Potential applications of outpatient nesiritide infusions in patients with advanced heart failure and concomitant renal insufficiency (from the Follow-Up Serial Infusions of Nesiritide [FUSION I] trial)

This retrospective substudy of the Follow-Up Serial Infusions of Nesiritide trial (FUSION I) assessed the feasibility of outpatient administration of nesiritide in 138 patients with co-morbid advanced heart failure and renal insufficiency (estimated creatinine clearance<60 ml/min). Patients received 1 of 3 treatments once weekly for 12 weeks: standard care (SC), SC plus nesiritide 0.005 microg/kg/min, or SC plus nesiritide 0.010 microg/kg/min. The addition of nesiritide to SC was well tolerated, with no evidence of worsening renal function, compared with SC only and was associated with a reduction in the rate of all-cause hospitalization or mortality through week 12, with hazard ratios of 2.027 (95% confidence interval 1.165 to 3.525) and 2.219 (95% confidence interval 1.233 to 3.992) for the SC-only group compared with the SC plus 0.005 microg/kg/min and SC plus 0.010 microg/kg/min nesiritide groups, respectively. These findings raise the hypothesis that adjunctive therapy with nesiritide on an outpatient basis may be beneficial for patients with advanced heart failure and renal insufficiency. Further study is warranted to test the validity of this finding.     

Treatment with B-Type Natriuretic Peptide for Chronic Decompensated Heart Failure: Insights Learned from the Follow-Up Serial Infusion of Nesiritide (FUSION) Trial

Several evidence-based treatment regimens are modestly effective in patients with moderately severe to severe heart failure, but truly effective therapies that improve symptoms, reduce hospitalizations, and extend meaningful survival do not exist for these patients. Only ventricular replacement therapy, with either heart transplantation or left ventricular assist devices, has been shown to significantly improve outcomes. Nesiritide, a recombinant B-type natriuretic peptide, is associated with significant reductions in filling pressure, with corresponding relief of symptoms, and diminished neurohormonal levels and has no inotropic effects and no evidence of proarrhythmia when given to patients with decompensated acute heart failure. Results of the Follow-Up Serial Infusion of Nesiritide (FUSION) trial suggest that a regimen incorporating nesiritide can be accomplished with a reasonable assurance of safety and tolerability; pre-study concerns regarding hypotension were not realized. A qualified look at outcomes data within FUSION I suggests that further study of this paradigm is reasonable, especially if the studied patient population includes patients with a low left ventricular ejection fraction and New York Heart Association (NYHA) class III disease with renal insufficiency, or patients with low left ventricular ejection fraction and NYHA class IV heart failure. Therefore, FUSION II, a double-blind, placebo-controlled trial, will randomly assign approximately 900 such patients to treatment with usual care plus nesiritide or usual care plus placebo and will use mortality/cardiorenal hospitalization as a composite end point. If positive data emerge from FUSION II that either confirm or strengthen the data in FUSION I, a new therapeutic option may be available for patients with chronic decompensated heart failure.     

Two-year clinical outcomes after large coronary stent (4.0 mm) placement: comparison of bare-metal stent versus drug-eluting stent

Background:

The absolute benefit of drug‐eluting stents (DES) in low‐risk patients and lesions is not well established.

Hypothesis:

The long term clinical outcomes after percutaneous coronary intervention in a single coronary artery disease may not be affected by the type of stent.

Methods:

This study assessed and compared 2‐year clinical outcomes of 304 consecutive patients (147 BMS patients and 157 DES patients) treated with a single coronary stent (4.0 mm) for single de novo large coronary artery disease in 3 referral cardiac centers. The primary outcome was a composite of major adverse cardiac events at 2 years after the index procedure.

Results:

The reference vessel diameter was similar in both groups (3.92 ± 0.29 mm in BMS vs 3.95 ± 0.24 mm in DES, P = 0.50). Late loss was larger in the BMS group (1.04 ± 0.83 mm vs 0.73 ± 0.91 mm in DES, P = 0.03). The incidence of major adverse cardiac events at the 2‐year clinical follow‐up was very low, 24 of 304 patients (7.9%), regardless of stent type deployed (7.5% in BMS vs 8.3% in DES, P = 0.83). The rate of target vessel revascularization was also similar in both groups (4.8% in BMS vs 5.7% in DES, P = 0.80).

Conclusions:

Two‐year clinical outcomes after PCI with a single large coronary stent (4.0 mm) were excellent. The clinical outcomes were not affected by the type of stent used. Copyright © 2010 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.     

C-reactive protein and cardiovascular outcomes in smokers versus nonsmokers in non-ST-elevation acute coronary syndrome (from the TACTICS-TIMI 18 trial)

We investigated the role of inflammation, as measured by high-sensitivity C-reactive protein (CRP) levels, in cardiovascular risk in smokers who have acute coronary syndrome. Despite fewer traditional risk factors, smokers who had acute coronary syndrome had higher CRP levels than did nonsmokers (7.0 vs 5.1 mg/L, p <0.001). CRP was associated with adverse cardiovascular outcomes in smokers and nonsmokers, even when adjusted for the presence of pulmonary disease.     

The Second Prevention of Syncope Trial (POST II)--a randomized clinical trial of fludrocortisone for the prevention of neurally mediated syncope: rationale and study design

BACKGROUND: Neurally mediated syncope is a common and frequently distressing problem. It is associated with a poor quality of life, which improves when the frequency of syncope is reduced. Few therapies for neurally mediated syncope have been proven effective. Fludrocortisone is commonly used to prevent recurrences of syncope but with little evidence to support its use. A placebo-controlled clinical trial of fludrocortisone for the prevention of neurally mediated syncope is needed. STRUCTURE OF STUDY: POST II is a multicenter, international, randomized, placebo-controlled study of fludrocortisone in the prevention of neurally mediated syncope. The primary end point is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive fludrocortisone 0.05 to 0.2 mg or matching placebo and followed for 1 year. Secondary end points include syncope frequency, presyncope, and quality of life. Primary analysis will be performed with an intention-to-treat approach, with a secondary on-treatment analysis. POWER CALCULATIONS: Assuming a 40% risk of syncope in the control arm, a relative reduction of 40% by fludrocortisone, and a dropout rate of 20%, the enrollment of 310 patients will give an 80% power of reaching a positive conclusion about fludrocortisone therapy, with P = .05. REGISTRATION: POST II is registered with both (ISRCTN 51802652) and (NCT00118482). IMPLICATIONS: This study will be the first adequately powered trial to determine whether fludrocortisone is effective in preventing neurally mediated syncope. If it is effective, then fludrocortisone may become the first-line medical therapy for this condition.     

Safety and feasibility of using serial infusions of nesiritide for heart failure in an outpatient setting (from the FUSION I trial)

The Follow-Up Serial Infusions of Nesiritide pilot study was designed to assess the safety and tolerability of outpatient serial infusions of nesiritide in 210 patients with decompensated heart failure who were randomly assigned to usual care only or usual care plus weekly infusions of nesiritide at dosages of 0.005 or 0.01 microg/kg/min for 12 weeks. The mean age +/- SD of the entire population was 67 +/- 13 years; 70% were men, and 80% were white. Mean baseline serum creatinine levels were 1.8 +/- 0.7 mg/dl, and mean left ventricular ejection fraction was 0.28 +/- 0.15%. Diabetes mellitus was present in 106 patients (50%), and atrial arrhythmias were present in 100 patients (48%). A totalof 1,645 nesiritide infusions was administered; 11 (< 1%) were discontinued due to an adverse event. All treatment groups had a similar frequency of adverse events and experienced improvements in quality of life. Administration of nesiritide resulted in acute decreases in aldosterone and endothelin-1 concentrations. Although there were no statistically significant differences among groups by outcome, prospectively defined higher risk subgroups demonstrated significant decreases in cardiovascular events. These results demonstrate the safety and feasibility of administering nesiritide in an outpatient setting. Additional studies are needed to determine the effect of outpatient serial infusions of nesiritide on rates of morbidity and mortality in advanced heart failure.     

Meta-analysis of efficacy and safety of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data

Background

Recommendations given for intravenous iron treatment are typically not supported by a high level of evidence. This meta-analysis addressed this by summarising the available date from clinical trials of ferric carboxymaltose using clinical trial reports and published reports.

Methods

Clinical trial reports were supplemented by electronic literature searches comparing ferric carboxymaltose with active comparators or placebo. Various outcomes were sought for efficacy (attainment of normal haemoglobin (Hb), increase of Hb by a defined amount, for example), together with measures of harm, including serious adverse events and deaths.

Results

Fourteen studies were identified with 2,348 randomised patients exposed to ferric carboxymaltose, 832 to oral iron, 762 to placebo, and 384 to intravenous iron sucrose. Additional data were available from cohort studies. Intravenous ferric carboxymaltose was given up to the calculated iron deficit (up to 1,000 mg in one week) for iron deficiency anaemia secondary to chronic kidney disease, blood loss in obstetric and gynaecological conditions, gastrointestinal disease, and other conditions like heart failure. The most common comparator was oral iron, and trials lasted 1 to 24 weeks. Intravenous ferric carboxymaltose improved mean Hb, serum ferritin, and transferrin saturation levels; the mean end-of-trial increase over oral iron was, for Hb 4.8 (95% confidence interval 3.3 to 6.3) g/L, for ferritin 163 (153 to 173) μg/L, and for transferrin saturation 5.3% (3.7 to 6.8%). Ferric carboxymaltose was significantly better than comparator in achievement of target Hb increase (number needed to treat (NNT) 6.8; 5.3 to 9.7) and target Hb NNT (5.9; 4.7 to 8.1). Serious adverse events and deaths were similar in incidence in ferric carboxymaltose and comparators; rates of constipation, diarrhoea, and nausea or vomiting were lower than with oral iron.

Conclusions

This review examined the available trials of intravenous ferric carboxymaltose using details from published papers and unpublished clinical trial reports. It increases the evidence available to support recommendations given for intravenous iron treatment, but there are limited trial data comparing different intravenous iron preparations.     

Clinical and virologic outcomes in patients with oseltamivir-resistant seasonal influenza A (H1N1) infections: results from a clinical trial

Nineteen patients with oseltamivir-resistant seasonal influenza A (H1N1) infections were randomized to receive oseltamivir or placebo. Nasopharyngeal swabs were obtained, and clinical and virologic outcomes were compared, stratified by early or late treatment. Neuraminidase inhibition assay and pyrosequencing for H275Y confirmed resistance. Twelve (63%) patients received oseltamivir; 8 (67%) received late treatment. Seven (37%) patients received placebo; 6 (86%) presented >48 hours after onset. Time to 50% decrease in symptom severity, complete symptom resolution, and first negative culture were shortest among the early treatment group. While sample size prohibits a strong conclusion, future studies should evaluate for similar trends.     

Weekend versus weekday hospital admission and outcomes during hospitalization for patients due to worsening heart failure: a report from Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)

The day of the week of admission may influence the length of stay and in-hospital death. However, the association between the admission day of the week and in-hospital outcomes has been inconsistent in heart failure (HF) patients among studies reported from Western countries. We thus analyzed this association in HF patients encountered in routine clinical practice in Japan. We studied the characteristics and in-hospital treatment in 1620 patients hospitalized with worsening HF by using the database of the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Patients were divided into two groups according to weekday (n = 1355; 83.6 %) or weekend admission (n = 265; 16.4 %). The mean age was 70.7 years and 59.4 % were male. Etiology was ischemic in 34.0 %, and mean left ventricular ejection fraction was 42.5 %. Patients admitted on the weekend were significantly older and had more comorbidities, and more severe symptoms and signs of HF on admission. Length of stay was comparable between weekend and weekday admission (35.2 ± 47.0 days vs 33.6 ± 32.0 days, P = 0.591). Crude in-hospital mortality did not differ between patients admitted on the weekend and weekdays (7.5 % vs 5.2 %, P = 0.136). Even after adjustment for covariates in multivariable modeling with patients admitted on weekday as the reference, in-hospital death was comparable between patients admitted on the weekend and weekdays (adjusted odds ratio 1.125, 95 % confidence interval 0.631–2.004, P = 0.691). Among patients hospitalized for worsening HF, admission day of the week did not affect in-hospital death and length of stay.     

The Midlands Trial of Empirical Amiodarone versus Electrophysiology-guided Interventions and Implantable Cardioverter-defibrillators (MAVERIC): a multi-centre prospective randomised clinical trial on the secondary prevention of sudden cardiac death.

AIMS: MAVERIC was a randomised clinical trial designed to test the possibility of prospectively identifying patients who would benefit most from the implantable cardioverter-defibrillator (ICD) by electrophysiology (EP) study in the context of secondary prevention of sudden cardiac death (SCD) through comparing EP-guided interventions (anti-arrhythmic drugs, coronary revascularization, and ICD) against empirical amiodarone therapy. METHODS: Two hundred and fourteen survivors of sustained ventricular tachycardia (VT), ventricular fibrillation (VF) or SCD were randomized to either treatment strategy, pre-stratified for haemodynamic status at index event, and followed up for a median of 5 years. RESULTS: Of the 106 amiodarone arm patients, 89 (84%) received the drug and 5 (5%) received an ICD after crossing over. Of the 108 EP arm patients, 31 (29%) received an ICD, 46 (43%) received anti-arrhythmic drugs only (mainly amiodarone or sotalol) and 18 (17%) received coronary revascularization but no ICD. No significant differences in survival or arrhythmia recurrence existed between the two treatment arms after 6 years. However, ICD recipients had a lower mortality than non-ICD recipients, regardless of allocated treatment (hazard ratio=0.54, p=0.0391). CONCLUSIONS: Prospective selection of patients to receive the ICD by EP study did not improve survival compared with empirical amiodarone therapy among survivors of VT, VF or SCD, whereas ICD implantation improved survival regardless of allocated treatment. On this basis, routine EP study has no role in the management of such patients, who should be offered empirical ICD therapy according to the results of other secondary prevention ICD trials.     

An index of patient reported outcomes (PRO-Index) discriminates effectively between active and control treatment in 4 clinical trials of adalimumab in rheumatoid arthritis

OBJECTIVE: To analyze 2 indices composed of the 3 patient reported outcomes (PRO) in the American College of Rheumatology (ACR) Core Data Set--physical function, pain, and global estimate--without joint count or laboratory data, for capacities to distinguish active from control treatments in 4 pivotal clinical trials. METHODS: Data from 4 clinical trials involving adalimumab, in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARD) or as monotherapy, versus control treatment were made available to analyze properties of various indices. A categorical PRO-Index M was defined as "majority" improvement in 2 of the 3 PRO measures at 20%, 50%, and 70% levels; results were evaluated to analyze agreement with ACR20, ACR50, ACR70 responses and an "all Core Data Set measures" index based on 4 of the 7 measures having such levels of improvement. A continuous PRO-Index C was defined as the median or 2nd highest of 3 percentage differences from baseline to endpoint; results were evaluated to analyze agreement with a continuous ACR-N, "all Core Data Set measures" index, and Disease Activity Score 28 (DAS28). RESULTS: All indices distinguished active versus control treatment at similar levels, including PRO-Index M versus ACR20, ACR50, and ACR70 responses, and PRO-Index C versus DAS28. CONCLUSION: PRO indices based only on patient questionnaire data, without joint counts or laboratory tests, may be useful quantitative measures of therapeutic efficacy for use in standard rheumatology clinical care.