Dihydropiridine Calcium Channel Blocker Research Articles

Polygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone

Pharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics. Outcomes included treatment discontinuation and heart failure. Pharmacogenetic variant rs10898815-A (NUMA1) increased discontinuation rates, highest in those with high polygenic scores for fat mass. The RYR3 variant rs877087 T-allele alone modestly increased heart failure risks versus non-carriers (HR:1.13, p = 0.02); in patients with high polygenic scores for fat mass, lean mass, and lipoprotein A, risks were substantially elevated (HR:1.55, p = 4 × 10−5). Incorporating polygenic scores for adiposity and lipoprotein A may improve risk estimates of key clinical outcomes in CCB treatment such as treatment discontinuation and heart failure, compared to pharmacogenetic variants alone.

Ranolazine in refractory and chronic stable angina

Aim/Objectives: The current Scottish Intercollegiate Guidelines Network (SIGN) guidelines recommend beta blockers and dihydropiridine calcium channel blockers as first-line agents for refractory angina pectoris. Despite being optimally treated with pharmacotherapy and revascularisation, up to 40% of patients still experience symptoms. Ranolazine, a piperazine derivative, selectively inhibits late sodium currents and is of particular interest as it is currently not recommended routinely by SIGN guidelines and Scottish Medicine Consortium (SMC) but has been prescribed in Tayside, initially through IPTR since 2017 and recently through a Local New Medicine Treatment Protocol and Stable Angina Pathway. Real world experience of ranolazine prescribing in patients with chronic and often refractory angina is not widely reported. We therefore audited its use in Tayside to understand its prescribing pattern within our patient population and assess its effects on angina symptom relief. Methods: Electronic health records and prescribing data between 1st January 2012 and 31st December 2018 were retrospectively analysed. Data on baseline characteristics, prescribing information, past medical history, and angina symptom control were collected. Standard descriptive statistics were used for analysis. Results: 35 patients were identified as suitable for inclusion in the audit. Mean age was 71.4 ± 12.5 years old and 68.6% were male. 23 patients (65.7%) had either a previous percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). The most common reason for ranolazine prescription was refractory angina (74.3%) with 375 mg BD being the most common dose. Prescription of guideline-recommended anti anginals was high with 80% of patients being on a beta blocker and a nitrate prior to commencing ranolazine. Encouragingly, 27 patients (77.1%) reported an improvement in Canadian Cardiovascular Society (CCS) angina class and the rate of non-responders was 22.9%. No adverse effects leading to discontinuation of ranolazine was found. Conclusion: Ranolazine may play a role as an additional anti anginal agent with reasonable achievement of symptom control in patients who have refractory angina despite the use of other guideline-recommended anti anginal agents.

Arterial hypertension after age 65: from epidemiology and pathophysiology to therapy Do we know where we stand?

Arterial hypertension is a prevalent disease with great harming potential. After the age of 55 years the remaining lifetime risk of hypertension amounts to 90%. Despite the constant advances some important issues such as the cut-off blood pressure for the initiation of antihypertensive therapy or the therapeutic goal are debated. In this review, we present - based on the available literature - the current concepts concerning the pathophysiology, epi-demiology and antihypertensive therapy in patients aged 65 years or older. The pathophysiology of hypertension in older patients in principle rests on stiffening of large conduit arteries, which leads to greater systolic and lower diastolic blood pressure. This in most older patients results in isolated systolic hypertension. Additionally most of these patients have low-renin hypertension. Data from large-scale clinical trials indicate that therapy of such individuals with thiazide-like diuretics and long-acting dihydropiridine calcium channel blockers as first-line medications reduces risk of complications. Based on results of recently published trials, meta-analyses, and prospective observations, the optimal on-treatment blood pressure values for most older hypertensive patients should be set within the 130-139 mmHg range. At present, lower values of standard office blood pressure in this group of patients have not been shown to be associ-ated with additional benefits, and may be associated with a greater risk of adverse events. In conclusion, we recommend that for most patients aged 65 years or more, standard office systolic blood pressure should be cautiously reduced to within 140 and 130 mmHg, preferably with a thiazide-like diuretic, long acting dihydropiridine calcium channel blocker or their combination.

Resistant hypertension: an overview.

Despite the availability of anti-hypertensive medications with proven efficacy and good tolerability, many hypertensive patients have blood pressure (BP) levels not at the goals set by international societies. Some of these patients are either non-adherent to the prescribed drugs or not optimally treated. However, a proportion has resistant hypertension (RH) defined as office BP above goal despite the use of ≥3 antihypertensive medications at maximally tolerated doses (one ideally being a diuretic). Diagnosis of RH based upon office measurements, however, needs confirmation through 24-h BP monitoring to exclude "white coat" RH since cardiovascular events and mortality rates follow mean ambulatory BPs. Standardized combination therapy based upon angiotensin converting enzyme inhibitors or angiotensin receptor blockers, amlodipine or other dihydropiridine calcium channel blockers and thiazide or thiazide-like diuretics has been advocated to treat RH with spironolactone as preferred fourth add-on drug. Interventional procedures such as renal denervation have been devised to treat RH and tested with insofar not positive results in series of patients not responding to medical treatment. It is unclear whether RH constitutes a specific phenotype of EH or should rather be considered a more serious form of uncontrolled hypertension. Whatever the case, its presence associates with an increased cardio- and cerebrovascular risk and deserves, therefore, particular care.

ST ELEVATION ACUTE CORONARY SYNDROME IN NON-OBSTRUCTIVE LESION OF CORONARY ST ELEVATION ACUTE CORONARY SYNDROME IN NON-OBSTRUCTIVE LESION OF CORONARY ARTERIES: DATA FROM THE REGISTRY RECORD-3

Material and methods . The data used, from the acute coronary syndrome registry RECORD-3, in the emergency cardiology department of Tomsk SRI of Cardiology, together with another 51 center in Russia. Based on the absence of presence of NOCA, patients with ST elevation myocardial infarction, who had undergone coronary arteriography, were selected to two independent groups: 27 with NOCA and 571 with OCA. Results. There were no significant differences in the clinical portrait of NOCA and OCA patient. However, palpitation followed angina attack in NOCA patients. In the NOCA, there was significantly lower number of persons with diagnostically relevant raise of cardio specific enzymes. Indirectly, it points on temporary ischemia with no necrosis, or that the area of necrotic myocardium is not large. In NOCA patients, statistically more significantly were absent reciprocal ECG changes. Endpoints as mortality and novel heart failure development had tendency to statistically more significant decrease of prevalence in NOCA patients. As final diagnosis at discharge, in NOCA patients more often another diagnosis was mentioned (including unstable angina, etc.), but not myocardial infarction. The key issues in hospital management of these two groups were identical, except more often prescription of dihydropiridine calcium channel blockers to NOCA patients, and rarer prescription of antiplatelet drugs at discharge. Conclusion. Regardless the fact that prognosis in ACS with NOCA and intact arteries is better than in OCA, it is necessary to analyze thoroughly pathogenesis of the disease in every case, as in this category of patients especially, it is most heterogenic. As these patients have comorbid factors, it is necessary to select the leading one, and to intensify efforts on this factor directly.

The role of amlodipin for the arterial hypertension therapy in patients with coronary artery disease

The article considers the drug treatment of the patients with arterial hypertension (AH) and coronary artery disease (CAD). Arterial hypertension is one of the main modifying risk factors of stroke, cardiovascular failure and CAD. Arterial hypertension and CAD are generally comorbid conditions having common pathogenic mechanisms. The great social impact of these diseases and their complications predetermine the search for new ways of improving treatment of patients with above mentioned combined pathology. Numerous clinical studies confirmed the advisability of dihydropiridine calcium channel blockers (CCB) as an effective therapy of hypertension associated with CAD. For example of CCB, in particular amlodipine, the efficiency CCB in hypertensive patients at high cardiovascular risk is demonstrated. Amlodipine is effective as both antihypertensive and antianginal agent with antiatherosclerotic and cardioprotective properties. Besides amlodipine has a high level of safety which explains its active use in clinical practice, in particular, for treating patients with hypertension associated with CAD.

Hypertension and stable coronary artery disease

Systemic hypertension is highly prevalent in stable coronary artery disease, a pervasive comorbidity complicating the diagnostic performance and interpretation of non-invasive provocative tests in chest pain patients because of the ischaemic signals generated, despite normal or near normal coronary arteries, by hearts structurally readapted by long-term exposure to raised systemic blood pressure. Additional and unresolved problems posed by arterial hypertension in patients with stable coronary artery disease regard the benefits of antihypertensive treatment due to reports of irrelevant, if not detrimental, effect of blood pressure (BP) lowering in averting coronary relapses as well as the lack of association between BP levels and incident coronary events in survivors from acute myocardial infarction. Uncertainties extend to BP-independent cardioprotective effects of antihypertensive drugs, although the efficacy of renin-angiotensin system blockers in the long-term prevention of cardiovascular events in stable coronary artery disease patients has been shown by several studies, particularly when combined with amlodipine, a dihydropiridine calcium channel blocker. In contrast, the long-term effect of beta-blockers, the antihypertensive class most used in that clinical category, is not supported by strong evidence except that generated in patients with systolic dysfunction and early postmyocardial infarction recovery periods.

The vanishing story of angiotensin II receptor blockers in the treatment of atrial fibrillation

This editorial refers to ‘Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study)’ by T. Yamashita et al. , on page 473. Pharmacological inhibition of the renin–angiotensin system (RAS) is a safe and beneficial intervention in patients with structural heart disease. Furthermore, there is good experimental evidence that AT-1 receptor blocker (ARB) therapy can prevent atrial structural remodelling in atrial fibrillation (AF).1–4 Experiments have proved that by angiotensin-converting enzyme (ACE) inhibitors and ARBs, the degree of atrial fibrosis and thereby the inducibility of AF can be reduced.2–4 In these settings, ACE inhibitors and ARBs were similarly effective. Of note, antiarrhythmic effects of ACE inhibitors and ARBs to prevent AF are supported by retrospective analyses of clinical trials including TRACE (Trandolapril Cardiac Evaluation), ValHeFT (Valsartan Heart Failure Trial), SOLVD (Studies of Left Ventricular Dysfunction), CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), and LIFE (Losartan Intervention For Endpoint reduction in hypertension).1,5 Given the observation that AF induces atrial fibrosis and contributes to electrophysiological changes, ARBs appear as a reasonable and safe additive antiarrhythmic therapy in AF, which is supported by recent meta-analyses.1,5 Yamashita et al .6 present the important data of J-RHYTHM II (Japanese Rhythm Management Trial II for Atrial …

Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study)

Atrial fibrillation (AF) is a common arrhythmia frequently associated with hypertension. This study was designed to test the hypothesis that lowering blood pressure by angiotensin II-receptor blockers (ARB) has more beneficial effects than by conventional calcium channel blockers (CCB) on the frequency of paroxysmal AF with hypertension. The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is an open-label randomized comparison between an ARB (candesartan) and a CCB (amlodipine) in the treatment of paroxysmal AF associated with hypertension. Using daily transtelephonic monitoring, we examined asymptomatic and symptomatic paroxysmal AF episodes during a maximum 1 year treatment. The primary endpoint was the difference in AF frequency between the pre-treatment period and the final month of the follow-up. The secondary endpoints included cardiovascular events, development of persistent AF, left atrial dimension, and quality-of-life (QOL). The study enrolled 318 patients (66 years, male/female 219/99, 158 in the ARB group and 160 in the CCB group) treated at 48 sites throughout Japan. At baseline, the frequency of AF episodes (days/month) was 3.8 ± 5.0 in the ARB group vs. 4.8 ± 6.3 in the CCB group (not significant). During the follow-up, blood pressure was significantly lower in the CCB group than in the ARB group (P < 0.001). The AF frequency decreased similarly in both groups, and there was no significant difference in the primary endpoint between the two groups. There were no significant differences between the two groups in the development of persistent AF, changes in left atrial dimension, occurrence of cardiovascular events, or changes in QOL. In patients with paroxysmal AF and hypertension, treatment of hypertension by candesartan did not have an advantage over amlodipine in the reduction in the frequency of paroxysmal AF (umin CTR C000000427).

Renoprotective effect of calcium channel blockers

The advancing chronic renal failure is at most the consequence of secondary haemodynamic and metabolic factors as intraglomerular hypertension and glomerular hypertrophy. Although tight blood pressure control is the major preventive mechanism for progressive renal failure, ACE inhibitors and angiotensin receptor blockers have some other renoprotective mechanisms beyond the blood pressure control. That is why these two groups of antihypertensive drugs traditionally have advantages in treating renal patients especially those with proteinuria over 400-1000 mg/day. Even if earlier experimental studies have shown renoprotective effect of calcium channel blockers, later clinical studies did not prove that calcium channel blockers have any advantages in renal protection over ACE inhibitors given as monotherapy or in combination with ACE inhibitors. It was explained by action of calcium channel blockers on afferent but not on efferent glomerular arterioles; a well known mechanism that leads to intraglomerular hypertension. New generations of dihydropiridine calcium channel blockers can dilate even efferent arterioles not causing unfavorable haemodynamic disturbances. This finding was confirmed in clinical studies which showed that renoprotection established by calcium channel blockers was not inferior to that of ACE inhibitors and that calcium channel blockers and ACE inhibitors have additive effect on renoprotection. Newer generation of dihydropiridine calcium channel blockers seem to offer more therapeutic possibilities in renoprotection by their dual action on afferent and efferent glomerular arterioles and, possibly by other effects beyond the blood pressure control.

Dihydropiridine calcium-channel blockers and perioperative mortality in aortic aneurysm surgery

BackgroundDihydropiridine calcium-channel blockers are often used as an alternative to beta-blockers for the treatment of hypertension in patients undergoing aortic aneurysm surgery. We studied the relation between dihydropiridine calcium-channel blocker use and perioperative mortality in patients undergoing aortic aneurysm surgery. MethodsWe studied 1000 patients [mean (range) age, 69 (22–95) yr; males 810] who underwent acute or elective abdominal or thoracoabdominal aortic aneurysm surgery between January 1999 and April 2007, at Semmelweis Medical University (Budapest, Hungary). Patients were evaluated for clinical risk factors, chronic medication use, and surgical characteristics. Propensity score analysis was used to adjust for the potential bias in dihydropiridine calcium-channel blocker use. Multivariable logistic regression analyses were applied to study the association between the likelihood of dihydropiridine calcium-channel blocker use and mortality occurring within 30 days of surgery. ResultsPerioperative mortality occurred in 85 (8.5%) patients. Thirty-day mortality was significantly higher in dihydropiridine calcium-channel blocker users compared with non-users, 14.0% vs 6.0%; crude odds ratio (OR) 2.6, 95% confidence interval (CI): 1.6–4.0, P<0.0001. Even after correcting for other baseline covariates and propensity for these agents dihydropiridine calcium-channel blocker use was associated with increased 30-day mortality, OR (95% CI) 2.5(1.3–4.6), P=0.003. ConclusionsDihydropiridine calcium-channel blocker use in patients with acute or elective aortic aneurysm surgery is independently associated with an increased incidence of perioperative mortality.

Dihydropiridine calcium-channel blockers and perioperative mortality in aortic aneurysm surgery

Dihydropiridine calcium-channel blockers and perioperative mortality in aortic aneurysm surgery

Determinants of evolution of ECG signs of left ventricular hypertrophy during long-term antihypertensive treatment in patients with high risk arterial hypertension

Objective: to study the evolution of ECG left ventricular hypertrophy (LVH) in patients with high risk arterial hypertension (AH) with during long-term antihypertensive treatment. Design and methods. 102 patients (48% males, average age 67,1+0,6) with AH of high risk were randomized to antihypertensive therapy based on AT1 angiotensine II receptors anatagonists (ARA) or dihydropiridine calcium channel blockers (CCB). To achieve target blood pressure (BP) 35 mV, Cornell voltage criteria>20 mV in females and > 28 mV in males and Cornell product >2442 msec*mV). Results: In 1 year of treatment regress of LVH was observed in 8 from 31 (25,85%) patients with initially ECG- LVH. Patients with regress of ECG - LVH were younger and had lower BMI versus patients with of ECG-LVH persistence (65,5±2,4 vs 66,7±5,9 years and 28,6±5,6 vs 29,2±4,3 kg/m 2 respectively, n.s.); and significantly lower systolic BP (SBP) after 1 year treatment (137,8±7,6 mmHg vs 142,3±6,2 mmHg respectively). Step logistic regression analysis revealed that SBP was the only independent factor related with regress of ECG-LVH. baseline. Those patients were non significantly older (69,4±6,4 vs 66,0±6,2 years) and had higher blood glucose and total cholesterol levels both at baseline and after 1-year treatment and higher SBP after 1 treatment. Independent correlation with ECG-LVH development was found only for SBP, glucose and total cholesterol vlaues after 1-year treatment. There was no correlation between evolution of LVH and the type of treatmen. Conclusion. Persistence and development of ECG-LVH in patients with high risk AH during long-term antihypertensive treatment is mainly associated with insufficient SBP control. Data on value of glucose and total cholesterol levels suggests potential benefit of treatment regimens with complex correction of risk factors for prevention of ECG-LVH development.

Perioperative Nimodipine and Postoperative Analgesia

There is experimental evidence that nimodipine, an L-type dihydropiridine calcium channel blocker with relatively high blood-brain barrier penetration, enhances the antinociceptive properties of morphine. We tested the hypothesis that oral nimodipine taken preoperatively and 6 hourly for 48 h postoperatively would reduce visual analog scale pain scores and morphine consumption in morphine-naive patients with acute postoperative pain. Forty patients undergoing total knee replacement surgery (age 70 +/- 7 yr, 28 male) were randomized by computer-generated numbers to receive capsules containing either nimodipine 30 mg or placebo in a double-blind study design. All patients received 3 capsules (nimodipine 90 mg or placebo) 1-2 h before induction of anesthesia followed by oral nimodipine 30 mg or placebo 6 hourly for 48 hours postoperatively. Spinal anesthesia was induced with hyperbaric bupivacaine 0.5% (2.4-3.0 mL) and fluids and ephedrine were given at the discretion of the anesthesiologist. Morphine patient-controlled analgesia (PCA, bolus 1 mg, lockout 5 min) was given for postoperative analgesia. Primary outcome measures were visual analog pain scores at rest and on moving (sitting forward) and PCA morphine consumption. Morphine consumption was significantly larger in nimodipine patients at 12 h (39 +/- 18 versus 29 +/- 15; P = 0.04), 24 h (62 +/- 23 versus 45 +/- 24; P = 0.02), and 48 h (88 +/- 34 versus 61 +/- 27; P = 0.01). There were no significant differences in pain scores at rest or moving or in time to first use of morphine analgesia. This study has demonstrated increased morphine consumption after 12 h in postoperative patients receiving nimodipine, suggesting that, in patients undergoing knee replacement surgery, it has no adjunctive analgesic effect and may actually inhibit the analgesic effect of morphine.

Effect of manidipine on gene expression and protein level of oxidative stress-related proteins: p22phox and HO-1: relevance for antihypertensive and anti-remodeling effects.

Oxidative stress (OxSt) is a major damaging factor in arterial hypertension and its long-term complications. This is why considerable attention is paid to the possible effects of antihypertensive drugs on OxSt. Manidipine is a dihydropiridine calcium channel blocker with reported nephroprotective activities, but no information is available on its effect on OxSt and related mechanisms. This study assessed the effect of manidipine on normal subjects' monocyte gene and protein expression of OxSt-related proteins such as p22(phox), a NAD(P)H oxidase system subunit, critical in generating O2-, and heme oxygenase-1 (HO-1), induced by and protective from OxSt, and compared manidipine with the ACE inhibitor captopril and the calcium channel blocker nifedipine, in the presence and absence of sodium arsenite (NaAsO2) as an inducer of OxSt.Co-incubation of manidipine with NaAsO2 dose-dependently decreased p22(phox) mRNA production from basal: 0.87 +/- 0.1 d.u., 0.69 +/- 0.06 and 0.66 +/- 0.09 at 100, 300 and 500 nM respectively versus 0.99 +/- 0.2, P < 0.04, while HO-1 mRNA production was increased by the same concentrations of the drug: 0.87 +/- 0.1 d.u., 0.92 +/- 0.1, 0.98 +/- 0.1 respectively versus 0.63 +/- 0.07; P < 0.03. Monocyte p22(phox) mRNA production was reduced both by manidipine and captopril: 0.48 +/- 0.04 d.u. and 0.43 +/- 0.08, respectively versus 0.58 +/- 0.07, P < 0.006, while no changes were induced by nifedipine (0.61 +/- 0.07, P = ns). Manidipine increased monocyte HO-1 mRNA production (1.6 +/- 0.4 versus 1.2 +/- 0.4, P < 0.008), while nifedipine and captopril showed no effect (1.2 +/- 0.3 and 1.1 +/- 0.3, respectively). The effects of M on p22(phox) and HO-1 gene expression in the presence of OxSt were also paralleled by the same effects at protein level. In conclusion, manidipine decreases p22(phox) and increases HO-1 mRNA production and protein level. The manidipine-induced increase of HO-1 gene and protein expression seems to be a peculiar effect of this drug since it is not observed with captopril and nifedipine. This effect, together with the reduction of p22(phox) mRNA production, could play a role in its protective mechanism against OxSt.

Dihydropiridine calcium channel blockers and dependent edema: a comparison between amlodipine and lercanidipine in essential hypertensive patients

Dihydropiridine calcium channel blockers and dependent edema: a comparison between amlodipine and lercanidipine in essential hypertensive patients

Reduction of risk of pneumonia associated with use of angiotensin I converting enzyme inhibitors in elderly inpatients

Pneumonia is a major direct cause of death in the elderly. Although aspiration based on a reduced cough reflex is one of the causes of pneumonia in the elderly, there are few studies of angiotensin-I converting enzyme inhibitors (ACE inhibitors), which are antihypertensive drugs that induce cough, as a factor influencing the incidence of pneumonia in institutionalized elderly subjects. To assess the effect of ACE inhibitors and dihydropiridine calcium-channel blockers on the incidence of pneumonia, we conducted a hospital-based case-control study. Cases were 55 pneumonia patients aged ≥ 65 years during a 1-year period. The controls were elderly subjects, frequency matched to the cases by age and gender (n = 220). Data were collected on known risk factors and on medication for hypertension, consisting of ACE inhibitors, calcium-channel blockers, and nonantihypertensive medication. The significance of differences in risk factors was analyzed using univariate and multivariate comparisons of cases and controls. After adjustment for potential confounding factors, the relative risk estimates for pneumonia were 0.38 (95% confidence interval [CI], 0.15–0.97) and 1.84 (95% CI, 0.89–3.78) for ACE inhibitors and calcium-channel blockers, respectively, relative to nonantihypertensive medication. The preventive effect of ACE inhibitors on pneumonia was apparent in long-acting ACE inhibitor users (0.24; 95% CI, 0.07–0.88). We conclude that ACE inhibitor use is an independent factor reducing risk of pneumonia among elderly inpatients.