Anemia and the potential role of erythropoiesis-stimulating agents in heart failure

The recognition of the high prevalence and the independent prognostic role of anemia in heart failure (HF) has contributed to intensification of the search for an effective treatment. A central role of erythropoietin in cardiorenal anemia syndrome has been proposed. Several clinical trials have established the safety and efficacy of erythropoiesis-stimulating agents in correcting anemia in patients with HF. The recognition of the pleiotropic effect of erythropoietin has expanded targets of therapy. The ongoing outcomes trial with darbepoetin alfa will determine the role of this novel therapy in the treatment of HF.     

How Should Subgroup Analyses Affect Clinical Practice? Insights from the Metoprolol Succinate Controlled-Release/Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF)

CONTEXT: The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization in patients with heart failure. While none of these trials are large enough to provide definitive results in any particular subgroup, it is of interest for physicians to examine the consistency of results as regards efficacy and safety for various subgroups or risk groups. OBJECTIVE: To summarize results from both predefined as well as post-hoc subgroup analyses performed in the MERIT-HF trial, and to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. For some subgroups we performed metaanalyses with data from the CIBIS II and COPERNICUS trials in order to obtain more robust data on mortality in subgroups with a small number of deaths (e.g. for women). SETTING: MERIT-HF was run in 14 countries, and randomized a total of 3,991 patients with symptomatic systolic heart failure (NYHA class II to IV with ejection fraction < or =0.40). Treatment was initiated with a very low dose with careful titration to a maximum target dose of 200 mg metoprolol succinate controlled release/extended release (CR/XL), or highest tolerated dose. MAIN OUTCOME MEASURES: Total mortality (first primary endpoint), total mortality plus all-cause hospitalization (second primary endpoint), and total mortality plus hospitalization for heart failure (first secondary endpoint) analyzed on a time to first event basis. RESULTS: Overall, MERIT-HF demonstrated a 34% reduction in total mortality ( p = 0.00009 nominal) and a 19% reduction for mortality plus all-cause hospitalization ( p = 0.00012). The first secondary endpoint of mortality plus hospitalization for heart failure was reduced by 31% ( p = 0.0000008). The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as nearly all post-hoc subgroups. Metoprolol CR/XL has been very well tolerated, overall as well as in all subgroups analyzed. Overall 87% of the patients reached a dose of 100 mg or more of metoprolol CR/XL once daily, and 64% reached the target dose of 200 mg once daily. CONCLUSION: Our results show that when carefully titrated, metoprolol CR/XL can safely be instituted for the overwhelming majority of outpatients with clinically stable systolic heart failure, with minimal side effects or deterioration. The time has come to overcome the barriers that physicians perceive to beta-blocker treatment, and to provide it to the large number of patients with heart failure in need of this therapy, including also high risk patients like elderly patients, patients with severe heart failure, and patients with diabetes. Because of the increased risk, these are the patients in whom treatment will have the greatest impact as shown by number of lives saved and number of hospitalizations avoided. The target dose should be strived for in all patients who tolerate this dose. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups due to small sample size in subgroups and due to chance. However, we believe that the best estimate of treatment effect for any particular subgroup should be the overall effect observed in the trial.     

Chronic therapy for congestive heart failure with benazepril HCl, a new angiotensin converting enzyme inhibitor

Benazepril HCl is an orally effective angiotensin converting enzyme (ACE) inhibitor previously shown to have significant acute hemodynamic benefits in patients with congestive heart failure. In this study, 21 patients with New York Heart Association Class III or IV congestive heart failure were treated with 2 to 15 mg of benazepril HCl as a single daily oral dose for 28 days to determine the clinical and hemodynamic value of chronic therapy. Each patient underwent clinical evaluation during the 28-day period, as well as invasive hemodynamic studies on the first two and last two days of the trial. Plasma ACE activity and aldosterone levels fell significantly and renin levels rose after therapy. Benazepril HCl produced significant (p less than 0.01) reductions in arterial pressure and systemic vascular resistance, with corresponding increases in cardiac output and decreases in pulmonary artery wedge pressure. Responses after 28 days of therapy were equivalent to those after the initial doses. Clinical effects included reduced rest, exertional and paroxysmal nocturnal dyspnea, as well as reduced peripheral edema. Only one patient developed symptomatic orthostatic hypotension. Thus, benazepril HCl, given once daily, is an effective and well tolerated oral agent for the chronic treatment of advanced congestive heart failure.     

Tracking the uptake of evidence: two decades of hospital practice trends for diagnosing deep vein thrombosis and pulmonary embolism

BACKGROUND: Advances in clinical research methods have led to prospective randomized controlled (level 1) clinical studies evaluating diagnostic modalities resulting in a paradigm shift in the literature for diagnosing deep vein thrombosis (DVT) and pulmonary embolism (PE). To assess whether these advances correlate with clinical practice, we analyzed 21-year trends in diagnostic testing for patients with venous thromboembolism. METHODS: We used discharge data from the National Hospital Discharge Survey (1979-1999) to determine DVT and PE cases annually. Procedure fields were screened to determine patients who had DVT or PE or who underwent venography, arteriography of the pulmonary arteries, pulmonary scintigraphy, or DVT ultrasonic scanning. Searching EMBASE, MEDLINE, and the American Thoracic Society guidelines, a literature-based time line of level 1 studies was derived and juxtaposed against trends and procedure use. RESULTS: Improved diagnostic tests resulted in diagnostic changes in patients with suspected venous thromboembolism. These observed changes correlated over time in subsequent years with level 1 studies. Diagnostic DVT approaches showed an initial marked increased use of venography followed by a rapid decline that coincided with increased use of Doppler ultrasonography. Diagnostic approaches to PE were characterized by initial marked increases in lung scanning followed by a rapid decline as use of ultrasonography considerably increased and pulmonary angiography modestly increased. CONCLUSIONS: Diagnostic approaches to DVT and PE have changed markedly during the past 2 decades, in temporal harmony with the evolving literature. Change in clinical practice occurs over years, and long-term follow-up is required to capture this change.     

A systematic review of tools for predicting severe adverse events following patient discharge from intensive care units

Introduction

The discharge of patients from the intensive care unit (ICU) to a hospital ward is a common transition of care that is associated with error and adverse events. Risk stratification tools may help identify high-risk patients for targeted interventions, but it is unclear if proper tools have been developed.

Methods

We searched Ovid EMBASE, Ovid MEDLINE, CINAHL, PUBMED and Cochrane Central Register of Controlled Trials from the earliest available date through March 2013, plus reference lists and citations of all studies included in the systematic review. Cohort studies were selected that described the derivation, validation or clinical impact of tools for predicting medical emergency team activation, ICU readmission or mortality following patient discharge from the ICU. Data were extracted on the study design, setting, population, sample size, tool (components, measurement properties) and outcomes.

Results

The literature search identified 9,926 citations, of which eight studies describing eight tools met the inclusion criteria. Reported outcomes included ICU readmission (n = 4 studies), hospital mortality (n = 3 studies) and both ICU readmission and hospital mortality (n = 1 studies). Seven of the tools were comprised of distinct measurable component variables, while one tool used subjective scoring of patient risk by intensive care physicians. The areas under receiver operator curves were reported for all studies and ranged from 0.66 to 0.92. A single study provided a direct comparative analysis between two tools. We did not find any studies evaluating the impact of risk prediction on processes and outcomes of care.

Conclusions

Eight risk stratification tools for predicting severe adverse events following patient discharge from ICU have been developed, but have undergone limited comparative evaluation. Although risk stratification tools may help clinician decision-making, further evaluation of the existing tools'' effects on care is required prior to clinical implementation.     

Resiniferatoxin (RTX) Causes a Uniquely Protracted Musculoskeletal Hyperalgesia in Mice by Activation of TRPV1 Receptors

Inactivation of transient receptor potential vanilloid-1 (TRPV1) receptors is one approach to analgesic drug development. However, TRPV1 receptors exert different effects on each modality of pain. Because muscle pain is clinically important, we compared the effect of TRPV1 ligands on musculoskeletal nociception to that on thermal and tactile nociception. Injected parenterally, capsaicin had no effect on von Frey fiber responses (tactile) but induced a transient hypothermia and hyperalgesia in both the tail flick (thermal) and grip force (musculoskeletal) assays, presumably by its agonistic action at TRPV1 sites. In contrast, resiniferatoxin (RTX) produced a chronic (>58 days) thermal antinociception, consistent with its reported ability to desensitize TRPV1 sites. In the same mice, RTX produced a transient hypothermia (7 hours) and a protracted (28-day) musculoskeletal hyperalgesia in spite of a 35.5% reduction in TRPV1 receptor immunoreactivity in muscle afferents. Once musculoskeletal hyperalgesia subsided, mice were tolerant to the hyperalgesic effects of either capsaicin or RTX whereas tolerance to hypothermia did not develop until after 3 injections. Musculoskeletal hyperalgesia was prevented but not reversed by SB-366791, a TRPV1 antagonist, indicating that TRPV1 receptors initiate but do not maintain hyperalgesia. Injected intrathecally, RTX produced only a brief musculoskeletal hyperalgesia (2 days), after which mice were tolerant to this effect.