Efficacy and Safety of Azelnidipine as an Antihypertensive Compared to Amlodipine: A Systematic Review and Meta-analysis.

INTRODUCTION: Azelnidipine is one of the newer Calcium Channel Blockers (CCB) approved in China, Japan, and India. Some studies have found that the blood pressure-lowering effect of azelnidipine is more than amlodipine, and others found the effect similar. AIM: This meta-analysis was conducted to evaluate the efficacy of azelnidipine in managing hypertensive patients by lowering Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) as compared to amlodipine. METHODS: PubMed/MEDLINE, Google Scholar, PROQUEST, and International Clinical Trial Registry Platform (ICTRP) were searched for published articles to evaluate the clinical efficacy of azelnidipine in the management of hypertension patients. Data were extracted from the selected 11 randomized clinical trials (RCTs). The risk of bias 2 (RoB2) tool was used for the quality assessment of the included studies, and the random-effects model was used to estimate the effect size. RESULTS: There were no statistically significant differences in the reduction of SBP (Mean Difference, MD: - 1.07; 95% CI: - 4.10, 1.95, p-value: 0.49) and DBP (MD: 0.27; 95% CI: - 2.66, 3.20, p-value: 0.86) between both the drugs. In terms of HR reduction, there was a statistically significant difference (MD: - 3.63; 95% CI: - 5.27, - 2.00, p-value: < 0.0001) between both drugs. Egger's test excluded any publication bias for the included studies (p = 0.21). Meta-regression excluded the effect of the duration of treatment on outcome parameters. CONCLUSION: Though no significant difference between azelnidipine and amlodipine was found, in terms of reduction in SBP and DBP, azelnidipine reduced heart rate significantly compared to amlodipine. PROSPERO REGISTRATION: CRD42023390361.

Hypoxia Associated With Dihydropyridine Calcium Channel Inhibitors: A Pharmacovigilance Study in VigiBase.

Due to their negative effects on hypoxic pulmonary vasoconstriction, dihydropyridine calcium channel inhibitors (DCCIs) can lead to hypoxia in patients with a pulmonary shunt. To date, only preclinical studies and case reports have focused on this potential adverse drug reaction. We aimed to assess the reporting association between DCCIs and hypoxia using the World Health Organization pharmacovigilance database (VigiBase). We performed a disproportionality analysis to evaluate the strength of the reporting association between i.v. clevidipine and nicardipine, thought to be a surrogate of patients in the intensive care unit, and hypoxia. The information component and the lower end of its 95% credibility interval were used to evaluate disproportionality. A description of the cases was made. Secondary outcomes included the association between all DCCIs and hypoxia compared with other treatments with similar indications, urapidil and labetalol, regardless of the route of administration. Association between oral nicardipine and hypoxia was also searched. A statistically significant signal of hypoxia was found for intravenous clevidipine and nicardipine. The time to onset was reported with a median of 2 days (interquartile range 1.5-4.5). Four dechallenges were performed with intravenous nicardipine, leading to the resolution of the symptoms. Regardless of the route of administration, a signal of hypoxia was also found for nimodipine but not for other drugs, including comparators. For nicardipine no signal of hypoxia was found with the oral route of administration. Our pharmacovigilance database analysis showed a significant association between the use of intravenous DCCIs and hypoxia.

The Risk for Prostate Cancer With Calcium Channel Blockers: A Systematic Review, Meta-Analysis, and Meta-Regression.

BACKGROUND: For decades, conflicting results were published regarding the increased risk of Prostate cancer (PCa) among calcium channel blocker (CCB) users. OBJECTIVE: We aimed to evaluate the association between PCa and CCB exposure and assess moderating factors. METHODS: We performed a systematic literature search in PubMed, Embase, and Cochrane databases for observational and randomized studies published until November 2020 with no language limitations, including data on the risk for PCa in CCB users compared with non-CCB users. We applied a random-effects model meta-analysis to pool results. In addition, we investigated potential moderating factors, such as CCB type, study type, participants' age, and duration of exposure, using meta-regression methods. RESULTS: In our primary analysis, we included 18 studies. A statistically significant 5% increase in the risk for PCa was observed among CCB users (risk ratio [RR] = 1.05; 95% confidence interval [CI]: 1.01-1.10), with no significant association between the duration of exposure to CCBs and the risk for PCa (RR = 1.08; 95% CI: 0.98-1.19 for exposure for < 5years and RR = 1.01; 95% CI: 0.9-1.14 for exposure ≥ 5 years). The association remained statistically significant for the subgroup of dihydropyridines (RR = 1.13; 95% CI: 1.05-1.22). In addition, the association was not influenced by participants' age. CONCLUSION AND RELEVANCE: CCBs are an important modality in treating hypertension. The 5% increased risk observed in the current meta-analysis could be influenced by residual confounding factors and should not affect hypertension treatment guidelines until more studies provide additional clinical information.

Gingival enlargement improvement following medication change from amlodipine to benidipine and periodontal therapy.

The use of calcium channel blockers (CCBs) is associated with gingival enlargement, which adversely affects oral function, hygiene and aesthetics. Although CCB-induced gingival enlargement is a known adverse effect, it is rarely or never caused by some CCBs. In this paper, we report the case of a late 80's female patient with hypertension who experienced amlodipine-induced gingival enlargement. The patient's antihypertensive medication was changed from amlodipine to another CCB of the same class, benidipine, which has not been reported to cause gingival enlargement. The patient also received periodontal therapy. A significant improvement in gingival enlargement was noted, and blood pressure control was maintained. This case indicates that it might be beneficial for patients with hypertension presenting CCB-induced gingival enlargement to switch from the CCB that caused gingival enlargement to another CCB with little to no risk.

Comparative peripheral edema for dihydropyridines calcium channel blockers treatment: A systematic review and network meta-analysis.

Dihydropyridine calcium channel blockers (DHPCCBs) are widely used to treat hypertension and chronic coronary artery disease. One common adverse effect of DHPCCBs is peripheral edema, particularly of the lower limbs. The side effect could lead to dose reduction or discontinuation of the medication. The combination of DHPCCBs and renin-angiotensin system blockers has shown to reduce the risk of DHPCCBs-associated peripheral edema compared with DHPCCBs monotherapy. We performed the current systematic review and network meta-analysis of randomized controlled trials (RCTs) to estimate the rate of peripheral edema with DHPCCBs as a class and with individual DHPCCBs and the ranking of the reduction of peripheral edema. The effects of renin-angiotensin system blockers on DHPCCBs network meta-analysis were created to analyze the ranking of the reduction of peripheral edema. A total of 3312 publications were identified and 71 studies with 56,283 patients were included. Nifedipine ranked highest in inducing peripheral edema (SUCRA 81.8%) and lacidipine (SUCRA 12.8%) ranked the least. All DHPCCBs except lacidipine resulted in higher relative risk (RR) of peripheral edema compared with placebo. Nifedipine plus angiotensin receptor blocker (SUCRA: 92.3%) did not mitigate peripheral edema and amlodipine plus angiotensin-converting enzyme inhibitors (SUCRA: 16%) reduced peripheral edema the most. Nifedipine ranked the highest and lacidipine ranked the lowest amongst DHPCCBs for developing peripheral edema when used for cardiovascular indications. The second or higher generation of DHPCCBs combination with ACEIs or ARBs or diuretics lowered the chance of peripheral edema development compared to single DHPCCB treatment.

Association between dihydropyridine calcium channel blockers and ischemic strokes in patients with nonvalvular atrial fibrillation.

Outside of clinical trials, the prophylactic effect of dihydropyridine calcium channel blockers (CCBs) on ischemic events in patients with nonvalvular atrial fibrillation (NVAF) has not been confirmed. We compared the effect of dihydropyridine CCBs on ischemic events in anticoagulated NVAF patients. We conducted a multicenter historical cohort study at 71 centers in Japan. The inclusion criterion was taking vitamin K antagonists for NVAF. The exclusion criteria were mechanical heart valves and a history of pulmonary thrombosis or deep vein thrombosis. Consecutive patients (N = 7826) were registered in February 2013 and were followed until February 2017. The primary outcomes were ischemic events and ischemic strokes; the secondary outcomes were all-cause mortality, major bleeding, and hemorrhagic strokes. The mean patient age was 73 years old, and 67% of the patients were male. Seventy-eight percent of the patients had hypertension, and dihydropyridine CCBs were used by 2693 (34%) patients (CCB group). The cumulative incidences of ischemic events and ischemic strokes at 4 years in the CCB and No-CCB groups were 5.9% vs. 5.2% and 5.6% vs. 4.8%, respectively. The adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of the CCB group for ischemic events and ischemic strokes were 1.22 (0.95-1.57) and 1.32 (1.02-1.71), respectively; the adjusted HRs (95% CIs) of the CCB group for all-cause mortality, major bleeding, and hemorrhagic strokes were 0.85 (0.69-1.04), 1.12 (0.92-1.35), and 1.08 (0.62-1.88), respectively. Dihydropyridine CCB use by anticoagulated NVAF patients significantly increased ischemic strokes in a real-world setting.

Differences in Health-Related Quality of Life Among Adults with a Potential Dihydropyridine Calcium Channel Blocker-Loop Diuretic Prescribing Cascade.

BACKGROUND: Dihydropyridine calcium channel blockers (DH CCBs) are commonly used for hypertension in older adults. However, loop diuretics can be inappropriately added to treat DH CCB-induced edema, putting individuals at increased risk for adverse events and potential decreases in quality of life. METHODS: We conducted a cross-sectional analysis using United States Medical Expenditure Panel Survey (MEPS) data from 2003 to 2015. Adults aged ≥ 55 years without congestive heart failure, nephrotic syndrome, chronic kidney disease, renal failure, and cirrhosis who had consecutive rounds of DH CCB use (round 1 and 2 or round 3 and 4) and completed the self-administered questionnaire (SAQ) were included. Patients initiated on loop diuretics in round 2 or 4 were compared to those not initiated. Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were analyzed using multivariable linear regression models. RESULTS: Among 5,458,467 DH CCB users (weighted), 3.4% of individuals were identified with new loop diuretic use (185,130 weighted). After adjusting for covariates, DH CCB plus loop diuretic use was associated with a PCS score 3.12 units lower (95% confidence interval - 5.40 to - 0.83; p = 0.008) than DH CCB use alone. We observed no significant difference in MCS score (p = 0.160) among DH CCB plus loop diuretic users compared to DH CCB users alone. CONCLUSIONS: New loop diuretic use was associated with lower physical functioning among DH CCB users. These findings suggest that this potential prescribing cascade may result in both significant and clinically meaningful decreases in health-related quality of life. It is important for clinicians to avoid or intervene on this inappropriate prescribing cascade when possible.

Calcium channel blockers for people with chronic kidney disease requiring dialysis.

BACKGROUND: Calcium channel blockers (CCBs) are used to manage hypertension which is highly prevalent among people with chronic kidney disease (CKD). The treatment for hypertension is particularly challenging in people undergoing dialysis. OBJECTIVES: To assess the benefits and harms of calcium channel blockers in patients with chronic kidney disease requiring dialysis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies to 27 April 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs that compared any type of CCB with other CCB, different doses of the same CCB, other antihypertensives, control or placebo were included. The minimum study duration was 12 weeks. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR), risk difference (RD) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: This review included 13 studies (24 reports) randomising 1459 participants treated with long-term haemodialysis. Nine studies were included in the meta-analysis (622 participants). No studies were performed in children or in those undergoing peritoneal dialysis. Overall, risk of bias was assessed as unclear to high across most domains. Random sequence generation and allocation concealment were at low risk of bias in eight and one studies, respectively. Two studies reported low risk methods for blinding of participants and investigators, and outcome assessment was blinded in 10 studies. Three studies were at low risk of attrition bias, eight studies were at low risk of selective reporting bias, and five studies were at low risk of other potential sources of bias. Overall, the certainty of the evidence was low to very low for all outcomes. No events were reported for cardiovascular death in any of the comparisons. Other side effects were rarely reported and studies were not designed to measure costs. Five studies (451 randomised adults) compared dihydropyridine CCBs to placebo or no treatment. Dihydropyridine CCBs may decrease predialysis systolic (1 study, 39 participants: MD -27.00 mmHg, 95% CI -43.33 to -10.67; low certainty evidence) and diastolic blood pressure level (2 studies, 76 participants; MD -13.56 mmHg, 95% CI -19.65 to -7.48; I2 = 0%, low certainty evidence) compared to placebo or no treatment. Dihydropyridine CCBs may make little or no difference to occurrence of intradialytic hypotension (2 studies, 287 participants; RR 0.54, 95% CI 0.25 to 1.15; I2 = 0%, low certainty evidence) compared to placebo or no treatment. Other side effects were not reported. Eight studies (1037 randomised adults) compared dihydropyridine CCBs to other antihypertensives. Dihydropyridine CCBs may make little or no difference to predialysis systolic (4 studies, 180 participants: MD 2.44 mmHg, 95% CI -3.74 to 8.62; I2 = 0%, low certainty evidence) and diastolic blood pressure (4 studies, 180 participants: MD 1.49 mmHg, 95% CI -2.23 to 5.21; I2 = 0%, low certainty evidence) compared to other antihypertensives. There was no evidence of a difference in the occurrence of intradialytic hypotension (1 study, 92 participants: RR 2.88, 95% CI 0.12 to 68.79; very low certainty evidence) between dihydropyridine CCBs to other antihypertensives. Other side effects were not reported. Dihydropyridine CCB may make little or no difference to predialysis systolic (1 study, 40 participants: MD -4 mmHg, 95% CI -11.99 to 3.99; low certainty evidence) and diastolic blood pressure (1 study, 40 participants: MD -3.00 mmHg, 95% CI -7.06 to 1.06; low certainty evidence) compared to non-dihydropyridine CCB. There was no evidence of a difference in other side effects (1 study, 40 participants: RR 0.13, 95% CI 0.01 to 2.36; very low certainty evidence) between dihydropyridine CCB and non-dihydropyridine CCB. Intradialytic hypotension was not reported. AUTHORS' CONCLUSIONS: The benefits of CCBs over other antihypertensives on predialysis blood pressure levels and intradialytic hypotension among people with CKD who required haemodialysis were uncertain. Effects of CCBs on other side effects and cardiovascular death also remain uncertain. Dihydropyridine CCBs may decrease predialysis systolic and diastolic blood pressure level compared to placebo or no treatment. No studies were identified in children or peritoneal dialysis. Available studies have not been designed to measure the effects on costs. The shortcomings of the studies were that they recruited very few participants, had few events, had very short follow-up periods, some outcomes were not reported, and the reporting of outcomes such as changes in blood pressure was not done uniformly across studies. Well-designed RCTs, conducted in both adults and children with CKD requiring both haemodialysis and peritoneal dialysis, evaluating both dihydropyridine and non-dihydropyridine CCBs against other antihypertensives are required. Future research should be focused on outcomes relevant to patients (including death and cardiovascular disease), blood pressure changes, risk of side effects and healthcare costs to assist decision-making in clinical practice.

Amlodipine Compared with Benidipine in the Management of Hypertension: A Systematic Review and Meta-Analysis.

INTRODUCTION: Benidipine and amlodipine are two well-known drugs used in hypertensive patients with chronic kidney disease (CKD). AIM: In this systematic review we aimed to compare benidipine and amlodipine in terms of efficacy in the management of hypertensive patients. METHODS: We searched PubMed, Cochrane CENTRAL, SCOPUS and Web of Science for relevant clinical trials and excluded observational studies. Quality appraisal was evaluated according to GRADE and we assessed the risk of bias using the Cochrane's risk of bias tool. We included the following outcomes: Systolic blood pressure, diastolic blood pressure, heart rate, estimated glomerular filtration rate (eGFR), and urinary albumin/creatinine ratio. Data were pooled as mean differences (MD) with relative 95% confidence intervals (CI). RESULTS: Eight studies were eligible for our meta-analysis. We found no significant difference between both drugs regarding systolic (MD = - 0.21 [- 1.48, 1.89], (P = 0.81) and diastolic (MD = 0.01[- 0.51, 0.53], (P = 0.97)) blood pressure measurements. The overall heart rate did not differ as well (MD = - 0.03 [- 1.63, 1.57], (P = 0.97)). We found that benidipine was statistically better than amlodipine in terms of eGFR (MD = 1.07 [0.43, 1.71], (P = 0.001)), and urinary albumin/creatinine ratio (MD = - 43.41 [- 53.53, - 33.29], (P < 0.00001)). CONCLUSIONS: Finally we conclude that benidipine seems to show more positive and promising results in the management of hypertensive patients with chronic kidney disease.

A post-marketing survey evaluating the safety and efficacy of a fixed-dose single-pill combination of cilnidipine and valsartan in patients with hypertension: Real-world JSH 2014 and 2019 implementations.

METHODS: : The home blood pressure control by a single-pill combination of cilnidipine and valsartan (HOPE-Combi) survey sought to evaluate the safety and efficacy of cilnidipine 10 mg/valsartan 80 mg single-pill combination (SPC of Cil/Val) treatment in patients with hypertension for over 12 months. Of 2622 subjects' data; we analyzed 2572 cases for safety and 2372 cases for efficacy. RESULTS: Adverse drug reaction (ADR) incidence rate was 3.77% (97 of 2572 patients). The frequency of ADRs did not differ between patients aged <75 years and those aged ≥75 years (3.70% vs. 3.93%, respectively); between patients with and without chronic liver disease (CLD; 6.44% vs. 3.54%, respectively); and between patients with and without chronic kidney disease (CKD; 5.26% vs. 3.59%, respectively). Office systolic blood pressure (BP) was reduced from 149.5 ± 19.6 mmHg to 133.5 ± 14.8 mmHg (-15.8 mmHg, P < .01); pulse rate was also reduced 75.5 ± 12.2 bpm to 73.5 ± 11.3 bpm (-1.8 bpm, P < .01) after 12 months. CONCLUSIONS: : The SPC of Cil/Val was safe and effective in treating BP of hypertensive patients in real-world settings.

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

BACKGROUND: 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 ß-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-ß-blocker group compared to the benidipine-thiazide group. OBJECTIVE AND METHODS: 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. RESULTS: 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. CONCLUSION: Blood pressure-lowering therapy with benidipine combined with an ARB, ß-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.

An Open Label Prospective Study on Evaluation of Safety and Efficacy of Cilnidipine Over Amlodipine in Stage 1 Hypertensive Patients.

Background Calcium channel blockers are considered the first line drug over renin-angiotensinaldosterone system inhibitor in black population and with renin-angiotensinaldosterone system inhibitor in non-black population with Hypertension. Amlodipine has longer biological half life and lower potential to stimulate SNS. But, is associated with reflex tachycardia and pedal oedema. Cilnidipine has potent inhibitory both on voltage gated L-type and N-type calcium channels with better anti-proteinuric effect and good tolerability. Hence, our study compared the efficacy, safety and compliance of cilnidipine over amlodipine in Stage 1 hypertensive subjects. Objective To find out antihypertensive and renoprotective effect of cilnidipine. Method The study was open-label, single centre, prospective, parallel design, randomized controlled was done in Outdoor Patient Department (OPD) of Medicine and Department of Pharmacology in Burdwan Medical College and Hospital (BMCH). Patients with stage 1 HTN received cilnidipine while the other group received amlodipine. There were 4 follow-up visits for each participant consisting of baseline, 1 week, 6 weeks and after 12 weeks. Clinical parameters including pulse rate, blood pressure and ankle oedema noted also laboratory investigations were done. Safety parameters with adverse events and compliance by traditional pill count method. Result Blood pressure was effectively decreased by both amlodipine and cilnidipine. Cilnidipine significantly decreased Pulse Rate while amlodipine increased it and the difference in Pulse Rate comparing both the groups was statistically significant. None of the ADRs were statistically significant except pedal oedema. Pedal oedema was noted only in amlodipine arm and was statistically significant. Compliance to both the drugs was excellent. Total cost of therapy was higher with cilnidipine. Conclusion Though amlodipine is preferred drug, cilnidipine should be a better alternative when we consider subjects with sympathetic over activity, proteinuria or pedal oedema.

Therapeutic potential of proteasome inhibitors for dihydropyridine-induced gingival overgrowth.

OBJECTIVES: NF-κB plays a crucial role in collagen overproduction in dihydropyridine-induced gingival overgrowth (DIGO) fibroblasts. We aim to investigate the role of the kappa B (IκB) kinase (IKK)-NF-κB pathway and downstream collagen type I (Col I) synthesis in DIGO cells and to demonstrate the therapeutic strategy of interference of this pathway with proteasome inhibitors. METHODS: Gingival fibroblasts from DIGO (n = 5) and healthy (n = 5) patients were selected and stimulated with IL-1ß, nifedipine, or both. All experiments were run in triplicate and independently for each primary cell sample. RESULTS: The results demonstrated that both drugs additively mediated NF-κB activity by activating IKKα/ß phosphorylation. They also triggered nuclear translocation of NF-κB, Rela, and p50 (*p < .05) and increased Col I production in both healthy and DIGO cells. The addition of proteasome inhibitors, including bortezomib and MG132, promoted the accumulation of phosphorylated p-IκBα, prevented the subsequent cytosol-to-nuclear translocation of p50 and Rela (*p < .05), and abbreviated the biosynthesis of Col I in DIGO cells. CONCLUSIONS: We suggested that IKK-IκBα activation is mediated by proinflammatory cytokines and CCBs in DIGO cells and triggers downstream NF-κB-Col I synthesis. Proteasome inhibitors may strategically interfere with the IKK-IκBα-NF-κB-Col I pathway and inhibit the etiopathogenesis of DIGO.

Efficacy and safety of a combination antihypertensive drug (olmesartan plus azelnidipine): "Issues with hypertension studies in real-world practice".

Background: This study investigated whether a combination drug containing an angiotensin II receptor blocker (ARB) and a calcium channel blocker (CCB) could provide effective antihypertensive therapy.Methods: A multicenter, prospective, open-label study was conducted at the clinics of Clinical Research Network. The subjects had uncontrolled blood pressure (BP) despite ARB or CCB monotherapy. The effect on both office and home BP was examined after patients switched to a combination drug (REZ: containing 20 mg of olmesartan [OL] and 16 mg of azelnidipine [AZ]).Results: A total of 78 patients were enrolled. After switching to REZ, a significant and sustained reduction of office BP was observed. The proportion of patients who achieved the target for both office and home BP was an increase from 0% to 55%. Switching from amlodipine to REZ resulted in a significant and sustained decrease of office and home BP. There was also a significant decrease of home pulse rate (PR), but office PR was unchanged. To determine the accuracy of the BP and PR values reported by patients, the frequency of each number as the first digit was determined. The frequency of "0" was extremely high for both office and home BP values, and the same was noted for home PR values.Conclusion: The results of this study suggested that switching from a single drug to combination therapy with REZ could achieve a stronger antihypertensive effect. However, concern was raised regarding the methods of BP and PR measurement and recording in this clinical trial involving general practitioners.

Magnitude of and Characteristics Associated With the Treatment of Calcium Channel Blocker-Induced Lower-Extremity Edema With Loop Diuretics.

Importance: Calcium channel blockers, specifically dihydropyridine calcium channel blockers (DH CCBs, eg, amlodipine), may cause lower-extremity edema. Anecdotal reports suggest this may result in a prescribing cascade, where DH CCB-induced edema is treated with loop diuretics. Objective: To assess the magnitude and characteristics of the DH CCB prescribing cascade. Design, Setting, and Participants: This cohort study used a prescription sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of DH CCBs among patients aged 20 years or older without heart failure. Data from a private insurance claims database from 2005 to 2017 was analyzed. Use of loop diuretics associated with initiation of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other commonly used medications was used as negative controls. Data were analyzed from March 2019 through October 2019. Exposures: Initiation of DH CCB or negative control medications. Main Outcomes and Measures: The temporality of loop diuretic initiation relative to DH CCB or negative control initiation. Secular trend-adjusted sequence ratios (aSRs) with 95% CIs were calculated using data from 360 days before and after initiation of DH CCBs. Results: Among 1 206 093 DH CCB initiators, 55 818 patients (4.6%) (33 100 [59.3%] aged <65 years; 32 916 [59.0%] women) had a new loop diuretic prescription 360 days before or after DH CCB initiation, resulting in an aSR of 1.87 (95% CI, 1.84-1.90). An estimated 1.44% of DH CCB initiators experienced the prescribing cascade. The aSR was disproportionately higher among DH CCB initiators who were prescribed high doses (aSR, 2.20; 95% CI, 2.13-2.27), initiated amlodipine (aSR, 1.89; 95% CI, 1.86-1.93), were men (aSR, 1.96; 95% CI, 1.91-2.01), and used fewer antihypertensive classes (aSR, 2.55; 95% CI, 2.47-2.64). The evaluation of ACE inhibitors or ARBs as negative controls suggested hypertension progression may have tempered the incidence of the prescribing cascade (aSR for ACE inhibitors and ARBs, 1.27; 95% CI, 1.24-1.29). Conclusions and Relevance: This study found an excessive use of loop diuretics following initiation of DH CCBs that cannot be completely explained by secular trends or hypertension progression. The prescribing cascade was more pronounced among those initially prescribed a high dose of DH CCBs.

Efonidipine-Induced Exanthematic Drug Eruption and Literature Review.

We report the case of an elderly woman who developed exanthematic drug eruption after administration of efonidipine. An 84-year-old woman presented to emergency department with complaints of generalized itching and erythema since 4 days. She was on human-soluble insulin since 11 years. In view of her hypertension and left anterior descending artery stenosis, she was initiated on aspirin, clopidogrel, atorvastatin, pantoprazole, nebivolol, aldactone, and efonidipine a week ago. Her presenting complaints were initially managed with parenteral pheniramine maleate and hydrocortisone. She was admitted, and all her medications except antiplatelets and insulin were discontinued. She was prescribed topical beclomethasone and oral antihistamines for better control of her symptoms. To confirm the drug precipitating the reaction, she was rechallenged with efonidipine, 20 mg once daily on the third day of admission. She developed itching 8 hours after administering the medication, and efonidipine was stopped and nebivolol 5 mg once daily was restarted for hypertension. She did not develop any adverse event when the remaining medications were reinitiated. World Health Organization-Uppsala Monitoring Centre causality assessment criteria indicated a "certain" association. To the best of the knowledge of the authors, this is one among the first reported cases of efonidipine-induced exanthematic drug eruption.