooper-DeHoff, RM, Gong, Y, Karnes, JH, Langaee, TY, Pepine, CJ, Johnson, JA, ,
The American journal of cardiology. 2007;(11):1549-54
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Abstract
Factors such as age and race/ethnicity might influence blood pressure (BP) response to drugs. Therapeutic response to the angiotensin-converting enzyme inhibitor trandolapril used as add-on therapy to stable calcium channel blocker therapy with verapamil sustained release 240 mg was addressed in a racially/ethnically diverse group of 1,832 hypertensive patients with coronary artery disease. Furthermore, the association with a polymorphism (1166A-->C) in the angiotensin II type 1 receptor gene (AGTR1) was tested. BP response was compared between groups using analysis of covariance after adjustment for covariates associated with BP response. Genotyping was performed using polymerase chain reaction and pyrosequencing. Trandolapril decreased mean unadjusted systolic and diastolic BPs by -9.1 +/- 17.3 (SD) and -4.1 +/- 10.1 mm Hg, respectively. The percentage of patients with BP under control (<140/90 mm Hg) increased from 6.7% to 41.3% (p <0.0001). Adjusted BP response was significantly associated with age and baseline systolic and diastolic BP (p <0.0001). Whereas the decrease in systolic BP was more pronounced in younger patients, the opposite was observed for diastolic BP decrease. Diastolic BP response was also significantly associated with race. Specifically, the adjusted diastolic BP decrease was significantly smaller in Hispanics and blacks than whites (p = 0.0032 and p = 0.0069, respectively). However, Hispanics achieved a decrease in systolic BP and an increase in BP control similar to the other ethnic groups. There was no genetic association between AGTR1 1166A-->C genotype and BP response. In conclusion, trandolapril add-on therapy was effective in increasing BP control, with age and baseline BP associated with both systolic and diastolic BP response. Race was associated with diastolic BP response, although the difference is likely not to be clinically significant and AGTR1 genotype was not associated with BP response.
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Verapamil versus digoxin and acute versus routine serial cardioversion for the improvement of rhythm control for persistent atrial fibrillation.
Hemels, ME, Van Noord, T, Crijns, HJ, Van Veldhuisen, DJ, Veeger, NJ, Bosker, HA, Wiesfeld, AC, Van den Berg, MP, Ranchor, AV, Van Gelder, IC
Journal of the American College of Cardiology. 2006;(5):1001-9
Abstract
OBJECTIVES The VERDICT (Verapamil Versus Digoxin and Acute Versus Routine Serial Cardioversion Trial) is a prospective, randomized study to investigate whether: 1) acutely repeated serial electrical cardioversions (ECVs) after a relapse of atrial fibrillation (AF); and 2) prevention of intracellular calcium overload by verapamil, decrease intractability of AF. BACKGROUND Rhythm control is desirable in patients suffering from symptomatic AF. METHODS A total of 144 patients with persistent AF were included. Seventy-four (51%) patients were randomized to the acute (within 24 h) and 70 (49%) patients to the routine serial ECVs, and 74 (51%) patients to verapamil and 70 (49%) patients to digoxin for rate control before ECV and continued during follow-up (2 x 2 factorial design). Class III antiarrhythmic drugs were used after a relapse of AF. Follow-up was 18 months. RESULTS At baseline, there were no significant differences between the groups, except for beta-blocker use in the verapamil versus digoxin group (38% vs. 60%, respectively, p = 0.01). At follow-up, no difference in the occurrence of permanent AF between the acute and the routine cardioversion groups was observed (32% [95% confidence intervals (CI)] 22 to 44) vs. 31% [95% CI 21 to 44], respectively, p = NS), and also no difference between the verapamil- and the digoxin-randomized patients (28% [95% CI 19 to 40] vs. 36% [95% CI 25 to 48] respectively, p = NS). Multivariate Cox regression analysis revealed that lone digoxin use was the only significant predictor of failure of rhythm control treatment (hazard ratio 2.2 [95% CI 1.1 to 4.4], p = 0.02). CONCLUSIONS An acute serial cardioversion strategy does not improve long-term rhythm control in comparison with a routine serial cardioversion strategy. Furthermore, verapamil has no beneficial effect in a serial cardioversion strategy.
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Chronotherapeutic oral drug absorption system verapamil is effective in reducing morning blood pressure in African Americans: a post hoc analysis of the chrono trial.
Prisant, LM, Weber, M, Black, HR
Journal of the National Medical Association. 2005;(3):377-83
Abstract
Results of several clinical trials have shown that verapamil is effective in reducing blood pressure (BP) in African Americans, a population at high risk for hypertension and target-organ damage. Nonetheless, adequate control of BP is perceived as difficult to achieve in this population. A post hoc analysis of data from the community-based CHRONO trial (Controlling Hypertension in the moRning with a ChrONO medication) was undertaken to assess racial/ethnic differences in the safety and efficacy of the Chronotherapeutic Oral Drug Absorption System (CODAS) formulation of verapamil in a real-world setting. Once-daily administration of the CODAS formulation of verapamil significantly reduced morning BP (P<0.0001) regardless of race or ethnicity. In the African-American population (N=466), the response rate for systolic BP (<140 mmHg or > or =10% reduction from baseline) and diastolic BP (<90 mmHg or reduction > or =10 mmHg from baseline) combined was 70.8%, and 60% of those individuals responded at the lowest (200 mg) dose. Of the 59.7% of African Americans who reached the target BP of <140/90 mmHg, 64% did so at the 200-mg dose. Response rates were not affected by gender, age or treatment history, and CODAS-verapamil was well tolerated in all ethnic/racial treatment groups. In a trial conducted in actual clinical practices, the CODAS formulation of verapamil was shown to be safe and effective in African Americans, Caucasians, Hispanics and Asians.
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Global differences in blood pressure control and clinical outcomes in the INternational VErapamil SR-Trandolapril STudy (INVEST).
Zineh, I, Cooper-Dehoff, RM, Wessel, TR, Arant, CB, Sleight, P, Geiser, EA, Pepine, CJ
Clinical cardiology. 2005;(7):321-8
Abstract
BACKGROUND The INternational VErapamil SR-Trandolapril Study (INVEST), a prospective, randomized, antihypertensive trial, found that two different medication regimens produced similar blood pressure (BP) control with equivalent cardiovascular (CV) outcomes (death from any cause, nonfatal myocardial infarction [MI], or nonfatal stroke). HYPOTHESIS The study was undertaken to investigate whether differences exist by global regions in demographics, treatment, and outcomes in the INVEST trial. METHODS Data were analyzed for 22,576 patients with stable coronary artery disease (CAD) enrolled in INVEST. We investigated differences in patient characteristics, treatment approaches, BP control, and clinical outcomes by creating three global regions based on geographical location: Northern Americas (NA), Caribbean (CA), and Eurasia (EA). RESULTS We observed significant regional differences in patient characteristics, treatment patterns, BP control, and CV outcomes. At baseline, patients from NA were older and had greater body mass index, higher rates of diabetes, peripheral vascular disease, and coronary revascularization, but lower rates of MI or left ventricular hypertrophy than patients in CA and EA. At 24 months, there were regional differences in both study and nonstudy antihypertensive drug use. Despite having higher mean baseline BP, patients from CA and EA achieved lower mean systolic BP throughout study follow-up. Furthermore, patients from both CA and EA had lower rates of all-cause mortality, fatal or nonfatal MI, fatal or nonfatal stroke, and newly diagnosed diabetes than patients from NA. CONCLUSIONS In INVEST, regional differences in medication utilization, BP control, and CV outcomes were identified. These disparities warrant further investigation to define appropriate care for patients with hypertension and stable CAD from an international public health perspective.
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Evaluation of the effect of oral verapamil on clinical outcome and angiographic restenosis after percutaneous coronary intervention: the randomized, double-blind, placebo-controlled, multicenter Verapamil Slow-Release for Prevention of Cardiovascular Events After Angioplasty (VESPA) Trial.
Bestehorn, HP, Neumann, FJ, Büttner, HJ, Betz, P, Stürzenhofecker, P, von Hodenberg, E, Verdun, A, Levai, L, Monassier, JP, Roskamm, H
Journal of the American College of Cardiology. 2004;(12):2160-5
Abstract
OBJECTIVES We investigated the effect of oral verapamil on clinical outcome and angiographic restenosis after percutaneous coronary intervention (PCI). BACKGROUND Thus far, there is no established systemic pharmacologic approach for the prevention of restenosis after PCIs. Five small studies reported encouraging results for calcium channel blockers. METHODS Our randomized double-blind trial included 700 consecutive patients with successful PCI of a native coronary artery. Patients received the calcium channel blocker verapamil, 240 mg twice daily for six months, or placebo. Primary clinical end point was the composite rate of death, myocardial infarction, and target vessel revascularization (TVR) during one-year follow-up; the angiographic end point was late lumen loss at the six-month follow-up angiography. RESULTS We obtained complete clinical follow-up in 95% of the patients, and scheduled angiography was performed in 94%. The proportion of patients treated with stents was 83%. The primary clinical end point was reached in 67 (19.3%) patients on verapamil and in 103 (29.3%) patients on placebo (relative risk [RR] 0.66 [95% confidence interval (CI) 0.48 to 0.89]; p = 0.002). This difference between the groups was driven by TVR (17.5% with verapamil vs. 26.2% with placebo; RR 0.67 [95% CI 0.49 to 0.93]; p = 0.006). Late lumen loss was 0.74 +/- 0.70 mm with verapamil and 0.81 +/- 0.75 mm with placebo (p = 0.11). Compared with placebo, verapamil reduced the rate of restenosis > or =75% (7.8% vs. 13.7%; RR 0.57 [95% CI 0.35 to 0.92]; p = 0.014). CONCLUSIONS Verapamil compared with placebo improves long-term clinical outcome after PCI of native coronary arteries by reducing the need for TVR. This was caused by a reduction in the rate of high-grade restenosis.