The management of patients with atrial fibrillation (AF) is often inadequate due to deficient adherence to the guidelines. A nurse-led AF clinic providing integrated chronic care to improve guideline ...adherence and activate patients in their role, may effectively reduce morbidity and mortality but such care has not been tested in a large randomized trial. Therefore, we performed a randomized clinical trial to compare the AF clinic with routine clinical care in patients with AF.
We randomly assigned 712 patients with AF to nurse-led care and usual care. Nurse-led care consisted of guidelines based, software supported integrated chronic care supervised by a cardiologist. The primary endpoint was a composite of cardiovascular hospitalization and cardiovascular death. Duration of follow-up was at least 12 months. Adherence to guideline recommendations was significantly better in the nurse-led care group. After a mean of 22 months, the primary endpoint occurred in 14.3% of 356 patients of the nurse-led care group compared with 20.8% of 356 patients receiving usual care hazard ratio: 0.65; 95% confidence interval (CI) 0.45-0.93; P= 0.017. Cardiovascular death occurred in 1.1% in the nurse-led care vs. 3.9% in the usual care group (hazard ratio: 0.28; 95% CI: 0.09-0.85; P= 0.025). Cardiovascular hospitalization amounted (13.5 vs. 19.1%, respectively, hazard ratio: 0.66; 95% CI: 0.46-0.96, P= 0.029).
Nurse-led care of patients with AF is superior to usual care provided by a cardiologist in terms of cardiovascular hospitalizations and cardiovascular mortality. Trial registration information: Clinicaltrials.gov identifier number: NCT00391872.
Depression following myocardial infarction is associated with poor cardiac prognosis. It is unclear whether antidepressant treatment improves long-term depression status and cardiac prognosis.
To ...evaluate the effects of antidepressant treatment compared with usual care in an effectiveness study.
In a multicentre randomised controlled trial, 2177 myocardial infarction patients were evaluated for ICD-10 depression and randomised to intervention (n=209) or care as usual (n=122). Both arms were evaluated at 18 months post-myocardial infarction for long-term depression status and new cardiac events.
No differences were observed between intervention and control groups in mean scores on the Beck Depression Inventory (11.0, s.d.=7.5 v.10.2, s.d.=5.1, P=0.45) or presence of ICD-10 depression (30.5 v. 32.1%, P=0.68). The cardiac event rate was 14% among the intervention group and 13% among controls (OR=1.07, 95% CI 0.57-2.00).
Antidepressant treatment did not alter long-term depression post-myocardial infarction status or improve cardiac prognosis.
Clinical probability assessment is combined with d-dimer testing to exclude pulmonary embolism (PE).
To compare the test characteristics of gestalt (a physician's unstructured estimate) and clinical ...decision rules for evaluating adults with suspected PE and assess the failure rate of gestalt and rules when used in combination with d-dimer testing.
Articles in MEDLINE and EMBASE in English, French, German, Italian, Spanish, or Dutch that were published between 1966 and June 2011.
3 reviewers, working in pairs, selected prospective studies in consecutive patients suspected of having PE. Studies had to estimate the probability of PE by using gestalt or a decision rule and verify the diagnosis by using an appropriate reference standard.
Data on study characteristics, test performance, and prevalence were extracted. Reviewers constructed 2 × 2 tables and assessed the methodological quality of the studies.
52 studies, comprising 55 268 patients, were selected. Meta-analysis was performed on studies that used gestalt (15 studies; sensitivity, 0.85; specificity, 0.51), the Wells rule with a cutoff value less than 2 (19 studies; sensitivity, 0.84; specificity, 0.58) or 4 or less (11 studies; sensitivity, 0.60; specificity, 0.80), the Geneva rule (5 studies; sensitivity, 0.84; specificity, 0.50), and the revised Geneva rule (4 studies; sensitivity, 0.91; specificity, 0.37). An increased prevalence of PE was associated with higher sensitivity and lower specificity. Combining a decision rule or gestalt with d-dimer testing seemed safe for all strategies, except when the less-sensitive Wells rule (cutoff value ≤4) was combined with less-sensitive qualitative d-dimer testing.
Studies had substantial heterogeneity due to prevalence of PE and differences in threshold. Many studies (63%) had potential bias due to differential disease verification.
Clinical decision rules and gestalt can safely exclude PE when combined with sensitive d-dimer testing. The authors recommend standardized rules because gestalt has lower specificity, but the choice of a particular rule and d-dimer test depend on both prevalence and setting.
Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control ...therapy can reduce this risk.
In this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed ≤1 year before enrollment) and cardiovascular conditions to receive either early rhythm control or usual care. Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation-related symptoms. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy. Secondary outcomes, including symptoms and left ventricular function, were also evaluated.
In 135 centers, 2789 patients with early atrial fibrillation (median time since diagnosis, 36 days) underwent randomization. The trial was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient. A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P = 0.005). The mean (±SD) number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively; P = 0.23). The percentage of patients with a primary safety outcome event did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care. Symptoms and left ventricular function at 2 years did not differ significantly between the groups.
Early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions. (Funded by the German Ministry of Education and Research and others; EAST-AFNET 4 ISRCTN number, ISRCTN04708680; ClinicalTrials.gov number, NCT01288352; EudraCT number, 2010-021258-20.).
The hypothesis that elimination of facultative and strict anaerobic microorganisms from the gastro-intestinal tract by antimicrobial drugs in the period of time around allogeneic bone marrow ...transplantation (BMT) prevents acute graft-versus-host disease (GVHD), was examined in a cohort of 112 children grafted between 1989 and 2002 for hematological malignancies. All patients received T-cell replete marrow from human leukocyte antigens (HLA) matched sibling donors under identical transplantation conditions. To eliminate microorganisms from the gastro-intestinal tract, total gastro-intestinal decontamination (GID) was applied by high doses of non-absorbable antimicrobial drugs while the graft recipient was maintained in strict protective isolation. About half of the children (51%) proved to be successfully decontaminated, and about half (49%) unsuccessfully. One recipient got acute GVHD in the first group and 8 in the second group (p = 0.013). The degree of success of total GID was decisive for the occurrence of acute GVHD, irrespective of the presence of other risk factors such as higher age of recipient and/or donor, female donor for male recipient and carriership or reactivation of herpesviruses. Our results demonstrate that successful total GID of the graft recipient prevents moderate to severe acute GVHD. We suppose that substantial translocation of gastro-intestinal microorganisms or parts of these, functioning as microbial-associated molecular patterns (MAMP's), triggering macrophages/dendritic cells via pattern recognizing receptors (PRR's) is prohibited. As a consequence the initiation and progression of an inflammatory process leading to acute GVHD is inhibited.
In chronic heart failure (CHF), reduced vagal activity correlates with increased mortality and acute decompensation. Experimentally, chronic vagus nerve stimulation (VNS) improved left ventricular ...(LV) function and survival; clinically, it is used for the treatment of drug-refractory epilepsy. We assessed safety and tolerability of chronic VNS in symptomatic CHF patients, using a novel implantable nerve stimulation system. The secondary goal was to obtain preliminary data on clinical efficacy.
This multi-centre, open-label phase II, two-staged study (8-patient feasibility phase plus 24-patient safety and tolerability phase) enrolled 32 New York Heart Association (NYHA) class II-IV patients age 56 ± 11 years, LV ejection fraction (LVEF) 23 ± 8%. Right cervical VNS with CardioFit (BioControl Medical) implantable system started 2-4 weeks after implant, slowly raising intensity; patients were followed 3 and 6 months thereafter with optional 1-year follow-up. Overall, 26 serious adverse events (SAEs) occurred in 13 of 32 patients (40.6%), including three deaths and two clearly device-related AEs (post-operative pulmonary oedema, need of surgical revision). Expected non-serious device-related AEs (cough, dysphonia, and stimulation-related pain) occurred early but were reduced and disappeared after stimulation intensity adjustment. There were significant improvements (P < 0.001) in NYHA class quality of life, 6-minute walk test (from 411 ± 76 to 471 ± 111 m), LVEF (from 22 ± 7 to 29 ± 8%), and LV systolic volumes (P = 0.02). These improvements were maintained at 1 year.
This open-label study shows that chronic VNS in CHF patients with severe systolic dysfunction may be safe and tolerable and may improve quality of life and LV function. A controlled clinical trial appears warranted.
Prognostic models are abundant in the medical literature yet their use in practice seems limited. In this article, the third in the PROGRESS series, the authors review how such models are developed ...and validated, and then address how prognostic models are assessed for their impact on practice and patient outcomes, illustrating these ideas with examples.
Objective To validate all diagnostic prediction models for ruling out pulmonary embolism that are easily applicable in primary care.Design Systematic review followed by independent external ...validation study to assess transportability of retrieved models to primary care medicine.Setting 300 general practices in the Netherlands.Participants Individual patient dataset of 598 patients with suspected acute pulmonary embolism in primary care.Main outcome measures Discriminative ability of all models retrieved by systematic literature search, assessed by calculation and comparison of C statistics. After stratification into groups with high and low probability of pulmonary embolism according to pre-specified model cut-offs combined with qualitative D-dimer test, sensitivity, specificity, efficiency (overall proportion of patients with low probability of pulmonary embolism), and failure rate (proportion of pulmonary embolism cases in group of patients with low probability) were calculated for all models.Results Ten published prediction models for the diagnosis of pulmonary embolism were found. Five of these models could be validated in the primary care dataset: the original Wells, modified Wells, simplified Wells, revised Geneva, and simplified revised Geneva models. Discriminative ability was comparable for all models (range of C statistic 0.75-0.80). Sensitivity ranged from 88% (simplified revised Geneva) to 96% (simplified Wells) and specificity from 48% (revised Geneva) to 53% (simplified revised Geneva). Efficiency of all models was between 43% and 48%. Differences were observed between failure rates, especially between the simplified Wells and the simplified revised Geneva models (failure rates 1.2% (95% confidence interval 0.2% to 3.3%) and 3.1% (1.4% to 5.9%), respectively; absolute difference −1.98% (−3.33% to −0.74%)). Irrespective of the diagnostic prediction model used, three patients were incorrectly classified as having low probability of pulmonary embolism; pulmonary embolism was diagnosed only after referral to secondary care.Conclusions Five diagnostic pulmonary embolism prediction models that are easily applicable in primary care were validated in this setting. Whereas efficiency was comparable for all rules, the Wells rules gave the best performance in terms of lower failure rates.
Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is ...not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation.
We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years.
The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 97.7%, vs. 203 67.0% in the strict-control group; P<0.001) with fewer total visits (75 median, 0, vs. 684 median, 2; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups.
In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.)
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a ...CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.
This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40–90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.
Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean LSM treatment difference of 10·0 percentage points 95% CI 7·4 to 12·6, p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference −45·1 mmol/L 95% CI −50·1 to −40·1, p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points 95% CI 11·8 to 23·0, p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor.
Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.
Vertex Pharmaceuticals.
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