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#301
14.07.2010, 16:44
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Pro-adrenomedullin levels predictive of death, HF
By Levels of mid-regional pro-adrenomedullin were prognostic of early mortality and HF, and helped to improve risk stratification, study findings indicated. The study included 745 patients with non-STEMI who had their plasma pro-adrenomedullin measured on admission and discharge. The primary endpoints over a mean follow-up of 760 days were a composite of death, HF, hospitalization and recurrent acute MI, whereas the events assessed individually were secondary endpoints. During follow-up, there were 65 (8.7%) HF hospitalizations, 77 (10.3%) recurrent acute MIs and 120 (16.1%) deaths. Compared with established normal ranges, levels of admission (median: 0.81 nmol/L; range 0.06-5.75 nmol/L) and discharge (median: 0.76 nmol/L; range 0.25-6.95 nmol/L) were increased. Multivariate adjusted Cox regression models indicated that levels of admission and discharge were associated with the primary endpoint (HR=9.75 on admission, 7.54 on discharge; both P<.001). Admission pro-adrenomedullin in particular correlated with early mortality (P<.001) and, when compared with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and Global Registry of Acute Coronary Events (GRACE) score, was the only independent predictor of this endpoint. According to researchers, this study represents the first report confirming activation of the adrenomedullin system in a cohort of patients with non-STEMI. “[Mid-regional pro-adrenomedullin] … represents a powerful new biomarker of risk of adverse events, death or HR rehospitalization beyond established clinical, biochemical or echocardiographic markers, NT-proBNP and GRACE score,” they wrote. “Admission [mid-regional pro-adrenomedullin] level is a particularly strong predictor of early mortality and, when >1.11 nmol/L, complemented the GRACE score to improve risk stratification.” – by Brian Ellis Dhillon O. J Am Coll Cardiol. 2010;56:125-133. ------------------------------------------------------------------------------------------------- Family history alone shown poor indicator for cholesterol screening in children By Children who qualify for pharmacologic treatment for dyslipidemia may go unnoticed if cholesterol screening is based solely on positive family history of cardiovascular disease, according to data from the Coronary Artery Risk Detection In Appalachian Communities project. According to the researchers, had they relied on family history to select children for screening, one-third of the children who met the criteria for pharmacologic treatment would have been left out. The study — designed to identify children and families at risk for coronary artery disease — included 20,266 fifth-grade children with a fasting lipid profile who had completed a family history questionnaire. The researchers determined the relationship between hyperlipidemia and family history using x2 analyses. They then used family history to predict the need for pharmacologic treatment in children with dyslipidemia. According to the National Cholesterol Education Program (NCEP) guidelines, selective screening is suggested for those with a family history of premature cardiovascular disease, parent total cholesterol of >240 mg/dL and unknown family history. Of those included in the study, 71.4% qualified for cholesterol screening based on positive family history; 8.3% had dyslipidemia (low-density lipoprotein ≥130 mg/dL) and 1.2% were considered for pharmacologic treatment (low-density lipoprotein ≥160 mg/dL). Nearly 10% of children who did not meet NCEP positive family history guidelines for screening had dyslipidemia; 1.7% qualified for treatment. Positive family history and hyperlipidemia (LDL ≥130 mg/dL) were related (P=.01), but the effect size was small (Cramer’s V=.02). Similarly, positive family history was associated with meeting treatment requirements (LDL ≥160 mg/dL; P=.004) but the effect size was small (Cramer’s V=.02). According to other analyses, using family history was not a good indicator of whether or not children need pharmacologic treatment (OR=0.692 [95% CI, 0.54-0.89], specificity = 0.63 [95% CI, 0.57-0.69] and sensitivity = 0.29 [95% CI, 0.28-0.29]). “Universal cholesterol screening in the pediatric population will allow early diagnosis and appropriate treatment of children with significant dyslipidemia secondary to genetic and/or adverse lifestyle factors, hopefully preventing arterial disease,” the researchers wrote. Ritchie SK. Pediatrics. 2010;126:260-266. 
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#302
14.07.2010, 16:46
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Patients’ persistence with antihypertensive medication found directly related to clinical decision-making
By Better clinical decision-making and data collection skills, as well as early modifications in therapy, improved the persistence among those taking an antihypertensive medication, study results suggested. The patients with hypertension (n=13,205) compiled for the study had started antihypertensive medication and entered a clinical practice in Quebec, between 1993 and 2007. Researchers used Medical Council of Canada licensing examination scores to determine medical management and communication ability, as well as population-based prescription and medical services databases to assess starting therapy, treatment changes, comorbidity and persistence with antihypertensive treatment. Within 6 months, 2,926 patients (22.2%) had discontinued all antihypertensive medication. The risk of non-persistence decreased in patients treated with better medical management (OR=0.74; 95% CI, 0.63-0.87); improved communication ability (OR=0.88; 95% CI, 0.78-1.00); and with early therapy changes, more follow-up visits and non-diuretics as the initial choice of therapy (OR=0.45; 95% CI, 0.37-0.54). Furthermore, medical management ability, particularly clinical decision-making, accounted for 15.8% (95% CI, 7.5%-23.3%) of persistence in the first 6 months. According to the researchers, the most fruitful way to support clinical decision-making and medication monitoring will be the development and evaluation of tools in the practice environment. “In particular, new information technologies that can be integrated with the electronic medical record may have the greatest promise for enhancing drug- and patient-specific follow-up of adverse effects and treatment effectiveness,” they concluded. “Technologies such as computerized decision support, community drug profiles from retail pharmacies, and follow-up monitoring tools such as interactive voice recording approaches have been shown to be effective in management of some chronic conditions, and their increased use in hypertension treatment should improve patient adherence and, ultimately, clinical outcome.” – by Brian Ellis Tamblyn R. Arch Intern Med. 2010;170:1064-1072.
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#303
15.07.2010, 14:17
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FDA panel: Keep rosiglitazone on market, but with more warnings, restrictions
By An FDA advisory committee has recommended that rosiglitazone stay on the U.S. market as a treatment option for patients with type 2 diabetes, but with restrictions on use and revised labeling that includes additional warnings about CV safety. Twelve of the 33 panel members voted to withdraw rosiglitazone (Avandia, GlaxoSmithKline) from the market. Ten recommended continued marketing with additional warnings about MI and congestive HF, and restrictions such as patient and provider education; just three recommended no changes to the current label. “I absolutely could not vote for withdrawal,” Arthur J. Moss, MD, PhD, professor of medicine and cardiology at the University of Rochester, N.Y., said of his vote. “I wanted to send a message to the FDA because a proper trial should have been done going all the way back to 1993 — and that trial still needs to be done.” Lamont G. Weide, MD, PhD, said his concern was taking away a drug that provides benefit to some patients. “I would hate to take away a drug without definitive evidence from the few patients who need it,” said Weide, chief of diabetes and endocrinology at University of Missouri-Kansas City. Alternative therapies to rosiglitazone are available, Abraham Thomas, MD, MPH, division head of endocrinology, diabetes, bone and mineral disorders at Henry Ford Hospital, said, adding that if rosiglitazone is banned “we can still take care of diabetes.” He said that black box warnings are not enough to convey the drug’s CV risks because the average physician “tends not to read them.” TIDE trial to continue? The joint Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee remained split on other votes, including whether the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial should be continued if rosiglitazone stays on the market. Twenty members recommended continuation, 10 recommended against, two abstained and one did not vote. The randomized prospective, controlled, postmarketing clinical trial was required by the FDA following the decision at the 2007 FDA meeting on the safety of rosiglitazone and subsequent black box warnings for TZDs. TIDE will determine whether TZDs reduce CV and serious health outcomes and whether rosiglitazone and pioglitazone (Actos, Takeda) have similar or different CV effects, study investigator Hertzel C. Gerstein, MD, MSc, said during a presentation to the panel. Study critics said the design is unethical and is designed to establish proof of harm. The panel agreed that evidence on rosiglitazone compared to pioglitazone remains inconclusive. “A definitive study needs to be done and this is the first time that the FDA can demand such,” Moss said. CV, mortality risks The committee also voted: 21-3 that available data suggest rosiglitazone increases the risk for cardiac ischemic events relative to pioglitazone; nine said data are insufficient. 18-6 that available data suggest rosiglitazone increases the risk for cardiac ischemic events relative to non-TZD antidiabetes drugs; nine said data are insufficient. 21-2 that available data do not suggest that rosiglitazone increases the risk for mortality relative to non-TZD antidiabetes drugs; 11 said data are insufficient. 7-12 that available data suggest that rosiglitazone increases the risk for mortality relative to pioglitazone; 14 said data are insufficient. While the FDA is not required to follow the recommendations of the advisory committee, it usually does. “The agency takes the advice of our committee’s very serious,” Janet Woodcock, MD, director of the FDA Center for Drug Evaluation and Research, said at the close of the two-day meeting. “We will evaluate these proceedings and the regulatory options that are available to us and will come to a decision as soon as possible.”
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#304
15.07.2010, 21:02
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Cardiac Origins of the Postural Orthostatic Tachycardia Syndrome
Fu Q, VanGundy TB, Galbreath M, et al. J Am Coll Cardiol 2010;55:2858-2868. Study Question: What is the mechanism of the postural orthostatic tachycardia syndrome (POTS)? Serum Markers of Collagen Turnover Predict Future Shocks in Implantable Cardioverter-Defibrillator Recipients With Dilated Cardiomyopathy on Optimal Treatment Kanoupakis EM, Manios EG, Kallergis EM, et al. J Am Coll Cardiol 2010;55:2753-2759. Study Question: Are markers of collagen turnover predictive of ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with nonischemic dilated cardiomyopathy (NIDC)? Low-Dose Combination Therapy With Rosiglitazone and Metformin to Prevent Type 2 Diabetes Mellitus (CANOE trial): A Double-Blind Randomized Controlled Study Zinman B, Harris SB, Neuman J, et al. Lancet 2010;Jun 2:[Epub ahead of print]. Study Question: What is the effect of low-dose combination therapy with rosiglitazone and metformin on development of type 2 diabetes? Tight Blood Pressure Control and Cardiovascular Outcomes Among Hypertensive Patients With Diabetes and Coronary Artery Disease Cooper-DeHoff RM, Gong Y, Handberg EM, et al. JAMA 2010;304:61-68. Study Question: Does tight blood pressure (BP) control reduce cardiovascular (CV) outcomes among patient with diabetes and coronary artery disease (CAD)? Coronary Microvascular Reactivity to Adenosine Predicts Adverse Outcome in Women Evaluated for Suspected Ischemia: Results From the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) Study Pepine CJ, Anderson D, Sharaf BL, et al. J Am Coll Cardiol 2010;55:2825-2832. Study Question: Does coronary microvascular dysfunction predict adverse outcomes among women with signs and symptoms of ischemia? Randomized Comparison of the Effects of Rosiglitazone vs. Placebo on Peak Integrated Cardiovascular Performance, Cardiac Structure, and Function McGuire DK, Abdullah SM, See R, et al. Eur Heart J 2010;Jul 2:[Epub ahead of print]. Study Question: The thiazolidinedione (TZD) drugs rosiglitazone and pioglitazone for type 2 diabetes mellitus (T2DM) cause peripheral edema, and less commonly, incident or worsening heart failure. What is the effect of rosiglitazone on cardiovascular performance and cardiac function? Angiographic Versus Functional Severity of Coronary Artery Stenoses in the FAME Study: Fractional Flow Reserve Versus Angiography in Multivessel Evaluation Tonino PA, Fearon WF, De Bruyne B, et al. J Am Coll Cardiol 2010;55:2816-2821. Study Question: What is the relationship between angiographic and functional severity of coronary artery stenoses in the FAME (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation) study? Predicting Survival in Pulmonary Arterial Hypertension. Insights From the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) Benza RL, Miller DP, Gomberg-Maitland M, et al. Circulation 2010;122:164-172. Study Question: Factors that determine survival in pulmonary arterial hypertension (PAH) drive clinical management. Can an effective quantitative survival prediction tool be established for research and clinical use? Treatments, Trends, and Outcomes of Acute Myocardial Infarction and Percutaneous Coronary Intervention Roe MT, Messenger JC, Weintraub WS, et al. J Am Coll Cardiol 2010;56:254-263. Perspective: The following are 10 points to remember about this report from the National Cardiovascular Data Registry (NCDR). Carotid Artery Stenting With Emboli Protection Surveillance Study: Outcomes at 1 Year Schreiber TL, Strickman N, Davis T, et al., on behalf of the CASES-PMS Investigators. J Am Coll Cardiol 2010;56:49-57. Study Question: What is the safety and efficacy of carotid artery stenting (CAS) for patients at high surgical risk, performed by physicians with varied experience? Prognostic Significance of Myocardial Fibrosis Quantification by Histopathology and Magnetic Resonance Imaging in Patients With Severe Aortic Valve Disease Azevedo CF, Nigri M, Higuchi M, et al. J Am Coll Cardiol 2010;56:278-287. Study Question: Does myocardial fibrosis (MF) in patients with severe aortic valve (AV) disease, assessed by histopathology or contrast-enhanced magnetic resonance imaging (ce-MRI), predict outcomes following surgical AV replacement? The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies in Atherosclerosis): Final Results and the Impact of Medication Adherence, Dose, and Treatment Duration Villines TC, Stanek EJ, Devine PJ, et al. J Am Coll Cardiol 2010;55:2721-2726. Study Question: ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies in Atherosclerosis) was terminated early on the basis of a prespecified interim analysis showing superiority of niacin over ezetimibe on change in carotid intima-media thickness (CIMT). Was there a relationship between cumulative exposures to the drugs and change in IMT?
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#305
15.07.2010, 21:08
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Цитата:
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#308
16.07.2010, 10:29
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Subcutaneous ICD successfully detected, converted ventricular fibrillation episodes
By An entirely subcutaneous implantable cardioverter defibrillator system was found to successfully and consistently detect and convert episodes of ventricular fibrillation in a group of small, non-randomized trials. The researchers conducted two short-term clinical trials to determine an appropriate device configuration and assess energy requirements. They evaluated four subcutaneous ICD configurations in a study population that included patients (n=78) who were candidates for ICD implantation. Subsequently, they also tested the best configuration in additional patients (n=49) to determine the subcutaneous defibrillation threshold in comparison with that of transvenous ICD. Long-term use of subcutaneous ICD use was also followed in a pilot study (n=6) and then in a larger trial (n=55). The best device configuration, researchers found, utilized a parasternal electrode and a left lateral thoracic pulse generator, which was as effective as a transvenous ICD for terminating induced ventricular fibrillation but with a higher mean energy requirement (36.6 ± 19.8 J vs. 11.1 ± 8.5 J). Ventricular fibrillation was detected in 100% of 137 induced episodes in patients who received a permanent subcutaneous ICD. Additionally, after a mean of 10 months, the device had detected and treated all 12 episodes of spontaneous, sustained ventricular tachyarrhythmia. According to researchers, these studies cannot show whether subcutaneous ICDs are superior to conventional transvenous ICDs regarding such characteristics as lead stability or failure, but they shed light on the feasibility of an entirely subcutaneous ICD. However, “the relative benefit of subcutaneous ICDs, as compared with transvenous ICDs, will need to be shown in large, long-term, randomized, prospective, multicenter clinical trials,” they wrote. Bardy GH. N Engl J Med. 2010;363:36-44. __________________________________________________ _______________________ Appropriate ICD interventions found lacking in women By Women had less appropriate implantable cardioverter defibrillator interventions compared with men, although there was no apparent difference with mortality, data from a study appearing in Heart Rhythm suggested. The Texas- and Italy-based researchers utilized PubMed, Central and other databases to find studies that examined gender differences in the specified endpoints, provided the HR obtained in multiple Cox regression analyses and adjusted for all confounding variables. They found five studies that enrolled patients (n=7,229, 22% women) with dilated cardiomyopathy. Women had no significant difference in overall mortality (HR=0.96; 95% CI, 0.67–1.39) vs. men, but had less appropriate ICD interventions (HR=0.63; 95% CI, 0.49–0.82). The ICD benefit on mortality was greater in men (HR=0.67; 95% CI, 0.58–0.78), whereas it did not attain statistical significance in women (HR=0.78; 95% CI, 0.57–1.05). Women tended to have more advanced disease than men, including a higher percentage of NYHA functional class >II (mean difference, 6.3%) and left bundle-branch block (mean difference, 7%), and more use of diuretics (mean difference, 8.7%). This study’s findings, the researchers wrote, challenge current left ventricular ejection fraction-based prophylactic ICD recommendations and raise concerns about generalizing such recommendations to underrepresented patients in primary prevention ICD trials. These findings, they added, “call for further research with appropriate economic and social analyses to determine the cost-effectiveness of this therapy in women.” Santangeli P. Heart Rhythm. 2010;7:876–882.
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#309
16.07.2010, 10:34
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Exercise-improved heart rate recovery increased cardiac survival in patients with recent MI
Hai J. Heart Rhythm. 2010;7:929-936. By Exercise training improved the heart rate recovery of patients who had recently experienced MI, which subsequently increased cardiac survival, suggested new study data. Researchers in this study enrolled 386 consecutive patients with recent MI into their cardiac rehabilitation program from 1996 to 2007. Patients underwent symptom-limited treadmill testing at baseline and after exercise training, and were prospectively followed in the outpatient clinic. What researchers found was that treadmill testing led to improved heart rate recovery after eight weeks of exercise training (17.5 ± 10.0 beats/min to 19.0 ± 12.3 beats/min, P=.011). After a 79 ± 41 month follow-up, 40 (10.4%) patients died from cardiac events. Multivariate Cox regression analysis revealed the following independent predictors of cardiac death: diabetes (HR=2.28; 95% CI, 1.01–5.19), statin use (HR=0.36; 95% CI, 0.16–0.80), baseline resting heart rate ≥65 beats/min (HR=5.37; 95% CI, 1.33–21.61), post-training heart rate recovery <12 beats/min (HR=2.49, 95% CI, 1.10–5.63), left ventricular ejection fraction ≤30% (HR=4.70; 95% CI, 1.34–16.46), and exercise capacity of or less than four metabolic equivalents (HR 3.63, 95% CI 1.17–11.28). Furthermore, patients who did not improve heart rate recovery from <12 beats/min to ≥12 beats/min after exercise training had higher mortality (HR=6.2; 95% CI, 1.3–29.2). These findings, wrote researchers, suggest that modulation of CV autonomic control with training may contribute to the long-term beneficial effects of a cardiac rehabilitation program. “Its clinical application as a therapeutic target for exercise prescription and medication titration needs to be further addressed in future studies,” they concluded. – By Brian Ellis This is an interesting study. What they are showing is that patients who have early abnormal heart rate recovery after exercise testing, which is associated with adverse outcomes, had improvement in this measure with exercise training. We know that exercise training provides benefits, and improvement in heart rate recovery may be one of the mechanisms that explains some of the benefits, at least in a subset that has abnormal heart rate recovery. __________________________________________________ _____________________ Nearly one-third of arrhythmias during repeat ablation procedures initiate in left atrial appendage DiBiase L. Circulation. 2010;122:109-118. By The left atrial appendage was responsible for the 27% of arrhythmias observed in patients with symptomatic AF presenting for repeat ablation procedures, results from a study suggested. Researchers screened 987 consecutive patients with symptomatic AF (29% with paroxysmal AF and 71% with nonparoxysmal AF) who underwent repeat ablation therapy and were resistant to drug therapy. Of those, 266 (27%) showed firings from the left atrial appendage and were designated as the study population. Patients were then divided into either those in whom left atrial appendage firing was not ablated (group 1, n=43), those in whom ablation was performed targeting a focal lesion (group 2, n=56) and those whose ablation was performed to achieve left atrial appendage isolation by placement of a circular catheter at the ostium of the appendage (group 3, n=167). The primary study endpoint was freedom from AF or atrial tachyarrhythmias (defined as no new episodes of AF or tachyarrhythmias without antiarrhythmic drugs lasting >32 seconds at follow-up). According to the results, 32 (74%) patients in group 1 had recurrence of AF vs. 38 (68%) patients in group 2 and 25 (15%) patients in group 3 (P<.001 for comparisons) at 12 ± 3 month follow-up. Following multivariate analysis and adjustment for confounders, it was determined that the type of AF at baseline (P=.043) and the left atrial appendage isolation strategy during redo (P=.014) were both strongly associated with AF recurrence. There were 4 (1.8%) pericardial effusions requiring pericardiocentesis, and all patients were discharged after a median hospital stay of 1 day. “This is the first study demonstrating the left atrial appendage as a potential trigger for AF, the prevalence of left atrial appendage firing in patients with recurrence of AF or atrial tachyarrhythmias after catheter ablation for AF, and the possibility that electric isolation of the left atrial appendage can improve success for the treatment of AF during the redo process,” the researchers wrote in the study. “The left atrial appendage appears to be responsible for recurrence of AF/tachycardia in at least 27% of patients presenting for repeat procedures. The clinical relevance of left atrial appendage isolation and its consequences with respect to potential complications requires further investigation.”
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#310
16.07.2010, 15:52
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Title: Treatments, Trends, and Outcomes of Acute Myocardial Infarction and Percutaneous Coronary Intervention
Date Posted: July 12, 2010 Authors: Roe MT, Messenger JC, Weintraub WS, et al. Citation: J Am Coll Cardiol 2010;56:254-263. Perspective: The following are 10 points to remember about this report from the National Cardiovascular Data Registry (NCDR). 1. Given the attendant risks of mortality and morbidity, acute myocardial infarction (AMI) remains a principal focus of cardiovascular therapeutics. 2. Percutaneous coronary intervention (PCI) remains a central therapy for patients with symptomatic coronary artery disease, particularly among patients with AMI. 3. The NCDR AR-G registry is a national, voluntary quality improvement registry program that is a partnership of the American College of Cardiology and American Heart Association, and includes data on the in-hospital treatment of patients with AMI, both ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). 4. The goal of this report was to evaluate contemporary clinical practice, as well as recent trends in treatments and outcomes, among AMI and PCI patients. 5. There were significant increases in the timeliness of AMI patient presentation after symptom onset, in the proportion of eligible STEMI patients receiving reperfusion therapy, and in the timeliness of reperfusion therapy for STEMI. 6. The use of early cardiac catheterization within 48 hours and the use of revascularization procedures increased in NSTEMI patients in the study cohort. 7. Furthermore, significant reductions in the rate of overdosing of antithrombotic agents were demonstrated among NSTEMI patients—a finding that highlights a new area of focus in the AMI performance measures. 8. Among patients in the registry, risk-adjusted in-hospital mortality rates decreased from 6.2% to 5.5% among STEMI patients, and decreased from 4.3% to 3.9% among NSTEMI patients during the study period. 9. There were declining rates of drug-eluting stent (DES) utilization in patients undergoing PCI for both acute coronary syndrome (ACS) and non-ACS from 2005 to 2009, but there has been a recent widespread incorporation of new DES technologies among patients receiving a DES in the CathPCI registry. 10. Overall, the report suggests that the contemporary profile of care patterns for patients with AMI and those undergoing PCI has changed over a relatively short time, while significant improvements in the receipt and timeliness of reperfusion therapy for STEMI, in the overdosing of antithrombotic therapies, in the safety and results of PCI procedures, and in composite measures of AMI care have occurred. Author(s): Debabrata Mukherjee, M.D., F.A.C.C.
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#311
16.07.2010, 15:56
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Trial Summary
BLOOM Title: Behavioral Modification and Lorcaserin for Overweight and Obesity Management Trial Sponsor: Arena Pharmaceuticals Year Published: 2010 Topic(s): General Cardiology, Prevention/Vascular Summary Posted: 07/14/2010 Writer: Dharam J. Kumbhani, M.D., S.M. Author Disclosure: NOTHING TO DISCLOSE Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C. Reviewer Disclosure: RESEARCH/RESEARCH GRANTS: The Medicines Company, Bristol Myers Squibb, Heartscape, Ethicon, Eisai, Astra Zeneca, Sanofi Aventis PLx Pharma, Takeda, Cogentus Description: Activation of 5-HT2C receptors (serotoninergic) has been shown to be associated with decreased food intake in basic science studies. An earlier phase II trial involving lorcaserin, a selective 5-HT2C receptor agonist, demonstrated dose-dependent weight loss with its use. BLOOM was a phase III trial designed to study the safety and efficacy of lorcaserin for weight management in obese patients. Hypothesis: Lorcaserin would be safe and effective for weight management, as compared with placebo, in obese patients. Drugs/Procedures Used: During the first year, patients were randomized to receive either lorcaserin 10 mg twice daily, or placebo. At the beginning of the second year, one-third of the patients in the lorcaserin arm crossed over to the placebo arm. Concomitant Medications: All patients underwent standardized nutritional and exercise counseling. All patients were advised to exercise moderately for 30 minutes daily, and to reduce daily caloric intake by 600 kcal below the individual World Health Organization estimate for daily requirements. Principal Findings: A total of 3,182 patients were randomized, 1,595 to lorcaserin and 1,587 to placebo. Baseline characteristics were fairly comparable between the two groups. The mean weight was about 100 kg, with a mean body mass index (BMI) of 36.2 kg/m2, and a mean waist circumference of 109.4 cm. Baseline mean laboratory values included low-density lipoprotein cholesterol of 113 mg/dl, fasting glucose of 94.2 mg/dl, glycated hemoglobin of 5.6, and a high-sensitivity C-reactive protein (hs-CRP) of 5.6 mg/L. Rates of completion of study medication at year 1 were low: 55.4% versus 45.1% in the lorcaserin and placebo arms, respectively. Only about 7% of these patients discontinued the study due to side effects. Lorcaserin was associated with a significant proportion of patients with ≥5% (47.5% vs. 20.3%, p < 0.001), and ≥10% (22.6% vs. 7.7%, p < 0.001) weight loss from baseline. The average weight loss was 5.8% versus 2.2% of baseline weight in the lorcaserin and placebo arms, respectively. Weight loss was noted as early as 4-8 weeks following drug initiation. Among patients with >5% weight loss from baseline, a greater proportion of patients in the lorcaserin arm who continued to receive the study medication maintained their weight loss, as compared with those who crossed over to the placebo arm (67.9% vs. 50.3%, p < 0.001). Other measures such as waist circumference (-6.8 cm vs. -3.9 cm, p < 0.001), BMI (-2.1 vs. -0.8, p < 0.001), systolic blood pressure (-1.4 mm Hg vs. -0.8 mm Hg, p = 0.04), diastolic blood pressure (-1.1 mm Hg vs. -0.6 mm Hg, p = 0.01), total cholesterol (-0.9% vs. 0.6%, p = 0.001), triglycerides (-6.2% vs. 0.1%, p < 0.001), fasting glucose (-0.8 mg/dl vs. 1.1 mg/dl, p < 0.001), and hs-CRP (-1.19 mg/L vs. -0.17 mg/L, p < 0.001) were significantly improved in the lorcaserin arm at the end of 1 year. Safety endpoints at 1 year were similar between the two arms, including pulmonary artery systolic pressure (-0.9 vs. -0.2 mm Hg, p = 0.14) and Beck Depression Inventory II (-1.1 vs. -0.9, p = 0.26), although heart rate was marginally lower in the lorcaserin arm (-2.0 vs. -1.6 bpm, p = 0.05). The incidence of adverse events, including serious adverse events, was similar between the two arms. The most frequent adverse events in the lorcaserin arm were headache, upper respiratory infection, nasopharyngitis, dizziness, and nausea. Serious side effects such as cardiac were infrequent. Food and Drug Administration (FDA)-defined valvulopathy at the end of the first and second years was similar between the two arms. Psychiatric events were very infrequent. Interpretation: The results of the BLOOM trial indicate that lorcaserin, a novel 5-HT2C receptor agonist, results in greater weight loss and an improvement in metabolic markers in obese patients, as compared with placebo, over 2 years of follow-up. Serious side effects are rare. Fenfluramine and dexfenfluramine, which were marketed for weight loss, were nonselective 5-HT2 receptor agonists, but gained notoriety due to an increased risk of serotonin-associated valvulopathy. Lorcaserin is a newer drug, with higher affinity for 5-HT2C receptors, whereas serotonin-associated valvulopathy is thought to occur via 5-HT2B receptor activation. Hence, it is unlikely to be associated with this side effect, which was confirmed in this trial. Limitations of this trial include the relatively short duration to assess for infrequent but serious side effects (such as psychiatric side effects), and the high rate of study drug discontinuation. Also, patients with diabetes or hypertension were excluded, which are significant coexisting conditions in obese patients. In addition, it should be noted that patients in this trial received intense nutritional and exercise counseling, which should be the cornerstone for weight management in obese patients. Lorcaserin has the potential to be an adjunct in obese patients in whom exercise and nutritional counseling alone has failed or is inadequate. Conditions: Prevention Therapies: Medical Study Design: Blinded. Crossover. Parallel. Placebo Controlled. Randomized. Primary Endpoints: Proportion of patients with ≥5% reduction in body weight from baseline at the end of year 1 Change in weight between baseline and year 1 Proportion of patients with ≥10% reduction in body weight from baseline at the end of year 1 Proportion of patients with ≥5% reduction in body weight from baseline at the end of year 1, and who maintained this at the end of year 2 Secondary Endpoints: Changes from baseline in lipids, glycemic variables, physical measures, inflammatory markers of cardiovascular risk, and quality of life Patient Population: Inclusion criteria: Age 18-65 years BMI 30-45 kg/m2 or 27-45 kg/m2 with at least one of the following: o Hypertension o Hyperlipidemia o Cardiovascular disease o Impaired glucose tolerance o Sleep apnea Total number of patients: 3,182 Duration of follow-up: 2 years Mean patient age: 44.1 years Percentage female: 83.5% Exclusions: Moderate or severe mitral regurgitation Mild or more severe aortic regurgitation Diabetes mellitus Systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg Depression needing treatment within the preceding 2 years Pregnancy or lactation References: Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363:245-56.
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#312
16.07.2010, 16:01
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Title: Prognostic Significance of Myocardial Fibrosis Quantification by Histopathology and Magnetic Resonance Imaging in Patients With Severe Aortic Valve Disease
Date Posted: July 12, 2010 Authors: Azevedo CF, Nigri M, Higuchi M, et al. Citation: J Am Coll Cardiol 2010;56:278-287. Study Question: Does myocardial fibrosis (MF) in patients with severe aortic valve (AV) disease, assessed by histopathology or contrast-enhanced magnetic resonance imaging (ce-MRI), predict outcomes following surgical AV replacement? Methods: Fifty-four patients (mean age 46.8 years, 78% male) with symptomatic severe aortic regurgitation (n = 26) or aortic stenosis (n = 28) were prospectively evaluated. All patients underwent preoperative quantitative assessment of MF by ce-MRI and had myocardial tissue samples obtained during surgery for histopathologic evaluation. Patients were grouped based on degree of MF and were compared to assess for differences in left ventricular (LV) functional improvement and survival postoperatively. Results: ce-MRI assessment of MF correlated well with histopathology (r = 0.69, p < 0.0001), and the degree of MF was higher in the study group than in normal controls. LV functional changes were evaluated in 25 patients who underwent follow-up MRI; LV mass was decreased and LV ejection fraction (EF) improved (EF 54 ± 10% pre-op vs. 59 ± 14% post-op, p = 0.02). LVEF improvement was inversely related to the degree of pre-op MF. Overall, those who died had more MF, and this increased burden of MF was associated with lower postoperative survival. Finally, on multivariate analysis, the amount of MF, along with advanced age, independently predicted all-cause mortality. Conclusions: In patients with severe AV disease, the amount of MF assessed by histopathology or ce-MRI is associated with LV function improvement and mortality. Perspective: This study suggests that in patients with severe AV disease, MF quantification may offer incremental information on LV functional recovery and survival in addition to traditional risk assessment (i.e., pre-op LV size and function, New York Heart Association functional class), and may therefore, influence timing of surgical intervention. Additionally, the data show that noninvasive ce-MRI correlates well with histopathologic evaluation of MF. However, as the authors note, the results of the multivariate analysis should be interpreted cautiously, as the small number of events can result in overestimating the significance of MF in predicting mortality. Although promising, larger studies utilizing this technology should be evaluated before routinely incorporating MF burden into clinical decision making in patients with severe AV disease. Author(s): Anna M. Booher, M.D. __________________________________________________ ____________________ Is a New Study on ARBs and Cancer Risk Cause for Alarm? [GUEST POST] by Jack Lewin July 13, 2010 08:50 This post comes to us from Jeffrey Anderson, M.D., F.A.C.C., chair-elect of the ACC/American Heart Association Task Force on Practice Guidelines and Vice Chair of the 2010 UA/NSTEMI Focused Update. Dr. Anderson also is the Associate Chief of Cardiology at Intermountain Medical Center in Murray, UT. Angiotensin-receptor blocker (ARB) agents drugs have shown substantial reductions in the risk of cardiovascular mortality, myocardial infarction and stroke in patients with hypertension and heart disease. However, a recent article in Lancet Oncology that looks at a pooled analysis of studies focused on the cardiovascular effects of ARBS, suggests these drugs may modestly increase the risk of a new cancer diagnosis. It should be noted that the absolute risk is small, the study is retrospective and exploratory, and that the question of class effect versus specific drug effect for the potential cancer risk is uncertain. The article, while not definitive, has generated a good deal of discussion within the cardiovascular community about how best to react in terms of both further study and in discussing with patients. As with any product used in the care of patients with cardiovascular disease, the ACC is a huge proponent of understanding both the product’s effectiveness and safety. In this particular case, the College is supportive of efforts to further clarify the association of ARBs and cancer and put the study’s potential findings into better perspective. For example, do the proven benefits of ARBs outweigh the risk of cancer? That being said, these new data should not warrant overreaction. In the interim, patients should not stop taking ARBs based upon these data, but should work with their care providers to determine the best medication regimen. (If you're looking for a good article to give your patients on the topic, see this CardioSmart article.) The study does not diminish the importance of treating hypertension or left ventricular systolic dysfunction with effective regiments prescribed by their physicians, which may include the use of ARBs. Current UA/NSTEMI and STEMI guidelines, as well as performance measures for heart failure at AMI, remain current in that they generally support ACE inhibitors as first-line therapy where appropriate. ARBs are recommended for patients who cannot tolerate ACE inhibitors.
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#313
21.07.2010, 13:22
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Myocardial fibrosis amount predictive of long-term survival after aortic valve replacement
Azevedo CF. J Am Coll Cardiol. 2010;56:278–287. Kramer CM. J Am Coll Cardiol. 2010;56:288–289. By Quantitative assessment of myocardial fibrosis was associated with the degree of left ventricular functional improvement, as well as all-cause mortality, study results suggested. Researchers from the Heart Institute, University of Sao Paulo Medical School, Brazil, examined 54 patients scheduled to undergo aortic valve replacement via contrast-enhanced MRI between 2001 and 2003. They used delayed enhancement for quantitative assessment of myocardial fibrosis and quantified interstitial myocardial fibrosis by histological analysis of myocardial samples gathered during CABG. There was a positive correlation between the amount of myocardial fibrosis measured by histopathology and by contrast-enhanced MRI (r=0.69, P<.001), whereas the amount of myocardial fibrosis had an inverse relationship with the degree of LV functional improvement after surgery (histopathology: r=–0.42, P=.04; contrast-enhanced MRI: r=–0.47, P=.02). Kaplan-Meier analyses indicated that higher degrees of myocardial fibrosis accumulation were linked with worse long-term survival. Independent predictors of all-cause mortality — as determined by multivariate Cox regression analyses — were patient age and the amount of myocardial fibrosis. “This is the first study to demonstrate that the amount of myocardial fibrosis, either by histopathology or by contrast-enhanced MRI, is also a predictor of long-term survival after aortic valve replacement,” the researchers wrote. “In the future, this marker of chronic myocardial injury, which can be noninvasively quantified by contrast-enhanced MRI, might have the potential to be useful in the difficult decision-making process regarding the best moment to indicate a valve replacement surgery in patients with severe aortic valve disease.” In an editorial accompanying the study, Christopher M. Kramer, MD, with the departments of medicine and radiology and the CV imaging center at the University of Virginia Health System in Charlottesville, said this study is an important demonstration of the role of myocardial fibrosis in aortic valve disease. “As the list of conditions associated with fibrosis that can be imaged by cardiac magnetic resonance grows, the imaging community must look toward ways of fine-tuning the imaging to delineate microscopic fibrosis,” Kramer wrote. “Once that is finalized, turning the identification of fibrosis into therapeutic advances is an essential next step.” __________________________________________________ __________________________________________________ _____ Comparable effectiveness observed between platinum chromium and stainless steel stents Kereiakes D. J Am Coll Cardiol. 2010;56:264-271. By A platinum chromium alloy stent proved to be equally efficacious and safe when compared with a stainless steel stent, according to results from the PERSEUS WH randomized controlled study. “The PERSEUS WH trial provides the necessary assurance of safety and relative efficacy of the novel platinum chromium Taxus Element paclitaxel-eluting stent (Boston Scientific) platform, demonstrating noninferiority to the Taxus Express paclitaxel-eluting stent (Boston Scientific) with respect to the incidence of target lesion failure at 12 months and the severity of residual angiographic stenosis at 9 months,” the researchers reported. They attained these results through the intent-to-treat analysis of 1,262 patients who were either treated with a stainless steel stent (Express; n=320) or a platinum chromium stent (Element; n=942). Patients had de novo coronary atherosclerotic lesions with a length ≤28 mm in reference vessels ≥2.75 m to ≤4 mm in diameter. The primary endpoint was the 12-month rate of target lesion failure, whereas the secondary endpoint was the 9-month angiographic in-segment percentage diameter stenosis. The platinum chromium stent was noninferior to the stainless steel stent in regards to the incidence of target lesion failure (platinum chromium, 5.57% vs. stainless steel, 6.14%) and diameter stenosis (platinum chromium, 3.09% vs. stainless steel, 3.12%). Researchers also reported no differences in clinical outcomes at 12 months between stent groups, as well as infrequent stent thrombosis (stainless steel, 0.3% vs. platinum chromium, 0.4%). “No safety concerns regarding either the novel metal alloy or modified stent design were observed,” the researchers said. “The PERSEUS WH trial demonstrates successful transfer of paclitaxel-eluting stent technology from stainless steel to a platinum chromium alloy platform.”
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#314
21.07.2010, 13:27
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Physician incompetency found under-reported by colleagues
DesRoches, CM. JAMA. 2010;304:187-193. By Peer monitoring and reporting of incompetent medical practice by physicians was found lacking in a new study published in the Journal of the American Medical Association. The study consisted of a nationally representative survey of 2,938 eligible physicians practicing anesthesiology, cardiology, family practice, general surgery, internal medicine, pediatrics and psychiatry in the United States in 2009. Overall, the physician response rate was 64.4% (n=1,891). Of the surveyed physicians, 64% agreed with the professional commitment to report physicians who are notably impaired or otherwise incompetent. Sixty-nine percent (n=1,208) of physicians reported being very or somewhat prepared to deal with impaired colleagues in their medical practice, and 64% (n=1126) reported being very or somewhat prepared to deal with incompetent colleagues. For the 17% (n=309) of physicians who had personal knowledge of an incompetent physician colleague, 67% (n=204) reported this colleague to the relevant authority. According to researchers, the most frequently cited reason for taking no action was the belief that someone else was taking care of the problem (19%), followed by the belief that nothing would happen as a result of the report (15%) and fear of retribution (12%). These findings, they wrote, “suggest that a large number of practicing physicians do not support the current process of self-regulation; it is underused and appears to have several major shortcomings, including a perceived lack of anonymity and efficacy. All health care professionals, from administrative leaders to those providing clinical care, must understand the urgency of preventing impaired or incompetent colleagues from injuring patients and the need to help these physicians confront and resolve their problems.” The results of this study were not a surprise to me. Physicians in general have been reluctant to police themselves—throughout their career they have been taught to be autonomous and not to rely on others. Because of this, they find it difficult to coach as well as to insure that others among their ranks are meeting all standards. Too often they feel "that is his or her problem and not mine" so I will remain quiet—someone else will probably take care of it. __________________________________________________ __________________________ DIAL: Telephone-based intervention improved outcomes in patients with HF Ferrante D. J Am Coll Cardiol. 2010;56:372–378. Konstam M. J Am Coll Cardiol. 2010;56:379-381. By Patients with HF whose physicians intervened over the telephone to assess major outcomes and compliance regarding lifestyle factors had a lower rate of death and hospitalization for HF vs. the non-intervention group, according to findings of the DIAL trial. The trial was a randomized, controlled, open-label, multicenter trial featuring 1,518 patients with HF. After the trial’s completion, researchers followed up with patients up to 3 years to determine major outcomes and evaluate three key compliance indicators — diet, weight control and treatment. The objective was to improve diet and treatment compliance, promote exercise, encourage early visits if signs of clinical deterioration were detected, and monitor symptoms, weight and edema. Researchers found that the rate of death and hospitalization was lower in the intervention group 1 year (37.2% vs. 42.6%; RR=0.81; 95% CI, 0.69-0.96) and 3 years (55.7% vs. 57.5%; RR= 0.88; 95% CI, 0.77-1.00) after the intervention ended. They concluded the main reason for this was because of the reduction in HF admission (after 3 years, 28.5% vs. 35.1%; RR=0.72; 95% CI, 0.60-0.87). Additionally, patients who showed improvement in one or more of the three compliance indicators had a lower risk of events. This led the researchers to conclude that the outcomes of patients with HF can improve with the implementation of simple and low-cost follow-up programs. “Patients who change their behavior early during the intervention are at lower risk of events. In the light of the available evidence, the implementation of these programs could become a standard of care for patients with HF,” they wrote. In an accompanying editorial, Marvin A. Konstam, MD, of Tufts Medical Center in Boston and Varda Konstam, PhD, of the University of Massachusetts in Boston, said the results point to the possibility of improving outcomes for the growing population with HF. “They challenge us to reconstruct our health care system into one that aligns providers to offer integrated, multidisciplinary, cost-effective programs — including empowerment of patients themselves — to generate a sustained improvement in health care outcomes,” they concluded.
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#315
21.07.2010, 18:58
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