Calcium Channel Blocker Treatment Research Articles

Pharmacogenomic Association of Nonsynonymous SNPs in SIGLEC12 , A1BG , and the Selectin Region and Cardiovascular Outcomes

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.

Fracture risk is increased by the complication of hypertension and treatment with calcium channel blockers in postmenopausal women with type 2 diabetes

Patients with type 2 diabetes mellitus (T2DM) frequently have other common diseases such as hypertension (HT), dyslipidemia (DL), and cardiovascular disease (CVD). However, it is unknown whether or not the complication of these diseases would affect fracture risk in T2DM patients. We evaluated prevalent morphometric vertebral fractures (VFs) and prior non-VFs in 155 and 195 Japanese T2DM postmenopausal women, respectively, and examined their association with HT, DL, or CVD. VF, non-VF, HT, DL, and CVD were found in 53 (34%), 30 (15%), 136 (70%), 124 (64%), and 45 (23%) women, respectively. Multivariate logistic regression analyses adjusted for age, body mass index (BMI), and serum creatinine showed that the presence of HT significantly increased VF risk [odds ratio (OR) 4.05, P=0.0047], but not non-VF risk. This result was still significant after an additional adjustment for each of blood pressure levels, treatments with anti-hypertensive medications, and a history of falls. In contrast, calcium channel blocker (CCB) treatment significantly increased VF and non-VF risks after adjustments for age, BMI, serum creatinine, and blood pressure levels (OR 2.33, P=0.0320 and OR 2.95, P=0.0150, respectively), while these significances disappeared after an additional adjustment for a history of falls. These findings suggest that the presence of HT increases VF risk independent of blood pressure levels, anti-hypertensive medications, or falls, and that CCB treatment increases both VF and non-VF risks possibly via falls in T2DM postmenopausal women.

L/T-type and L/N-type calcium-channel blockers attenuate cardiac sympathetic nerve activity in patients with hypertension

Sympathetic nerve activity is augmented by calcium-channel blocker treatment as a result of decreased blood pressure. Dihydropyridine calcium-channel blockers are divided into three different types. The purpose of the present study was to investigate whether treatment effects on hemodynamics, cardiac autonomic nerve activity and plasma norepinephrine levels differ among amlodipine (L type), efonidipine (L + T type) and cilnidipine (L + N type). We enrolled 14 hypertensive patients (seven males, seven females, 70 ± 6 years old) undergoing a monotherapy of amlodipine, efonidipine or cilnidipine into this prospective, open-labeled, randomized, crossover study. At baseline and every 6 months of the treatment period, we repeated the evaluation of hemodynamics, spectral analysis of heart rate variability and plasma norepinephrine levels. Blood pressure and pulse rate were comparable among the three treatments. The low-frequency (LF)/high-frequency (HF) power ratio, an index of cardiac sympathovagal balance, was significantly lower with efonidipine and cilnidipine than with amlodipine, while the HF/total power ratio, an index of cardiac vagal activity, revealed the opposite results. There was no significant correlation between the LF/HF ratio and plasma norepinephrine levels. Antihypertensive monotherapy with efonidipine or cilnidipine attenuates cardiac sympathetic nerve activity more effectively than amlodipine monotherapy.

Prognosis of patients with coronary vasospasm after successful resuscitation from ventricular fibrillation

Ventricular fibrillation (VF) is an important cause of sudden cardiac death in patients with coronary vasospasm. Intensive medical treatment against coronary vasospasm is most important for prevention of VF recurrence, and the efficacy of implantable cardioverter-defibrillator (ICD) devices is controversial. We examined 19 consecutive patients with coronary spasm who had been successfully resuscitated from VF between 1993 and 2010, 13 of whom underwent ICD implantation. There were no apparent differences in the results of coronary angiography and acetylcholine provocation test or in medical therapy among them. Six patients underwent electrophysiological tests during the acetylcholine provocation test, and 3 of them showed ventricular arrhythmia. Three patients had recurrent VF under treatment with single calcium channel blocker (CCB), nitrates, and/or nicorandil. Two of them were without ICDs and were left in vegetative states, and the third was successfully resuscitated by an appropriate ICD discharge. The results of our study suggest that dual or multiple CCB treatment is preferable to prevent VF recurrence, and that combined treatment with ICD may be effective for some patients with coronary vasospasm who have been successfully resuscitated from VF. However, reasonable risk stratification for ICD implantation in these patients needs to be established in the future.

Antialbuminuric advantage of cilnidipine compared with L-type calcium channel blockers in type 2 diabetic patients with normoalbuminuria and microalbuminuria

We evaluated the antialbuminuric advantage of cilnidipine, an N/L-type calcium channel blocker (CCB), compared with L-type CCBs in diabetic patients with normoalbuminuria and microalbuminuria. The study was a multicenter, non-randomized crossover trial. Participants were 90 type 2 diabetic patients exhibiting either normo- or microalbuminuria, and undergoing CCB treatment for ≥6 months prior to study entry. The CCB at the time of entry was continued for the first 6 months (Period 1). Treatment was subsequently switched from cilnidipine to an L-type CCB, or vice versa, for the second 6-month observation period (Period 2). During Period 1, the L-type CCB group showed a significant increase of urinary albumin excretion (UAE) over time, while the cilnidipine group showed no significant elevation. During Period 2, switching of the treatment from the L-type CCB to cilnidipine resulted in significant reduction of the UAE, whereas switching from cilnidipine to the L-type CCB resulted in no significant change in the UAE. This study demonstrated that the antialbuminuric effect of Cilnidipine, but not the L-type CCBs, was sustained even in patients treated for a long time. In addition, the antialbuminuric effect can be anticipated after switching from an L-type CCB to cilnidipine, but not vice versa.

A case of Brugada syndrome coexisting with vasospastic angina: Caution should be taken when using calcium channel blockers

Although calcium channel blockers have been reported to aggravate Brugada-type electrocardiogram (ECG) abnormalities, there have been few reports in clinical settings. We present a case of Brugada syndrome coexisting with vasospastic angina, in whom Brugada-type ST-segment elevation was aggravated and ventricular fibrillation attacks occurred by calcium channel blocker treatment. When prescribing calcium channel blockers to patients with Brugada syndrome, it is important to pay careful attention to changes in their ECG pattern.

Meta-Analysis-based Examination regarding the Efficacy of Angiotensin II Receptor Blockers and Calcium Channel Blockers in Borderline Diabetes and Diabetes Patients

We performed a meta-analysis to assess antihypertensive effect, lipid metabolism, insulin resistance index, and body weight changes in patients with borderline diabetes and diabetes treated with angiotensin II receptor blockers (ARB) and dihydropyridine calcium channel blockers (CCB). Literatures for analysis were searched in MEDLINE, the Cochrane Library, and Japana Centra Revuo Medicina. Reports on randomized controlled trials in which the therapeutic results in borderline and diabetic patients were compared between those treated with ARB and CCB were retrieved, and 16 reports met the objective of this study. The efficacy in the two drug treatment groups were divided into 8 outcomes and evaluated. The efficacy outcomes on handling continuous data were integrated using the weighted mean difference, in which the random-effects model was selected for the statistical model. The statistical heterogeneity of each outcome was also tested. The systolic and diastolic blood pressures were significantly reduced in the CCB compared to the ARB treatment group. No significant differences were noted between the two groups in the triglyceride or low-density lipoprotein cholesterol level or body weight changes. It was shown that the CCB was more effective than ARB for the improvement of systolic and diastolic blood pressures in patients with borderline diabetes and diabetes, while no significant differences were noted in the efficacy other than the antihypertensive effect between ARB and CCB treatment groups. This study would provide information in selecting antihypertensive agents for borderline and diabetic patients.

Keeping Your Arteries Young: Vascular Health

quoted saying ‘‘you’re only as old as your arteries.’’ 4 At a pathobiological level, aortic wall stiffness has been associated with processes involving wall matrix, inflammation, and mechanical stress. Increased collagen content and extracellular matrix (arteriosclerosis) is commonly seen in hypertension and aging. In contrast, atherosclerosis relates to endovascular inflammation, increased cellular oxidative stress, and plaque formation; however, both processes can lead to increased vascular stiffness. 5 Patients with increased aortic stiffness have increased aortic pulse wave velocity and reduced arterial compliance. 6 The clinical implication of increased aortic stiffness results in increased afterload on the left ventricle; alteration in coronary perfusion, which affects cardiac diastolic relaxation; and increased myocardial oxygen consumption. Moreover, these surrogates have been tested in multiple trials with important CV outcomes data. Based on the studies so far, it is evident that increased aortic pulse wave velocity is a strong independent predictor of CV risk, regardless of whether it plays a causative role in CV risk or merely serves as a marker of CV disease already present. One example is found in the Strong Heart Study, 7 which evaluated 2405 patients without CV disease at entry with a 5-year follow-up. During this period, 344 patients had CV events that were significantly associated with high central pulse pressure, thus associating high central pulse pressure with increased arterial stiffness. 1 Another study, the Conduit Artery Function Evaluation (CAFE) trial 8 substudy (on behalf of the Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT] Investigators), evaluated the differential impact of BPlowering drugs on central aortic pressure and clinical outcomes. The study enrolled 2073 patients from 5 ASCOT centers after being on treatment for about 1 year. A total of 19,257 patients were enrolled in the ASCOT trial. All patients had hypertension and 3 additional risk factors. They were randomized in a 2 2 factorial design to receive 1 of 2 antihypertensive regimens: amlodipine (5 ⁄10 mg) with or without perindopril (4 ⁄8 mg) or atenolol (50 ⁄100 mg) with or without a diuretic. Despite similar brachial arm systolic BPs in the two treatment arms, there was a significant decrease in both central aortic pulse pressure and central aortic systolic pressure in the angiotensin-converting enzyme (ACE) inhibitor ⁄calcium channel blocker (CCB) arm vs the b-blocker ⁄diuretic arm. This study suggested that ACE inhibitor ⁄CCB treatment was significantly better. In addition, using the Cox proportional hazards modeling, they determined that central aortic pulse pressure was significantly associated with a post hoc‐defined composite outcome of total CV events (unadjusted P<.0001; P<.05 after adjustment for baseline variables). Based on these data, it can be inferred that arterial stiffness and its components do affect CV outcomes. The vascular etiologies of these vessel wall changes require a closer look.

Administration of an Angiotensin-Converting Enzyme Inhibitor Improves Vascular Function and Urinary Albumin Excretion in Low-Risk Essential Hypertensive Patients Receiving Anti-Hypertensive Treatment with Calcium Channel Blockers. Organ-Protecting Effects Independent of Anti-Hypertensive Effect

Concomitant administration of calcium channel blockers (CCBs) and angiotensin-converting enzyme inhibitors (ACEIs) to hypertensive patients at high risk for cardiovascular disease can prevent cardiovascular disease occurrence, but the effects of this treatment on renal and vascular function in low-risk hypertensive patients are unknown. The current study was an open-label prospective study. Hypertensive patients with no history of cardiovascular disease who had not met their blood pressure (BP) goals with CCB treatment were administered perindopril and followed for 6 months. Both home and office BP were significantly lowered by perindopril administration. The morning/evening (M/E) ratios calculated from home BP were 1.31 and 1.05 for systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. When the patients were divided into two groups based on the presence or absence of an anti-hypertensive response, urinary albumin excretion, and cardio ankle vascular index were significantly reduced by perindopril administration in all the subjects, irrespective of the presence or absence of anti-hypertensive reaction. In low-risk hypertensive patients, perindopril improves renal and vascular function probably via its persistent anti-hypertensive effects and the concomitant effects of CCB.

Arterial-Cardiac Destiffening Following Long-Term Antihypertensive Treatment

We examined whether in addition to producing a greater degree of improvement of the arterial stiffness, long-term angiotensin II receptor blocker (ARB) treatment might also have a more beneficial effect on the cardiac diastolic dysfunction than long-term calcium-channel blocker (CCB) treatment; we also evaluated the association between the improvements of the two variables brought about by ARB treatment in subjects with stage I or II hypertension. One hundred and thirteen patients were randomly allocated to treatment with an ARB (candesartan) or a CCB (amlodipine). Echocardiography and measurement of the brachial-ankle pulse wave velocity (PWV) were conducted in both groups at the start of the treatment and at the end of 2-3-years' treatment. After adjustments for covariates, the extent of reduction of the brachial-ankle PWV (-200 ± 18 cm/s vs. -141 ± 18 cm/s, P = 0.03) and that of the increase of the E/A ratio (0.08 ± 0.03 vs. 0.01 ± 0.03, P = 0.04) were significantly greater in the candesartan group than in the amlodipine group. A significant relationship was identified between the delta changes of the brachial-ankle PWV and delta changes of the E/A ratio observed following long-term candesartan treatment. Long-term candesartan treatment may have a more beneficial effect on the stiffness of the large- to- middle-sized arteries than long-term amlodipine treatment, and this treatment may also concomitantly improve the cardiac diastolic dysfunction; a significant association appeared to exist between the improvements of the two variables observed following long-term candesartan treatment.

Antifertility effect of calcium channel blockers on male rats: association with oxidative stress

Calcium ions are vital in many biologic processes including a variety of enzymatic reactions, activation of excitable cells, coupling of electrical activation to cellular secretion, haemostasis, bone metabolism and sperm functions. Calcium channel blockers (CCB) appear to have a reversible anti-fertility effect on male rats which does not occur through inhibition of the pituitary-gonadal axis. While the effects of CCB on male reproductive function have been investigated, less information is available regarding other reproductive indices and the underlying mechanism in the pathogenesis of male reproductive dysfunction. Therefore, the involvement of oxidative mechanisms in the adverse manifestation induced by CCB on male reproductive functions is investigated in this study. For this purpose, lipid peroxidation; enzymatic antioxidants such as superoxide dismutase, catalase and glutathione reduced; epididymal sperm count, motility; histopathology of the testes, epididymis, seminal vesicle, prostate glands; and reproductive performance were determined. CCB administration in rats causes significant oxidative stress in the male reproductive milieu in term of increase in malondialdehyde (MDA) level and a concomitant decrease in catalase, superoxide dismutase and reduced glutathione enzyme activities in the testes. In addition, CCB treatment significantly decreased the sperm count, sperm motility, fertility index, implantation count, and litter size in this study. There is substantial evidence that CCB induces significant oxidative stress in the testes, which appears to be responsible for the adverse effects of decreased sperm count and motility ultimately leading to reduced fertility in rats.

Influence of calcium channel blockers in patients with gastrointestinal disease in Japanese community pharmacies

Calcium channel blockers (CCBs), which have been widely used for the treatment of hypertension and angina pectoris, decrease lower oesophageal sphincter pressure and, as a result, can exacerbate gastrointestinal disease. In a previous study, increased risk of exacerbation of gastrointestinal disease among elderly patients following treatment with CCBs was identified. The prevalence of gastrointestinal diseases has increased in elderly patients, and it is possible that treatment with CCBs may have undesirably influenced this increase. The change in risk of gastrointestinal disease can be estimated by analysing changes in the prescription of antisecretory drugs as an outcome of exacerbation of gastrointestinal disease caused by CCBs. It was hypothesized that patients who were prescribed CCBs would also change their use of antisecretory drugs. From September 2005 to August 2009, a dynamic retrospective cohort study was performed at five community pharmacies in Nagasaki, Japan, to assess alteration of antisecretory drug therapy following treatment with CCBs. Correlations with alterations of antisecretory drug therapy were determined by the Cox proportional hazards model. The proposed study included 260 patients who were prescribed CCBs and 155 controls. During the study period, 53 patients were prescribed CCBs and 13 controls altered their antisecretory drug therapy; the hazard ratio was 2·22 (95% CI 1·25-4·26). Calcium channel blocker treatment of patients with gastrointestinal disease was associated with alteration in frequency of prescription and an increase in dosage of antisecretory drugs. For clinical management of hypertension, alternative antihypertensive drugs may be considered for patients with gastrointestinal diseases. Further studies are required to determine the influence of CCB therapy on gastroesophageal diseases, suggested by the increase in use of antisecretory drugs.

Genetic Variation in the β2 Subunit of the Voltage-Gated Calcium Channel and Pharmacogenetic Association With Adverse Cardiovascular Outcomes in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES)

Single-nucleotide polymorphisms (SNPs) within the regulatory β2 subunit of the voltage-gated calcium channel (CACNB2) may contribute to variable treatment response to antihypertensive drugs and adverse cardiovascular outcomes. SNPs in CACNB2 from 60 ethnically diverse individuals were identified and characterized. Three common SNPs (rs2357928, rs7069292, and rs61839258) and a genome-wide association study-identified intronic SNP (rs11014166) were genotyped for a clinical association study in 5598 hypertensive patients with coronary artery disease randomized to a β-blocker (BB) or a calcium channel blocker (CCB) treatment strategy in the INternational VErapamil SR-Trandolapril STudy GENEtic Substudy (INVEST-GENES). Reporter gene assays were conducted on the promoter SNP, showing association with clinical outcomes. Twenty-one novel SNPs were identified. A promoter A>G SNP (rs2357928) was found to have significant interaction with treatment strategy for adverse cardiovascular outcomes (P for interaction, 0.002). In whites, rs2357928 GG patients randomized to CCB were more likely to experience an adverse outcome than those randomized to BB treatment strategy, with adjusted hazard ratio (HR) (CCB versus BB) of 2.35 (95% CI, 1.19 to 4.66; P=0.014). There was no evidence for such treatment difference in AG (HR, 1.16; 95% CI, 0.75 to 1.79; P=0.69) and AA (HR, 0.63; 95% CI, 0.36 to 1.11; P=0.11) patients. This finding was consistent in Hispanics and blacks. CACNB2 rs11014166 showed similar pharmacogenetic effect in Hispanics, but not in whites or blacks. Reporter assay analysis of rs2357928 showed a significant increase in promoter activity for the G allele compared to the A allele. These data suggest that genetic variation within CACNB2 may influence treatment-related outcomes in high-risk patients with hypertension.

The Maze of Vasodilator Response Criteria

With great interest we read the article of Barst et al. [1]. We agree with their statement that the definition of a positive acute vasodilator response in patients with pulmonary arterial hypertension (PAH) remains controversial. We believe it is very important to minimize this controversy and use uniform criteria when studying the acute pulmonary vasodilator response in patients with PAH. In their article, Barst and coworkers defined acute response criteria based on a 20% or more decrease in mean pulmonary arterial pressure (mPAP) with no decrease in cardiac index, or on a 25% or more decrease in the pulmonary vascular resistance index (PVRI) with no decrease in cardiac index (the latter only in case of an unrestricted shunt at the ventricular or ductal level). We do not recognise these criteria from previously published reports. A review of the literature provides the following definitions of a positive response to acute pulmonary vasodilator tests: An mPAP decrease of 20% or more, no decrease in cardiac index and no change or a decrease in the pulmonary-to-systemic vascular resistance ratio [2, 3] A decrease of more than 20% in both mPAP and PVRI [4, 6] A fall in total pulmonary resistance of more than 30% [7] A decrease in mPAP of 10 mmHg or more, reaching an mPAP of 40 mmHg or less and a normal cardiac output [5]. To our knowledge, the criteria used in the current article have not been published previously. The use of different response criteria in different studies results in different prevalences of acute vasodilator response and different predictive values for identifying long-term responders to calcium-channel blocker treatment and patients with improved survival [5]. Furthermore, as a result, data from these studies cannot be compared directly. For example, the prevalence of acute responders among children with PAH (42%) is reported to be higher than among adults (12–26%) [2, 4, 5]. However, because the criteria used differed between children and adults, this comparison does not hold. We commend Barst and coworkers for their success in comparing the use of different vasodilating agents (inhaled nitric oxide, oxygen, or the combination of the two) for vasodilator testing in children. However, the introduction again of new response criteria prohibits interpretation of these data in the perspective of previously published data. It is not our intention to discourage the quest for new response criteria aimed at reaching better prediction of treatment effect or survival or at expanding its use to broader patient populations other than those with idiopathic PAH (iPAH) or familial PAH (FPAH). However, in view of the ongoing discussion on the optimal definition of acute response criteria, we strongly advocate presenting the use of new criteria in a manner comparative with the use of previously published criteria.

Angiotensin receptor blocker/diuretic combination preserves insulin responses in obese hypertensives.

Thiazide diuretics can impair glucose metabolism and increase new-onset diabetes. Adding an angiotensin receptor blocker to diuretics may protect against these metabolic effects; however, the mechanism of this protection is unclear. To explore potential mechanisms, a 16-week multicenter trial was conducted to ascertain the relative glucose metabolism effects of combined hydrochlorothiazide and angiotensin receptor blocker (valsartan) therapy compared with hydrochlorothiazide and calcium channel blocker (amlodipine) treatment in 412 centrally obese hypertensive individuals (BMI = 35 +/- 7 kg/m, seated BP = 159 +/- 8/94 +/- 8 mmHg, and mean age 56 years). Individuals were randomized to valsartan/hydrochlorothiazide, with force-titration to 320/25 mg or hydrochlorothiazide, with titration to hydrochlorothiazide 25 mg and amlodipine 10 mg, respectively. Changes from baseline to week 16 in fasting and 2-h postprandial glucose and insulin levels after an oral glucose load were measured. At week 16, clinic blood pressure reductions were similar (P > 0.05) in both groups. Fasting and 2-h glucose levels increased (P < 0.05) with the amlodipine combination but not with the valsartan combination. In concert with these glucose responses, postprandial insulin increases from baseline were substantially greater with valsartan than with amlodipine plus hydrochlorothiazide group (P = 0.001). The glucose responses were inversely related to insulin responses at the study conclusion. The novel observation of this investigation was that the combination of valsartan and hydrochlorothiazide was associated with greater glucose-stimulated insulin secretory and lesser glycemic excursion responses than the amlodipine combination group. Thus, this data suggests that adding an angiotensin receptor blocker attenuates the negative effects of thiazides on pancreatic beta-cell glucose-induced insulin secretion.

Do Diuretics Diminish the Predicted Benefits on Ischemic Heart Disease Events of Lowering Blood Pressure in Hypertension?

Do Diuretics Diminish the Predicted Benefits on Ischemic Heart Disease Events of Lowering Blood Pressure in Hypertension?

COMPARATIVE EFFECTS OF AMLODIPINE AND CILNIDIPINE ON SYMPATHETIC NERVOUS MODULATION IN PATIENTS WITH HYPERTENSION: PP.32.265

Objective: Sympathetic nervous activity may be augmented with the calcium channel blocker (CCB) treatment as a result of decreased blood pressure despite the advent of long-acting CCBs. A dihydropyridine CCB, cilnidipine blocks not only L type but also N type of calcium channels. Accordingly, we compared the effects of amlodipine and cilnidipine on autonomic nervous activity in hypertensive patients. Design and Methods: Eighteen hypertensive patients under the treatment of amlodipine monotherapy for at least 6 months were randomized to the 2 treatment arms. In 8 patients (70±9 (SD) years, 1 man and 7 women), amlodipine monotherapy was further continued for 6 months. In 10 patients (70±4 years, 3 men and 7 women), amlodipine treatment was switched to cilnidipine treatment. Before and after 6-month treatment with amlodipine or cilnidipine, each patient underwent 30 min resting electrocardiographic recording in the morning after an overnight fasting. By using spectral analysis of heart rate variability, frequency-domain measures were calculated. The low frequency (LF: 0.04 to 0.15 Hz)/high frequency (HF: 0.15 to 0.40 Hz) power ratio was used as an index of sympathovagal balance, and HF/total power (TP) ratio was used as an index of vagal activity. Plasma norepinephrine levels were measured by radioimmunoassay. Results: In patients with continuous amlodipine treatment, systolic and diastolic blood pressures (SBP, DBP) and heart rate (HR) remained unchanged. LF/HF and HF/TP ratios also remained unchanged (LF/HF 1.77±1.05 vs. 1.83±1.22, HF/TP 0.419±0.122 vs. 0.402±0.116). Plasma norepinephrine levels were comparable (370±88 pg/ml vs. 491±137 pg/ml). In patients switched to cilnidipine, SBP, DBP and HR were similar before and after switching. Interestingly, LF/HF ratio decreased significantly (p = 0.012) from 2.37±1.56 to 1.89±1.42, and HF/TP ratio increased significantly (p = 0.049) from 0.366±0.132 to 0.417±0.156, despite the comparable HR. Plasma norepinephrine concentrations decreased significantly (p = 0.009) from 359±65 pg/ml to 282±72 pg/ml. Conclusions: These findings suggest that cilnidipine may provide beneficial prognosis for hypertensive patients because it suppresses sympathetic nervous activity.

The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response

Clopidogrel is a prodrug that has to be converted in vivo to its active metabolite by cytochrome (CYP)P450 iso-enzymes. As calcium channel blockers (CCBs) are inhibitors of CYP3A4, concomitant use of these drugs might play a role in the wide inter-individual variability in the response to clopidogrel. However, some CCBs also have strong inhibitory effects on the drug transporter P-glycoprotein (Pgp), which mediates clopidogrel's intestinal absorption. It was the aim of this study to evaluate the effect of co-administration of Pgp-inhibiting and non-Pgp-inhibiting CCBs on on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective percutaneous coronary intervention (PCI). In a total of 623 consecutive patients undergoing elective PCI treated with clopidogrel and aspirin, platelet reactivity to 5 and 20 muM adenosine diphospate (ADP) and clopidogrel poor-response (defined as > 70% platelet aggregation to 20 muM ADP) were evaluated by light transmittance aggregometry. A total of 222 patients (35.6%) were on CCB treatment, of which 98 used Pgp-inhibiting CCBs (verapamil, nifedipine, diltiazem, barnidipine) and 124 patients used the non-Pgp-inhibiting CCB amlodipine. Adjusted mean ADP-induced on-clopidogrel platelet reactivity was significantly higher in both users of Pgp-inhibiting CCBs and amlodipine as compared to CCB non-users (all p<0.05). However, only the use of amlodipine was significantly associated with a 2.3-fold increased risk of clopidogrel poor-response. This study demonstrates that concomitant use of Pgp-inhibiting CCBs and amlodipine increases on-clopidogrel platelet reactivity. Only amlodipine was associated with clopidogrel poor-response. The drug-drug interaction between clopidogrel and amlodipine might be more clinically relevant as compared to P-glycoprotein-inhibiting CCBs.

POSITIONS OF CALCIUM CHANNEL BLOCKER LERCANIDIPINE ACCORDING TO EVIDENCE BASED CARDIOLOGY

Data of evidence based cardiology including results of international clinical trials on efficacy and safety of the modern calcium channel blocker (CCB), lercanidipine, are presented. Results of these trials show the firm position of lercanidipine in the modern cardiology and confirm that treatment with lercanidipine leads to significant reduction of systolic and diastolic blood pressure (BP) with no effect on heart rate (HR). Peripheral edema (the common side effect of CCBs) occurs rarer with lercanidipine treatment than this with any other CCB treatment. Lercanidipine can be recommended to patients with concomitant diseases due to its additional features.

Abstract 5789: Prevention of Peripheral Arterial Disease With Calcium Channel Blockers in Patients With Hypertension: A Meta-analysis of Randomized Trials

Background: Peripheral arterial disease (PAD) is a manifestation of atherosclerosis and associated with increased morbidity and mortality. Several preclinical studies suggest that calcium channel blockers (CCB) may prevent the development of atherosclerosis in high-risk patients. Aim : This study sought to evaluate the effect of CCB treatment for the primary prevention of PAD in patients with hypertension. Methods : We searched the published literature (MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE) for trials published after 1990 reporting the effect of CCB on the development of PAD. Criteria for inclusion included a study duration &gt;6 months, use of a randomized control group not receiving CCB, and availability of outcome data on PAD. We conducted a meta-analysis with random and fixed effects models to combine the results of these studies. Results: Of 2,006 potentially relevant studies, a total of 7 studies (65,925 patients) met our inclusion criteria. Patients randomized to the control group received either placebo or active treatment with ACE-inhibitors, beta-blockers or diuretics. In patients receiving CCB, 535 of 24,678 (2.2%) developed PAD versus 1,249 of 39,833 (3.1%) in the control group. CCB reduced the relative risk for PAD development by 25% (95% confidence interval 33% to 17%, p&lt;0.001). In the subset of 6 studies with 64,511 participants taking dihydropyridines vs control, dihydropyridines were associated with a significant risk reduction in PAD of 26% (95% CI 33% to 18%, p&lt;0.001). Conclusion: Based on the results of this study, calcium-channel blockers appear to be effective in the prevention of PAD in patients with hypertension.