Long-acting Calcium Channel Blocker Research Articles

The Rationale for Using Fixed-Dose Combination Therapy in the Management of Hypertension in Colombia: A Narrative Review.

Hypertension is a major risk factor for cardiovascular disease and the leading cause of death in Colombia. While the rate of hypertension awareness in Colombia is generally high, rates of treatment initiation, adherence, and blood pressure (BP) control are suboptimal. Major international hypertension guidelines recommend starting treatment with a combination of antihypertensive agents, and the use of a single-pill combination (SPC) to maximize adherence. In contrast, Colombian hypertension guidelines recommend starting treatment with diuretic monotherapy in most patients, and only initiating combination therapy in those with BP > 160/100 mmHg. Therefore, the aim of the current narrative review is to examine the rationale for using SPCs to treat hypertension in Colombia, in the context of the major issues for BP controlthere. There is evidence of widespread therapeutic inertia in hypertension management, particularly in primary care, in Colombia. Moreover, combination therapy, angiotensin-converting enzyme inhibitors, and long-acting calcium channel blockers, which are internationally recommended as first-line drug therapies, are underutilized there. Adherence to antihypertensive therapy is low in Colombia and may be enhanced by use of SPCs as well as better patient education and follow-up. While there are promising national initiatives to improve BP management, more needs to be done by individual physicians. Antihypertensive SPCs are available on the national essential medicines list and may help to overcome some of the problems with suboptimal adherence, therapeutic inertia, and low rates of BP control that contribute to the high cardiovascular death rate in Colombia.

Resistant arterial hypertension: modern view of the problem

In clinical practice, uncontrolled arterial hypertension remains a difficult but solvable task, given the available arsenal of antihypertensive drugs. However, resistant arterial hypertension is diagnosed in 10%–15% of these cases. A significantly higher risk of cardiovascular complications indicates the extreme importance of the successful treatment of this pathology. Resistant hypertension is defined as above-goal high blood pressure in a patient despite concurrent use of three antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a renin–angiotensin blocker (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. All antihypertensive drugs should be administered at maximum or maximally tolerated doses. Resistant hypertension also includes cases in which blood pressure targets are achieved with ≥4 antihypertensive medications. The diagnosis of resistant hypertension requires assurance of antihypertensive medication adherence and exclusion of the “white-coat effect” (office blood pressure above goal but out-of-office blood pressure at or below the target). Once antihypertensive medication adherence is confirmed and out-of-office blood pressure recordings exclude a white-coat effect, the evaluation includes the identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. The management of resistant hypertension includes the maximization of lifestyle interventions, correction of sleep disorders, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower blood pressure if blood pressure remains high.

Abstract 13555: Effect of Calcium Channel Blockers on Clinical Outcomes in Patients After Percutaneous Coronary Intervention With Left Ventricular Dysfunction

Although calcium channel blockers (CCBs) are effective in hypertension and IHD, short-acting CCBs are not recommended for heart failure due to have negative inotropic effects. On the other hand, long-acting CCBs have been reported to be safe for use in patients with cardiac dysfunction, but details are still unclear. In this study, we investigated the relationship between the effects of CCBs on CAD patients and left LV function. Methods: We enrolled 7173 consecutive CAD patients (Age; 69 [61-76] years and male; 78%) who underwent successful PCI for AP or ACS between April 2008 and March 2020 from prospective, multicenter registry (FUJISUN registry). Of the enrolled patients, 5307 analyzable patients were divided by LVEF <40 or ≥40%. Patients were prospectively followed for a maximum of 8 years or until the occurrence of the cardiac events (CEs): cardiac death, nonfatal MI. Results: During the follow-up period (3.6 [1.4-6.7] years), 230 (4%) CEs occurred (109 Cardiac death, 121 MI). Both patients with LVEF <40% and ≥40% had higher prevalence of HT and lower levels of BNP in CCB group than in non-CCB group. Propensity match analysis was performed to reduced selection bias for CCB use in each group. In patients with LVEF <40%, Kaplan-Meier analysis showed that CCB group had significantly lower probability of CEs than non-CCB group, whereas in those with LVEF ≥40%, the probability of CE was similar in both groups. Multivariate Cox proportional hazards analysis showed that CCB group had significantly lower probabilities of CEs compared with non-CCB group in patients with LVEF<40%, (HR 0.25; 95% CI 0.09-0.71, p <0.01), but not in those with LVEF≥40% (HR 1.13; 95% CI 0.80-1.60, p = 0.50). Conclusions: Long-acting CCBs may improve clinical outcomes in post-PCI CAD patients with LV dysfunction.

Beyond Conventional Control: Insights Into Drug-Resistant Hypertension.

It is believed that 9-18% of patients with hypertension have resistant hypertension, a serious medical disease. The increased cardiovascular risk associated with this illness demands appropriate diagnosis and treatment. It is necessary to conduct an in-depth investigation of the various etiologies, indicators of risk, and multiple disorders of resistant hypertension. This is crucial in order to establish the diagnosis and make the best decisions regarding therapy. Treatment should also take lifestyle changes into account in addition to medicinal and interventional therapy. When there is a suspicion of resistant hypertension, examining the medications used to treat the hypertensive patient after ruling out pseudo hypertension, improper blood pressure monitoring and control, and the white-coat effect are necessary. Resistant hypertension, according to a specific definition, is a condition that cannot be treated with more than two antihypertensive drugs, including a diuretic. An effective multidrug therapy for the treatment of resistant hypertension includes angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, diuretics, long-acting calcium channel blockers, and mineralocorticoid receptor antagonists. However, alternative, cutting-edge treatments, such as renal denervation or baroreflex activation, could develop a brand-new avenue for decreasing blood pressure. These new surgical interventions might prove out to be of immense importance in coming times. Secondary causes of resistant hypertension, such as obstructive sleep apnea, coronary artery diseases, nephropathy, or endocrinal diseases, must be checked out in order to make an accurate diagnosis of this illness. This review article briefly summarizes the epidemiology, risk factors, causes, pathogenesis, diagnosis, and treatment approaches that may help with the long-term management of resistant hypertension.

Review of Long-Term Blood Pressure Control After Intracerebral Hemorrhage: Challenges and Opportunities.

Blood pressure (BP) is the most important modifiable risk factor for intracerebral hemorrhage (ICH). Elevated BP is associated with an increased risk of ICH, worse outcome after ICH, and in survivors, higher risks of recurrent ICH, ischemic stroke, myocardial infarction, and cognitive impairment/dementia. As intensive BP control probably improves the chances of recovery from acute ICH, the early use of intravenous or oral medications to achieve a systolic BP goal of <140 mm Hg within the first few hours of presentation is reasonable for being applied in most patients. In the long-term, oral antihypertensive drugs should be titrated as soon as possible to achieve a goal BP <130/80 mm Hg and again in all ICH patients regardless of age, location, or presumed mechanism of ICH. The degree of sustained BP reduction, rather than the choice of BP-lowering agent(s), is the most important factor for optimizing risk reduction, with varying combinations of thiazide-type diuretics, long-acting calcium channel blockers, ACE (angiotensin-converting enzyme) inhibitors or angiotensin receptor blockers, being the mainstay of therapy. As most patients will require multiple BP-lowering agents, and physician inertia and poor adherence are major barriers to effective BP control, single-pill combination therapy should be considered as the choice of management where available. Increased population and clinician awareness, and innovations to solving patient, provider, and social factors, have much to offer for improving BP control after ICH and more broadly across high-risk groups. It is critical that all physicians, especially those managing ICH patients, emphasize the importance of BP control in their practice.

Calcium channel blockers are associated with lower gastric cancer risk: A territory-wide study with propensity score analysis.

Prior studies showed that calcium channel blockers (CCBs) could modify cancer risk, but data on gastric cancer (GC) are limited. We aimed to investigate whether CCBs could modify GC risk in Helicobacter pylori-eradicated patients. H pylori-infected patients with hypertension who are aged ≥50 and had received clarithromycin-based triple therapy between 2003 and 2016 were identified from a territory-wide healthcare database. Patients with eradication failure, GC diagnosed within 6 months after HP eradication, and gastric ulcer were excluded. Time-fixed Cox model with one-to-one propensity score matching was used to calculate hazard ratio (HR) of GC with CCBs. Sensitivity analysis using time-dependent multivariable Cox model in which CCB use was treated as time-varying covariate was also performed to address immortal time bias. 17 622 (29.6%) H pylori-eradicated patients with hypertension were included. During a median follow-up of 8.6 years, 105 (0.6%) developed GC. After PS matching, CCBs were associated with a lower GC risk (HR: 0.56; 95% CI: 0.32-0.97). Time-dependent analysis showed consistent result (aHR: 0.50; 95% CI: 0.33-0.75). A longer duration of CCB use was associated with even lower GC risk (adjusted HR [aHR]: 0.69; 95% CI: 0.61-0.79 for every 1-year increase in use). Long-acting CCBs (aHR: 0.47; 95% CI: 0.29-0.76) and dihydropyridines (aHR: 0.49; 95% CI: 0.32-0.73) conferred greater benefit than short-acting ones (aHR: 0.60; 95% CI: 0.36-1.03) and nondihydropyridines (aHR: 0.76; 95% CI: 0.24-2.48). The aHR was 0.57 (95% CI: 0.34-0.97) for noncardia and 0.59 (95% CI: 0.27-1.31) for cardia cancer. Use of CCBs was associated with lower risk of GC development in H pylori-eradicated patients, in a duration- and dose-response manner.

Oxidative stress status in hypertensive patients on amlodipine treatment

Background: Oxidative stress may contribute to the etiology of hypertension in humans. Oxidative stress is an imbalance between reactive oxygen species (ROS) and antioxidant defense mechanisms, causing damage to biological macromolecules and dysregulation of normal metabolism and physiology. Amlodipine as an antihypertensive agent is a long-acting calcium channel blocker that dilates blood vessels and improves blood flow. The aim of this study was to assess the oxidative stress in hypertensive patients on Amlodipine treatment through the assessment of salivary Malondialdehyde (MDA) and superoxide dismutase (SOD) as a marker of oxidative stress.&#x0D; Material and method: 60 individuals were included in this study, divided into two groups; the first group composed of 30 hypertensive patients on Amlodipine antihypertensive agent. The second group, the control group, composed of 30 healthy subjects without any systemic disease and with almost healthy oral hygiene. Intraoral examination was done for each individual and salivary samples were collected with the salivary flow rate (F/R) which was calculated in ml per minute and pH was measured by pH meter. Salivary MDA and SOD were analyzed by using ELISA kit based on the principle of competitive enzyme immunoassay technique; the concentrations of markers were measured by spectrophotometer at 450nm in a microplate reader.&#x0D; Results: Salivary MDA was significantly higher in hypertensive patients compared to control, while salivary SOD was significantly lower in patients than control group. Salivary flow rate and pH was significantly lower in patients as compared to the control group.&#x0D; Conclusions: There is a relation between oxidative stress and hypertension. Salivary MDA and SOD can be used as potential marker for monitoring patients with Hypertension.&#x0D; Keywords: hypertension, Oxidative stress, Amlodipine, MDA and SOD

Effects of an Antihypertensive Combination in Japanese Hypertensive Outpatients Based on the Long-acting Calcium Channel Blocker Benidipine on Vascular and Renal Events: A Sub-analysis of the COPE Trial

In the trial known as COPE (Combination Therapy of Hypertension to Prevent Cardiovascular Events), three benidipine (a Calcium Channel Blocker; CCB) regimens were compared. Hypertensive Japanese outpatients aged 40-85 years (n=3,293) who did not achieve the target blood pressure of <140/90 mmHg with benidipine 4 mg/day were treated with the diuretic thiazide (n=1,094) or a β-blocker (n=1,089) or an additional Angiotensin Receptor Blocker (ARB; n=1,110). A significantly higher incidence of hard cardiovascular composite endpoints and of fatal or non-fatal strokes was observed in the benidipine-β-blocker group compared to the benidipine-thiazide group. We further evaluated the treatment effects of the three benidipine-based regimens on vascular and renal events in a sub-analysis of the COPE patients. A total of 10 vascular events (0.8 per 1,000 person-years) including one aortic dissection (0.1 per 1,000 person-years) and nine cases of peripheral artery disease (0.8 per 1,000 person-years) were documented, as was a total of seven renal events (0.6 per 1,000 person-years). No significant differences in vascular and renal events were revealed among the three treatment groups: vascular events, p=0.92; renal events, p=0.16, log-rank test. Blood pressure-lowering therapy with benidipine combined with an ARB, β-blocker, or thiazide was similarly effective in the prevention of vascular and renal events in hypertensive outpatients, although there are not enough events to compare the difference in the three treatment groups.

Periodontal management of a patient with chronic kidney disease: a case report

Introduction: The association between periodontal disease and chronic kidney disease (CKD) has been recognized over the years. Gingival overgrowth may be a side effect of some of the drugs prescribed for patients with CKD. Objective: The objective of this manuscript was to report the dental management of a patient with chronic renal disease who presented periodontitis and gingival overgrowth. Case report: A 55 years old male patient sought dental treatment, and was diagnosed with generalized periodontitis in advanced stage and gingival overgrowth. The overgrowth was associated to the use of amlodipine, a longacting calcium channel blocker. The treatment consisted of interruption of amlodipine, sessions of oral hygiene instruction and basic periodontal therapy. Thereafter, conventional periodontal therapy, with scaling and root planning of the four hemiarches, surgical periodontal therapy and gingivectomy of the overgrowth were performed. Considering periodontal sites with a probing depth (PD) > 4mm at baseline, mean PD was reduced (baseline: 5.94 ± 1.80; follow-up: 2.76 ± 1.38), as well as mean clinical attachment loss (baseline: 5.55 ± 1.51; followup: 4.52 ± 1.47). Periodontal disease was controlled and there was no recurrence of gingival overgrowth after 18 months of follow-up. Conclusion: The management of the reported patient with CKD and periodontal involvement included discontinuation of amlodipine, basic and advanced periodontal therapy and gingivectomy. Proper oral hygiene may help to prevent recurrence of the gingival overgrowth and to maintain periodontal health.

Formulation and Stability Studies of Fast Disintegrating Tablets of Amlodipine Besylate

Abstract: Introduction: Among tablets, fast dissolving technology has gained considerable popularity due to their rapid onset of action. Amlodipine besylate (ADB) is a longacting calcium channel blocker that is used in the treatment of angina and hypertension which are life-threatening conditions and require immediate relief. Currently, no fast dissolving tablet dosage form of ADB is commercially available. Methods: A total of seven fast disintegrating tablets of Amlodipine besylate (ADB) have been prepared by direct compression method employing various excipients (Disintegrants and binders) in different concentrations. Pre-compression and post-compression studies were performed along with the storage in the stability chambers under real (30±2ºC / 65±5% RH) and accelerated conditions (40±2ºC / 75±5% RH) for six months. The assay of ADB was performed using a validated UV spectrometric method at 361 nm. Results: The release of ADB from tablets has been found to be very fast with almost more than 85% drug released within 15 min. The release of drug from all the tablet formulations followed Higuchi model. Conclusion: The use of sodium bicarbonate as super disintegrant has greatly promoted the rapid release of the active drug. The binder has been shown to affect the tensile strength of the tablets. The stability studies for six months in aluminum blister packaging indicated no significant change in concentration in the majority of the formulations. This study provides basic groundwork related to the formulation of fast disintegrating tablets of ADB. Key words: Amlodipine besylate, Direct compression, Drug release, Fast disintegrating tablets, Model dependent and independent methods, Pre-compression and postcompression studies.

Visit-to-visit Blood Pressure Variability and Arterial Stiffness: Which Came First: The Chicken or the Egg?

Earlier studies have shown that visit-to-visit blood pressure (BP) variability (VVV) served as a significant independent risk factor of stroke, specifically, in the high-risk elderly of cardiovascular disease (CVD). Although the mechanism is not clearly understood, arterial remodeling such as carotid artery, coronary artery and large aortic artery would be a strong moderator in the relationship between VVV and CVD incidence. Recent studies have provided evidence that VVV predicted the progression of arterial stiffness. While the class of antihypertensive agents is suggested to be an important determinant of VVV, long-acting calcium channel blockers use (CCBs) is associated with the reduction of VVV, and thus, is suggested to decrease the arterial stiffness. Specifically, the relationship between VVV and coronary arterial remodeling has never been reviewed until now. This article summarizes the recent literature on these topics. In the elderly hypertensives, strict BP control using CCBs could play a pivotal role in suppressing arterial stiffening via VVV reduction.

Treatment of Resistant and Refractory Hypertension.

Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting calcium channel blocker, and a blocker of the renin- angiotensin system, either an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin receptor blocker), at maximal or maximally tolerated doses. Antihypertensive medication nonadherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. RHTN is a high-risk phenotype, leading to increased all-cause mortality and cardiovascular disease outcomes. Healthy lifestyle habits are associated with reduced cardiovascular risk in patients with RHTN. Aldosterone excess is common in patients with RHTN, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of ≥5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic and an MR (mineralocorticoid receptor) antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying RHTN, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.

Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association.

Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. The diagnosis of RH requires assurance of antihypertensive medication adherence and exclusion of the "white-coat effect" (office BP above goal but out-of-office BP at or below target). The importance of RH is underscored by the associated risk of adverse outcomes compared with non-RH. This article is an updated American Heart Association scientific statement on the detection, evaluation, and management of RH. Once antihypertensive medication adherence is confirmed and out-of-office BP recordings exclude a white-coat effect, evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised.

Effects of Long- and Intermediate-Acting Dihydropyridine Calcium Channel Blockers in Hypertension: A Systematic Review and Meta-Analysis of 18 Prospective, Randomized, Actively Controlled Trials.

Dihydropyridine calcium channel blockers are a heterogeneous group of antihypertensive drugs. Long-acting dihydropyridine agent amlodipine is widely used for monotherapy and combination therapy for hypertension in clinical practice, while intermediate-acting dihydropyridine agents have shown inconsistent results in randomized clinical trials (RCTs). A meta-analysis of 18 RCTs enrolling a total of 80,483 patients with hypertension followed for a mean of 51.4 months was performed. Amlodipine therapy was associated with 25% higher risk of heart failure (relative risk [RR]: 1.25, 95% confidence interval [CI], 1.05-1.49, P = .019) but 17% lower risk of stroke (RR: 0.83, [95% CI, 0.72-0.97], P = .009) without statistically significant effect on acute myocardial infarction (AMI) compared to major alternative antihypertensive therapy (MAAT), including β-blocker, diuretic, angiotensin-converting enzyme inhibitor, or angiotensin-receptor blocker. Intermediate-acting dihydropyridine calcium channel blocker therapy was associated with 25% higher risk of heart failure (RR: 1.25, [95% CI, 1.06-1.47], 0.005, P = .005) and 26% higher risk of AMI (RR: 1.26, [95% CI, 1.05-1.51], 0.019, P = .019) compared to MAAT. Results of the subgroup analysis suggested that the intermediate-acting dihydropyridine calcium channel blocker was associated with higher risk of heart failure (RR: 1.30, [95% CI, 1.08-1.56], P = .005) and AMI (RR: 1.50, [95% CI, 1.01-2.22], P = .043) compared to renin-angiotensin system blockers and a trend toward higher risk of AMI (RR: 1.17, [95% CI, 0.99-1.38], P = .064) compared to conventional therapy, including β-blockers and diuretics. Meta-regression analyses suggested that long-acting dihydropyridine calcium channel blocker is associated with lower risk of AMI ( B: -0.327, [95% CI, -0.530 to -0.123], P = .002) with a trend toward lower risk of stroke ( B: -0.203, [95% CI, -0.410 to 0.003] P = .054). This study suggests that Amlodipine offers greater protection against major complications of hypertension compared to intermediate-acting dihydropyridine calcium channel blockers.

Pharmacokinetics of talinolol is modified by barnidipine: implication of P-glycoprotein modulation.

Concomitant administration of P-glycoprotein substrates and inhibitors may cause pharmacokinetic drug interactions leading to increased concentrations associated with serious side effects and toxicities. Barnidipine is a longacting calcium-channel blocker and potent inhibitor of P-glycoprotein in vitro, and talinolol is a beta-blocker and probe substrate of P-glycoprotein. This study was designed to investigate the effects of single and repeated oral doses of barnidipine on talinolol pharmacokinetics in rats. In the single-dose study, talinolol (20 mg/kg) alone and with barnidipine at low (1 mg/kg) and high doses (10 mg/kg) were orally administered to rats. In the repeated-dose study, rats were treated with barnidipine (1 mg/kg/day) or vehicle only for four days, then with talinolol (20 mg/kg, on day 5). Blood samples were collected at 0.5, 1, 2, 4, 6 h following last dose and plasma talinolol levels were determined by HPLC. Compared to the control, Cmax of talinolol elevated 10% (p=0.79) and 110% (p<0.05); plasma AUC0-6h increased 33% (p=0.41) and 46% (p<0.05) following low and high single doses of barnidipine co-administration, respectively. In the repeated-dose study, Cmax and AUC0-6h of talinolol increased 131% (p<0.05) and 130% (p<0.05) respectively, following co-administration of a low barnidipine dose. Double-peaks were observed when single or repeated low doses of barnidipine were co-administered. There may be coupling between occurrence of double-peak phenomenon and P-glycoprotein inhibition. Increment of talinolol bioavailability upon low and high doses of barnidipine co-administration may be due to P-glycoprotein inhibition. The higher increase of talinolol plasma AUC0-6h due to the repeated doses of barnidipine may be explained by downregulation of P-glycoprotein.

Effects of Antihypertensive Therapy on Blood Pressure Variability.

The study aims to summarize the effect of antihypertensive therapy on various types of BP variability in hypertensives. Visit-to-visit, day-by-day, and ambulatory BPV are markers of target organ damage and cardiovascular prognosis, as was shown in the LIFE study, which showed that visit-to-visit variability in BP predicted cardiovascular events in treated hypertensive patients with left ventricular hypertrophy. Long-acting calcium channel blockers (CCBs) may be a preferable treatment in reducing BPV measures. Non-adherence to antihypertensive medication is also a very important component of increased BPV, and improving the adherence is also a key for the favorable prognosis. BPV cannot be a target of antihypertensive treatments because of the lack of definitive evidence. However, in high-risk patients, those with cardiovascular or cerebrovascular diseases, the clinical significance should be considered in individual basis. Especially, reduction of BPV would be an important strategy for these patients.

Resistant Hypertension.

Resistant hypertension is a severe medical condition which is estimated to appear in 9-18% of hypertensive patients. Due to higher cardiovascular risk, this disorder requires special diagnosis and treatment. The heterogeneous etiology, risk factors and comorbidities of resistant hypertension stand in need of sophisticated evaluation to confirm the diagnosis and select the best therapeutic options, which should consider lifestyle modifications as well as pharmacological and interventional treatment. After having excluded pseudohypertension, inappropriate blood pressure measurement and control as well as the white coat effect, suspicion of resistant hypertension requires an analysis of drugs which the hypertensive patient is treated with. According to one definition - ineffective treatment with 3 or more antihypertensive drugs including diuretics makes it possible to diagnose resistant hypertension. A multidrug therapy including angiotensin - converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers, diuretics, long-acting calcium channel blockers and mineralocorticoid receptor antagonists has been demonstrated to be effective in resistant hypertension treatment. Nevertheless, optional, innovative therapies, e.g. a renal denervation or baroreflex activation, may create a novel pathway of blood pressure lowering procedures. The right diagnosis of this disease needs to eliminate the secondary causes of resistant hypertension e.g. obstructive sleep apnea, atherosclerosis and renal or hormonal disorders. This paper briefly summarizes the identification of the causes of resistant hypertension and therapeutic strategies, which may contribute to the proper diagnosis and an improvement of the long term management of resistant hypertension.

On the molecular dynamics in long-acting calcium channel blocker lacidipine: solid-state NMR, neutron scattering and periodic DFT study

A new-generation lipophilic calcium channel blocker lacidipine (LCDP) has been thoroughly explored by combining solid-state nuclear magnetic resonance (NMR) with high-flux quasi-elastic (QENS) and inelastic neutron scattering (INS) experiments.

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Objective: Received wisdom suggests that treatments which reduce heart rate (HR), or avoid cardio-acceleration, are associated with improved cardiovascular (CV) outcomes. However, in the SIGNIFY trial in 12,049 patients with symptomatic angina, a sub-group analysis demonstrated a small but significant increase in the combined risk of CV death or non-fatal MI with the new anti-anginal agent, ivabradine, which is designed to reduce heart rate. The safety and efficacy of the long-acting calcium channel blocker, Nifedipine GITS (an established anti-anginal agent) has been confirmed via the positive results in the placebo-controlled ACTION trial in patients with stable symptomatic coronary artery disease (CAD). This further, retrospective analysis of the ACTION database has evaluated the inter-relationships between baseline HR, and its on-treatment changes, on subsequent cardiovascular outcomes. Design and method: The retrospective analyses of the ACTION trial were performed for quintiles of HR, using the multivariate Cox proportional hazard model, for baseline HR and the achieved HR after 6 weeks of the trial (by which time titration of both placebo and nifedipine GITS was complete). Results: For baseline HR, the risk in the lowest (<56 bpm) was significantly reduced when compared to the highest quintile (HR > 72BPM) for the primary trial endpoint (HR = 0.81 CI 0.70, 0.94); any cardiovascular (CV) event (HR = 0.82 CI 0.70, 0.96); and new onset heart failure (HR = 0.48 CI 0.31, 0.74). No significant differences were apparent for myocardial infarction (MI) or debilitating stroke. In contrast, there was no evidence that on-treatment HR was predictive of outcome: for example, for the primary efficacy endpoint (any CV event, HF, MI and debilitating stroke) the event rates were similar across the quintiles of HR. Correspondingly, there was no significant HR-related treatment effect (comparing nifedipine GITS and placebo). Conclusions: Whilst retrospective analyses must always be interpreted with caution, these results suggest that with “best practice therapy”, CV risk is lowest at baseline in those patients with the lowest HR. However, when compared to placebo, the addition of nifedipine GITS improved overall outcomes and had no deleterious effects across the quintiles of achieved HR.

Effects of an Antihypertensive Combination Based on the Long-Acting Calcium Channel Blocker Benidipineon Vascular and Renal Events

Background: The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial compared three regimens based on the calcium channel blocker (CCB) benidipine.Hypertensive outpatients between the ages of 40–85 years who did not achieve the target blood pressure (<140/90 mmHg) with 4 mg/day of benidipine received an additional angiotensin receptor blocker (ARB), β-blocker, or thiazide. The analysis included 3,293 patients who received an ARB (n = 1,110), β-blocker (n = 1,089), or thiazide (n = 1,094) in addition to benidipine and were followed for a median of 3.61 years. The COPE trial demonstrated a significantly higher incidence of hard cardiovascular composite endpoints and of fatal or non-fatal strokes in the benidipine-β-blocker group than in the benidipine-thiazide group (P = 0.0201, P = 0.0109, respectively). Objective and Methods: In this pre-specified sub-analysis, we further evaluated treatment effects of the three benidipine-based regimens on vascular and renal events. Results: We observed a total of 10 vascular events(0.8 per 1,000 person-years) including 9 cases ofperipheral artery disease (0.8 per 1,000 person-years) and 1 aortic dissection (0.1 per 1,000 person-years). We also observed a total of 7 renal events (0.6 per 1,000 person-years).Few differences were observed among the three treatment groups regarding vascular and renal events (vascular events, P = 0.29; renal events, P = 0.16, Log-rank test). Conclusions: This sub-analysis of the COPE trial demonstrated that blood pressure-lowering therapy with benidipine combined with an ARB, β-blocker, or thiazide diuretic was similarly effective in the prevention of vascular and renal events in hypertensive outpatients.