Shelly L. Sayre

Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.

CONTEXT Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00824005.

Effect of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells 2 to 3 Weeks Following Acute Myocardial Infarction on Left Ventricular Function The LateTIME Randomized Trial

CONTEXT Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation. OBJECTIVE To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI. DESIGN, SETTING, AND PATIENTS A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction [LVEF] ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011. INTERVENTIONS Intracoronary infusion of 150 × 10(6) autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing. MAIN OUTCOME MEASURES Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size. RESULTS A total of 87 patients were randomized (mean [SD] age, 57 [11] years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, -3.00; 95% CI, -7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, -0.70; 95% CI, -2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, -2.60; 95% CI, -6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline. CONCLUSION Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00684060.

Determining predictors of attrition in an outpatient substance abuse program

Determining pre-treatment variables that predict attrition in an outpatient cocaine abuse program is critically important in efforts to enhance retention and ultimately improve client outcome. Potential predictors have been identified, such as treatment history, deviant behaviors, and level of drug use; however there is not widespread agreement on their applicability across treatments and populations. This study examines the relationship of demographic, drug use severity, and psychosocial factors with treatment attrition and the time of dropout. One hundred and sixty-five individuals from the Houston area, seeking treatment for cocaine dependence, completed a pre-treatment assessment battery prior to starting 12 weeks of outpatient treatment. A series of regression analyses showed that treatment dropouts were more likely to be separated from their spouses, have poorer family/social functioning, have fewer years of education, and to be female. Those participants with higher education levels and those with poorer psychiatric functioning tended to remain in treatment longer. The implications of these findings are discussed.

Rationale and design for TIME: A phase II, randomized, double-blind, placebo-controlled pilot trial evaluating the safety and effect of timing of administration of bone marrow mononuclear cells after acute myocardial infarction.

Several previous studies have demonstrated that administration of autologous bone marrow-derived mononuclear cells (BMMNCs) improves cardiac function in patients after acute myocardial infarction (AMI). However, optimum timing of administration has not been investigated in a clinical trial. The Cardiovascular Cell Therapy Research Network was developed and funded by the National Heart, Lung, and Blood Institute to address important questions such as timing of cell delivery and to accelerate research in the use of cell-based therapies. The TIME trial is a randomized, phase II, double-blind, placebo-controlled clinical trial. The 5 member clinical sites of the Cardiovascular Cell Therapy Research Network will enroll 120 eligible patients with moderate-to-large anterior AMIs who have undergone successful percutaneous coronary intervention of the left anterior descending coronary artery and have a left ventricular (LV) ejection fraction </=45% by echocardiography. Participants will have bone marrow aspirations and intracoronary infusions of 150 x 10(6) BMMNCs or placebo on day 3 or day 7 post-AMI. Objectives of this study are (1) to evaluate effects of BMMNCs on regional and global LV function compared to placebo therapy in patients with acute AMI as assessed by cardiac magnetic resonance imaging at 6 months and (2) to assess whether effects of BMMNC infusion on global and regional LV function and safety are influenced by the time of administration. This study will provide further insight into the clinical feasibility and appropriate timing of autologous BMMNC therapy in high-risk patients after AMI and percutaneous coronary intervention.

Cognitive–behavioral Treatment of Bipolar Disorder and Substance Abuse: A Preliminary Randomized Study

ObjectiveThis article describes a two-group outcome study designed to evaluate the feasibility and potential efficacy of cognitive–behavioral therapy (CBT) in conjunction with pharmacotherapy for dually diagnosed patients (bipolar disorder and substance use disorder). MethodsForty-six randomly assigned outpatients received up to 12 weeks of medication monitoring (MM) plus individual CBT (MM + CBT) or MM only. ResultsSixty percent of subjects in the MM + CBT group completed treatment compared with 33% of subjects in the MM group (P < 0.08), with session attendance significantly higher in the MM + CBT group (P < 0.01). The two groups did not differ in substance use outcomes during treatment, but there was some indication of greater improvement in the MM + CBT group with regard to outcomes related to medication compliance and mood symptoms. ConclusionsThis article documents a preliminary attempt to develop and evaluate a new, integrated treatment approach for patients with bipolar disorder who have coexisting substance abuse, and to address effectively those aspects of bipolar disorder that are not impacted by medication alone.

Treatment of Cocaine–Alcohol Dependence with Naltrexone and Relapse Prevention Therapy

This study evaluates whether patients with cocaine-alcohol dependence might benefit from naltrexone (NTX) pharmacotherapy when delivered in conjunction with psychotherapy. Eighty outpatients meeting DSM-IV criteria for alcohol and cocaine dependence were randomly assigned to receive NTX (placebo or 50 mg/d) combined with psychotherapy (Relapse Prevention [RP] or Drug Counseling [DC]) for twelve weeks. It was hypothesized that the skills training focus of RP therapy, in combination with NTX 50 mg/d, would produce greater reductions in cocaine and alcohol use. Outcome measures included self- and objective reports of substance use, treatment retention, medication compliance, and adverse effects. During the first four weeks of treatment, the percentage of cocaine-positive urine screens was significantly lower for those receiving RP therapy (22%) than those receiving DC (47%); however, this difference subsequently diminished. No medication effects were found. All groups reported less alcohol use at the end of treatment. Treatment retention was the same among the groups, with about 33% of the subjects completing all twelve weeks of treatment. The active medication group showed better medication compliance, while the number of adverse events was low overall and not significantly different by group. In conclusion, NTX at 50 mg/d did not reduce cocaine or alcohol use. These findings stand in contrast to previously reported positive findings for NTX and RP in patients with a single diagnosis of cocaine dependence.

Detailed analysis of bone marrow from patients with ischemic heart disease and left ventricular dysfunction BM CD34, CD11b, and clonogenic capacity as biomarkers for clinical outcomes

Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%–2.7% in other cohorts; P<0.05). BM-derived endothelial colonies were significantly decreased (P<0.05). Increased BM CD11b+ cells associated with worse LV ejection fraction (LVEF) after AMI (P<0.05). Increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P=0.03, for patients with AMI and +6.6% versus −0.02%; P=0.021 for patients with chronic IHD). In addition, decreased BM CD34+ percentage in patients with chronic IHD correlated with decrement in LVEF (−2.9% versus +0.7%; P=0.0355). Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. Clinical Trial Registrations: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00684021, NCT00684060, and NCT00824005Rationale: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). Objective: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. Methods and Results: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34+ cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%–2.7% in other cohorts; P <0.05). BM-derived endothelial colonies were significantly decreased ( P <0.05). Increased BM CD11b+ cells associated with worse LV ejection fraction (LVEF) after AMI ( P <0.05). Increased BM CD34+ percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P =0.03, for patients with AMI and +6.6% versus −0.02%; P =0.021 for patients with chronic IHD). In addition, decreased BM CD34+ percentage in patients with chronic IHD correlated with decrement in LVEF (−2.9% versus +0.7%; P =0.0355). Conclusions: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. Clinical Trial Registrations: URL: . Unique identifiers: [NCT00684021][1], [NCT00684060][2], and [NCT00824005][3] # Novelty and Significance {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684021&atom=%2Fcircresaha%2F115%2F10%2F867.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00684060&atom=%2Fcircresaha%2F115%2F10%2F867.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00824005&atom=%2Fcircresaha%2F115%2F10%2F867.atom

Medication Compliance During a Smoking Cessation Clinical Trial: A Brief Intervention Using MEMS Feedback

This study examined the role of a Medication Event Monitoring System (MEMS) to assess pill-taking behavior and enhance compliance within a randomized trial of bupropion-SR for smoking cessation. Female participants (N = 97) received MEMS bottles containing bupropion-SR 150 mg or placebo, to be taken twice daily. A randomly selected “feedback” group of participants was told about the recording device in the bottle cap and received weekly graphic feedback showing their pill-taking behavior with specific instructions for improving compliance. A “no-feedback” group was not informed about the MEMS bottles, and did not receive further instruction or feedback beyond the standard dosing instructions. Compliance outcomes were the total doses taken and number of doses taken within the prescribed time interval. Results indicated significantly higher compliance over time for the feedback group. Participation in the feedback group predicted higher compliance beyond demographic, smoking, and health belief variables, suggesting significant benefit in providing brief feedback and instruction throughout the medication regimen.

Cocaine dependence with and without comorbid depression: a comparison of patient characteristics.

This study compared depressed cocaine dependent patients (CD, N=50) with patients who were cocaine dependent only (CO, N=101) on pre-treatment psychiatric symptomatology, substance use, and psychosocial functioning. Results indicated that the CD group had more overall distress and poorer psychiatric functioning than the CO group. CD individuals scored higher on all subscales of the SCL-90-R, had a higher prevalence of antisocial personality disorder, reported higher craving for cocaine, lower self-efficacy to refrain from drug use, and lower perceived social support. These findings support the need for more intensive treatment approaches for dually-diagnosed patients.

Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction (First Mononuclear Cells injected in the US [FOCUS]): Rationale and design

BACKGROUND The increasing worldwide prevalence of coronary artery disease (CAD) continues to challenge the medical community. Management options include medical and revascularization therapy. Despite advances in these methods, CAD is a leading cause of recurrent ischemia and heart failure, posing significant morbidity and mortality risks along with increasing health costs in a large patient population worldwide. TRIAL DESIGN The Cardiovascular Cell Therapy Research Network (CCTRN) was established by the National Institutes of Health to investigate the role of cell therapy in the treatment of chronic cardiovascular disease. FOCUS is a CCTRN-designed randomized, phase II, placebo-controlled clinical trial that will assess the effect of autologous bone marrow mononuclear cells delivered transendocardially to patients with left ventricular (LV) dysfunction and symptomatic heart failure or angina. All patients need to have limiting ischemia by reversible ischemia on single-photon emission computed tomography assessment. RESULTS After thoughtful consideration of both statistical and clinical principles, we will recruit 87 patients (58 cell treated and 29 placebo) to receive either bone marrow-derived stem cells or placebo. Myocardial perfusion, LV contractile performance, and maximal oxygen consumption are the primary outcome measures. CONCLUSIONS The designed clinical trial will provide a sound assessment of the effect of autologous bone marrow mononuclear cells in improving blood flow and contractile function of the heart. The target population is patients with CAD and LV dysfunction with limiting angina or symptomatic heat failure. Patient safety is a central concern of the CCTRN, and patients will be followed for at least 5 years.