Transdermal application of H100 gel to the penile shaft in patients with Peyronie's disease infiltrates the tunica albuginea.

Treatment options for Peyronie's disease (PD) remain limited. Topical H100 gel, (Hybrid Medical, Edina, USA), which contains nicardipine, super oxide dismutase and emu oil showed safety and efficacy in a previous small double-blind placebo-controlled pilot study. The present study evaluates if topically applied H100 gel applied to the penile shaft infiltrates the tunica albuginea. Nicardipine is a key active ingredient in H100 and serves as a surrogate marker. Three men already scheduled to undergo a planned surgical procedure for PD applied commercially available H100 gel twice daily to the penile shaft for up to 30 days prior to the procedure. Tunica albuginea samples were obtained at surgery. Nicardipine evaluation was performed using isotope dilution technique via liquid-chromatograph-mass spectrometry (LCMS). All three patients tolerated H100 gel application without side effects. All three tunica albuginea specimens showed detectable nicardipine in the tunical tissue. Transdermal application of commercially available H100 gel is able to penetrate the tunica albuginea tissue and is detectable in men with acute and chronic PD. This finding may support the encouraging results found in the prior H100 pilot study.

Utility of nicardipine in the management of hypertensive crises in adults with reduced ejection fractions.

BACKGROUND: Nicardipine is commonly used in the management of hypertensive crises, except those involving cardiac contractility defects despite its ability to reduce afterload and pulmonary congestion. Consequently, there is limited literature evaluating nicardipine's role for this indication. The purpose of this study was to evaluate the efficacy and safety of nicardipine in adults with reduced ejection fractions presenting with acute heart failure with hypertension (AHF-H). METHODS: This was a retrospective study conducted at an academic Level 1 trauma center with an annual Emergency Department (ED) volume surpassing 100,000. The purpose of this study was to determine the efficacy and safety of nicardipine in adults with reduced ejection fractions presenting to the ED with AHF-H. Efficacy was determined by achievement of the physician prescribed blood pressure target range. The primary safety endpoints included the number of individuals who experienced bradycardia (< 60 beats per minute, bpm) or hypotension (systolic blood pressure, SBP, < 90 mmHg) while receiving nicardipine and for up to 15 min after its discontinuation. Patients were included if they were ≥ 18 years of age, received a continuous intravenous nicardipine infusion within six hours of presenting to the ED, and had an ejection fraction ≤ 40% per an echocardiogram obtained within three months of the study visit. Pregnant and incarcerated patients were excluded. RESULTS: Of the 500 patient charts reviewed, 38 met inclusion criteria. The median (interquartile, IQR) ejection fraction and brain natriuretic peptide (BNP) were 35% (25-40) and 731 pg/nL (418-3277), respectively. The median baseline heart rate and SBP were 90 bpm and 193 mmHg, respectively. The median physician specified SBP goal was 160 mmHg and all patients met this endpoint in a median time of 18 min. One (2.6%) patient in the total population developed both hypotension and bradycardia. This patient had an ejection fraction of 20%, was intubated, and received nicardipine in addition to esmolol for an aortic dissection without experiencing an adverse event until 30 min after dexmedetomidine was initiated. CONCLUSION: In this non-interventional study evaluating the use of nicardipine in patients with reduced ejection fractions presenting to the ED with AHF-H, nicardipine was found to be safe and effective. To our knowledge this is the largest study to date evaluating nicardipine in this patient population and positively contributes to the existing literature.

Hypertensive Emergency: Parenteral Antihypertensives and Population Data.

PURPOSE OF REVIEW: Review parenteral therapeutic choices in treatment of hypertensive crises by mechanism of action and summarize recent literature on the management of hypertensive crises. RECENT FINDINGS: Recent data have documented the safety and efficacy of labetalol and nicardipine in treatment of hypertensive crises as well as characterized the hypertensive emergency population to a much greater extent. Based on recent data, hypertensive emergencies are seen in 0.5% of all emergency room visits. Ischemic stroke and heart failure/pulmonary edema are the most common forms of organ damage seen in hypertensive emergencies. There are many therapeutic choices in treatment of hypertensive crises with varied mechanisms of action. Large randomized, controlled trial evidence is lacking in this therapeutic area; however, recent data have documented the safety and efficacy of labetalol and nicardipine.

Nicardipine is a putative EED inhibitor and has high selectivity and potency against chemoresistant prostate cancer in preclinical models.

BACKGROUND: It is imperative to develop novel therapeutics to overcome chemoresistance, a significant obstacle in the clinical management of prostate cancer (PCa) and other cancers. METHODS: A phenotypic screen was performed to identify novel inhibitors of chemoresistant PCa cells. The mechanism of action of potential candidate(s) was investigated using in silico docking, and molecular and cellular assays in chemoresistant PCa cells. The in vivo efficacy was evaluated in mouse xenograft models of chemoresistant PCa. RESULTS: Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via inducing apoptosis and cell cycle arrest. Computational, molecular, and cellular studies identified nicardipine as a putative inhibitor of embryonic ectoderm development (EED) protein, and the results are consistent with a proposed mechanism of action that nicardipine destabilised enhancer of zeste homologue 2 (EZH2) and inhibited key components of noncanonical EZH2 signalling, including transducer and activator of transcription 3, S-phase kinase-associated protein 2, ATP binding cassette B1, and survivin. As a monotherapy, nicardipine effectively inhibited the skeletal growth of chemoresistant C4-2B-TaxR tumours. As a combination regimen, nicardipine synergistically enhanced the in vivo efficacy of docetaxel against C4-2 xenografts. CONCLUSION: Our findings provided the first preclinical evidence supporting nicardipine as a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes.

Therapeutic and safety outcomes of intracoronary nicardipine in coronary artery disease patients: a systematic review.

Aim: This systematic review aimed to shed light on the efficacy of intracoronary (IC) nicardipine in treating no reflow with CAD undergoing revascularization. Methods: Literature search was performed on databases with following eligibility criteria: adult patients with CAD; clinical trials or observational studies; IC nicardipine as intervention; therapeutic and safety outcome reported. Results: A total of 1249 papers were yielded during the literature search. Of these, 11 studies were finalized for this systematic review. Complete restoration of TIMI 3 flow was observed in 98.6% of the patients receiving IC nicardipine. A significant increase in the CBF after infusion of IC nicardipine (p < 0.05) was also observed. Conclusion: IC nicardipine significantly increases CBF and decreases coronary vascular resistance.

Coronary artery disease (CAD) is a condition that results in the narrowing or blockage of heart arteries. Arteries are blood vessels that bring oxygen-rich blood from your heart to the rest of your body's cells. We aimed to evaluate the effects of intracoronary (IC) nicardipine, a drug that blocks calcium from entering the muscle cells and blood vessels of the heart, which causes the vessels to relax and widen, allowing for blood to flow more easily, on a phenomenon known as coronary slow flow (CSF). CSF is defined as a delayed widening of the blood vessels of the heart. CSF or the no reflow phenomenon is a major negative complication associated with surgical procedures such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), both of which are used to open up blocked arteries. The systematic search identified studies that evaluated the effect of IC nicardipine in patient during CAD treatment, undergoing PCI, CABG, or having confirmed or suspected narrowing of the aortic valve or one of the four valves of the heart, which results in restricted blood flow from the heart to the body. From the results of studies discussed in the review, it can be concluded that IC nicardipine significantly increases blood flow to the heart and can help prevent the no reflow phenomenon in patients undergoing PCI. Nicardipine proved to be a safe and effective option in the management of complications such as no reflow in patients receiving therapies to restore blood flow following CAD.

Comparison between clevidipine and nicardipine in cerebrovascular diseases: A systematic review and meta-analysis.

PURPOSE: The term "cerebrovascular diseases (CVDs)" refers to a broad category of diseases that affect the brain's blood vessels and cerebral circulation. Controlling acute hypertension (HTN) by antihypertensive drugs such as clevidipine and nicardipine can be a highly efficient method of lowering the incidence of CVDs. METHODS: This is a systematic review and meta-analysis study. The PubMed, Scopus, and Web of Science online databases and a gray literature search were performed to identify potentially eligible studies. The included studies were observational studies that compared adult patients receiving clevidipine or nicardipine for controlling HTN in the setting of CVD. RESULTS: We reviewed 5 final included articles, including 546 patients. The pooled standardized mean difference (SMD) for time to goal SBP was - 0.04 (95 % CI: [-0.66; 0.58], p-value: 0.86, I2: 79.0 %, pooled MD: -12.90 min), meaning that the clevidipine group had a shorter time to goal systolic blood pressure (SBP) than the nicardipine group. The pooled SMD for total volume infusion was - 0.52 (95 % CI: [-0.93; -0.12], p-value: 0.03, I2: 0.0 %, pooled MD: -1118.81 mL), showing a notably lower total volume infused into patients in the clevidipine group. CONCLUSIONS: We found that clevidipine reaches the SBP goal faster than nicardipine; however, there was no statistically significant difference between the two drugs. The total volume infused to achieve the goal SBP was significantly lower in the clevidipine group. Further prospective studies are needed to compare clevidipine and nicardipine in CVD patients on a large scale.

Comparative Study of Clevidipine to Nicardipine for Perioperative Hypertension in Patients Undergoing Cardiac Surgery.

Objective: The primary objective of this study was to compare the efficacy of clevidipine to nicardipine in the treatment of perioperative acute hypertension in patients undergoing cardiac surgery. Methods: This was a single-center retrospective study which included patients who received either clevidipine or nicardipine. Patients were followed for the duration of study drug infusion or for a maximum of 48 hours. Outcomes assessed included the percent of time spent within patient specific goal blood pressure, incidence of hypertensive events per patient, safety outcomes, and cost of medication treatment. Results: There were 201 cardiac surgeries performed between August 2018-January 2019 and July 2019-February 2020. Sixty-seven patients met our inclusion criteria of receiving either clevidipine (n = 29) or nicardipine (n = 38). The median percent of time spent within goal blood pressure range for clevidipine was 55.2% compared to 36.4% for nicardipine treatment (P = .036). The median number of hypertensive episodes per patient was 3 for clevidipine and 2 for nicardipine (P = .211). There were no identified differences in safety outcomes such as hypotension, vasopressor use, serum creatinine elevation, tachycardia, and atrial fibrillation. The median cost of treatment required for the observed 48-hour period with clevidipine was $128.58 compared to $55.74 for nicardipine (P < .001). Conclusion: Our findings suggest that patients undergoing cardiac surgery on clevidipine had better perioperative blood pressure control compared to nicardipine, with a negligible increase in cost, and no observed difference in safety.

Nicardipine versus Labetalol for Hypertension during Acute Stroke: A Systematic Review and Meta-Analysis.

Background and Objective: Current recommendations prescribe either nicardipine or labetalol as the first-line treatment for acute hypertension due to ease of use, availability, and low price. However, it is unclear if these drugs have different effectiveness and safety profiles. This systematic review and meta-analysis aimed to compare the efficacy and safety of labetalol and nicardipine in patients with acute stroke. Materials and Methods: MEDLINE via PubMed, Scopus, Embase, and Google Scholar databases were electronically searched for the eligible publications from inception until March 2022. All full-text journal papers in English which compared the efficacy of nicardipine with that of labetalol on lowering blood pressure (BP; or treating hypertension) in all subtypes of acute stroke were included. The Cochrane Collaboration tool was used to assess the risk of bias. Data were analyzed using specific statistical methods. Results: Following the abstract and full-text screening, this meta-analysis included five retrospective cohorts and one prospective pseudorandomized cohort. Nicardipine's effect on time at goal BP was significantly superior to that of labetalol in patients with acute stroke (0.275 standardized mean difference [SMD], 95% confidence interval [CI]: 0.112-0.438, P = 0.001). The incidence of adverse events was significantly higher in the nicardipine group than that in the labetalol group. The pooled odds ratio (OR) was 1.509 (95% CI: 1.077-2.113, I2 = 0.00%, P = 0.757). The quality of included studies was found to be low. Conclusion: More prospective, comparative trials are needed to investigate the efficacy of BP management as well as clinical outcomes in acute stroke patients receiving continuous labetalol and nicardipine infusions.

Brain Oxygen-Directed Management of Aneurysmal Subarachnoid Hemorrhage. Temporal Patterns of Cerebral Ischemia During Acute Brain Attack, Early Brain Injury, and Territorial Sonographic Vasospasm.

BACKGROUND: Neurocritical management of aneurysmal subarachnoid hemorrhage focuses on delayed cerebral ischemia (DCI) after aneurysm repair. METHODS: This study conceptualizes the pathophysiology of cerebral ischemia and its management using a brain oxygen-directed protocol (intracranial pressure [ICP] control, eubaric hyperoxia, hemodynamic therapy, arterial vasodilation, and neuroprotection) in patients with subarachnoid hemorrhage, undergoing aneurysm clipping (n = 40). RESULTS: The brain oxygen-directed protocol reduced Lbo2 (Pbto2 [partial pressure of brain tissue oxygen] <20 mm Hg) from 67% to 15% during acute brain attack (<24 hours of ictus), by increasing Pbto2 from 11.31 ± 9.34 to 27.85 ± 6.76 (P < 0.0001) and then to 29.09 ± 17.88 within 72 hours. Day-after-bleed, Fio2 change, ICP, hemoglobin, and oxygen saturation were predictors for Pbto2 during early brain injury. Transcranial Doppler ultrasonography velocities (>20 cm/second) increased at day 2. During DCI caused by territorial sonographic vasospasm (TSV), middle cerebral artery mean velocity (Vm) increased from 45.00 ± 15.12 to 80.37 ± 38.33/second by day 4 with concomitant Pbto2 reduction from 29.09 ± 17.88 to 22.66 ± 8.19. Peak TSV (days 7-12) coincided with decline in Pbto2. Nicardipine mitigated Lbo2 during peak TSV, in contrast to nimodipine, with survival benefit (P < 0.01). Intravenous and cisternal nicardipine combination had survival benefit (Cramer Φ = 0.43 and 0.327; G2 = 28.32; P < 0.001). This study identifies 4 zones of Lbo2 during survival benefit (Cramer Φ = 0.43 and 0.3) TSV, uncompensated; global cerebral ischemia, compensated, and normal Pbto2. Admission Glasgow Coma Scale score (not increased ICP) was predictive of low Pbto2 (ß = 0.812, R2 = 0.661, F1,30 = 58.41; P < 0.0001) during early brain injury. Coma was the only credible predictor for mortality (odds ratio, 7.33/>4.8∗; χ2 = 7.556; confidence interval, 1.70-31.54; P < 0.01) followed by basilar aneurysm, poor grade, high ICP and Lbo2 during TSV. Global cerebral ischemia occurs immediately after the ictus, persisting in 30% of patients despite the high therapeutic intensity level, superimposed by DCI during TSV. CONCLUSIONS: We propose implications for clinical practice and patient management to minimize cerebral ischemia.

Nicardipine for treating severe antepartum hypertension during pregnancy: Nine years of experience in more than 800 women.

INTRODUCTION: Women with severe hypertension during pregnancy require prompt stabilization with a combination of magnesium sulfate and rapidly acting intravenously administered antihypertensives. It remains unknown which antihypertensive is best suited for pregnancy. The present study evaluated the intravenous use of the calcium antagonist, nicardipine. MATERIAL AND METHODS: This multicenter, retrospective case series included all pregnant women beyond 20 weeks of gestation with severe antepartum hypertension that were treated with intravenous nicardipine. PRIMARY OUTCOME MEASURES: successful treatment, time to successful treatment, and maternal safety. Severe hypertension was defined as systolic blood pressure (SBP) of 160 mm Hg or more and/or diastolic blood pressure (DBP) of 110 mm Hg or more. RESULTS: This study included 830 women. After 1 h of treatment, two-thirds of the women had SBP below 160 mm Hg and DBP below 100 mm Hg. In three out of four women, the mean arterial pressure was below 120 mm Hg. Within 2 h of treatment, 77.4% of women achieved successful treatment. In all cases, nicardipine was eventually effective. Within the first 2 h, 42.7% of women experienced temporary low DBP (ie below 70 mm Hg) without clinical consequences for the mother or fetus. In all cases, the low DBP resolved after discontinuing or reducing the dosage of nicardipine. One case of fetal distress was attributable to maternal hypotension, and a cesarean section was performed at more than 2 h after initiating therapy. During treatment, headache, nausea, and vomiting decreased significantly. CONCLUSIONS: To date, this was the largest case-series study on the use of nicardipine for treating severe antepartum hypertension in pregnancy. We found that nicardipine could effectively and safely treat this condition. Based on its high success rate and acceptable safety profile, nicardipine should be considered a first-line treatment in women with severe hypertension in pregnancy.

Early Hyperchloremia is Independently Associated with Death or Disability in Patients with Intracerebral Hemorrhage.

BACKGROUND: On the basis of increased mortality associated with hyperchloremia among critically ill patients, we investigated the effect of occurrence of early hyperchloremia on death or disability at 90 days in patients with intracerebral hemorrhage (ICH). METHODS: We analyzed the data from Antihypertensive Treatment of Cerebral Hemorrhage 2 trial, which recruited patients with spontaneous ICH within 4.5 h of symptom onset. Patients with increased serum chloride levels (110 mmol/L or greater) at either baseline or 24, 48, or 72 h after randomization were identified. We further graded hyperchloremia into one occurrence or two or more occurrences within the first 72 h. Two logistic regression analyses were performed to determine the effects of hyperchloremia on (1) death within 90 days and (2) death or disability at 90 days after adjustment for potential confounders. RESULTS: Among the total of 1,000 patients analyzed, hyperchloremia within 72 h was seen in 114 patients with one occurrence and in 154 patients with two or more occurrences. Patients with one occurrence of hyperchloremia (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and those with two or more occurrences (OR 2.6, 95% CI 1.3-5.0) had significantly higher odds of death within 90 days after adjustment for age, race and ethnicity, National Institutes of Health Stroke Scale score strata, hematoma volume, presence or absence of intraventricular hemorrhage, cigarette smoking, previous stroke, and maximum hourly dose of nicardipine. Patients with two or more occurrences of hyperchloremia (OR 3.4, 95% CI 2.1-5.6) had significantly higher odds of death or disability at 90 days compared with patients without hyperchloremia after adjustment for the abovementioned potential confounders. CONCLUSIONS: The independent association between hyperchloremia and death or disability at 90 days suggests that avoidance of hyperchloremia may reduce the observed death or disability in patients with ICH. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01176565.

Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trials.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality and morbidity. We aimed to determine the relative benefits of pharmacological prophylactic treatments in patients with aneurysmal subarachnoid hemorrhage by performing a network meta-analysis of randomized trials. METHODS: We searched Medline, Web of Science, Embase, Scopus, ProQuest, and Cochrane Central to February 2020. Pairs of reviewers independently identified eligible trials, extracted data, and assessed the risk of bias. Eligible trials compared the prophylactic effects of any oral or intravenous medications or intracranial drug-eluting implants to one another or placebo or standard of care in adult hospitalized patients with confirmed aneurysmal subarachnoid hemorrhage. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the certainty of the evidence. RESULTS: We included 53 trials enrolling 10 415 patients. Nimodipine likely reduces all-cause mortality compared to placebo (odds ratio [OR],0.73 [95% CI, 0.53-1.00]; moderate certainty; absolute risk reduction (ARR), -3.35%). Nimodipine (OR, 1.46 [95% CI, 1.07-1.99]; high certainty; absolute risk increase, 8.25%) and cilostazol (OR, 3.73 [95% CI, 1.14-12.18]; moderate certainty; absolute risk increase, 23.15%) were the most effective treatments in improving disability at the longest follow-up. Compared to placebo, clazosentan (10 mg/kg; OR, 0.39 [95% CI, 0.22-0.68]; high certainty; ARR, -16.65%), nicardipine (OR, 0.48 [95% CI, 0.24-0.94]; moderate certainty; ARR, -13.70%), fasudil (OR, 0.55 [95% CI, 0.31-0.98]; moderate certainty; ARR, -11.54%), and magnesium (OR, 0.66 [95% CI, 0.46-0.94]; high certainty; ARR, -8.37%) proved most effective in reducing the likelihood of delayed cerebral ischemia. CONCLUSIONS: Nimodipine and cilostazol are likely the most effective treatments in preventing morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage. Clazosentan, nicardipine, fasudil, and magnesium showed beneficial effects on delayed cerebral ischemia and vasospasm but they were not found to reduce mortality or disability. Future trials are warranted to elaborately investigate the prophylactic effects of medications that may improve mortality and long-term functional outcomes, such as cilostazol and clazosentan. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019122183.

Comparative Study of Vasodilatation After Intra-arterial Nicardipine or Dantrolene Infusion in Animal Model of Cerebral Vasospasm.

PURPOSE: Intra-arterial (IA) infusion of calcium channel blockers (CCBs) has been widely applied in treating medically refractory vasospasm; however, surprisingly little is known regarding their vasodilatory duration. This study was undertaken to compare attributes of nicardipine and dantrolene, focusing on efficacy and capacity for sustained vasodilation. METHODS: In New Zealand white rabbits (N = 22), vasospasm was individually provoked through experimentally induced subarachnoid hemorrhage and confirmed via conventional angiography, grouping animals by IA-infused drug (nicardipine vs. dantrolene). Controls received normal saline. After chemoangioplasty, follow-up angiography was performed at intervals of 1-3 h for 6 h to compare vasospastic and dilated (i.e., treated) arterial diameters. Drug efficacy, duration of action, and changes in mean arterial pressure (relative to baseline) were analyzed by group. RESULTS: Compared with controls, effective vasodilation was evident in both nicardipine and dantrolene test groups after IA infusion. Vasodilatory effects of nicardipine peaked at 1 h, returning to former vasospastic states at 3 h. In dantrolene recipients, vasodilation endured longer, lasting >6 h. Only the nicardipine group showed a significant 3­h period of lowered blood pressure. CONCLUSION: Unlike the vasodilatory action of a CCB, sustained for < 3 h after IA infusion, the effect of dantrolene endured for > 6 h. This outcome suggests that IA dantrolene infused alone or together with a conventional CCB infusion may be a new means of prolonging vasodilatory effect. Further research is needed to assess durations of IA-infused vasodilatory drug based on perfusion status.

Intensive blood pressure lowering with nicardipine and outcomes after intracerebral hemorrhage: An individual participant data systematic review.

BACKGROUND AND AIMS: Nicardipine has strong, rapidly acting antihypertensive activity. The effects of acute systolic blood pressure levels achieved with intravenous nicardipine after onset of intracerebral hemorrhage on clinical outcomes were determined. METHODS: A systematic review and individual participant data analysis of articles before 1 October 2020 identified on PubMed were performed (PROSPERO: CRD42020213857). Prospective studies involving hyperacute intracerebral hemorrhage adults treated with intravenous nicardipine whose outcome was assessed using the modified Rankin Scale were eligible. Outcomes included death or disability at 90 days, defined as the modified Rankin Scale score of 4-6, and hematoma expansion, defined as an increase ≥6 mL from baseline to 24-h computed tomography. SUMMARY OF REVIEW: Three studies met the eligibility criteria. For 1265 patients enrolled (age 62.6 ± 13.0 years, 484 women), death or disability occurred in 38.2% and hematoma expansion occurred in 17.4%. Mean hourly systolic blood pressure during the initial 24 h was positively associated with death or disability (adjusted odds ratio (aOR) 1.12, 95% confidence interval (CI) 1.00-1.26 per 10 mmHg) and hematoma expansion (1.16, 1.02-1.32). Mean hourly systolic blood pressure from 1 h to any timepoint during the initial 24 h was positively associated with death or disability. Later achievement of systolic blood pressure to ≤140 mmHg increased the risk of death or disability (aOR 1.02, 95% CI 1.00-1.05 per hour). CONCLUSIONS: Rapid lowering of systolic blood pressure by continuous administration of intravenous nicardipine during the initial 24 h in hyperacute intracerebral hemorrhage was associated with lower risks of hematoma expansion and 90-day death or disability without increasing serious adverse events.

Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

BACKGROUND: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. METHODS: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. RESULTS: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. CONCLUSIONS: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

Does intrathecal nicardipine for cerebral vasospasm following subarachnoid hemorrhage correlate with reduced delayed cerebral ischemia? A retrospective propensity score-based analysis.

OBJECTIVE: Cerebral vasospasm and delayed cerebral ischemia (DCI) contribute to poor outcome following subarachnoid hemorrhage (SAH). With the paucity of effective treatments, the authors describe their experience with intrathecal (IT) nicardipine for this indication. METHODS: Patients admitted to the Emory University Hospital neuroscience ICU between 2012 and 2017 with nontraumatic SAH, either aneurysmal or idiopathic, were included in the analysis. Using a propensity-score model, this patient cohort was compared to patients in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository who did not receive IT nicardipine. The primary outcome was DCI. Secondary outcomes were long-term functional outcome and adverse events. RESULTS: The analysis included 1351 patients, 422 of whom were diagnosed with cerebral vasospasm and treated with IT nicardipine. When compared with patients with no vasospasm (n = 859), the treated group was significantly younger (mean age 51.1 ± 12.4 years vs 56.7 ± 14.1 years, p < 0.001), had a higher World Federation of Neurosurgical Societies score and modified Fisher grade, and were more likely to undergo clipping of the ruptured aneurysm as compared to endovascular treatment (30.3% vs 11.3%, p < 0.001). Treatment with IT nicardipine decreased the daily mean transcranial Doppler velocities in 77.3% of the treated patients. When compared to patients not receiving IT nicardipine, treatment was not associated with an increased rate of bacterial ventriculitis (3.1% vs 2.7%, p > 0.1), yet higher rates of ventriculoperitoneal shunting were noted (19.9% vs 8.8%, p < 0.01). In a propensity score comparison to the SAHIT database, the odds ratio (OR) to develop DCI with IT nicardipine treatment was 0.61 (95% confidence interval [CI] 0.44-0.84), and the OR to have a favorable functional outcome (modified Rankin Scale score ≤ 2) was 2.17 (95% CI 1.61-2.91). CONCLUSIONS: IT nicardipine was associated with improved outcome and reduced DCI compared with propensity-matched controls. There was an increased need for permanent CSF diversion but no other safety issues. These data should be considered when selecting medications and treatments to study in future randomized controlled clinical trials for SAH.

Comparison of Clevidipine and Nicardipine for Acute Blood Pressure Reduction in Hemorrhagic Stroke.

BACKGROUND: Intracranial hemorrhage is associated with high mortality and morbidity. Lowering systolic blood pressure (SBP) with an intravenous antihypertensive, such as nicardipine or clevidipine, may reduce the risk of hematoma expansion and rebleeding. Previous studies comparing nicardipine and clevidipine in patients with stroke found no significant difference in blood pressure management. The inclusion of patients with ischemic stroke limited those studies because of convoluted results related to faster door-to-needle times. The purpose of this study was to compare clevidipine with nicardipine in time to goal SBP in hemorrhagic stroke. METHODS: This single-center retrospective observational cohort study evaluated adult hemorrhagic patients with stroke who received clevidipine or nicardipine from January 1, 2015, to December 31, 2020. Patients were excluded if they had trauma-related hemorrhage, received concurrent continuous intravenous antihypertensives, received the study drug for less than 1-h duration, had a less than 24-h washout period between agents, required any dialysis, were pregnant, or were incarcerated. The primary outcome was time to goal SBP. Secondary outcomes included need for additional antihypertensives, percentage of time at goal SBP, all-cause mortality, 30-day readmission, rebleeding, total volume of antihypertensive infusion, hematoma expansion, intensive care unit length of stay (LOS), hospital LOS, and cost of infusion. Safety outcomes included hypotension, severe hypotension, rebound hypertension, bradycardia, tachycardia, onset of atrial fibrillation, and acute kidney injury. RESULTS: Of 89 patients included in this study, 60 received nicardipine and 29 received clevidipine. There was no significant difference between nicardipine and clevidipine in time to goal SBP in the unmatched cohort (30 vs. 45 min; p = 0.73) or the propensity-score-matched cohort (30 vs. 45 min; p = 0.47). Results were not affected by potential confounders in the multiple linear regression. The nicardipine group had a higher total volume from infusion compared with the clevidipine group (1410 vs. 330 mL; p < 0.0001) but significantly lower cost ($99.6 vs. $497.4; p < 0.0001). There were no significant differences in need for additional antihypertensives, percentage of time at goal SBP, all-cause mortality, 30-day readmission, rebleeding, hematoma expansion, intensive care unit LOS, and hospital LOS. Compared with the clevidipine group, the nicardipine group had less rebound hypertension (40% vs. 75.9%; p = 0.0017) and less bradycardia (23.3% vs. 44.8%; p = 0.05). There were no significant differences in hypotension, severe hypotension, tachycardia, and acute kidney injury. CONCLUSIONS: In patients with hemorrhagic stroke, nicardipine appeared to have similar efficacy as clevidipine in SBP reduction, with a more likely reduction of rebound hypertension and drug cost. This retrospective study was underpowered, which may limit these implications. Further prospective studies are warranted to confirm these results.

Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage.

One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.

Impact of Renal Impairment on Intensive Blood-Pressure-Lowering Therapy and Outcomes in Intracerebral Hemorrhage: Results From ATACH-2.

BACKGROUND AND OBJECTIVE: The clinical effect of renal impairment on intracerebral hemorrhage (ICH) is unknown. This study sought to assess whether estimated glomerular filtration rate (eGFR) affects clinical outcomes or modifies the efficacy of intensive systolic blood pressure (BP) control (target, 110-139 mm Hg) against the standard (target, 140-179 mm Hg) among patients with ICH. METHODS: We conducted post hoc analyses of ATACH-2, a randomized, 2-group, open-label trial. The baseline eGFR of each eligible patient was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. The outcome of interest was death or disability at 90 days. Multivariate logistic regression models were used for analysis. RESULTS: Among the 1,000 patients randomized, 974 were analyzed. The median baseline eGFR was 88 (interquartile range, 68, 99) mL/min/1.73 m2; 451 (46.3%), 363 (37.3%), and 160 (16.4%) patients had baseline eGFR values of ≥90, 60-89, and <60 mL/min/1.73 m2, respectively. Compared with normal eGFR (≥90 mL/min/1.73 m2), higher odds of death or disability were noted among those with eGFR values of <60 mL/min/1.73 m2 (adjusted odds ratio [OR], 2.02; 95% confidence interval [CI], 1.25-3.26) but not among those with eGFR values of 60-89 mL/min/1.73 m2 (OR, 1.01; 95% CI, 0.70-1.46). The odds of death or disability were significantly higher in the intensive arm among patients with decreased eGFR; the ORs were 0.89 (95% CI, 0.55-1.44), 1.13 (0.68-1.89), and 3.60 (1.47-8.80) in patients with eGFR values of ≥90, 60-89, and <60 mL/min/1.73 m2, respectively (p for interaction = 0.02). DISCUSSION: Decreased eGFR is associated with unfavorable outcomes following ICH. The statistically significant interaction between the eGFR group and treatment assignment raised safety concerns for the intensive BP-lowering therapy among patients with renal impairment. TRIAL REGISTRATION INFORMATION: Clinicaltrials.gov identifier: NCT01176565. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in spontaneous ICH, decreased eGFR identifies patients at risk of death or disability following intensive BP control.