American Heart Journal

Apixaban for Reduction In Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial: Design and rationale

2010-03-01

Atrial fibrillation (AF) is associated with increased risk of stroke that can be attenuated with vitamin K antagonists (VKAs). Vitamin K antagonist use is limited, in part, by the high incidence of complications when patients' international normalized ratios (INRs) deviate from the target range. The primary objective of ARISTOTLE is to determine if the factor Xa inhibitor, apixaban, is noninferior to warfarin at reducing the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism in patients with AF and at least 1 additional risk factor for stroke. We have randomized 18,206 patients from over 1,000 centers in 40 countries. Patients were randomly assigned in a 1:1 ratio to receive apixaban or warfarin using a double-blind, double-dummy design. International normalized ratios are monitored and warfarin (or placebo) is adjusted aiming for a target INR range of 2 to 3 using a blinded, encrypted point-of-care device. Minimum treatment is 12 months, and maximum expected exposure is 4 years. Time to accrual of at least 448 primary efficacy events will determine treatment duration. The key secondary objectives are to determine if apixaban is superior to warfarin for the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism, and for all-cause death. These will be tested after the primary objective using a closed test procedure. The noninferiority boundary is 1.38; apixaban will be declared noninferior if the 95% CI excludes the possibility that the primary outcome rate with apixaban is >1.38 times higher than with warfarin. ARISTOTLE will determine whether apixaban is noninferior or superior to warfarin in preventing stroke and systemic embolism; whether apixaban has particular benefits in the warfarin-naïve population; whether it reduces the combined rate of stroke, systemic embolism, and death; and whether it impacts bleeding.

Rivaroxaban—Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: Rationale and Design of the ROCKET AF study

The Executive Steering Committee, on behalf of the ROCKET AF Study Investigators — 2010-03-01

Background: Atrial fibrillation (AF), the most common significant cardiac arrhythmia, increases the risk of stroke, particularly in the elderly. Warfarin is effective in reducing stroke risk but is burdensome to patients and is difficult to control. Rivaroxaban is an oral direct factor Xa inhibitor in advanced development as an alternative to warfarin for the prevention and treatment of thromboembolic disorders.Methods: ROCKET AF is a randomized, double-blind, double-dummy, event-driven trial, which aims to establish the noninferiority of rivaroxaban compared with warfarin in patients with nonvalvular AF who have a history of stroke or at least 2 additional independent risk factors for future stroke. Patients are randomly assigned to receive rivaroxaban, 20 mg once daily (od), or dose-adjusted warfarin titrated to a target international normalized ratio (INR) of 2.5 (range 2.0-3.0, inclusive) using point-of-care INR devices to receive true or sham INR values, depending on the study drug allocation. The primary efficacy end point is a composite of all-cause stroke and noncentral nervous system systemic embolism. The primary safety end point is the composite of major and clinically relevant nonmajor bleeding events. Over 14,000 patients have been randomized at 1,100 sites across 45 countries, and will be followed until 405 primary outcome events are observed.Conclusion: The ROCKET AF study will determine the efficacy and safety of rivaroxaban as an alternative to warfarin for the prevention of thromboembolism in patients with AF.

Rationale and design of AVERROES: Apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment

2010-03-01

Background: Many patients with atrial fibrillation (AF) at moderate or high risk for stroke are not treated with a vitamin K antagonist (VKA). Presently, the only alternative to a VKA with a labeled indication for AF is antiplatelet therapy with acetylsalicylic acid (ASA), which is much less effective than a VKA for prevention of stroke. The novel oral factor Xa inhibitor, apixaban, is being developed for prevention of stroke in AF. A noninferiority trial of apixaban versus a VKA (warfarin) is being conducted but does not address the large unmet need of AF patients at risk of stroke who are unsuitable for or unwilling to take a VKA. Apixaban may be an attractive alternative to ASA for prevention of stroke in patients with AF who cannot or will not take a VKA.Design: AVERROES is a double-blind, double-dummy superiority trial of apixaban 5 mg twice daily (2.5 mg twice daily in selected patients) compared with ASA 81 to 324 mg once daily in patients with AF and at least 1 risk factor for stroke who have failed or are unsuitable for VKA therapy. The primary outcome is stroke or systemic embolism, and the primary safety outcome is major bleeding. The trial is event driven and is expected to enroll at least 5,600 patients.Conclusions: By evaluating the use of apixaban as a replacement for ASA in AF patients who are not treated with a VKA, the AVERROES study is addressing an important unmet clinical need. The results of AVERROES will be complementary to those of a parallel noninferiority trial comparing apixaban with VKA therapy in patients with AF who are able to receive a VKA.

Rationale and design of Enhanced Angiogenic Cell Therapy in Acute Myocardial Infarction (ENACT-AMI): The first randomized placebo-controlled trial of enhanced progenitor cell therapy for acute myocardial infarction

2010-03-01

Background: Despite the widespread use of pharmacological and/or interventional reperfusion therapies, recovery of cardiac function in myocardial infarction (MI) patients is often modest or even absent. Unlike classical pharmacological treatments, the use of progenitor cells could potentially restore functional tissue in regions that otherwise would form only scar. However, a major limitation of autologous cell therapy is the deleterious influence of age and cardiac risk factors on progenitor cell activity.Trial Design: The ENACT-AMI trial is a phase IIb, double-blind, randomized placebo-controlled trial, using transplantation of autologous early endothelial progenitor cells (EPCs) for patients who have suffered large MI. Circulating mononuclear cells (MNCs) are obtained by apheresis and subjected to differential culture for 3 days to select a population of highly regenerative, endothelial-like, culture modified MNCs (E-CMMs), often referred to as “early EPCs.” A total of 99 patients will be randomized to placebo (Plasma-Lyte A), autologous E-CMMs, or E-CMMs transfected with human endothelial nitric oxide synthase delivered by coronary injection into the infarct-related artery. The primary efficacy end point is change from baseline to 6 months in global left ventricular ejection fraction by cardiac MRI; secondary endpoints include regional wall motion, wall thickening, infarct volume, time to clinical worsening, and quality of life.Conclusions: This will be the first clinical trial to include a strategy designed to enhance the function of autologous progenitor cells by overexpressing endothelial nitric oxide synthase, and the first to use combination gene and cell therapy for the treatment of cardiac disease.

Rationale, design, and baseline data of the Japanese Primary Prevention Project (JPPP)—A randomized, open-label, controlled trial of aspirin versus no aspirin in patients with multiple risk factors for vascular events

2010-03-01

Background: Prevention of atherosclerotic disease has become an important public health priority in Japan due to the aging of the population and changes in diet and lifestyle factors.Methods: The Japanese Primary Prevention Project (JPPP) is a multicenter, open-label, randomized, parallel-group trial that is evaluating primary prevention with low-dose aspirin in Japanese patients aged 60 to 85 years with hypertension, dyslipidemia, or diabetes mellitus. The study cohort will be followed for a mean of 4 years. The primary end point is a composite of death from cardiovascular causes (including fatal myocardial infarction [MI], fatal stroke, and other cardiovascular death), nonfatal stroke (ischemic or hemorrhagic), and nonfatal MI. Key secondary end points include a composite of cardiovascular death, nonfatal stroke, nonfatal MI, transient ischemic attack, angina pectoris, or arteriosclerotic disease requiring surgery or intervention; each component of the primary end point; noncerebrovascular and noncardiovascular death; and extracranial hemorrhage requiring transfusion or hospitalization. End point assessment is done by a central adjudication committee that is blinded to treatment assignments.Results: Enrollment began in March 2005 and was completed in June 2007. A total of 14,466 patients were randomly allocated to receive enteric-coated aspirin, 100 mg/d, or no aspirin. At randomization, the study cohort had a mean (SD) age of 70.6 (6.2) years; 57.8% were women, 85.0% had hypertension, 71.7% had dyslipidemia, and 33.9% had diabetes. In the study cohort, 80.4% of patients had ≥3 risk factors.Conclusion: The JPPP is the largest primary prevention trial of aspirin in a Japanese population that is investigating whether the benefit of aspirin in reducing risk of vascular events outweighs any bleeding risk in elderly patients with multiple risk factors.

In-hospital management of patients with atrial flutter

Nancy M. Allen LaPointe, Jie-Lena Sun, Sigal Kaplan — 2010-03-01

Background: Little is known about the use of drugs or procedures for management of atrial flutter (AFl) in routine clinical practice. We describe the extent of use of conversion therapies during AFl hospitalizations.Methods: We examined hospitalizations for primary diagnoses of AFl using hospital claims from January 2000 to December 2004. Patients who received antiarrhythmic drugs, ablation, and/or electrical cardioversion for AFl were categorized as receiving a conversion therapy. Characteristics associated with use of conversion therapy versus no conversion therapy were determined.Results: The study cohort included 19,825 hospitalizations. Of these, 13,059 (65.9%) included in-hospital use of ≥1 conversion therapies. Care by a noncardiologist (adjusted odds ratio [OR] 0.37, 95% CI 0.33-0.41), female sex (adjusted OR 0.84, 95% CI 0.79-0.90), nonwhite race (adjusted OR 0.83, 95% CI 0.74-0.92), and increasing age >70 years (adjusted OR 0.88, 95% CI 0.85-0.91) were associated with lower odds of conversion versus no-conversion therapy. Cardiomyopathy (adjusted OR 1.33, 95% CI 1.17-1.51), heart failure (adjusted OR 1.17, 95% CI 1.06-1.28), coronary artery disease (adjusted OR 1.14, 95% CI 1.05-1.22), secondary diagnosis of atrial fibrillation (adjusted OR 1.28, 95% CI 1.18-1.38), and hospitalization in 2000 or 2001 versus later years (adjusted OR 1.22, 95% CI 1.12-1.33) were associated with greater odds of conversion therapy versus no conversion therapy.Conclusion: One or more methods of conversion to sinus rhythm were used in two thirds of the hospitalizations with a primary diagnosis of AFl. Greater use of conversion therapies in patients with other heart disease were expected; however, lower use among elderly persons, females, and racial minorities may indicate some disparities in use and warrant further study.

Evidence of disparity in the application of quality improvement efforts for the treatment of acute myocardial infarction: The American College of Cardiology's Guidelines Applied in Practice Initiative in Michigan

2010-03-01

Background: Racial disparities exist in the management of patients with cardiovascular disease in the United States. The aim of the study was to evaluate if a structured initiative for improving care of patients with acute myocardial infarction (Guidelines Applied in Practice [GAP]) led to comparable care of white and nonwhite patients admitted to GAP hospitals in Michigan.Methods: Medicare patients comprised 2 cohorts: (1) those admitted before GAP implementation (n = 1,368) and (2) those admitted after GAP implementation (n = 1,489). The main outcome measure was adherence to guideline-based medications/recommendations and use of the GAP discharge tool. χ2 and Fisher exact tests were used to determine differences between white patients (n = 2,367) and nonwhite patients (n = 490).Results: In-hospital GAP tool and aspirin use significantly improved for white and nonwhite patients. β-Blocker use in hospital improved significantly for nonwhite patients only (66% vs 83.3%; P = .04). At discharge, nonwhite patients were 28% and 64% less likely than white patients to have had the GAP discharge tool used (P = .004) and receive smoking cessation counseling (P < .001), respectively. Among white patients, GAP improved discharge prescription rates for aspirin by 10.8% (P < .001) and β-blockers by 7.0% (P = .047). Nonwhite patients' aspirin prescriptions increased by 1.0% and β-blocker prescriptions decreased by 6.0% (both P values nonsignificant).Conclusions: The GAP program led to significant increases in rates of evidence-based care in both white and nonwhite Medicare patients. However, nonwhite patients received less quality improvement discharge tool and smoking cessation counseling. Policies designed to reduce racial disparities in health care must address disparity in the delivery of quality improvement programs.

Variations in prevalent cardiovascular disease and future risk by metabolic syndrome classification in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study

Todd M. Brown, Jenifer H. Voeks, Vera Bittner, Monika M. Safford — 2010-03-01

Background: The International Diabetes Federation (IDF) and Adult Treatment Panel (ATP) III define metabolic syndrome (MetSyn) differently, with unclear implications for cardiovascular disease (CVD) risk.Methods: We examined 22,719 participants in the REGARDS study. We classified participants as: no MetSyn, MetSyn by ATP-III and IDF criteria, MetSyn by ATP-only, or MetSyn by IDF-only. To assess current CVD, we determined the odds of self-reported CVD by MetSyn category using multivariable logistic regression, controlling for socio-demographic and behavioral factors. To estimate future coronary heart disease risk, we calculated Framingham risk scores (FRS).Results: Overall, 10,785 individuals (47%) had MetSyn. Of these, 79% had MetSyn by both definitions, 6% by ATP-only, and 14% by IDF-only. Compared to those without MetSyn, ATP-only individuals had the highest odds of current CVD and of having a FRS >20%. Also compared to those without MetSyn, IDF-only individuals had 43% higher odds of current CVD and 2-fold increased odds of having a FRS >20%.Conclusions: Consistent with previous reports, ATP-III MetSyn criteria identified individuals with increased odds of CVD and elevated future coronary heart disease risk. However, the IDF definition identified a clinically important number of additional individuals at excess CVD risk.

Differences in mortality in acute coronary syndrome symptom clusters

2010-03-01

Background: The timely and accurate identification of symptoms of acute coronary syndrome (ACS) is a challenge for patients and clinicians. It is unknown whether response times and clinical outcomes differ with specific symptoms. We sought to identify which ACS symptoms are related—symptom clusters—and to determine if sample characteristics, response times, and outcomes differ among symptom cluster groups.Methods: In a multisite randomized clinical trial, 3522 patients with known cardiovascular disease were followed up for 2 years. During follow-up, 331 (11%) had a confirmed ACS event. In this group, 8 presenting symptoms were analyzed using cluster analysis. Differences in symptom cluster group characteristics, delay times, and outcomes were examined.Results: The sample was predominately male (67%), older (mean 67.8, S.D. 11.6 years), and white (90%). Four symptom clusters were identified: Classic ACS characterized by chest pain; Pain Symptoms (neck, throat, jaw, back, shoulder, arm pain); Stress Symptoms (shortness of breath, sweating, nausea, indigestion, dread, anxiety); and Diffuse Symptoms, with a low frequency of most symptoms. Those in the Diffuse Symptoms cluster tended to be older (P = .08) and the Pain Symptoms group was most likely to have a history of angina (P = .01). After adjusting for differences, the Diffuse Symptoms cluster demonstrated higher mortality at 2 years (17%) than the other 3 clusters (2%-5%, P < .001), although prehospital delay time did not differ significantly.Conclusion: Most ACS symptoms occur in groups or clusters. Uncharacteristic symptom patterns may delay diagnosis and treatment by clinicians even when patients seek care rapidly. Knowledge of common symptom patterns may facilitate rapid identification of ACS.

Cuff and aortic pressure differences during dobutamine infusion: A study of the effects of systolic blood pressure amplification

Harold Smulyan, Ratnakar Mukherjee, Paul R. Sheehe, Michel E. Safar — 2010-03-01

Background: Central aortic systolic blood pressures (SBPs) differ from and are preferable to cuff pressures when calculating cardiac work, left ventricular wall stress, and rate-pressure product. Despite the widespread use of dobutamine, differences between aortic and brachial SBP (pulse amplification) and pulse transmission during dobutamine infusion have not been previously studied. This study assessed these differences and used applanated radial pulses with the Sphygmocor (AtCor Medical, Sydney, Australia) device to investigate the effects of dobutamine on arterial pulse transmission and pulse amplification.Methods: Using a cuff oscillometer, brachial arterial pressures were measured simultaneously with directly recorded aortic pressures at rest and during increasing dobutamine infusion rates in 25 patients. In 15 of those patients, applanated radial pulses were fed into the Sphygmocor device and calibrated in 2 ways to predict aortic pressures.Results: At peak dobutamine infusion, SBP amplification averaged 14.9 mm Hg, with a maximum difference of 43 mm Hg. When radial artery pulses were calibrated using cuff pressures, the Sphygmocor underestimated the aortic SBP at all dobutamine doses. However, when radial artery pulses were calibrated using the more accurate aortic mean and diastolic BPs, the Sphygmocor accurately predicted the aortic SBP at baseline, but not at the higher dobutamine doses.Conclusions: Similar to exercise, dobutamine induced cuff SBPs and pulse pressures higher than those measured in the aorta—uncorrected by the cuff-calibrated Sphygmocor. This increasing pulse amplification was explained by the effects of dobutamine on the properties of the conduit arterial walls, on changes in pulse wave velocity, on increasing heart rate, and on reflected waves.

Relationships between emerging measures of heart failure processes of care and clinical outcomes

2010-03-01

Background: Previous studies have not confirmed associations between some current performance measures for inpatient heart failure processes of care and postdischarge outcomes. It is unknown if alternative measures are associated with outcomes.Methods: Using data for 20,441 Medicare beneficiaries in OPTIMIZE-HF from March 2003 through December 2004, which we linked to Medicare claims data, we examined associations between hospital-level processes of care and patient outcomes. Performance measures included any β-blocker for patients with left ventricular systolic dysfunction (LVSD); evidence-based β-blocker for patients with LVSD; warfarin for patients with atrial fibrillation; aldosterone antagonist for patients with LVSD; implantable cardioverter-defibrillator for patients with ejection fraction ≤35%; and referral to disease management. Outcome measures were unadjusted and adjusted associations of each process measure with 60-day and 1-year mortality and cardiovascular readmission at the hospital level.Results: Adjusted hazard ratios for 1-year mortality with a 10% increase in hospital- level adherence were 0.94 for any β-blocker (95% CI, 0.90-0.98; P = .004), 0.95 for evidence-based β-blocker (95% CI, 0.92-0.98; P = .004); 0.97 for warfarin (95% CI, 0.92-1.03; P = .33); 0.94 for aldosterone antagonists (95% CI, 0.91-0.98; P = .006); 0.92 for implantable cardioverter-defibrillator (95% CI, 0.87-0.98; P = .007); and 1.01 for referral to disease management (95% CI, 0.99-1.03; P = .21).Conclusions: Several evidence-based processes of care are associated with improved outcomes, can discriminate hospital-level quality of care, and could be considered as clinical performance measures.

Myocardial structure and function by echocardiography in relation to glucometabolic status in elderly subjects from 2 population-based cohorts: A cross-sectional study

2010-03-01

Background: Left ventricular (LV) diastolic dysfunction has been associated with impaired glucometabolic status. However, studies of older subjects are lacking. We examined associations between echocardiographic indices of LV diastolic function and LV mass index (LVMI) and glucometabolic status among middle-aged and elderly subjects free from heart disease, hypothesizing that the associations would be comparative to younger cohorts.Methods: We examined the Age Gene/Environment Susceptibility Reykjavik Study (Iceland; n = 607, 76 ± 6 years) and the Malmö Preventive Project Re-Examination Study (MPP-RES) cohorts (Sweden; n = 1,519, 67 ± 6 years), evaluating associations with multivariable regression analysis.Results: In the Age Gene/Environment Susceptibility Reykjavik Study, LVMI was positively correlated with glycosylated hemoglobin (HbA1c) (P = .001). Otherwise, echocardiographic variables were not associated with glucometabolic status. In the MPP-RES, LVMI increased with increasing glucometabolic disturbance among both older (70-80 years) and middle-aged (57-69 years) subjects. Among older subjects, HbA1c was positively correlated with 2 variables reflecting LV diastolic function: late transmitral peak flow velocity (A) (P = .001) and early transmitral peak flow velocity (E)/early diastolic peak tissue velocity (Em) (P = .046). In middle-aged MPP-RES subjects, increasing glucometabolic disturbance was correlated with increasing late diastolic peak tissue velocity (Am) (P = .002) and, after age adjustment, with increasing A (P = .001) and decreasing Em/Am (P = .009). With age adjustment, Am and A were positively correlated with fasting glucose and HbA1c.Conclusions: Contrary to our hypothesis, in 2 independent cohorts of older individuals, associations between glucometabolic status and LV diastolic function were generally weak. These contrast with previous reports, as well as with observations among middle-aged subjects in the present study. Changes in LV diastolic function may be more age-related than associated with glucose metabolism in older subjects.

Detection of elevated right atrial pressure using a simple bedside ultrasound measure

2010-03-01

Aims: Accurate assessment of right atrial pressure (RAP) often requires invasive measurement. With normal RAP, Valsalva increases right internal jugular vein (RIJV) cross sectional area (CSA) 20% to 30%. With high RAP, when venous compliance is low, we hypothesized that the increase in CSA would be blunted and could be detected non-invasively with bedside ultrasound.Methods and Results: RIJV ultrasound images were obtained in 67 patients undergoing right heart catheterization. The median RAP at end-expiration was 7 mm Hg (interquartile range [IQR] 5-9 mm Hg) in patients with normal RAP (n = 47) versus 15 mm Hg (IQR 12-22 mm Hg) in patients with elevated RAP (n = 20). With Valsalva, the median percent change in RIJV CSA was 35% (IQR 19%-79%) versus 5% (IQR 3%-14%) for normal and high RAP, respectively. By receiver operating curve analysis, a <17% increase in RIJV CSA with Valsalva predicted elevated RAP (≥12 mmHg) with 90% sensitivity, 74% specificity, 94% negative predictive value, and 60% positive predictive value (area under the curve 0.86, P < .001).Conclusions: An increase in RIJV CSA >17% during Valsalva effectively rules out elevated RAP. This simple bedside technique may be useful to assess central venous pressure and reduce the need for invasive pressure measurement.

Propranolol and the risk of hospitalized myopathy: Translating chemical genomics findings into population-level hypotheses

Soko Setoguchi, John M. Higgins, Helen Mogun, Vamsi K. Mootha, Jerry Avorn — 2010-03-01

Background: A recent large-scale, chemical screening study raised the hypothesis that propranolol may increase the risk of myopathy. We tested this hypothesis in a large population to assess whether (1) propranolol use is associated with an increased risk of myopathy and (2) the concurrent use of propranolol with a statin may further increase risk of myopathy.Methods: New users of propranolol and other β-blockers (BBs) aged ≥65 were identified using data from Medicare and drug benefit programs in 2 states (1994-2005). The primary end point studied was hospitalization for myopathy or rhabdomyolysis. We used stratified Cox proportional hazards regression to estimate the multivariate-adjusted effect of propranolol compared to other BBs and controlled for demographic variables, risk factors for myopathy, other comorbidities, and health service use measures. We also assessed whether co-use of propranolol and statin further increases the risk, by including an interaction term for use of propranolol and statins.Results: We identified 9,304 initiators of propranolol and 130,070 initiators of other BBs and found 30 cases of hospitalized myopathy in 15,477 person-years (PYs) of propranolol use and 523 in 343,132 PYs of other BB use. Comparing propranolol with other BB users, the adjusted hazard ratio was 1.45 (95% CI 1.00-2.11) for myopathy and 1.48 (95% CI 0.82-2.67) for rhabdomyolysis. We could not detect interaction between propranolol and statins due to limited power. Similar results were observed when propranolol users were compared to other antihypertensive drug users.Conclusions: Propranolol may be associated with a 45% increased risk of hospitalized myopathy in the elderly. Our study illustrates how results from in vitro chemical screens can be translated into hypotheses about drug toxicity at the population level.

Clinical relevance of clopidogrel unresponsiveness during elective coronary stenting: Experience with the point-of-care Platelet Function Assay–100 C/ADP

2010-03-01

Background: Early identification of nonresponders to clopidogrel may be important in identifying subgroups of patients that might be at risk for future thrombotic events.Methods: We prospectively assessed postclopidogrel platelet reactivity in 250 consecutive patients scheduled for elective percutaneous coronary intervention (PCI). All patients received dual antiplatelet therapy with 160 mg aspirin and a 300 mg loading dose of clopidogrel >12 hours before PCI. A platelet aggregation test was performed at the time of the intervention using a point-of-care assay, the Platelet Function Assay (PFA-100C/ADP; Dade-Behring, Deerfield, IL). Nonresponders were defined as having a PFA closure time of <71 seconds under dual oral antiplatelet therapy, reflecting normal platelet reactivity. Myonecrosis post-PCI constituted the primary end point and was defined as the release of creatine kinase–MB >1× the upper limit of normal on a sample taken 12 to 24 hours after intervention. The secondary end point was a composite end point of major adverse cardiac events including death, myocardial infarction, and stent thrombosis after 6 months.Results: The PFA closure time was available in 242 patients and ranged from 31 to 300 seconds with a mean value of 147 seconds. Nonresponders represented 7% (17/242) of the cases. Myonecrosis post-PCI occurred in 29 patients (12%) and was more common in nonresponders than in normal responders (29% vs 11%, respectively; P = .03 on multivariate analysis). Major adverse cardiac events at 6 months occurred in 13 patients (1 sudden death possibly related to stent thrombosis and 12 post-PCI myocardial infarctions) and were more common in the nonresponder group (12% vs 5%, respectively; P = .06 on multivariate analysis).Conclusions: Unresponsiveness to clopidogrel as assessed by the point-of-care test PFA-100C/ADP is an independent major risk factor for thrombotic complications after coronary intervention.

Mechanisms of nonfatal acute myocardial infarction late after stent implantation: The relative impact of disease progression, stent restenosis, and stent thrombosis

2010-03-01

Background: The impact of stent restenosis, stent thrombosis, or progression of disease at another site as responsible mechanisms of acute myocardial infarction (AMI) after stent implantation is not clear.Methods: By searching our catheterization laboratory database for a 4-year period, 91 cases of nonfatal AMI at least 1 month after stent implantation (32.6% drug-eluting stents) were identified. By detailed comparison of post-AMI with the initial percutaneous coronary intervention angiogram, the mechanism of AMI was analyzed.Results: Acute myocardial infarction was attributed to disease progression at another site in 42 (46.2%), stent restenosis in 35 (38.4%), and stent thrombosis in 10 (11%) cases. The AMI mechanism could be either stent related or disease progression (nonidentifiable culprit lesion) in 4 cases (4.4%). The median time from percutaneous coronary intervention to AMI was 27, 19, and 9 months for disease progression at another site, restenosis, and stent thrombosis group, respectively (P = .03). ST-elevation myocardial infarction occurred in 38.1% of the disease progression, in 20% of the restenosis, and in 60% of the stent thrombosis cases (P = .046).Conclusions: In a “real world” population, late after stent implantation, a patient has an almost equal probability to have suffered a nonfatal AMI from either stent restenosis/thrombosis or disease progression at another site. Continuous research efforts are necessary to equally address both stent therapy and disease progression.

Does “late catch-up” exist in drug-eluting stents: Insights from a serial quantitative coronary angiography analysis of sirolimus versus paclitaxel-eluting stents

2010-03-01

Background: Recent studies have suggested the possibility of late catch-up after drug-eluting stent implantation. There are limited data on whether late catch-up exists in sirolimus-eluting stents (SESs) and paclitaxel-eluting stents (PESs).Methods: Consecutive patients were routinely recommended 2 serial angiographic follow-ups (at 6-9 and 18-24 months post–percutaneous coronary intervention). A serial quantitative coronary angiographic analysis was performed in lesions not receiving target lesion revascularization at first follow-up. Early luminal loss (LL) was defined as the difference in minimal luminal diameter between the first angiographic follow-up and immediate post–percutaneous coronary intervention, and delayed LL was defined as the difference in minimal luminal diameter between the second and first angiographic follow-up.Results: Four hundred twelve lesions in the main cohort (PES 128, SES 284) and 47 lesions in the secondary hybrid cohort (PES 23, SES 24), which received serial angiographic follow-ups without target lesion revascularization, were included. In the main cohort, early LL was higher in PES compared with SES (0.56 vs 0.20 mm, P < .01), whereas delayed LL occurring after the first angiographic follow-up was higher in SES (0.10 vs 0.28 mm, P < .01), suggesting more prominent late catch-up in SES. Early LL showed better correlation with total LL (correlation coefficient 0.82 vs 0.30) in PES, whereas delayed LL showed better correlation with total LL (correlation coefficient 0.42 vs 0.91) in SES. Such observations were reproducible in the hybrid cohort, where both SES and PES were implanted at index procedure.Conclusion: Late catch-up occurs in both PES and SES with greater delayed late loss in SES. Our data suggest that the process of neointima formation after SES and PES implantation may follow a slightly different timeline.

Long-term outcome of percutaneous catheter intervention for de novo coronary bifurcation lesions with drug-eluting stents or bare-metal stents

2010-03-01

Background: The purpose of this study was to assess the long-term risks and benefits of drug-eluting stents (DESs) compared with bare-metal stents (BMSs) for treatment of coronary bifurcation lesions.Methods: Our registry comprised 1,038 patients treated for coronary bifurcation lesion according to the provisional T-stenting strategy who were followed up for 3 years.Results: Target lesion revascularization rates were 24.3% for BMSs (n = 337), 15.6% for sirolimus-eluting stents (SESs, n = 422), and 17.3% for paclitaxel-eluting stents (PESs, n = 279) (P = .003 BMSs vs DESs, P = .54 SESs vs PESs). The respective incidences were 11.4%, 9.5%, and 14.8% (P = .65, P = .13) for death and myocardial infarction and 9.9%, 6.5%, and 10.6% (P = .72, P = .19) for death. Propensity score adjusted hazard ratios (95% CI) for DESs versus BMSs were 0.49 (0.35-0.68, P < .001) for target lesion revascularization, 0.94 (0.64-1.40, P = .078) for death and myocardial infarction, and 0.85 (0.55-1.32, P = .47) for death. We did not find any significant differences between SESs and PESs, except for an increased risk of death after PESs compared with SESs (but not BMSs) in the subgroup receiving a side-branch stent (adjusted hazard ratio 2.45, 95% CI 1.05-5.73, P = .035).Conclusions: Compared with BMSs, both PESs and SESs substantially reduced the long-term need for repeated revascularization but did not increase the risk of death and myocardial infarction.

Clopidogrel use and clinical events after drug-eluting stent implantation: Findings from the HealthCore Integrated Research Database

2010-03-01

Background: Relationships between long-term use and level of dual antiplatelet therapy and outcomes after drug-eluting stent implantation are not well established.Methods: This is a retrospective cohort study of 9,256 patients receiving drug-eluting stents between January 2003 and August 2006. We classified patients according to tertiles of clopidogrel use during the 12 months after stent implantation. We used inverse probability weighting to account for differential selection into levels of clopidogrel use and logistic regression to estimate propensity scores for levels of clopidogrel use. We used Cox proportional hazards models to estimate effects of level of clopidogrel use on risk of bleeding events, death, and death or nonfatal myocardial infarction.Results: There were 3,102 patients in the high-use group, 3,069 in the medium-use group, and 3,085 in the low-use group. Compared with the high-use group, risk of death or nonfatal myocardial infarction was greater in the medium-use group (hazard ratio [HR] 1.46, 95% CI 1.09-1.99, P = .01) and the low-use group (HR 1.59, 95% CI 1.18-2.14, P = .002). The risk of bleeding events was lower in the medium-use group (HR 0.84, 95% CI 0.71-0.98, P = .03) and the low-use group (HR 0.77, 95% CI 0.65-0.90, P = .002).Conclusions: Higher clopidogrel use 12 months after drug-eluting stent implantation was associated with a greater risk of subsequent bleeding events. Lower use was associated with a greater risk of death or nonfatal myocardial infarction.

Health-related quality of life and long-term mortality in patients treated with percutaneous coronary intervention

2010-03-01

Background: Health status has become increasingly important as an outcome measure in patients with cardiovascular disease. Poor patient-rated health status has been shown to predict mortality in patients with coronary artery disease and heart failure. In patients treated with percutaneous coronary intervention (PCI), we examined whether poor health status predicts 6-year mortality and whether a decline in health status is associated with adverse clinical outcome.Methods: Consecutive patients (N = 872) treated with PCI as part of the RESEARCH registry, completed the 36-item Short-Form Health Survey (SF-36) at 1 and 12 months post-PCI.Results: The SF-36 domains physical functioning (hazard ratio [HR] 2.59, 95% CI 1.61-4.16), social functioning (HR 2.76, 95% CI 1.74-4.37), role limitations due to physical functioning (HR 2.45, CI 1.52-3.92), mental health (HR 2.12, 95% CI 1.35-3.31), vitality (HR 1.73, 95% CI 1.09-2.74), bodily pain (HR 2.25, 95% CI 1.43-3.54), and general health (HR 2.46, 95% CI 1.57-3.87) were associated with 6-year mortality. A decline in health status was not related with higher 6-year mortality.Conclusions: Health status domains as measured with the SF-36 predicted death at 6-year follow-up in PCI patients treated with drug-eluting stenting, independent of demographic and clinical characteristics. In contrast, a decline in health status between 1 and 12 months post index procedure, as measured with the SF-36, was not associated with 6-year mortality in PCI patients treated with drug-eluting stenting.

Trends in echocardiography utilization in the Veterans Administration Healthcare System

Kingston Okrah, Mary Vaughan-Sarrazin, Peter Cram — 2010-03-01

Background: There is growing concern over the impact of accelerating use of diagnostic imaging services on health care spending. Echocardiography is an important cardiovascular imaging procedure, but little is known about trends in its use or utilization. We examine trends in the utilization of echocardiography in a national health care system.Methods: We used administrative data from the Veterans Healthcare Administration (VA) from 2000 to 2007 to identify patients receiving regular medical care (VA users) or echocardiograms at the VA. We then examined the number of echocardiograms performed each year within the VA and echocardiogram utilization (rates per 1,000 VA users). We examined changes in echocardiogram use and utilization over time and potential overuse of echocardiography.Results: The number of echocardiograms increased from 92,269 in 2000 to 195,767 in 2007 (a 112.2% increase). Alternatively, echocardiogram utilization remained relatively stable, increasing from 68.8 per 1,000 VA users in 2000 to 71.5 per 1,000 VA users in 2007 because the number of VA users increased by 104.2% over the study period. The mean number of scans per year in echocardiogram recipients remained constant at 1.1/y, and the proportion of recipients receiving multiple scans remained constant at <10%.Conclusions: Use of echocardiography in the VA increased dramatically between 2000 and 2007, but utilization rates increased only modestly. Our results suggest that, within the VA, growth in the use of echocardiography resulted from an increase in the number of patients receiving care from the VA on regular basis rather than the performance of a greater number of echocardiograms on a fixed patient population.

Temporal trends in compliance with appropriateness criteria for stress single-photon emission computed tomography sestamibi studies in an academic medical center

Raymond J. Gibbons, J. Wells Askew, David Hodge, Todd D. Miller — 2010-03-01

Background: The purpose of this study was to apply published appropriateness criteria for single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in a single academic medical center to determine if the percentage of inappropriate studies was changing over time. In a previous study, we applied the American College of Cardiology Foundation/American Society of Nuclear Cardiology (ASNC) appropriateness criteria for stress SPECT MPI and reported that 14% of stress SPECT studies were performed for inappropriate reasons.Methods: Using similar methodology, we retrospectively examined 284 patients who underwent stress SPECT MPI in October 2006 and compared the findings to the previous cohort of 284 patients who underwent stress SPECT MPI in May 2005.Results: The indications for testing in the 2 cohorts were very similar. The overall level of agreement in characterizing categories of appropriateness between 2 experienced cardiovascular nurse abstractors was good (κ = 0.68), which represented an improvement from our previous study (κ = 0.56). There was a significant change between May 2005 and October 2006 in the overall classification of categories for appropriateness (P = .024 by χ2 statistic). There were modest, but insignificant, increases in the number of patients who were unclassified (15% in the current study vs 11% previously), appropriate (66% vs 64%), and uncertain (12% vs 11%). Only 7% of the studies in the current study were inappropriate, which represented a significant (P = .004) decrease from the 14% reported in the 2005 cohort.Conclusions: In the absence of any specific intervention, there was a significant change in the overall classification of SPECT appropriateness in an academic medical center over 17 months. The only significant difference in individual categories was a decrease in inappropriate studies. Additional measurements over time will be required to determine if this trend is sustainable or generalizable.

Timing of nonemergent coronary artery bypass grafting and mortality after non-ST elevation acute coronary syndrome

2010-03-01

Background: The purpose of this study was to determine the association between time to coronary artery bypass grafting (CABG) and mortality among patients admitted with non-ST elevation acute coronary syndrome (NSTEACS). Patients are increasingly being referred for CABG soon after NSTEACS, although few data exist to guide the optimal timing of bypass surgery.Methods: We identified a cohort of all patients who underwent nonemergent CABG within 60 days of hospitalization for NSTEACS in the province of Alberta, Canada, from 2000 to 2004. Time from admission to CABG was categorized as early (2-7 days), intermediate (8-14 days), or late (15-60 days—reference group). The primary outcome was mortality occurring within 30 days of surgery.Results: Of the total cohort of 1,454 patients, 213 (14.6%) underwent early, 637 (43.8%) underwent intermediate, and 707 (48.6%) underwent late CABG surgery. In the final adjusted model time to CABG was not statistically significant as an independent predictor of short-term mortality. Compared to late CABG, there was a nonsignificant increased risk of mortality for those undergoing early (hazard ratio 2.36, 95% CI 0.72-7.76) and intermediate (hazard ratio 1.68, 95% CI 0.76-3.72) CABG surgery.Conclusions: Time from admission to CABG was not associated with an increased risk of short-term mortality. However, there was a trend toward increased mortality with early CABG, and this study does not exclude the presence of a modest risk association between timing of CABG and short-term mortality.

Factors associated with cardiac conduction disorders and permanent pacemaker implantation after percutaneous aortic valve implantation with the CoreValve prosthesis

2010-03-01

Background: Cardiac conduction disorders and requirement for permanent pacemaker implantation (PPI) are not uncommon after surgical aortic valve replacement and have important clinical implications. We aimed to investigate the incidence of cardiac conduction disorders after percutaneous aortic valve implantation (PAVI) and to identify possible clinical factors associated with their development.Methods: We studied 34 patients (mean age 80 ± 8 years, 18 male) who underwent PAVI with the CoreValve bioprosthesis (Corevalve Inc, Irvine, CA). Electrocardiographic evaluation was performed pre- and postprocedurally, and at 1-week and 1-month follow-up. Other clinical variables were obtained from the medical history, echocardiography, and angiography.Results: After PAVI, 7 patients required PPI, all of whom developed total atrioventricular block within 3 days postprocedurally. A smaller left ventricular outflow tract diameter (20.3 ± 0.5 vs 21.6 ± 1.8 cm, P = .01), more left-sided heart axis (−20° ± 29° vs 19° ± 36°, P = .02), more mitral annular calcification (10 ± 1 vs 5 ± 4 mm, P = .008), and a smaller postimplantation indexed effective orifice area (0.86 ± 0.20 vs 1.10 ± 0.26 cm2/m2, P = .04) were associated with PPI. The incidence of new left bundle-branch block (LBBB) was 65% and was associated with a deeper implantation of the prosthesis: 10.2 ± 2.3 mm in the new-LBBB group versus 7.7 ± 3.1 mm in the non-LBBB group (P = .02).Conclusions: Percutaneous aortic valve implantation with the CoreValve prosthesis results in a high incidence of total atrioventricular block requiring PPI and new-onset LBBB. Preexisting disturbance of cardiac conduction, a narrow left ventricular outflow tract, and the severity of mitral annular calcification predict the need for permanent pacing, whereas the only factor shown to be predictive for new-onset LBBB is the depth of prosthesis implantation.

Effect of interval (V-V) optimization in ischemic versus nonischemic patients after cardiac resynchronization therapy

Fu Yi, Jin Yu, Bing Liu — 2010-03-01

It is with great interest that we read the article published in the November 2009 issue of the Journal by Marsan et al. We applaud the authors for the report of acute effect of interventricular pacing interval (V-V) optimization on left ventricular (LV) systolic performance, and dyssynchrony in ischemic versus nonischemic patients received cardiac resynchronization therapy (CRT). The limitations of the work were elucidated by the authors. However, we have some questions about the paper.

Reply to the Letter to the Editor by Yi et al

Nina Ajmone Marsan, Jeroen J. Bax — 2010-03-01

We thank Yi et al for the interest in our study and for the questions raised, which help to stimulate the discussion and to conceive further studies. Regarding their doubt about potential differences in response to cardiac resynchronization therapy (CRT) between ischemic and nonischemic patients despite interventricular pacing interval (V-V) optimization, we strongly believe that the effect of CRT may be influenced by the underlying myocardial disease. The cited study of Molhoek et al was a preliminary report on 74 patients that could not demonstrate significant differences in outcome between ischemic and nonischemic patients. However, data from clinical trials suggested that at mid- and long-term follow-up after CRT, the improvement in left ventricular (LV) size and function is significantly larger in non-ischemic patients as compared to ischemic patients. In a recent study, we also demonstrated that acutely after CRT the reduction of LV end-systolic volume is significantly greater in nonischemic as compared to ischemic patients. With the current study we suggested that V-V optimization might compensate for the conduction abnormalities due to the presence of scar tissue and lead to a more favorable response to CRT at short-term follow-up. In our opinion, these findings are of great pathophysiologic and clinical interest, but larger studies are needed to confirm these results.

Brain natriuretic peptide for cardiovascular events independent of left ventricular end-diastolic pressure

Viroj Wiwanitkit — 2010-03-01

I read the recent publication by Rogers et al with great interest. Rogers et al assessed the prognostic value of brain natriuretic peptide (BNP) for cardiovascular events independent of left ventricular end-diastolic pressure (LVEDP) and reached the conclusion that plasma BNP level was not a is not just a prognostic surrogate for elevated LV filling pressure. Indeed, the clinical value of plasma BNP relating to LV function is still a topic to be studied. Recently, Oyamada et al reported that plasma BNP value did not have a significant association with the LVEDP. Oyamada et al showed that tissue Doppler imaging combined with pulsed-wave Doppler echocardiography has a better clinical usefulness. Indeed, the BNP has no underlying biological process relating to LVEDP. Nevertheless, the use of BNP has its limitation in laboratory concern due to the problem of false positive that can be the result of both preanalytical and analytical interferences in the laboratory process.

Author response: B-type natriuretic peptide for cardiovascular events independent of left ventricular end-diastolic pressure

Kevin Rogers — 2010-03-01

Thank you for your interest in our study. We agree that the clinical application of B-type natriuretic peptide (BNP) as a prognostic marker is still evolving. We do believe that the body of evidence supports a relationship between BNP and left ventricular end-diastolic pressure in adults with left ventricular dysfunction. The lack of such a relationship in the study by Oyamada et al may instead be related to their unique study population of infants with ventricular septal defects. The issue of false positives as a limitation to BNP testing is acknowledged but may be more germane to the use of BNP as a diagnostic, rather than a prognostic, marker and reinforces that the strength of BNP as a diagnostic test is its high negative predictive value. Nonetheless, implementation of BNP into clinical practice as a prognostic marker will be facilitated by better understanding and adjustment for clinical covariates that affect BNP levels.

Low vitamin D may explain the link between preeclampsia and cardiovascular disease

William B. Grant — 2010-03-01

The recent review and meta-analysis of cardiovascular sequelae of preeclampsia found large increases in risk of cardiovascular diseases for those who suffered preeclampsia and an increased risk with increasing severity of preeclampsia. Preeclampsia is also associated with increased risk of cancer. I would like to suggest that the link is low serum 25-hydroxyvitamin D (25[OH]D), which has been reported as a risk factor for preeclampsia as well as for cardiovascular disease. Serum 25(OH)D levels are associated with important cardiovascular disease risk factors in US adults. Low serum 25(OH)D is also an important risk factor for many types of cancer. It has been suggested that pregnant and nursing women should be taking 4,000 to 6,000 IU/d of vitamin D. For optimal health in general, serum 25(OH)D levels should be >32 ng/mL (80 nmol/L). One thousand international units per day raises serum 25(OH)D by about 10 ng/mL.

“High-intensity interval training may reduce in-stent restenosis following percutaneous coronary intervention with stent implantation: A randomized controlled trial evaluating the relationship to endothelial function and inflammation.” Am Heart J 2009;158:734-41

2010-03-01

The paper of Munk et al adds potential reduction of in-stent restenosis to the list of the multiple benefits of high-intensity aerobic interval training (HIIT) in a broad spectrum of patients with cardiovascular disease, which have been extensively studied by several Norwegian groups.

2010-03-01

Editorial Board

2010-03-01

Information for Readers

2010-03-01

American Heart Journal

Apixaban for Reduction In Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial: Design and rationale

Rivaroxaban—Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: Rationale and Design of the ROCKET AF study

Rationale and design of AVERROES: Apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment

Rationale and design of Enhanced Angiogenic Cell Therapy in Acute Myocardial Infarction (ENACT-AMI): The first randomized placebo-controlled trial of enhanced progenitor cell therapy for acute myocardial infarction

Rationale, design, and baseline data of the Japanese Primary Prevention Project (JPPP)—A randomized, open-label, controlled trial of aspirin versus no aspirin in patients with multiple risk factors for vascular events

In-hospital management of patients with atrial flutter

Evidence of disparity in the application of quality improvement efforts for the treatment of acute myocardial infarction: The American College of Cardiology's Guidelines Applied in Practice Initiative in Michigan

Variations in prevalent cardiovascular disease and future risk by metabolic syndrome classification in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study

Differences in mortality in acute coronary syndrome symptom clusters

Cuff and aortic pressure differences during dobutamine infusion: A study of the effects of systolic blood pressure amplification

Relationships between emerging measures of heart failure processes of care and clinical outcomes

Myocardial structure and function by echocardiography in relation to glucometabolic status in elderly subjects from 2 population-based cohorts: A cross-sectional study

Detection of elevated right atrial pressure using a simple bedside ultrasound measure

Propranolol and the risk of hospitalized myopathy: Translating chemical genomics findings into population-level hypotheses

Clinical relevance of clopidogrel unresponsiveness during elective coronary stenting: Experience with the point-of-care Platelet Function Assay–100 C/ADP

Mechanisms of nonfatal acute myocardial infarction late after stent implantation: The relative impact of disease progression, stent restenosis, and stent thrombosis

Does “late catch-up” exist in drug-eluting stents: Insights from a serial quantitative coronary angiography analysis of sirolimus versus paclitaxel-eluting stents

Long-term outcome of percutaneous catheter intervention for de novo coronary bifurcation lesions with drug-eluting stents or bare-metal stents

Clopidogrel use and clinical events after drug-eluting stent implantation: Findings from the HealthCore Integrated Research Database

Health-related quality of life and long-term mortality in patients treated with percutaneous coronary intervention

Trends in echocardiography utilization in the Veterans Administration Healthcare System

Temporal trends in compliance with appropriateness criteria for stress single-photon emission computed tomography sestamibi studies in an academic medical center

Timing of nonemergent coronary artery bypass grafting and mortality after non-ST elevation acute coronary syndrome

Factors associated with cardiac conduction disorders and permanent pacemaker implantation after percutaneous aortic valve implantation with the CoreValve prosthesis

Effect of interval (V-V) optimization in ischemic versus nonischemic patients after cardiac resynchronization therapy

Reply to the Letter to the Editor by Yi et al

Brain natriuretic peptide for cardiovascular events independent of left ventricular end-diastolic pressure

Author response: B-type natriuretic peptide for cardiovascular events independent of left ventricular end-diastolic pressure

Low vitamin D may explain the link between preeclampsia and cardiovascular disease

“High-intensity interval training may reduce in-stent restenosis following percutaneous coronary intervention with stent implantation: A randomized controlled trial evaluating the relationship to endothelial function and inflammation.” Am Heart J 2009;158:734-41

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