Incremental Lowering of Low-Density Lipoprotein Cholesterol With Ezetimibe 20 mg vs 10 mg Daily in Patients Receiving Concomitant Statin Therapy

Background

Ezetimibe is typically administered at a dose of 10 mg daily, with few reports of use at other doses. We compared plasma concentrations of low-density lipoprotein (LDL) cholesterol and other lipid variables in patients with dyslipidemia who were receiving ezetimibe 10 mg and then 20 mg daily.

Methods

A retrospective chart review identified 27 patients who received ezetimibe 10 mg and then 20 mg daily at different times; 15 participants were receiving stable statin therapy and 12 were not receiving concomitant statins. Plasma concentrations of lipids, creatine kinase (CK), and aspartate transaminase (AST) were determined. Plasma concentrations of ezetimibe and ezetimibe glucuronide were measured in a second group of patients.

Results

Patients taking statins and ezetimibe 20 mg had further reductions in total and LDL cholesterol of 7.1% and 10.3%, respectively (both P < 0.05) than did those receiving the 10-mg dose. No difference between 20-mg and 10-mg dosing was seen among patients not receiving statins. Plasma concentrations of ezetimibe and its active metabolite were about 2-fold higher (P < 0.05) in patients taking ezetimibe 20 mg than in those receiving 10 mg daily. All patients tolerated ezetimibe 20 mg without side effects.

Conclusions

Ezetimibe 20 mg daily reduced total and LDL cholesterol further in patients receiving statin therapy compared with 10 mg daily. Prospective studies are required to show whether the higher plasma levels of ezetimibe and its active metabolite in patients taking the 20-mg dose have any detrimental effects. Increasing the ezetimibe dose to 20 mg daily might be an interesting potential approach for patients who fail to reach lipid targets on ezetimibe 10 mg daily along with maximally tolerated doses of statin.     

Safety and tolerability of nevirapine-based antiretroviral therapy in HIV-infected patients receiving fluconazole for cryptococcal prophylaxis: a retrospective cohort study

Background  

To compare the adverse events after initiation of nevirapine-based ART among HIV-infected patients who did not receive fluconazole (group A), received fluconazole 400 mg/week (group B), and received fluconazole 200 mg/day (group C).     

Cryptococcal meningitis post autologous stem cell transplantation

Disseminated Cryptococcus disease occurs in patients with defective T‐cell immunity. Cryptococcal meningitis following autologous stem cell transplant (SCT) has been described previously in only 1 patient, 4 months post SCT and while off antifungal prophylaxis. We present a unique case of Cryptococcus meningitis pre‐engraftment after autologous SCT, while the patient was receiving fluconazole prophylaxis. A 41‐year‐old man with non‐Hodgkin's lymphoma underwent autologous SCT. Post‐transplant prophylaxis consisted of fluconazole 400 mg daily, levofloxacin 500 mg daily, and acyclovir 800 mg twice daily. On day 9 post transplant, he developed fever and headache. Peripheral white blood cell count (WBC) was 700/μL. Magnetic resonance imaging of the brain showed lesions consistent with meningoencephalitis. Cerebrospinal fluid (CSF) analysis revealed a WBC of 39 with 77% lymphocytes, protein 63, glucose 38, CSF pressure 20.5 cmH₂O, and a positive cryptococcal antigen. CSF culture confirmed Cryptococcus neoformans. The patient was treated with liposomal amphotericin B 5 mg/kg intravenously daily, and flucytosine 37.5 mg/kg orally every 6 h. He was switched to fluconazole 400 mg daily after 3 weeks of amphotericin therapy, with sterilization of the CSF with negative CSFCryptococcus antigen and negative CSF culture. Review of the literature revealed 9 cases of cryptococcal disease in recipients of SCT. Median time of onset was 64 days post transplant. Only 3 meningitis cases were described; 2 of them after allogeneic SCT. Fungal prophylaxis with fluconazole post autologous SCT is recommended at least through engraftment, and for up to 100 days in high‐risk patients. A high index of suspicion is needed to diagnose and treat opportunistic infections, especially in the face of immunosuppression and despite adequate prophylaxis. Infection is usually fatal without treatment, thus prompt diagnosis and therapy might be life saving.     

Use of micafungin versus fluconazole for antifungal prophylaxis in neutropenic patients receiving hematopoietic stem cell transplantation

A prospective randomized clinical trial assessed the efficacy and tolerance of micafungin compared with that of standard fluconazole treatment in patients undergoing hematopoietic stem cell transplantation (HSCT). Adult patients (n = 106) were randomly assigned to receive prophylaxis with either micafungin 150 mg (n = 52), or fluconazole 400 mg (n = 52). Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and the absence of proven or probable IFI through the end of the 4-week period following treatment. The overall efficacy of micafungin was comparable to that of fluconazole (94 vs. 88%; difference 6.0%; 95% confidence interval, −5.4 to +17.4%; P = 0.295). A total of 2 (4.0%) of 50 patients in the micafungin arm and 6 (12.0%) of 50 patients in the fluconazole arm received empirical antifungal therapy (P = 0.06). Micafungin treatment did not result in increasing adverse effects and had a safe profile as fluconazole in neutropenic patients. This randomized trial indicates that the efficacy and tolerance of micafungin 150 mg was comparable to that of fluconazole 400 mg, suggesting that micafungin at 150 mg daily represents a valuable new treatment option for antifungal prophylaxis in HSCT recipients.     

Fluconazole for empiric antifungal therapy in cancer patients with fever and neutropenia

Background  

Several clinical trials have demonstrated the efficacy of fluconazole as empiric antifungal therapy in cancer patients with fever and neutropenia. Our objective was to assess the frequency and resource utilization associated with treatment failure in cancer patients given empiric fluconazole antifungal therapy in routine inpatient care.     

An updated systematic review of HIV-associated cryptococcal meningitis treatment strategies

Background

The purpose of this systematic review is to provide updated evidence on the preferred induction therapy for the treatment of HIV-associated cryptococcal meningitis considering the most recent evidence available in order to inform the need for updates to WHO guidelines.

Methods

We searched Medline via PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov for published or completed randomized clinical trials that evaluated induction treatment of first episode HIV-associated cryptococcal meningitis from 9 July 2018 (date of last search) to 1 September 2021.

Results

One randomized clinical trial of 844 people with HIV-associated cryptococcal meningitis met the inclusion criteria. Participants were randomized to: (1) amphotericin deoxycholate for 7 days, with flucytosine and fluconazole (control); or (2) a single dose of liposomal amphotericin 10 mg/kg with flucytosine and fluconazole (intervention). In the intention-to-treat analysis, 10-week mortality was 24.8% [95% confidence interval (CI): 20.7–29.3%] in the single-dose liposomal amphotericin group compared with 28.7% (95% CI: 24.4–33.4%) in the control group. The absolute difference in 10-week mortality was −3.9% with an upper one-sided 95% CI of 1.2%, within the 10% pre-specified non-inferiority margin. Fewer participants had grade 3 and 4 adverse events in the intervention arm compared with the control arm (50.0% vs. 62.3%, p < 0.001).

Conclusions

In the single study included in this systematic review, single high-dose liposomal amphotericin B with flucytosine and fluconazole was non-inferior to the WHO-recommended standard of care induction therapy for HIV-associated cryptococcal meningitis, with significantly fewer adverse events.     

Economic evaluation of high-dose (80 mg/day) atorvastatin treatment compared with standard-dose (20 mg/day to 40 mg/day) simvastatin treatment in Canada based on the Incremental Decrease in End-Points Through Aggressive Lipid-Lowering (IDEAL) trial

BACKGROUND:

The Incremental Decrease in End-Points Through Aggressive Lipid-Lowering (IDEAL) trial demonstrated incremental cardiovascular benefit of treatment with high-dose atorvastatin (80 mg/day) versus standard-dose simvastatin (20 mg/day to 40 mg/day) in 8888 patients with a previous myocardial infarction (MI) over a median follow-up period of 4.8 years.

OBJECTIVES:

To assess the cost-effectiveness of high-dose atorvastatin versus standard-dose simvastatin treatment in patients with a history of MI from a Canadian societal perspective.

METHODS:

In a within-trial analysis, end point-related events, resources used and productivity losses occurring during the IDEAL trial were aggregated by treatment arm on an intention-to-treat basis to calculate the incremental cost per event avoided. Additionally, quality-adjusted survival was projected using a lifetime Markov model. Transition probabilities, workdays lost, use of study medication and cardiovascular hospitalization rates were based on IDEAL trial data. Hospitalization, study medication and productivity costs were included. Probabilistic and deterministic sensitivity analyses were performed.

RESULTS:

Compared with standard-dose simvastatin, atorvastatin 80 mg led to 0.099 fewer events per patient and cost savings over 4.8 years of treatment. Over a lifetime horizon, atorvastatin 80 mg led to 0.023 quality-adjusted life years (QALYs) gained per patient at an incremental cost of $26,795/QALY gained. The incremental cost-effectiveness ratio remained below $50,000/QALY in 78% of 1000 simulations. Exclusion of indirect costs resulted in an incremental cost-effectiveness ratio of $38,834/QALY. Results were relatively sensitive to baseline age, but robust with respect to sex, baseline low-density lipoprotein cholesterol levels, diabetes status and hospitalization costs.

CONCLUSION:

From a Canadian societal perspective, high-dose atorvastatin is cost-effective compared with standard-dose simvastatin in patients with a previous MI.     

Decline of Mean Initial Prednisone Dosage From 10.3 to 3.6 mg/day to Treat Rheumatoid Arthritis Between 1980 and 2004 in One Clinical Setting,With Long‐Term Effectiveness of Dosages Less Than 5 mg/day

Objective

To analyze prednisone treatment from 1980–2004 in 308 patients with rheumatoid arthritis (RA), including 75 monitored over 4–8 years and 73 monitored over >8 years, for initial dose, long‐term doses and effectiveness, and adverse events.

Methods

A database of all patients of a single rheumatologist included medications and Multidimensional Health Assessment Questionnaire (MDHAQ) scores at each visit. Proportions of patients whose initial prednisone dosages were >5, 5, or <5 mg/day were computed in 5‐year periods: 1980–1984, 1985–1989, 1990–1994, 1995–1999, and 2000–2004. Mean changes in MDHAQ function, pain, and Routine Assessment of Patient Index Data 3 (RAPID3) scores were compared in patients treated with <5 versus ≥5 mg/day of prednisone; scores and adverse events were analyzed in quartiles by treatment duration of ≤1, 1.1–4, 4.1–8, and >8 years.

Results

In the respective 5‐year periods, the mean initial prednisone dosages were 10.3, 6.5, 5.1, 4.1, and 3.6 mg/day, with >5 mg/day in 49%, 16%, 7%, 7%, and 3% of patients, 5 mg/day in 51%, 80%, 70%, 26%, and 10% of patients, and <5 mg/day in 0%, 4%, 23%, 67%, and 86% of patients. Most patients received early concomitant methotrexate after 1990, and prednisone <5 mg/day was maintained indefinitely. Patients treated with prednisone ≥5 mg/day had poorer clinical status as baseline and followup. MDHAQ scores improved similarly in patients treated with <5 or ≥5 mg/day. Primary adverse events were skin thinning and bruising. New hypertension, diabetes mellitus, and cataracts occurred in <10% of all patients, and <13% of those treated longer than 8 years.

Conclusion

The data suggest that many patients with RA might be treated effectively with initial and long‐term prednisone <5 mg/day, although further research and observational data are needed to characterize more fully effectiveness and safety.     

Safety and efficacy of AK0529 in respiratory syncytial virus-infected infant patients: A phase 2 proof-of-concept trial

Background

Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available.

Methods

This was a Phase 2 study of the oral RSV fusion protein inhibitor AK0529 in infants aged 1–24 months, hospitalized with RSV infection. In Part 1, patients (n = 24) were randomized 2:1 to receive a single dose of AK0529 up to 4 mg/kg or placebo. In Part 2, patients (n = 48) were randomized 2:1 to receive AK0529 at 0.5, 1, or 2 mg/kg bid or placebo for 5 days. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modelling. Safety, tolerability, viral load, and respiratory signs and symptoms were assessed daily during treatment.

Results

No safety or tolerability signals were detected for AK0529: grade ≥3 treatment-emergent adverse events occurring in 4.1% of patients in AK0529 and 4.2% in placebo groups, respectively, and none led to death or withdrawal from the study. In Part 2, targeted drug exposure was reached with 2 mg/kg bid. A numerically greater reduction in median viral load with 2 mg/kg bid AK0529 than with placebo at 96 h was observed. A −4.0 (95% CI: −4.51, −2.03) median reduction in Wang Respiratory Score from baseline to 96 h was observed in the 2 mg/kg group compared with −2.0 (95% CI: −3.42, −1.82) in the placebo group.

Conclusions

AK0529 was well tolerated in hospitalized RSV-infected infant patients. Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and Wang Respiratory Score.

Clinical Trials Registration

NCT02654171.     

Plasma nevirapine levels,adverse events and efficacy of antiretroviral therapy among HIV-infected patients concurrently receiving nevirapine-based antiretroviral therapy and fluconazole

Background  

The clinical data of plasma NVP level, safety and efficacy of antiretroviral therapy (ART) for the concurrent use of nevirapine (NVP)-based ART and fluconazole (FLU) is scanty.     

Combination therapy of disseminated coccidioidomycosis with caspofungin and fluconazole

Background  

The current recommended therapy for diffuse coccidioidal pneumonia involves initial treatment with amphotericin B deoxycholate or high-dose fluconazole, followed by an azole after clinical improvement. Amphotericin B is more frequently used as initial therapy if the patient's deterioration is rapid.     

Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events : A Meta-Analysis of Statin Trials

Background

Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented.

Objectives

The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk.

Methods

This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.

Results

Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB.

Conclusions

The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.     

A pilot study to compare tobramycin 80 mg injectable preparation with 300 mg solution for inhalation in cystic fibrosis patients

BACKGROUND:

Inhaled tobramycin has been shown to improve lung function in cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. However, to date no comparative data are available for different dose regimens used in clinical practice.

OBJECTIVES:

To compare the clinical efficacy of the two most commonly used treatment regimens of inhaled tobramycin in patients with CF.

METHODS:

In an open crossover study of CF patients, subjects were randomly allocated to receive either 80 mg tobramycin twice-daily continuous treatment or 300 mg tobramycin twice daily in cycles of 28 days on and 28 days off treatment. After three months, patients were switched to the alternative treatment regimen.

RESULTS:

A total of 32 patients with a mean (± SD) age of 18.5±8.6 years were included in the study. Compared with the treatment period using colistin, forced expiratory volume in 1 s decreased by −2.1±13.8% in the 80 mg tobramycin group and increased by +2.3±13.0% in the 300 mg group. Similar changes were observed in forced vital capacity (−2.5±12.9% in the 80 mg tobramycin group versus +2.5±9.6% in the 300 mg tobramycin group). Variability in responses was large but the differences were not statistically significant. Personal preference indicated that the majority of patients preferred the high-dose cycle compared with the lower dose continuous inhalation, but this was not linked to objective data on efficacy.

CONCLUSIONS:

The present trial fails to provide convincing evidence for superiority in efficacy of either of the two treatment regimens of inhaled tobramycin in CF patients.     

Safety and effectiveness of 100 mg/kg/day deferiprone in patients with thalassemia major: a two-year study

Deferiprone at a dose of 75 mg/kg/day is not sufficiently effective to maintain iron stores at a level which has been considered safe in all patients with iron overload. Our main aim was to determine the safety of long-term therapy with high-dose (100 mg/kg/day) deferiprone. A secondary aim was to determine the efficacy of this high dose. Twelve thalassemia major patients received deferiprone at a dose of 100 mg/kg/day over 2 years. Transient aspartate aminotransferase increase (8 patients), gastrointestinal discomfort (3 patients) and arthralgia (2 patients) were the most commonly reported side effects. None of the patients discontinued therapy. The mean serum ferritin level fell from 3,901 +/- 3,618 to 1,790 +/- 2,205 microg/l after 2 years (p < 0.05). Five of the 12 patients continued to receive deferiprone for an additional 3 years. No new side effects were encountered. The mean serum ferritin level in this subgroup was initially 2,510 +/- 332 microg/l and dropped to 1,511 +/- 664 microg/l after 5 years (p < 0.05). Liver iron levels at the end of the 2-year study ranged from 1.0 to 30.9 mg/g dry weight, 3 of the patients having levels above 15 mg/g.     

Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: Results of a randomized,double‐blind,placebo‐controlled trial

Objective

To assess the efficacy and safety of milnacipran at a dosage of 100 mg/day (50 mg twice daily) for monotherapy treatment of fibromyalgia.

Methods

A double‐blind, placebo‐controlled trial was performed to assess 1,025 patients with fibromyalgia who were randomized to receive milnacipran 100 mg/day (n = 516) or placebo (n = 509). Patients underwent 4–6 weeks of flexible dose escalation followed by 12 weeks of stable‐dose treatment. Two composite responder definitions were used as primary end points to classify the response to treatment. The 2‐measure composite response required achievement of ≥30% improvement from baseline in the pain score and a rating of “very much improved” or “much improved” on the Patient's Global Impression of Change (PGIC) scale. The 3‐measure composite response required satisfaction of these same 2 improvement criteria for pain and global status as well as improvement in physical function on the Short Form 36 (SF‐36) physical component summary (PCS) score.

Results

After 12 weeks of stable‐dose treatment, a significantly greater proportion of milnacipran‐treated patients compared with placebo‐treated patients showed clinically meaningful improvements, as evidenced by the proportion of patients meeting the 2‐measure composite responder criteria (P < 0.001 in the baseline observation carried forward [BOCF] analysis) and 3‐measure composite responder criteria (P < 0.001 in the BOCF). Milnacipran‐treated patients also demonstrated significantly greater improvements from baseline on multiple secondary outcomes, including 24‐hour and weekly recall pain score, PGIC score, SF‐36 PCS and mental component summary scores, average pain severity score on the Brief Pain Inventory, Fibromyalgia Impact Questionnaire total score (all P < 0.001 versus placebo), and Multidimensional Fatigue Inventory total score (P = 0.036 versus placebo). Milnacipran was well tolerated by most patients, with nausea being the most commonly reported adverse event (placebo‐adjusted rate of 15.8%).

Conclusion

Milnacipran administered at a dosage of 100 mg/day improved pain, global status, fatigue, and physical and mental function in patients with fibromyalgia.

     

Tadalafil 5 mg Once Daily Improves Lower Urinary Tract Symptoms and Erectile Dysfunction: A Systematic Review and Meta‐analysis

Objectives

We carried out a systematic review and meta‐analysis to assess tadalafil 5 mg once‐daily for the treatment of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED).

Methods

A literature review was performed to identify all published randomized double‐blind, placebo‐controlled trials of tadalafil 5 mg once‐daily for the treatment of LUTS and ED. The search included the following databases: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated.

Results

Thirteen publications involving a total of 3973 patients were used in the analysis, including 13 RCTs that compared tadalafil 5 mg once‐daily with placebo. We found that tadalafil 5 mg once‐daily was effective in improving LUTS suggestive of BPH and treating ED over 12 weeks in our meta‐analysis. Total International Prostate Symptom Score (IPSS) (SMD = ? 2.02, 95% CI = ? 2.52 to ?1.53, P < 0.00001); Benign Prostatic Hyperplasia Impact Index (BPH‐II) (SMD = ?0.58, 95% CI = ?0.84 to ?0.33, P < 0.00001); International Index of Erectile Function‐erectile function (IIEF) domain (standardized mean difference [SMD] = 5.18, 95% confidence interval [CI] = 4.13–6.23, P < 0.00001) indicated that tadalafil 5 mg once‐daily was more effective than the placebo. Safety assessments included discontinuations due to adverse event (odds ratio (OR) = 1.79, 95% CI = 1.12–2.85, P = 0.01) indicated that tadalafil 5 mg once‐daily was well tolerated.

Conclusions

This meta‐analysis indicates that tadalafil 5 mg once‐daily to be an effective treatment for LUTS and ED with a low occurrence of side effects.     

Candidemia in a tertiary care cancer center: in vitro susceptibility and its association with outcome of initial antifungal therapy

Since the 1990s, changing trends have been documented in species distribution and susceptibility to bloodstream infections caused by Candida species in cancer patients. However, few data are available regarding the association between in vitro antifungal susceptibility and outcome of candidemia in this patient population. We therefore evaluated the association of in vitro antifungal susceptibility and other risk factors with failure of initial antifungal therapy in cancer patients with candidemia. Candidemia cases in cancer patients from 1998 to 2001 (n = 144) were analyzed retrospectively along with their in vitro susceptibility to amphotericin B, fluconazole, and itraconazole (National Committee for Clinical and Laboratory Standards M27-A method). Patients were evaluable for outcome analysis if they received continuous unchanged therapy with either fluconazole or amphotericin B for >/=5 days. We excluded cases of mixed candidemia. In vitro susceptibility testing data of the first Candida bloodstream isolate were analyzed. Appropriate therapy was defined as that using an active in vitro antifungal for >/=5 days. For fluconazole susceptible-dose dependent Candida species, we defined appropriate therapy as a fluconazole dose of >/=600 mg/day. The Candida species distribution was 30% Candida albicans, 24% Candida glabrata, 23% Candida parapsilosis, 10% Candida krusei, 9% Candida tropicalis, and 3% other. Overall, amphotericin B was the most active agent in vitro, with only 3% of the isolates exhibiting resistance to it (>1 mg/L). Dose-dependent susceptibility to fluconazole and itraconazole was seen in 13% and 21% of the isolates, respectively, while resistance to fluconazole and itraconazole was seen in 13% and 26%, respectively.Eighty patients were evaluable for outcome analysis. In multivariate analysis, the following factors emerged as independent predictors of failure of initial antifungal therapy: leukemia (p = 0.01), bone marrow transplantation (p = 0.006), and intensive care unit stay at onset of infection (p = 0.02). Inappropriate antifungal therapy, as defined by daily dose and in vitro susceptibility, was not shown consistently to be a significant factor (it was significant in multivariate analysis, p = 0.04, but not in univariate analysis), indicating the complexity of the variables that influence the response to antifungal treatment in cancer patients with candidemia.     

Heart rate control with oral ivabradine in computed tomography coronary angiography: A randomized comparison of 7.5 mg vs 5 mg regimen

Background

Heart rate (HR) reduction is essential to achieve optimal image quality and diagnostic accuracy with computed tomography coronary angiography (CTCA). Administration of oral ivabradine seems to be more effective than beta-blockade in reducing HR in patients referred for CTCA.

Methods

Two-hundred-fifty-nine consecutive patients referred for CTCA were prospectively enrolled. Patients not receiving beta-blocker at baseline (group 1) and those with beta-blocker therapy (group 2) were enrolled in the study. Each group was randomized into 3 parallel arms with 1:1:1 allocation. Patients who did not receive beta-blocker at baseline: underwent CTCA without beta blocker (n = 49), and received ivabradine 5 mg (n = 48), or 7.5 mg ivabradine (n = 48). Patients with beta-blocker therapy: continued with the prior beta-blocker without any dose modification (n = 38), and received ivabradine 5 mg (n = 38), or ivabradine 7.5 mg (n = 38).

Results

HR and blood pressure were assessed at admission (T0), immediately before CTCA (T1) and during CTCA (T2). Administration of ivabradine 7.5 mg significantly reduced mean relative HR at T1 and T2 (p < 0.01), the rate of patients not achieving target HR at T1 (p < 0.001) and T2 (p < 0.01), and the percentage of patients needing additional IV beta-blockade prior to CTCA (p < 0.01). Results remained statistically significant even after correction for age, gender, ejection fraction, risk factors and HR at T0, in a multivariable analysis.

Conclusions

Ivabradine 7.5 mg is more effective than ivabradine 5 mg in increasing the rate of patients at target HR in patients referred for CTCA.     

Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum

Objectives

Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum.

Methods

The participants were HIV‐1‐infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady‐state 12‐h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration–time curve (AUC_0–12) was ≥10th percentile NFV AUC_0–12 in non‐pregnant historical controls (18.5 μg h/mL).

Results

Of 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (C_max), 12‐h post‐dose concentration (C₁₂) and AUC_0–12 were significantly lower during the third trimester compared to postpartum (P≤0.03). The metabolite hydroxyl‐tert‐butylamide (M8) AUC_0–12 and the M8/NFV AUC ratio were lower during the third trimester compared to postpartum (P<0.01). The NFV AUC_0–12 exceeded the AUC_0–12 target for 15/27 (56%) and 21/22 (95%) of third trimester and postpartum patients, respectively. The minimum concentration (C_min) was above the suggested minimum trough concentration (0.8 μg/mL) in 15% (third trimester) and 18% (postpartum). The plasma viral load was <400 HIV‐1 RNA copies/mL in 81% of patients at delivery.

Conclusions

These results suggest that higher doses of NFV should be considered during pregnancy.