Craig M. Pratt

The Coronary Artery Calcium Score and Stress Myocardial Perfusion Imaging Provide Independent and Complementary Prediction of Cardiac Risk

OBJECTIVESnThis study sought to examine the relationship between coronary artery calcium score (CACS) and single-photon emission computed tomography (SPECT) results for predicting the short- and long-term risk of cardiac events.nnnBACKGROUNDnThe CACS and SPECT results both provide important prognostic information. It is unclear whether integrating these tests will better predict patient outcome.nnnMETHODSnWe followed-up 1,126 generally asymptomatic subjects without previous cardiovascular disease who had a CACS and stress SPECT scan performed within a close time period (median 56 days). The median follow-up was 6.9 years. End points analyzed were total cardiac events and all-cause death/myocardial infarction (MI).nnnRESULTSnAn abnormal SPECT result increased with increasing CACS from <1% (CACS < or =10) to 29% (CACS >400) (p < 0.001). Total cardiac events and death/MI also increased with increasing CACS and abnormal SPECT results (p < 0.001). In subjects with a normal SPECT result, CACS added incremental prognostic information, with a 3.55-fold relative increase for any cardiac event (2.75-fold for death/MI) when the CACS was severe (>400) versus minimal (< or =10). Separation of the survival curves occurred at 3 years after initial testing for all cardiac events and at 5 years for death/MI.nnnCONCLUSIONSnThe CACS and SPECT findings are independent and complementary predictors of short- and long-term cardiac events. Despite a normal SPECT result, a severe CACS identifies subjects at high long-term cardiac risk. After a normal SPECT result, our findings support performing a CACS in patients who are at intermediate or high clinical risk for coronary artery disease to better define those who will have a high long-term risk for adverse cardiac events.

Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial

BACKGROUNDnEvidence suggests that inflammatory mediators contribute to development and progression of chronic heart failure. We therefore tested the hypothesis that immunomodulation might counteract this pathophysiological mechanism in patients.nnnMETHODSnWe did a double-blind, placebo-controlled study of a device-based non-specific immunomodulation therapy (IMT) in patients with New York Heart Association (NYHA) functional class II-IV chronic heart failure, left ventricular (LV) systolic dysfunction, and hospitalisation for heart failure or intravenous drug therapy in an outpatient setting within the past 12 months. Patients were randomly assigned to receive IMT (n=1213) or placebo (n=1213) by intragluteal injection on days 1, 2, 14, and every 28 days thereafter. Primary endpoint was the composite of time to death from any cause or first hospitalisation for cardiovascular reasons. The study continued until 828 primary endpoint events had accrued and all study patients had been treated for at least 22 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00111969.nnnFINDINGSnDuring a mean follow-up of 10.2 months, there were 399 primary events in the IMT group and 429 in the placebo group (hazard ratio 0.92; 95% CI 0.80-1.05; p=0.22). In two prespecified subgroups of patients--those with no history of previous myocardial infarction (n=919) and those with NYHA II heart failure (n=689)--IMT was associated with a 26% (0.74; 0.57-0.95; p=0.02) and a 39% (0.61; 95% CI 0.46-0.80; p=0.0003) reduction in the risk of primary endpoint events, respectively.nnnINTERPRETATIONnNon-specific immunomodulation may have a role as a potential treatment for a large segment of the heart failure population, which includes patients without a history of myocardial infarction (irrespective of their functional NYHA class) and patients within NYHA class II.

Coronary Artery Calcium Scoring in the Emergency Department: Identifying Which Patients With Chest Pain Can Be Safely Discharged Home

STUDY OBJECTIVEnCoronary artery calcium scoring (CACS) is a simple and readily available test for identifying coronary artery disease. Our objective is to evaluate whether a CACS of zero will identify chest pain patients who can be safely discharged home, without need for further cardiac testing.nnnMETHODSnThis was a prospective observational cohort study conducted at an urban tertiary care hospital of stable patients presenting to the emergency department (ED) with chest pain of uncertain cardiac cause. Patients with a normal initial troponin level, nonischemic ECG, and no history of coronary artery disease had stress myocardial perfusion imaging (SPECT) and CACS within 24 hours of ED admission. Cardiac events were defined as an acute coronary syndrome during the index hospitalization or in follow-up. CACS results were assessed in relation to SPECT findings and cardiac events.nnnRESULTSnThe 1,031 patients enrolled (mean [SD] age 54 [13] years) had a median CACS of 0 (61% with CACS of 0). The frequency of an abnormal SPECT ranged from 0.8% (CACS of 0) to17% (CACS>400). Cardiac events occurred in 32 patients (3.1%) during the index hospitalization (N=28) or after hospital discharge (N=4) (mean 7.4 [3.3] months). Only 2 events occurred in 625 patients with a CACS of 0 (0.3%; 95% confidence interval 0.04% to 1.1%). Thus, 2 of 32 patients with a cardiac event had a CACS of 0 (6%; 95% confidence interval 0.8% to 21%). Both of these patients developed increased troponin levels during their index visit but had normal serial ECG and SPECT study results and no cardiac events at 6-month follow-up.nnnCONCLUSIONnA majority of patients (61% in our sample) evaluated for chest pain of uncertain cardiac cause have a CACS of 0, which predicts both a normal SPECT result and an excellent short-term outcome. Our results suggest that patients with a CACS of 0 can be discharged home, without further cardiac testing.

Value of CACS Compared With ETT and Myocardial Perfusion Imaging for Predicting Long-Term Cardiac Outcome in Asymptomatic and Symptomatic Patients at Low Risk for Coronary Disease: Clinical Implications in a Multimodality Imaging World

OBJECTIVESnThis prospective, observational study in 988 asymptomatic or symptomatic low-risk patients without prior coronary artery disease was conducted to define the relative value of coronary artery calcium score (CACS), exercise treadmill testing (ETT), and stress myocardial perfusion single-photon emission computed tomography (SPECT) variables in predicting long-term risk stratification.nnnBACKGROUNDnCACS, ETT, and stress myocardial perfusion SPECT results predict patients outcome. There are currently no data comparing their relative value in long-term risk stratification.nnnMETHODSnPatients were stratified by Framingham risk score (FRS), with a median follow-up of 6.9 years. Cardiac events were defined as a composite of cardiac death, nonfatal myocardial infarction, and the need for coronary revascularization. Most patients (87%) were considered appropriate candidates for functional testing as defined by current appropriate use criteria.nnnRESULTSnThe long-term cardiac event rate was 11.2% (1.6% per year). Multivariate risk predictors in all patients and in the appropriate use cohort were abnormal SPECT (hazard ratio [HR]: 1.83 and 1.99), ETT ischemia (HR:xa01.70 and 1.76), decreasing exercise capacity (HR: 1.11 and 1.17), decreasing Duke treadmill score (HR: 1.07 for both), and CACS severity (HR: 1.29 for both), respectively. Throughout the 10-year follow-up, CACS improved risk prediction, with event rates ranging from 0.6% per year (CACSxa0≤10) to 3.7% per year (CACS >400) (pxa0< 0.0001). CACS also improved risk prediction in all patients, in the appropriate use cohort and among those with low-risk ETT and SPECT results (all, pxa0< 0.001). Area under the receiver-operating characteristic curve was increased when CACS variables (from 0.63 to 0.70; pxa0= 0.01) but not ETTxa0variables (from 0.63 to 0.65) were added to FRS. Moreover, net reclassification improvement was significantly increased when CACS was added to FRSxa0+ functional variables in all patients and in the appropriate use cohort (both, pxa0<xa00.0001).nnnCONCLUSIONSnCACS significantly improved long-term risk stratification beyond FRS, ETT, and SPECT results across the spectrum of clinical risk and importantly even among those who are currently considered appropriate candidates for functional testing or have low-risk functional test results. Our findings support CACS as a first-line test over ETT or SPECT for accurately assessing long-term risk in such patients.

Can Antiarrhythmic Drugs Survive Survival Trials

Sudden cardiac death due to arrhythmic events is the major cause of mortality among early post-myocardial infarction (MI) patients, accounting for > 250,000 deaths annually in the United States alone. Antiarrhythmic drugs can be used in such patients as well as in those who have not had a recent MI but are at high risk for sudden cardiac death (e.g., those with ventricular tachycardia/fibrillation, or who have survived cardiac arrest). Most antiarrhythmic drugs available, however, have limitations arising from their toxic and proarrhythmic potential. Thus, research and development of new agents and treatment modalities are desirable. This article seeks to enumerate the lessons of past clinical trials with these agents and to provide guidelines for future trials. That a variety of antiarrhythmic drugs have been associated with an increased mortality has been a disturbing observation. It is therefore imperative that candidates for antiarrhythmic therapy be selected appropriately. We recommend that future clinical trials use stringent criteria for the identification of patients at high risk for arrhythmia or sudden cardiac death, and limit recruitment to such patients. Traditional markers, such as the increased frequency and complexity of ventricular premature beats, and low left ventricular ejection fraction, have not been successful in identifying these high-risk patients. However, decreased heart rate variability and cardiac late potentials recorded on a signal-over-aged electrocardiogram appear to be more specific markers of post-MI arrhythmia or sudden cardiac death and may, in conjunction with the traditional markers, be used to improve selection of trial populations. Since the risk of sudden cardiac death diminishes with time after MI, it is also recommended that the temporal window of treatment with antiarrhythmic agents be limited to 1 year post-MI. It is also important to define clearly the endpoints of efficacy evaluations. A short-term reduction on markers like ventricular ectopic beats, for example, does not translate into a long-term decrease in arrhythmia-related mortality. Therefore, a reduction in overall mortality is the only meaningful endpoint to define the true risk-benefit ratio. To limit exposure to the potentially adverse effects of these agents, target populations for prophylactic antiarrhythmic drugs should be limited to recent post-MI patients at high risk for sudden cardiac death due to arrhythmia. Avoiding exposure of low-risk patients to antiarrhythmic drugs is equally imperative. Low risk of all-cause mortality includes the group of post-MI patients with a left ventricular ejection fraction >36%. Risk must be continuously evaluated in the setting of other pharmacologic (angiotensin-converting enzyme [ACE] inhibitors, aspirin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors [statins], and others) and/or nonpharmacologic interventions (coronary artery bypass graft, angioplasty, implantable cardioverter/defibrillator). There is also a need to improve noninvasive techniques for identifying patients in the high-risk category-at present, the presence of ventricular premature beats and a left ventricular ejection fraction <36% is considered somewhat predictive of sudden cardiac death. Thus, patients with a recent MI and moderately low left ventricular ejection fraction (< or = 36% but not <20%) may be considered for antiarrhythmic therapy. A subset analysis of patients with low heart rate variability can provide valuable additional information. It is important to note that although all-cause mortality is a valid endpoint for such trials, stratification by specific cause of mortality is desirable.

A study to assess the effects of a broad-spectrum immune modulatory therapy on mortality and morbidity in patients with chronic heart failure: The ACCLAIM trial rationale and design

BACKGROUNDnEvidence has accumulated regarding the importance of inflammatory mediators in the development and progression of heart failure (HF). Although targeted anticytokine treatment strategies, specifically antitumour necrosis factor-alpha, have yielded disappointing results, this may simply reflect the redundancy of the cytokine cascade and the fact that antitumour necrosis factor-alpha therapies do not stimulate increased activity of the anti-inflammatory arm of the immune system. Ex vivo exposure of autologous blood to controlled oxidative stress and subsequent intramuscular administration is a device-based procedure shown in experimental studies to have a broad-spectrum effect on a number of immune mediators. These studies have demonstrated that this approach downregulates inflammatory cytokines, whereas several anti-inflammatory cytokines are increased. In a feasibility study of 73 patients with moderate to severe HF, active therapy (versus placebo) had a significant benefit on both mortality and hospitalization, and was not associated with adverse hemodynamic or metabolic effects.nnnMETHODSnThe Advanced Chronic heart failure CLinical Assessment of Immune Modulation therapy (ACCLAIM) trial is a multicentre, randomized, double-blind, placebo-controlled clinical trial of New York Heart Association functional class II to IV chronic HF patients with left ventricular ejection fraction of 30% or less. Enrolling approximately 2400 subjects at 177 sites, the primary end point of the study was the cumulative incidence (time to first event) of the combined end point of total mortality or hospitalization for cardiovascular causes. The study was completed in late 2005, when 701 primary end point events had occurred and all patients had been treated for six months.nnnCONCLUSIONSnIf the ACCLAIM trial confirms earlier results, this approach represents a novel nonpharmacological treatment for HF that targets a pathogenic mechanism contributing to progression of this syndrome not addressed by current therapies.

Case report: Severe hypercalcemia mimicking ST-segment elevation myocardial infarction.

The identification of ST-segment elevation on the electrocardiogram is an integral part of decision making in patients who present with suspected ischemia. Unfortunately, ST-segment elevation is nonspecific and may be caused by noncardiac causes such as electrolyte abnormalities. We present a case of ST-segment elevation secondary to hypercalcemia in a patient with metastatic cancer.

New strategies in cardiovascular disease management: Summary of round table discussion

From the University Hospital, European Center of Pharmaceutical Medicine, Basel, Switzerland, the *Cardiovascular Division, University of Minnesota Medical School, Minneapolis, Minnesota, USA, the †Oregon Regional Primate Research Center, Oregon Health Sciences University, Beaverton, Oregon, USA, the Centre for Cardiovascular Preventive Medicine, Broussais Hospital, Paris, France, the §Department of Clinical Pharmacology, Georgetown University Medical Center, Washington, DC, USA, the International Clinical Research Department, Roche Laboratories, Nutley, New Jersey, USA, and the **Department of Medicine and Cardiology, Baylor College of Medicine, The Methodist Hospital, Houston, Texas, USA.

IN-HOSPITAL USE OF POTENTIALLY HARMFUL DRUGS IN HEART FAILURE: IMPACT ON LENGTH OF STAY AND MORTALITY

To evaluate prevalence of in-hospital use of potentially harmful drugs (PHD) in heart failure (HF) patients and analyze their impact on length of stay and in-hospital mortality.nnThe University HealthSystem Consortium Database was queried for admissions with the primary diagnosis of HF during 2011-

New agents to prevent strokes in nonvalvular atrial fibrillation.

Anticoagulation for atrial fibrillation has been dependant on warfarin for the past 30 years. However, the recent FDA approvals of dabigatran and rivaroxaban and the expected approval for apixaban have provided several new alternatives for our patients. Many factors must be considered when selecting the most appropriate agent for preventing stroke in nonvalvular atrial fibrillation. The following trials have provided the foundation for decision making when considering alternatives to warfarin therapy.