Cost-effectiveness evaluation of the PROPPR trial transfusion protocols.

BACKGROUND: There have been no prior investigations of the cost effectiveness of transfusion strategies for trauma resuscitation. The Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR) study was a Phase III multisite, randomized trial in 680 subjects comparing the efficacy of 1:1:1 transfusion ratios of plasma and platelets to red blood cells with the 1:1:2 ratio. We hypothesized that 1:1:1 transfusion results in an acceptable incremental cost-effectiveness ratio, when estimated using patients' age-specific life expectancy and cost of care during the 30-day PROPPR trial period. STUDY DESIGN AND METHODS: International Classification of Diseases, Ninth Revision codes were prospectively collected, and subjects were matched 1:2 to subjects in the Healthcare Utilization Program State Inpatient Data to estimate cost weights. We used a decision tree analysis, combined with standard costs and estimated years of expected survival to determine the cost effectiveness of the two treatments. RESULTS: The 1:1:1 group had higher overall costs for the blood products but were more likely to achieve hemostasis and decreased hemorrhagic death by 24 hours (p = 0.006). For every 100 patients treated in the 1:1:1 group, eight more achieved hemostasis than in the 1:1:2 group. At 30 days, the total hospital cost per 100 patients was $5.6 million in the 1:1:1 group compared with $5.0 million in the 1:1:2 group. For each 100 patients, the 1:1:1 group had 218.5 more years of life expectancy. This was at a cost of $2994 per year gained. CONCLUSION: The 1:1:1 transfusion ratio in severely injured hemorrhaging trauma patients is a very cost-effective strategy for increasing hemostasis and decreasing trauma deaths.

Factors associated with self-reported anal cancer screening history in men who have sex with men.

Background Men who have sex with men (MSM) are at greater risk of developing anal cancer caused by human papillomavirus (HPV) than the rest of the general population. Currently, there are no formal national guidelines in the US advising men how and when to get anal cancer screening. We sought to assess differences in demographics, familiarity and anxiety about anal cancer among men who report having had anal cancer screening (i.e. anal cytology and/or a digital anorectal examination (DARE)). METHODS: MSM were recruited to participate in a study to assess the feasibility of teaching self and partner anal examinations as a means of screening for anal cancer. Data for this secondary analysis were obtained using a written pre-test and a computer-assisted self-interview. Factors associated with screening were assessed with multivariable logistic regression to allow calculation of adjusted odds ratios (aORs). RESULTS: Of the 197 participants with data, 145 (73.6%) reported having had anal cancer screening (either anal cytology, DARE or both) during their lifetime. Men who were younger, Black and HIV-negative were associated with decreased odds of reporting any type of anal cancer screening. For example, compared with White men, Black men were 80% less likely to report screening (aOR 0.2; 95% confidence interval (CI) 0.1-0.5). Self-perception of anal cancer knowledge was not associated with screening in multivariable analysis (aOR 1.6; 95% CI 0.6-3.9). CONCLUSIONS: Age, race and HIV status were independently associated with a history of anal cancer screening.

A phase II clinical study to assess the feasibility of self and partner anal examinations to detect anal canal abnormalities including anal cancer.

OBJECTIVE: Anal cancer is a common cancer among men who have sex with men (MSM); however, there is no standard screening protocol for anal cancer. We conducted a phase II clinical trial to assess the feasibility of teaching MSM to recognise palpable masses in the anal canal which is a common sign of anal cancer in men. METHODS: A clinician skilled in performing digital anorectal examinations (DARE) used a pelvic manikin to train 200 MSM, aged 27-78 years, how to do a self-anal examination (SAE) for singles or a partner anal examination (PAE) for couples. The clinician then performed a DARE without immediately disclosing results, after which the man or couple performed an SAE or PAE, respectively. Percentage agreement with the clinician DARE in addition to sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the SAE, PAE and overall. RESULTS: Men had a median age of 52 years, 42.5% were African American and 60.5% were HIV positive. DARE detected abnormalities in 12 men while the men's SAE/PAEs detected 9 of these. A total of 93.0% of men classified the health of their anal canal correctly (95% CI 89.5 to 96.5). Overall percentage agreement, sensitivity and specificity were 93.0%, 75.0% and 94.2%, respectively, while PPV and NPV were 45.0% and 98.3%, respectively. The six men who detected the abnormality had nodules/masses ≥3 mm in size. More than half of men (60.5%) reported never checking their anus for an abnormality; however, after performing an SAE/PAE, 93.0% said they would repeat it in the future. CONCLUSION: These results suggest that tumours of ≥3 mm may be detectable by self or partner palpation among MSM and encourage further investigation given literature suggesting a high cure rate for anal cancer tumours ≤10 mm.

A qualitative investigation among men who have sex with men on the acceptability of performing a self- or partner anal exam to screen for anal cancer.

PURPOSE: Persistent infection with oncogenic human papillomavirus (HPV) is the primary cause of anal cancer, a disease that disproportionately affects men who have sex with men (MSM); however, there is no uniform screening protocol to detect anal cancer. This qualitative study explores whether a self-anal exam (SAE) or partner anal exam (PAE), that includes self-palpation or palpation of a partner's anal canal, is an acceptable and self-efficacious screening test, which will cue appropriate follow-up care in MSM. METHODS: Twenty-four MSM living in Houston took part in four focus group sessions eliciting their responses to a study teaching them to perform an SAE or PAE (SAE/PAE). Participants were asked about the acceptability and feasibility of executing an SAE/PAE routinely. Thematic analysis of session transcripts was used to identify common patterns in participant responses. RESULTS: Overall, participants expressed self-efficacy for performing an SAE/PAE and voiced a preference for being taught the procedure by a clinician. Participants agreed that they would consult with a clinician if they ever discovered an abnormality while performing an SAE/PAE. A lack of knowledge about anal cancer among MSM may present a barrier to adopting SAE/PAE. In discussing their experience of the exams, some participants suggested that it could become a routine practice for them. CONCLUSIONS: Our findings suggest that SAE and PAE, as a screen for anal cancer, are acceptable and feasible to MSM. Future research should explore attitudes and beliefs of MSM, with the aim of improving anal cancer education and understanding of pathologic findings.

Making thawed universal donor plasma available rapidly for massively bleeding trauma patients: experience from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial.

BACKGROUND: The Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial was a randomized clinical trial comparing survival after transfusion of two different blood component ratios for emergency resuscitation of traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of request. STUDY DESIGN AND METHODS: At the 12 Level 1 trauma centers participating in PROPPR, blood components transfused and delivery times were tabulated, with a focus on universal donor (UD) plasma management. The adequacy of site plans was assessed by comparing the bedside blood availability times to study goals and the new American College of Surgeons guidelines. RESULTS: Eleven of 12 sites were able to consistently deliver 6 units of thawed UD plasma to their trauma-receiving unit within 10 minutes and 12 units in 20 minutes. Three sites used blood group A plasma instead of AB for massive transfusion without complications. Approximately 4700 units of plasma were given to the 680 patients enrolled in the trial. No site experienced shortages of AB plasma that limited enrollment. Two of 12 sites reported wastage of thawed AB plasma approaching 25% of AB plasma prepared. CONCLUSION: Delivering UD plasma to massively hemorrhaging patients was accomplished consistently and rapidly and without excessive wastage in high-volume trauma centers. The American College of Surgeons Trauma Quality Improvement Program guidelines for massive transfusion protocol UD plasma availability are practicable in large academic trauma centers. Use of group A plasma in trauma resuscitation needs further study.

Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial.

IMPORTANCE: Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE: To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS: Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS: Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES: Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS: No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, -4.2% [95% CI, -9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, -3.7% [95% CI, -10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, -5.4% [95% CI, -10.4% to -0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE: Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01545232.

Characteristics and long-term follow-up of participants with peripheral arterial disease during ALLHAT.

BACKGROUND: Hypertension is a major risk factor for peripheral artery disease (PAD). Little is known about relative efficacy of antihypertensive treatments for preventing PAD. OBJECTIVES: To compare, by randomized treatment groups, hospitalized or revascularized PAD rates and subsequent morbidity and mortality among participants in the Antihypertensive and Lipid-Lower Treatment to Prevent Heart Attack Trial (ALLHAT). DESIGN: Randomized, double-blind, active-control trial in high-risk hypertensive participants. PARTICIPANTS: Eight hundred thirty participants with specified secondary outcome of lower extremity PAD events during the randomized phase of ALLHAT. INTERVENTIONS/EVENTS: In-trial PAD events were reported during ALLHAT (1994-2002). Post-trial mortality data through 2006 were obtained from administrative databases. Mean follow-up was 8.8 years. MAIN MEASURES: Baseline characteristics and intermediate outcomes in three treatment groups, using the Kaplan-Meier method to calculate cumulative event rates and post-PAD mortality rates, Cox proportional hazards regression model for hazard ratios and 95 % confidence intervals, and multivariate Cox regression models to examine risk differences among treatment groups. KEY RESULTS: Following adjustment for baseline characteristics, neither participants assigned to the calcium-channel antagonist amlodipine nor to the ACE-inhibitor lisinopril showed a difference in risk of clinically advanced PAD compared with those in the chlorthalidone arm (HR, 0.86; 95 % CI, 0.72-1.03 and HR, 0.98; 95 % CI, 0.83-1.17, respectively). Of the 830 participants with in-trial PAD events, 63 % died compared to 34 % of those without PAD; there were no significant treatment group differences for subsequent nonfatal myocardial infarction, coronary revascularizations, strokes, heart failure, or mortality. CONCLUSIONS: Neither amlodipine nor lisinopril showed superiority over chlorthalidone in reducing clinically advanced PAD risk. These findings reinforce the compelling need for comparative outcome trials examining treatment of PAD in high-risk hypertensive patients. Once PAD develops, cardiovascular event and mortality risk is high, regardless of type of antihypertensive treatment.

Long-term follow-up of participants with heart failure in the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).

BACKGROUND: In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participants, risk of new-onset heart failure (HF) was higher in the amlodipine (2.5-10 mg/d) and lisinopril (10-40 mg/d) arms compared with the chlorthalidone (12.5-25 mg/d) arm. Similar to other studies, mortality rates following new-onset HF were very high (≥50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases. METHODS AND RESULTS: With the use of national databases, posttrial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups, with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81-1.12) and 1.05 (0.89-1.25), respectively, for amlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fractions (84%) and preserved ejection fractions (81%), with no significant differences by randomized treatment arm. CONCLUSIONS: Once HF develops, risk of death is high and consistent across randomized treatment groups. Measures to prevent the development of HF, especially blood pressure control, must be a priority if mortality associated with the development of HF is to be addressed. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

Cardiovascular risk assessment: addition of CKD and race to the Framingham equation.

BACKGROUND/AIMS: The value of the Framingham equation in predicting cardiovascular risk in African Americans and patients with chronic kidney disease (CKD) is unclear. The purpose of the study was to evaluate whether the addition of CKD and race to the Framingham equation improves risk stratification in hypertensive patients. METHODS: Participants in the ALLHAT were studied. Those randomized to doxazosin, older than 74 years, and those with a history of coronary heart disease were excluded. Two risk stratification models were developed using Cox proportional hazards models in a two-thirds developmental sample. The first model included the traditional Framingham risk factors. The second model included the traditional risk factors plus CKD, defined by estimated glomerular filtration rate categories, and stratification by race (black vs non-black). The primary outcome was a composite of fatal coronary heart disease, nonfatal myocardial infarction, coronary revascularization, and hospitalized angina. RESULTS: There were a total of 19,811 eligible subjects. In the validation cohort, there was no difference in C-statistics between the Framingham equation and the ALLHAT model including CKD and race. This was consistent across subgroups by race and sex and among those with CKD. One exception was among Non-Black women where the C-statistic was higher for the Framingham equation (0.68 vs 0.65, P = .02). In addition, net reclassification improvement was not significant for any subgroup based on race and sex, ranging from -5.5% to 4.4%. CONCLUSION: The addition of CKD status and stratification by race does not improve risk prediction in high-risk hypertensive patients.

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 the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial.

CONTEXT: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. OBJECTIVES: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. DESIGN, SETTING, AND PATIENTS: A randomized, 2 × 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤ 45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. INTERVENTIONS: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. MAIN OUTCOME MEASURES: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. RESULTS: The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P = .96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (−0.9% [95% CI, −6.6% to 4.9%], P = .76) or day 7 (1.1% [95% CI, −4.7% to 6.9%], P = .70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. CONCLUSION: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00684021.

Developing mechanistic insights into cardiovascular cell therapy: Cardiovascular Cell Therapy Research Network Biorepository Core Laboratory rationale.

Moderate improvements in cardiac performance have been reported in some clinical settings after delivery of bone marrow mononuclear cells to patients with cardiovascular disease. However, mechanistic insights into how these cells impact outcomes are lacking. To address this, the National Heart, Lung and Blood Institute (NHLBI) Cardiovascular Cell Therapy Research Network (CCTRN) established a Biorepository Core for extensive phenotyping and cell function studies and storing bone marrow and peripheral blood for 10 years. Analyzing cell populations and cell function in the context of clinical parameters and clinical outcomes after cell or placebo treatment empower the development of novel diagnostic and prognostics. Developing such biomarkers that define the safety and efficacy of cell therapy is a major Biorepository aim.

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.

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.

Management of blunt cerebrovascular injury (BCVI) in the multisystem injury patient with contraindications to immediate anti-thrombotic therapy.

INTRODUCTION: Practice management guidelines for screening and treatment of patients with blunt cerebrovascular injury (BCVI) have been associated with a decreased risk of ischemic stroke. TREATMENT: of patients with BCVI and multisystem injuries that delays immediate antithrombotic therapy remains controversial. The purpose of this study was to determine the timing of BCVI treatment initiation, the incidence of stroke, and bleeding complications as a result of antithrombotic therapy in patients with isolated BCVI in comparison to those with BCVI complicated by multisystem injuries. MATERIALS AND METHODS: This study was a retrospective review of all adult blunt trauma patients admitted to a level 1 trauma center from 2009 to 2014 with a diagnosis of BCVI. RESULTS: A total of 28,305 blunt trauma patients were admitted during the study period. Of these, 323 (1.1%) had 481 BCEVIs and were separated into two groups. Isolated BCVI was reported in 111 (34.4%) patients and 212 (65.6%) patients had accompanying multisystem injuries (traumatic brain injury (TBI), solid organ injury, or spinal cord injury) that contraindicated immediate antithrombotic therapy. TREATMENT: started in patients with isolated BCVI at a median time of 30.3 (15, 52) hours after injury in contrast to 62.4 (38, 97) hours for those with multisystem injuries (p<0.001). The incidence of stroke was identical (9.9%) between groups and no bleeding complications related to antithrombotic therapy were identified. CONCLUSION: The lack of bleeding complications and equivalent stroke rates between groups suggests that the presence of TBI, solid organ injury, and spinal cord injury are not contraindications to anti-thrombotic therapy for stroke prevention in patients with BCVI.

Constraint-induced movement therapy during early stroke rehabilitation.

BACKGROUND: Limited data are available about the effectiveness of early rehabilitation after stroke. OBJECTIVE: This is the 1st randomized controlled trial of constraint-induced movement therapy (CIMT) in subacute stroke to investigate neurophysiologic mechanisms and long-term outcome. METHODS: Within 2 weeks after stroke, 23 patients with upper extremity (UE) weakness were randomized to 2 weeks of CIMT or traditional therapy at an equal frequency of up to 3 h/day. Motor function of the affected UE was blindly assessed before treatment, after treatment, and 3 months after stroke. Transcranial magnetic stimulation (TMS) measured the cortical area evoking movement of the affected hand. RESULTS: Long-term improvement in motor function of the affected UE did not differ significantly between patients who received CIMT versus intensive traditional therapy. All outcome comparisons showed trends favoring CIMT over intensive traditional therapy, but none was statistically significant except for improvements in the Fugl-Meyer (FM) UE motor scale immediately following treatment and in reported quality of hand function at 3 months. Improvement in UE motor function on the FM was associated with a greater number of sites on the affected cerebral hemisphere where responses of the affected hand were evoked by TMS. CONCLUSIONS: Future trials of CIMT during early stroke rehabilitation need greater statistical power, more inclusive eligibility criteria, and improved experimental control over treatment intensity. The relationship between changes in motor function and in evoked motor responses suggests that motor recovery during the 1st 3 months after stroke is associated with increased motor excitability of the affected cerebral hemisphere.

Dependence, hyper-dependence and hypothesis testing in clinical trials.

While investigators designing clinical trials face the important issue of endpoint selection, an equally troublesome concern can be the a priori selection of the endpoint analysis. In this latter circumstance, there may be only one endpoint of interest in the clinical trial, but several competing endpoint analyses are available (e.g., an analysis of the endpoint that is adjusted for clinical center versus an analysis that is adjusted for geographic region versus an unadjusted analysis). An example that demonstrates the unsatisfactory conclusions that ambiguous choices can produce is offered. A procedure utilizing conditional probability is provided that permits the conservation of type I error when the investigators have one endpoint and several worthy competitor endpoint analyses that are each prospectively identified and carried out at the trial's conclusion. When the high levels of dependence among these analyses are taken into account, it is possible to carry out the hypothesis tests in a way that 1) provides practicable type I error levels for each analysis, and 2) conserves the familywise type I error. In circumstances in which the endpoint and all members of the family of analyses are selected during the design phase of the trial, this procedure provides confirmatory conclusions as opposed to exploratory findings.

Outcomes after concomitant traumatic brain injury and hemorrhagic shock: A secondary analysis from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios trial.

BACKGROUND: Often the clinician is faced with a diagnostic and therapeutic dilemma in patients with concomitant traumatic brain injury (TBI) and hemorrhagic shock (HS), as rapid deterioration from either can be fatal. Knowledge about outcomes after concomitant TBI and HS may help prioritize the emergent management of these patients. We hypothesized that patients with concomitant TBI and HS (TBI + HS) had worse outcomes and required more intensive care compared with patients with only one of these injuries. METHODS: This is a post hoc analysis of the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. TBI was defined by a head Abbreviated Injury Scale score greater than 2. HS was defined as a base excess of -4 or less and/or shock index of 0.9 or greater. The primary outcome for this analysis was mortality at 30 days. Logistic regression, using generalized estimating equations, was used to model categorical outcomes. RESULTS: Six hundred seventy patients were included. Patients with TBI + HS had significantly higher lactate (median, 6.3; interquartile range, 4.7-9.2) compared with the TBI group (median, 3.3; interquartile range, 2.3-4). TBI + HS patients had higher activated prothrombin times and lower platelet counts. Unadjusted mortality was higher in the TBI + HS (51.6%) and TBI (50%) groups compared with the HS (17.5%) and neither group (7.7%). Adjusted odds of death in the TBI and TBI + HS groups were 8.2 (95% confidence interval, 3.4-19.5) and 10.6 (95% confidence interval, 4.8-23.2) times higher, respectively. Ventilator, intensive care unit-free and hospital-free days were lower in the TBI and TBI + HS groups compared with the other groups. Patients with TBI + HS or TBI had significantly greater odds of developing a respiratory complication compared with the neither group. CONCLUSION: The addition of TBI to HS is associated with worse coagulopathy before resuscitation and increased mortality. When controlling for multiple known confounders, the diagnosis of TBI alone or TBI+HS was associated with significantly greater odds of developing respiratory complications. LEVEL OF EVIDENCE: Prognostic study, level II.

Argatroban tPA stroke study: study design and results in the first treated cohort.

BACKGROUND: The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute stroke is linked to clot lysis and artery recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. There are no human data on this combination. DESIGN: We report the first phase of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose-escalation, safety and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 hours. After standard-dose intravenous rtPA administration, a 100-mug/kg bolus of argatroban followed by infusion of 1 mug/kg per minute for 48 hours was adjusted to a target partial thromboplastin time of 1.75 times that of the control group. RESULTS: Fifteen patients (including 10 men) were enrolled, with a mean +/- SD age of 61 +/- 13 years. All patients had middle cerebral artery occlusions. Baseline median National Institute of Health Stroke Scale score was 14 (range, 4-25). The mean +/- SD time from symptom onset to argatroban bolus administration was 172 +/- 53 minutes. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 1 patient and there was 1 death. Recanalization was complete in 6 patients and partial in another 4, and reocclusion occurred in 3 within 2 hours of rtPA bolus administration. CONCLUSION: The safety of low-dose argatroban combined with intravenous rtPA may be within acceptable limits, and its efficacy for producing fast and complete recanalization is promising, but a larger cohort of patients is required to confirm these preliminary observations.

Assessing protocol adherence in a clinical trial with ordered treatment regimens: Quantifying the pragmatic, randomized optimal platelet and plasma ratios (PROPPR) trial experience.

BACKGROUND: Medication dispensing errors are common in clinical trials, and have a significant impact on the quality and validity of a trial. Therefore, the definition, calculation and evaluation of such errors are important for supporting a trial's conclusions. A variety of medication dispensing errors can occur. In this paper, we focus on errors in trials where the intervention includes multiple therapies that must be given in a pre-specified order that varies across treatment arms and varies in duration. METHODS: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was a Phase III multi-site, randomized trial to compare the effectiveness and safety of 1:1:1 transfusion ratios of plasma and platelets to red blood cells with a 1:1:2 ratio. In this trial, these three types of blood products were to be transfused in a pre-defined order that differed by treatment arm. In this paper, we present approaches from the PROPPR trial that we used to define and calculate the occurrence of out of order blood transfusion errors. We applied the proposed method to calculate protocol adherence to the specified order of transfusion in each treatment arm. RESULTS: Using our proposed method, protocol adherence was greater in the 1:1:1 group than in the 1:1:2 group (96% vs 93%) (p<0.0001), although out of order transfusion errors in both groups were low. Final transfusion ratios of plasma to platelets to red blood cells for the 1:1:1 ratio group was 0.93:1.32:1, while the transfusion ratio for the 1:1:2 ratio group was 0.48:0.48:1. CONCLUSIONS: Overall, PROPPR adherence to blood transfusion order pre-specified in the protocol was high, and the required order of transfusions for the 1:1:2 group was more difficult to achieve. The approaches proposed in this manuscript were useful in evaluating the PROPPR adherence and are potentially useful for other trials where a specific treatment orders with varying durations must be maintained.