John E. Strobeck

Effects of Vesnarinone on Morbidity and Mortality in Patients with Heart Failure

BACKGROUND Inotropic therapy, other than with digitalis glycosides, has had limited success in patients with chronic congestive heart failure. We investigated whether vesnarinone, a new positive inotropic agent, reduces morbidity and mortality and improves the quality of life of patients with symptomatic heart failure. METHODS Patients receiving concomitant therapy with digoxin (87 percent) and an angiotensin-converting-enzyme inhibitor (90 percent) who had ejection fractions of 30 percent or less were randomly assigned to receive double-blinded therapy with 60 mg of vesnarinone per day, 120 mg of vesnarinone per day, or placebo. Afer 253 patients had been enrolled, randomization to the 120-mg vesnarinone group had to be stopped because of a significant increase in early mortality in this group. Thereafter, patients were randomly assigned only to 60 mg of vesnarinone per day (a total of 239 patients) or placebo (a total of 238 patients). RESULTS Significantly fewer patients in the group receiving 60 mg of vesnarinone than in the group receiving placebo (26 vs. 50 patients; P = 0.003) died or had worsening heart failure during the six-month study period. The reduction in risk was 50 percent (95 percent confidence interval, 20 to 69 percent). Similarly, there was a 62 percent reduction (95 percent confidence interval, 28 to 80 percent) in the risk of dying from any cause among the patients receiving vesnarinone. Furthermore, quality of life improved to a greater extent in the vesnarinone group than in the placebo group over 12 weeks (P = 0.008). The principal side effect associated with vesnarinone was reversible neutropenia, which occurred in 2.5 percent of the patients. CONCLUSIONS Six months of therapy with 60 mg of vesnarinone per day resulted in lower morbidity and mortality and improved the quality of life of patients with congestive heart failure. However, a higher dose of vesnarinone (120 mg per day) increased mortality, suggesting that this drug has a narrow therapeutic range; the long-term effects of vesnarinone are unknown.

Current concepts in cardiology. Derived indexes of ventricular and myocardial function.

Ventricular dysfunction generally results from a combination of abnormal loading and depression or loss of myocardium. Thus, in the presence of reduced ventricular performance, it is necessary to d...

The STICH trial unravelled

The STICH trial was designed to compare coronary bypass (CABG) alone vs. CABG plus surgical ventricular reconstruction (SVR) in patients with left ventricular (LV) dysfunction and akinetic or dyskinetic LV segments from prior anterior wall myocardial infarction (MI). It reported that adding SVR to coronary bypass CABG was not associated with a greater improvement in symptoms, exercise tolerance, or reduced intermediate mortality. This trial was federally funded to provide evidence-based methodology for this comparison, but its implementation was faulty in many ways. Surgical ventricular reconstruction treats congestive heart failure (CHF) by reducing LV volume, perhaps the most powerful predictor of mortality in dilated cardiomyopathy and more predictive than ejection fraction (EF) –4 (Figures 1 and 2). The 490 patients who underwent SVR in STICH was predicated on favourable reports of recovery in over 5000 patients worldwide and registry data from approximately 1200 patients that decreased LV endsystolic volume index (LVESVI) 40% (ranging 30–58%, Table 1), –8 but had different results. Is SVR an improper concept or was the STICH trial improperly executed? Eligibility for STICH required that ‘all patients will be evaluated further for appropriateness of SVR indicated by evidence of absent viability in the anterior ventricle by nuclear scan determination, LVESVI ≥60 ml/m, and akinesia ≥35% of the anterior wall’ (http://clinicaltrials.gov/archine/NTC00023595/2005_06_23). Echocardiography was specifically excluded for measuring LV volume because of its inaccuracy when regional asynergy is present. Selection of STICH centres was based on capability to measure volume by cardiac magnetic resonance (CMR) imaging (Excerpt 1). However, STICH enrolled a quite different group of patients, namely those with NYHA Class II– IV CHF (within 3 months of entry), coronary artery disease that was amenable to CABG, an EF ≤35% [defined by echocardiogram, left ventriculogram, CMR, or gated single photon (SPECT) studies], and ‘dominant anterior left ventricular dysfunction’. Accurate viability and LV volume were not done in all patients as planned. STICH required that all patients have dyskinesia or akinesia with evidence of non-viability in 35% of the anterior ventricular wall (Excerpt 2). Dyskinesia is caused by no reperfusion of the LV after infarction. Akinesia accompanies early thrombolysis or angioplasty and results in a dilated but thick LV. STICH, however, reports that only half of patients had akinesia or dyskinesia and 13% had no prior history of infarction. Surgical ventricular reconstruction has never been reported or recommended in patients with regional dysfunction alone and absent scar. The STICH surgical therapy committee specifically defined SVR as ‘any ventricular reconstruction method that consistently results in a low operative mortality, an average EF increase of ≥10%, and an average LVESVI decrease of ≥30% as assessed on the four-month post-operative CMR measurement’ (Excerpt 3). STICH, however, measured LVESVI in only 212 of 490 patients (43%) in the CABG-only group and in 161 of 490 patients (33%) in the CABG plus SVR group by echocardiography. The number of CMR measurements is not given. STICH reported that SVR lowered LVESVI an average of only 19%. Patients should be excluded from the analysis if the originally defined goals were not met. Patients in the SVR trial underwent SVR based on qualitative rather than quantitative assessment. Perhaps they had hibernation of ischaemic areas or post-infarction stunning, both of which are clearly not indications for SVR. Surgeons cannot know when SVR should be performed without accurate viability and volume information. The STICH patients cannot be compared with previously reported patients with SVR. Dor’s 1000 patients and the 1198 patients in the RESTORE group had prior history of MI, akinesia, or dyskinesia involving ≥35% of the LV, reduced EF, and LVESVI ≥60 mL/m. Furthermore, only 49% of patients in STICH had NYHA class III or IV CHF vs. .66% in the RESTORE registry. STICH trial original protocol deviations can be viewed in ‘history of changes’ on: http://clinicaltrials.gov/show/NCT00023595. Why was accurate LVESVI by CMR or nuclear study retracted? The principal investigator may change the protocol, but only with approval from the NIH grant administration officer. Though it does not require approval from other trial participants, the grant administrator must assume the responsibility for investigational review board (IRB) notification of changes for all trial participants. The STICH publication does not report changes during the trial.

Benefit and Safety of Enhanced External Counterpulsation in Treating Coronary Artery Disease Patients with a History of Congestive Heart Failure

Enhanced external counterpulsation (EECP) is used to noninvasively treat refractory angina patients, including those with a history of heart failure. The International EECP Patient Registry was used to examine the benefit and safety of EECP treatment, including a 6-month follow-up, in 1,957 patients, 548 with a history of heart failure. The heart failure cohort was older, with more females, a greater duration of coronary artery disease, more prior infarcts and revascularizations. Significantly fewer heart failure patients completed the course of EECP, and exacerbation of heart failure was more frequent, though overall major adverse cardiac events (MACE, i.e. death, myocardial infarction, revascularization) during treatment were not significantly different. The angina class improved in 68%, with comparable quality of life benefit, in the heart failure cohort. At 6 months, patients with congestive heart failure maintained their reduction in angina but were significantly more likely to have experienced a MACE end point.

OPC-8212 in the treatment of congestive heart failure: Results of a pilot study

SummaryTo characterize the effects of OPC-8212, a quinolone inotropic agent, in patients with heart failure, we utilized invesive homodynamics, exercise testing, 24-hour ambulatory electrocardiograms, and two patient self-assessment questionnaires, before and after 1 month of treatment with OPC-8212, in 17 patients with moderate to severe congestive heart failure. There were no significant changes from baseline in heart rate (83±8 beats/min), mean arterial pressure (70±15 mmHg), pulmonary wedge pressure (18±7 mmHg), or cardiac index (2.3±0.4 L/min/m2) following treatment with OPC-8212. Both exercise duration (5.3±1.6 min) and peak oxygen consumption (12.0±2.9 mL/kg/min) were unchanged by OPC-8212. Two independent patient self-assessment scores, the Sickness Impact Profile and the Minnesota Living with Heart Failure Questionnaire, showed improvements from 6.8 to 5.4 and 49 to 38, respectively (both p<.05), suggesting that the patients reported an improvement in daily functioning. The median ventricular premature contraction count and frequency were reduced from 1,118 beats to 243 beats (p<0.05) and 11/1,000 beats to 2,4/1,000 beats (0.05<p<0.10), respectively. Two patients developed agranulocytosis during longer-term treatment following this 1-month study. These data demonstrate that OPC-8212 did not have significant effects on hemodynamics or exercise tolerance. However, the improvement in patient self-assessment scores and the trend for improvement in ventricular arrhythmia profiles suggest that OPC-8212 may have some benefit for patients with congestive heart failure, but additional placebo-controlled, double-blind studies are necessary.

Surgical ventricular reconstruction.

To the Editor: Jones et al. (April 23 issue)1 discount the possibility that the selection of patients was a factor in the negative outcome of the Surgical Treatment for Ischemic Heart Failure (STICH) trial (ClinicalTrials.gov number, NCT00023595). Their argument, however, would be much strengthened by providing information on the clinical profile and number of patients who were eligible for the trial but were not enrolled. Such information is sorely needed to determine the generalizability of the findings of a trial in which the yearly recruitment averaged only three patients per site.

Stroke Prevention in Atrial Fibrillation: Managing the Risks in Light of New Oral Anticoagulants

Anticoagulation in patients with atrial fibrillation is essential to reduce morbidity and mortality associated with stroke, but at the same time the risk of bleeding needs to be carefully considered. There have been many recent developments in anticoagulation to improve medical management of these patients. CHA2DS2-VASc and HAS-BLED are two new algorithms that clinicians may use prior to initiating anticoagulation to estimate the risk of stroke and bleeding in patients with atrial fibrillation. In addition, new classes of oral anticoagulants such as direct thrombin inhibitors and selective Factor Xa inhibitors have emerged and consist of agents that aim to address many of the practical management challenges of warfarin. In this review of the literature, results of the clinical trials involving these new agents will be discussed and compared, with a focus on the balance between efficacy and safety.

Reversibility of diabetic cardiomyopathy with insulin in rats

Diabetes appears to cause a cardiomyopathy independent of atherosclerotic coronary artery disease and hypertension. Left ventricular papillary muscle function studies in rats made severely diabetic with streptozotocin have shown a slowing of relaxation and a depression of shortening velocity. However, the effects of insulin therapy on the myocardial mechanics of diabetic rats have not been studied. Therefore, rats diabetic for 6–10 weeks were treated with PZI insulin for 2, ft, 10, or 28 days and the mechanical performance of their left ventricular papillary muscles was compared to that of untreated diabetics and age-matched controls; cardiac contractile protein enzymatic activity was also measured. Neither 2 nor 6 days of therapy had any effects on the depressed cardiac muscle performance of diabetic animals, although plasma glucose concentration was restored to normal. By 10 days of therapy, recovery of mechanical performance was nearly complete, and by 28 days of therapy, complete reversal of the altered myocardial mechanics was observed. Crystalline insulin added to the bath (9 mU/ml) had no effect on myocardial mechanics in either diabetics or controls. A gradual recovery of actomyosin and myosin ATPase activity In the hearts of insulin-treated diabetic aoinials was also found, complementing the mechanical studies. In addition to demonstrating a gradual but complete reversibility of the abnormalities in papillary muscle function in diabetic rats (although control of hyperglycemia was less than ideal), this study confirms that this model of a cardiomyopathy is not a result of streptozotocin-induced cardiac toxicity. Additional data are provided indicating that depressed thyroid hormone levels in diabetic rats are not responsible for the mechanical changes observed.

Happy New Decade, CHF: Withstanding the Test of Time

We measure the passage of time in many ways. The coming of a new year carries fond (and not so fond, perhaps) memories of the year past and hope and ambition for the year ahead. When 10 of these years pass, there is an exponential increase in the abundance of milestones and accomplishments over that substantial period commonly called a decade. And so, with Congestive Heart Failure we mark our time and consequently our progress now in decades. The journal originated by John Strobeck, MD, PhD, in 1994, commenced publication to reflect the growing need for effective communication of heart failure knowledge to a provider group much larger than heart failure specialist physicians alone. The journal’s mission was and continues to be aptly stated in its subtitle: “Serving Specialists and Primary Care Clinicians Treating Heart Failure—Modalities, Concepts, Management.” A decade later, the journal is true to its roots. Upon reflection, Congestive Heart Failure has made astonishing strides toward disseminating pertinent clinical information to the ever-expanding heart failure community that has enhanced our collective abilities to diagnose and treat all modalities of heart failure. We are most pleased to see that this past decade has been one of incredible learning for all who are involved in the care of patients with heart failure or those who are at risk for developing heart failure. The Editors and the Editorial Board are in agreement that a multidisciplinary approach works best and that the “heart failure team” is broad and inclusive. Looking back at the issues of the past decade is nostalgic and rewarding. We are grateful for those who have contributed the guest edited issues, original papers, reviews, case reports, and difficult cases—we have learned from them all. We have re-read the amazing four-part “Masters of Heart Failure Series” of “nuggets, pearls, and vignettes of master heart failure clinicians” collected from our peers by Carl Leier, MD, in 2002. We know that many physicians make these available to each group of residents and fellows as they rotate through so that they may sort out which experiences and techniques of the masters work for them today and in the decades ahead. There have been many more editorial successes in Congestive Heart Failure, and here are just a few of the incredible guest-edited issues that highlight its offerings: • July/August 2003: Mandeep R. Mehra, MD; Patricia A. Uber, PharmD, Guest Editors: Diverse Populations, New Techniques: Non-Surgical Advances in Heart Failure 2003. • September/October 2002: Barry H. Greenberg, MD; Denise D. Herman, MD, Guest Editors: Neurohormonal Blockade in the Treatment of Heart Failure: Where Do We Go From Here? • May/June 2002: A. Maziar Zafari, MD, PhD; David G. Harrison, MD, Guest Editors: Free Radicals in Heart Failure: Therapeutic Targets for Old and New Drugs. • January/February 2002: Karl T. Weber, MD, Guest Editor: Congestive Heart Failure: A House Divided. The guest-edited issues continue with this issue as Clyde W. Yancy, MD, presents papers from distinguished authors on heart failure in African Americans. Later this year, Congestive Heart Failure will be publishing a cutting-edge guest-edited issue compiled by William T. Abraham, MD, on pharmacogenetics that deals primarily with polymorphisms. Congestive Heart Failure is much more than a repository replete with medical content, it provides a gathering place for the community to take sophisticated science and research and distill it for clinicians to enable them to take better care of their patients. As we flipped back through the Editorial Boards, authors, and columnists of the past decade, we noted that many of the original members of the team are still on board. While we grieved colleagues who have passed away, we warmly reflected on the wisdom they imparted on our pages for others to appreciate and use. The success of Congestive Heart Failure is entirely due to the active participation and concerted efforts of its contributors and Editorial Board; without these individuals, a journal is nothing but its covers. The fact that Congestive Heart Failure has withstood a decade of turmoil in www.lejacq.com ID:3234