BACKGROUND:This review delves into the intricate landscape of cardiorenal syndrome (CRS) and highlights the pivotal role of Blood Volume Analysis (BVA) in improving patient care and outcomes. SUMMARY:BVA offers a direct and highly accurate quantification of intravascular volume, red blood cell volume, and plasma volume, complete with patient-specific norms. This diagnostic tool enhances the precision of diuretic and red cell therapies, significantly elevating the effectiveness of conventional care. KEY MESSAGES:· Comprehensive Understanding: Our objectives encompass a comprehensive understanding of how BVA informs the evaluation and treatment of CRS, including its subtypes, pathophysiology, and clinical significance. · BVA Principles and Advantages: We delve into BVA principles, techniques, and measurements, elucidating its diagnostic potential and advantages compared to commonly used surrogate measures. · Clinical Relevance: We dissect the clinical relevance of BVA in various CRS scenarios, emphasizing its unique contributions to each subtype. · Improving patient outcomes: By assessing the tangible impact of BVA on patient outcomes through meticulous analysis of relevant clinical studies, we unveil its potential to enhance health outcomes and optimize resource utilization. · Multidisciplinary Collaboration: Acknowledging the challenges and limitations associated with BVA's clinical implementation, we underscore the importance of multidisciplinary collaboration among cardiologists, nephrologists, and other clinicians. · Future Directions: Finally, we identify research gaps and propose future directions for BVA and CRS, contributing to ongoing advancements in this field and patients affected by this complicated clinical syndrome.

OBJECTIVES This study performed a retrospective outcome analyses of a large cohort of mixed ejection fraction patients admitted for acute heart failure (HF), whose inpatient care was guided by individual quantitative blood volume analysis (BVA) results. BACKGROUND Decongestion strategies in patients hospitalized for HF are based on clinical assessment of volume and have not integrated a quantitative intravascular volume metric. METHODS Propensity score control matching analysis was performed in 245 consecutive HF admissions to a community hospital (September 2007 to April 2014; 78 t 10 years of age; 50% with HF with reduced ejection fraction [HFrEF]; and 30% with Stage 4 chronic kidney disease). Total blood volume (TBV), red blood cell volume (RBCV), and plasma volume (PV) were measured at admission by using iodine-131-labeled albumin indicator-dilution technique. Decongestion strategy targeted a TBV threshold of 6% to 8% above patient-specific normative values. Anemia was treated based on cause. Hematocrit (Hct) measurements were monitored to assess effectiveness of interventions. Control subjects derived from Centers for Medicare and Medicaid Services data were matched 10:1 for demographics, comorbidity, and year of treatment. RESULTS Although 66% of subjects had PV expansion, only 37% were hypervotemic (TBV >10% excess). True anemia (RBCV >= 10% deficit) was present in 62% of subjects. Treatment of true anemia without hypervotemia resulted in a rise in peripheral Hct of 2.7 is. 2.9% (p < 0.001), and diuretic treatment of hypervotemia in cases without anemia caused a 4.5 +/- 3.9% (p < 0.001) increase in peripheral Hct at 11.3 +/- 7.5 days after admission. Subjects had tower 30-day rates of readmission (12.2% vs. 27.7%, respectively; p < 0.001), of 30-day mortality (2.0% vs. 11.1%, respectively; p < 0.001), and of 365-day mortality (4.9% vs. 35.5%, respectively; p < 0.001) but longer lengths of stay (7.3 vs. 5.6 days, respectively; p < 0.001) than control subjects. CONCLUSIONS Retrospective outcomes using volume-guided HF therapy versus propensity-matched controls support the benefit of BVA in guiding volume management and reducing death and rehospitalization due to HF. (C) 2018 by the American College of Cardiology Foundation.

Background : Heart failure patients have wide variations in intravascular volumes which form the basis for disease initiation and progression and contribute to confusion in treatment strategies. Blood volume analysis (BVA) is a bedside blood test that measures with 98% accuracy intravascular volumes of a HF patient, including plasma and red blood cell volume (RBCV). Extremes in excess of red blood cell volume (polycythemia (P)) in HF patients have been associated with poorer outcomes including mortality. A not uncommon BVA phenotype is that of secondary P, with or without hypervolemia(P/Hypervol). We sought to further clarify the clinical correlates and outcomes associated with this phenotype in a mixed LVEF cohort of hospitalized HF patients and whether this phenotype would be detectable utilizing pHct or Hgb measures. Methods/Results : In a cohort of 245 consecutively admitted HF patients (142 men/103 women) with mixed EFs who underwent BVA guided care, 25 patients (10.2%) had P/Hypervol and 3 patients (1.2%) had P with normal or low total blood volume. The presence of this phenotype was equal in patients with HFrEF and HFpEF (52%/48%). P/Hypervol was observed less frequently in patients over 75 (p=0.03), and among patients with BMI>35 (p=0.07). Despite P, the peripheral Hct (pHct) was either normal (57.1%), or >10% below normal (39.3%), indicating that in a majority of patients excess red cells were accompanied by an excess of plasma and that pHct would not indicate P. The BVA-provided RBCV showed that in 93% of patients with P that diuresis alone would not be able to achieve euvolemia without extreme hemoconcentration. Patients with P or P/Hypervol were treated with therapeutic phlebotomy or sent for hematology consults to achieve euvolemia. In terms of outcomes at 30 days post-discharge, 12% of the phenotype were readmitted, similar to those with other phenotypes; no deaths occurred in the P/Hypervol phenotype within 30 days or 365 days. 30-day readmissions did occur (56%) in the phenotype similar to other phenotypes (62.3%). Conclusions : The P/Hypervol phenotype is common and worrisome for several reasons. Neither the pHct, the BMI or age is sufficient to identify this phenotype. The plasma and red blood cell volume (RBCV) expansion may hasten disease progression accounting for underrepresentation of older patients in this cohort. Further, the discrepancy in the pHct might lead clinicians to suspect that the patient has a dilutionally low pHct, when, in fact, they have an increased RBCV and a diuretic strategy alone will only hemoconcentrate the patient, increasing viscosity and risk of thrombotic events while not achieving euvolemia. BVA-guided assessment demonstrated the specificity to identify this phenotype. and raise the value of therapeutic phlebotomy to optimize volume and RBCV; this cohort merits improved BVA-guided evaluation to better discern the impact of this phenotype on HF outcomes. : Heart failure patients have wide variations in intravascular volumes which form the basis for disease initiation and progression and contribute to confusion in treatment strategies. Blood volume analysis (BVA) is a bedside blood test that measures with 98% accuracy intravascular volumes of a HF patient, including plasma and red blood cell volume (RBCV). Extremes in excess of red blood cell volume (polycythemia (P)) in HF patients have been associated with poorer outcomes including mortality. A not uncommon BVA phenotype is that of secondary P, with or without hypervolemia(P/Hypervol). We sought to further clarify the clinical correlates and outcomes associated with this phenotype in a mixed LVEF cohort of hospitalized HF patients and whether this phenotype would be detectable utilizing pHct or Hgb measures. : In a cohort of 245 consecutively admitted HF patients (142 men/103 women) with mixed EFs who underwent BVA guided care, 25 patients (10.2%) had P/Hypervol and 3 patients (1.2%) had P with normal or low total blood volume. The presence of this phenotype was equal in patients with HFrEF and HFpEF (52%/48%). P/Hypervol was observed less frequently in patients over 75 (p=0.03), and among patients with BMI>35 (p=0.07). Despite P, the peripheral Hct (pHct) was either normal (57.1%), or >10% below normal (39.3%), indicating that in a majority of patients excess red cells were accompanied by an excess of plasma and that pHct would not indicate P. The BVA-provided RBCV showed that in 93% of patients with P that diuresis alone would not be able to achieve euvolemia without extreme hemoconcentration. Patients with P or P/Hypervol were treated with therapeutic phlebotomy or sent for hematology consults to achieve euvolemia. In terms of outcomes at 30 days post-discharge, 12% of the phenotype were readmitted, similar to those with other phenotypes; no deaths occurred in the P/Hypervol phenotype within 30 days or 365 days. 30-day readmissions did occur (56%) in the phenotype similar to other phenotypes (62.3%). : The P/Hypervol phenotype is common and worrisome for several reasons. Neither the pHct, the BMI or age is sufficient to identify this phenotype. The plasma and red blood cell volume (RBCV) expansion may hasten disease progression accounting for underrepresentation of older patients in this cohort. Further, the discrepancy in the pHct might lead clinicians to suspect that the patient has a dilutionally low pHct, when, in fact, they have an increased RBCV and a diuretic strategy alone will only hemoconcentrate the patient, increasing viscosity and risk of thrombotic events while not achieving euvolemia. BVA-guided assessment demonstrated the specificity to identify this phenotype. and raise the value of therapeutic phlebotomy to optimize volume and RBCV; this cohort merits improved BVA-guided evaluation to better discern the impact of this phenotype on HF outcomes.

Background Patients with heart failure often have wide variations in intravascular volume (Total Blood Volume (TBV) and Red Blood Cell Volume (RBCV)) that are part of the pathophysiology, symptomatology, and disease progression of their syndrome. Indirect volume measurements cannot measure intravascular volume with precision, often leaving clinicians without clear volume-guided treatment strategies. Ultrafiltration (UF) is a treatment capable of removing fluid from the body without changing RBCV or removing serum proteins and large molecules. Blood volume analysis (BVA) provides several patient specific metrics including TBV, plasma volume (PV), and RBCV as well as providing a normalized hematocrit (nHct), a reflection of the anticipated pHct after volume correction. Goals of using UF are safe removal of fluid without creation of hypovolemia and without exceeding the plasma refill rate. We report below two cases of heart failure patients co-managed using BVA and UF. Methods/Results Two men aged 83 and 64 years were admitted to the hospital for volume overload and management. Each was initially treated with intense IV diuresis which produced worsening renal insufficiency. At that time BVA confirmed increased total intravascular volume for which UF was initiated. Monitoring of the gap between the peripheral hematocrit and the normalized hematocrit allowed safe and adequate decongestion. Significant volume removal corelated with clinical improvement and the patients were discharged 3-4 days following combined use of BVA and UF. Table 1 summarizes these outcomes and documents the rise in pHct (Patient 2) as it approaches the nHct, signaling sufficient volume removal. Conclusions While the synergy of combining BVA with UF has been envisioned for more than a decade, limited information is available to understand the optimal use and define the value of combining these valuable tools. Earlier use of BVA in these two patients could have prevented acute renal injury from intensified diuresis, and by instituting UF, the kidneys could be provided with a 'diuretic holiday'. Further, the normalized hematocrit, determined by BVA, provides clinicians with a specific metric to monitor UF progress and adequacy. Combined use of BVA and UF should improve outcomes in hospitalized diuretic-resistant or renal insufficient patients. Clinical trials of their combination need to be designed and completed. Patients with heart failure often have wide variations in intravascular volume (Total Blood Volume (TBV) and Red Blood Cell Volume (RBCV)) that are part of the pathophysiology, symptomatology, and disease progression of their syndrome. Indirect volume measurements cannot measure intravascular volume with precision, often leaving clinicians without clear volume-guided treatment strategies. Ultrafiltration (UF) is a treatment capable of removing fluid from the body without changing RBCV or removing serum proteins and large molecules. Blood volume analysis (BVA) provides several patient specific metrics including TBV, plasma volume (PV), and RBCV as well as providing a normalized hematocrit (nHct), a reflection of the anticipated pHct after volume correction. Goals of using UF are safe removal of fluid without creation of hypovolemia and without exceeding the plasma refill rate. We report below two cases of heart failure patients co-managed using BVA and UF. Two men aged 83 and 64 years were admitted to the hospital for volume overload and management. Each was initially treated with intense IV diuresis which produced worsening renal insufficiency. At that time BVA confirmed increased total intravascular volume for which UF was initiated. Monitoring of the gap between the peripheral hematocrit and the normalized hematocrit allowed safe and adequate decongestion. Significant volume removal corelated with clinical improvement and the patients were discharged 3-4 days following combined use of BVA and UF. Table 1 summarizes these outcomes and documents the rise in pHct (Patient 2) as it approaches the nHct, signaling sufficient volume removal. While the synergy of combining BVA with UF has been envisioned for more than a decade, limited information is available to understand the optimal use and define the value of combining these valuable tools. Earlier use of BVA in these two patients could have prevented acute renal injury from intensified diuresis, and by instituting UF, the kidneys could be provided with a 'diuretic holiday'. Further, the normalized hematocrit, determined by BVA, provides clinicians with a specific metric to monitor UF progress and adequacy. Combined use of BVA and UF should improve outcomes in hospitalized diuretic-resistant or renal insufficient patients. Clinical trials of their combination need to be designed and completed.

Introduction: Anemia is a common and serious co-morbidity of heart failure (HF) that is undertreated, impacting outcomes for HF patients and the overall economics of HF. Studies have shown that anemia is associated with worse outcomes in HF, but to date interventional studies aimed at treating anemia in HF have failed to demonstrate conclusive outcome improvements. A common feature of past studies is that they generally defined anemia via a threshold of peripheral Hct (or via Hemoglobin, which has a direct linear relationship to Hct). Methods: In a recently published study of a mixed-LVEF cohort of 245 HF patients, red cell volume status relative to patient norms was quantified using direct blood volume analysis (BVA, Daxor, Oak Ridge, TN). We evaluated the suitability of a Hct for detecting true anemia (as measured by BVA) in this group. Although Hct was somewhat correlated (R 2 =0.43) with red cell volume (RCV) deviation from ideal (as measured directly by BVA), actual RCV status was heterogeneous. We performed an analysis of the specificity and sensitivity of Hct as an indicator of true anemia, defined as RCV < 90% of normal value. Results: The distribution of true anemia is shown in Figure 1. Visual inspection shows mixed anemia status across a broad range of Hct values. We examined three Hct thresholds for determining true anemia. Two thresholds were defined based on deviations from normal Hct (M=45, F=40); a third threshold was chosen at 24 for both genders, corresponding to a common transfusion trigger. Using a moderate 10% deviation threshold yielded a sensitivity of 96%, but a specificity of only 50%, due to a False Positive (dilutional anemia) rate of 19%. Using a more extreme 25% deviation threshold yielded a specificity of 90%, but a sensitivity of only 62%, due to a False Negative (FN) rate of 23%. The transfusion trigger had a FN rate of 61%. Conclusions: Hct lacks sensitivity and specificity for detecting true anemia. Interventions for anemia in HF would benefit from BVA.

Expansion in blood volume (BV) is a well-recognized response to arterial underfilling secondary to impaired cardiac output in heart failure (HF). However, the effectiveness of this response in terms of outcomes remains inadequately understood. Prospective analysis was undertaken in 110 patients with HF hospitalized and treated for fluid overload. BVs were measured in a compensated state at the hospital discharge using the indicator-dilution methodology. Data were analyzed for composite 1-year HF-related mortality/first rehospitalization. Despite uniform standard of care, marked heterogeneity in BVs was identified across the cohort. The cohort was stratified by BV expansion greater than or equal to +25% above normal (51% of cohort), mild-moderate expansion (22%), and normal BV (27%). Kaplan-Meier (K-M) survival estimates and regression analyses revealed BV expansion (greater than or equal to +25%) to be associated with better event-free survival relative to normal BV (P = 0.038). Increased red blood cell mass (RBCm; RBC polycythemia) was identified in 43% of the overall cohort and 70% in BV expansion greater than or equal to +25%. K-M analysis demonstrated polycythemia to be associated with better outcomes compared with normal RBCm (P < 0.002). Persistent BV expansion to include RBC polycythemia is common and, importantly, associated with better clinical outcomes compared with normal total BV or normal RBCm in patients with chronic HF. However, compensatory BV expansion is not a uniform physiological response to the insult of HF with marked variability in BV profiles despite uniform standard of care diuretic therapy. Therefore, recognizing the variability in volume regulation pathophysiology has implications not only for impact on clinical outcomes and risk stratification but also potential for informing individualized volume management strategies.NEW & NOTEWORTHY The novel findings of this study demonstrate that intravascular volume profiles among the patients with chronic heart failure (HF) vary substantially even with similar clinical compensation. Importantly, a profile of blood volume (BV) expansion (compared with a normal BV) is associated with lower HF mortality/morbidity. Furthermore, RBC polycythemia is common and independently associated with improved outcomes. These observations support BV expansion with RBC polycythemia as a compensatory mechanism in chronic HF.

Background Total Blood Volume (TBV) overload frequently causes shortness of breath and fatigue in heart failure (HF)-related hospital admissions. Red cell volume (RBCV) variations in the same population, unrecognized and largely untreated without quantitative blood volume analysis, suggest an independent causal role in symptom production, short, and long-term outcomes. RBCV phenotypes, their prevalence, distribution, and impact on length of stay (LOS) were studied in a previously published series of hospitalized heart failure patients. Methods In a series of 245 consecutive HF admissions to a community hospital (Sept 2007-Apr 2014, age 78±10 yrs., HFrEF 46%, Stage 4 CKD 30%), Total blood volume (TBV) and Red Cell Volume (RBCV) were measured at admission by blood volume analysis (BVA), an I-131 labeled albumin indicator-dilution technique (Daxor BVA-100). True anemia was diagnosed with a RBCV deficit >10% of ideal RBCV and polycythemia was diagnosed with a RBCV excess of >10% of ideal RBCV. True anemia was corrected with IV iron, epoetin, and/or packed red blood cells when appropriate. Results Only 37% of these patients were hypervolemic (TBV >10% excess), but 62% had true anemia (> 10% deficit from ideal RBCV); true anemia was equally distributed across ejection fraction (EF) ranges, 50.3% of patients with reduced EF (<40%), and 49.7% of patients with preserved EF (≥40%) demonstrated true anemia. The most prevalent RBCV Phenotypes were Anemia with Normovolemia (50%), Anemia with Hypervolemia (TBV > 10% excess from ideal TBV) (12%), and Polycythemia (> 10% excess from ideal RBCV) with Hypervolemia (10%). Peripheral hematocrit measured at the time of blood volume analysis was unable to distinguish between RBCV phenotypes. True Anemia was present in 44/60 patients whose hospital length of stay (LOS) exceeded 10 days compared to 16/60 patients without anemia and a > 10 day LOS (p < 0.033). Conclusion True anemia was a surprisingly consistent feature in 62% of the HHF patients. Only 27% of patients in the series presented with a normal RBCV. Peripheral hematocrit could not be used to identify RBCV phenotypes. True anemia was present in nearly three times as many patients with LOS > 10 days, indicating it is a marker of disease severity that must be recognized and treated early in the hospital course. Treatment should be guided by the specific RBCV phenotype and the laboratory evaluation of the anemia or polycythemia. Further controlled evaluation of the impact of RBCV phenotype on short- and long-term outcomes in HHF patients following volume-guided treatment is necessary. Total Blood Volume (TBV) overload frequently causes shortness of breath and fatigue in heart failure (HF)-related hospital admissions. Red cell volume (RBCV) variations in the same population, unrecognized and largely untreated without quantitative blood volume analysis, suggest an independent causal role in symptom production, short, and long-term outcomes. RBCV phenotypes, their prevalence, distribution, and impact on length of stay (LOS) were studied in a previously published series of hospitalized heart failure patients. In a series of 245 consecutive HF admissions to a community hospital (Sept 2007-Apr 2014, age 78±10 yrs., HFrEF 46%, Stage 4 CKD 30%), Total blood volume (TBV) and Red Cell Volume (RBCV) were measured at admission by blood volume analysis (BVA), an I-131 labeled albumin indicator-dilution technique (Daxor BVA-100). True anemia was diagnosed with a RBCV deficit >10% of ideal RBCV and polycythemia was diagnosed with a RBCV excess of >10% of ideal RBCV. True anemia was corrected with IV iron, epoetin, and/or packed red blood cells when appropriate. Only 37% of these patients were hypervolemic (TBV >10% excess), but 62% had true anemia (> 10% deficit from ideal RBCV); true anemia was equally distributed across ejection fraction (EF) ranges, 50.3% of patients with reduced EF (<40%), and 49.7% of patients with preserved EF (≥40%) demonstrated true anemia. The most prevalent RBCV Phenotypes were Anemia with Normovolemia (50%), Anemia with Hypervolemia (TBV > 10% excess from ideal TBV) (12%), and Polycythemia (> 10% excess from ideal RBCV) with Hypervolemia (10%). Peripheral hematocrit measured at the time of blood volume analysis was unable to distinguish between RBCV phenotypes. True Anemia was present in 44/60 patients whose hospital length of stay (LOS) exceeded 10 days compared to 16/60 patients without anemia and a > 10 day LOS (p < 0.033). True anemia was a surprisingly consistent feature in 62% of the HHF patients. Only 27% of patients in the series presented with a normal RBCV. Peripheral hematocrit could not be used to identify RBCV phenotypes. True anemia was present in nearly three times as many patients with LOS > 10 days, indicating it is a marker of disease severity that must be recognized and treated early in the hospital course. Treatment should be guided by the specific RBCV phenotype and the laboratory evaluation of the anemia or polycythemia. Further controlled evaluation of the impact of RBCV phenotype on short- and long-term outcomes in HHF patients following volume-guided treatment is necessary.

Background In a recent retrospective study, the use of early blood volume analysis (BVA) to guide treatment in Hospitalized Heart Failure (HHF) patients was associated with significantly lower readmission rates and mortality. A cost-effectiveness analysis was undertaken to quantify this benefit economically, based on the results of the study. Methods Costs for HHF with and without BVA were estimated from published data. Effectiveness was derived by modeling survival using outcomes from the retrospective study. A 3-state Markov simulation was performed, with all patients initially in state “In Hospital with Heart Failure”, with additional states “Not in Hospital with Heart Failure” and “Dead”. Transition probabilities and uncertainties for in-hospital mortality and readmission were determined by the observed outcomes of the retrospective study. Other parameters for the analysis (transitions, quality adjustments, etc.) were derived from published sources of large population studies. Probabilistic and deterministic sensitivity analysis was performed. Results The incremental cost-effectiveness ratio (ICER) for a 30-year simulation was $10,700. This was derived from an average life-extension of 2.32 quality-adjusted life years (QALYs) per patient, at an incremental cost of $24,800 per patient. Sensitivity analysis showed that the most critical parameters of the simulation were the long-term hospitalization rate for chronic heart failure, the age of the patients, the assumed cost of a single hospitalization, and the marginal cost assumed to be associated with longer Length of Stay (LOS) for subjects. Uncertainty analysis returned an estimate of ICER = $14,200±$5,620, based on incremental QALY = 2.69±1.76 and incremental cost=$35,400±$22,500. A goal-seeking analysis showed that an ICER of $50,000 would be achieved if the reduction in mortality and readmission was as little as 12%. Conclusion Use of BVA to guide treatment was demonstrated to be extremely cost-effective, as ICER values for all scenarios considered were far below the threshold of $50,000 which is generally taken to represent good value for health care. In a recent retrospective study, the use of early blood volume analysis (BVA) to guide treatment in Hospitalized Heart Failure (HHF) patients was associated with significantly lower readmission rates and mortality. A cost-effectiveness analysis was undertaken to quantify this benefit economically, based on the results of the study. Costs for HHF with and without BVA were estimated from published data. Effectiveness was derived by modeling survival using outcomes from the retrospective study. A 3-state Markov simulation was performed, with all patients initially in state “In Hospital with Heart Failure”, with additional states “Not in Hospital with Heart Failure” and “Dead”. Transition probabilities and uncertainties for in-hospital mortality and readmission were determined by the observed outcomes of the retrospective study. Other parameters for the analysis (transitions, quality adjustments, etc.) were derived from published sources of large population studies. Probabilistic and deterministic sensitivity analysis was performed. The incremental cost-effectiveness ratio (ICER) for a 30-year simulation was $10,700. This was derived from an average life-extension of 2.32 quality-adjusted life years (QALYs) per patient, at an incremental cost of $24,800 per patient. Sensitivity analysis showed that the most critical parameters of the simulation were the long-term hospitalization rate for chronic heart failure, the age of the patients, the assumed cost of a single hospitalization, and the marginal cost assumed to be associated with longer Length of Stay (LOS) for subjects. Uncertainty analysis returned an estimate of ICER = $14,200±$5,620, based on incremental QALY = 2.69±1.76 and incremental cost=$35,400±$22,500. A goal-seeking analysis showed that an ICER of $50,000 would be achieved if the reduction in mortality and readmission was as little as 12%. Use of BVA to guide treatment was demonstrated to be extremely cost-effective, as ICER values for all scenarios considered were far below the threshold of $50,000 which is generally taken to represent good value for health care.

Volume overload congestion is a primary reason for heart failure (HF) readmissions. Decongestion strategies to effectively treat HHF patients (pts) need to be individualized due to the multiple confounders. To date decongestion strategies have lacked the integration of a quantitative measure of

Introduction: Decongestion strategy in hospitalized HF patients (pts) must be individualized due to the heterogeneity of HF. Volume evaluation by clinical assessment and/or indirect metrics using Echo Doppler or direct hemodynamic measurement is challenging, and anemia is difficult to identify as volume overload confounds serum tests. BVA directly quantifies excess or deficit in total blood volume (TBV) and red blood cell volume (RBCV) and is currently being integrated into HF management at Lankenau Medical Center. Methods: Exploratory analysis was performed to analyze risk factors at discharge for 30-day readmissions among the first 50 patients undergoing BVA on admission or during the hospital stay for signs or symptoms of HF. Since BVA was not routinely performed at discharge, imputed TBV and RBCV at discharge were calculated based on normalized Hct (nHct) per BVA and discharge serum Hct, assuming stable RBC status. Strict/severe risk thresholds were set for congestion (TBV excess >+22%) and anemia (nHct < 30% F/ < 33% M). Results: Among the 47 analyzable patients, TBV heterogeneity at discharge was high, with 34% of patients congested, 26% mildly hypervolemic (+8%-+22% excess), 34% normovolemic, and 10% hypovolemic (<−8% deficit) (TBV range: −27.9% to 73.7%). 27% were anemic and 17% polycythemic (nHct range: 16.3% to 62.4%). Of 17 patients who had a 30-day readmission, 15/17 had persistent congestion (n = 7) or anemia (n = 8) at discharge. 30-day readmissions rates (RR) were 62% and 44% for those anemic and congested at discharge, respectively; 52% for those with ≥1 risk factor; and 14% for those with near normal RBCV and normovolemic or mildly hypervolemic at discharge (2/14 readmitted). Risk factor analysis was not attempted for polycythemia or hypovolemia (n = 8 and n = 3, respectively). Conclusions: In this first cohort of HF patients to be evaluated by BVA at Lankenau Medical Center we identified a strong association of severe persistent congestion and/or anemia with 30-day readmission risk. Best practices are currently being established for optimal utilization of BVA in the HF setting, and strategies to reduce readmissions may include direct assessment of decongestion adequacy prior to discharge, more proactive management of anemia, and targeting those with greater TBV and RCBV derangement for more intense post-discharge follow-up. Variance in TBV and RBCV was higher than expected, suggesting an unmet medical need for accurate TBV and RBCV quantification to enable individualized management.

Anticoagulation in patients with atrial fibrillation is essential to reduce morbidity and mortality associated with stroke, but at the same time the risk of bleeding needs to be carefully considered. There have been many recent developments in anticoagulation to improve medical management of these patients. CHA(2)DS(2)-VASc and HAS-BLED are two new algorithms that clinicians may use prior to initiating anticoagulation to estimate the risk of stroke and bleeding in patients with atrial fibrillation. In addition, new classes of oral anticoagulants such as direct thrombin inhibitors and selective Factor Xa inhibitors have emerged and consist of agents that aim to address many of the practical management challenges of warfarin. In this review of the literature, results of the clinical trials involving these new agents will be discussed and compared, with a focus on the balance between efficacy and safety.

BACKGROUND:An analysis of the US National Cardiovascular Data Registry has revealed that only 38% of patients referred for coronary angiography after non-invasive coronary testing have relevant coronary obstruction (CO) (≥70%) of one or more coronary arteries.METHODS:A single-center trial was undertaken in 165 consecutive, symptomatic patients with either known or suspected coronary disease and/or valve disease(VHD) who agreed to undergo cardiac catheterization and coronary angiography if stress myocardial perfusion imaging was abnormal. A total of 116 patients with abnormal SPECT MPI tests, persistent chest pain, or significant VHD underwent final analysis. An MCG coronary obstruction (CO) score of ≥ 4.0 was considered indicative of relevant CO (≥70%) in one or more coronary arteries. Angiographic results were finalized by consensus of two angiographers.RESULTS:CO (≥70%) was present in 53 of 116 patients (46%). The MCG CO score was significantly higher for patients with relevant CO (5.4 ± 1.9 vs. 2.5 ± 1.9). The MCG correctly classified 103 of the 116 patients (89%) enrolled in the study as either having or not having CO (≥70%) (sensitivity- 91%; specificity- 87%; NPV- 92%; PPV- 86%). SPECT MPI was abnormal in 99 of the 116 (85%) patients undergoing catheterization, but correctly classified only 54 of the 116 patients (47%) entered in the study as either having or not having relevant CO (sensitivity-85%; specificity-14%; NPV - 53%; PPV- 45%).CONCLUSIONS:The MCG was shown in this paired-comparison trial with SPECT MPI to safely and accurately identify patients with relevant CO (≥70%) prior to catheterization.

Many physicians treating patients with heart failure utilize the serum B-Natriuretic Peptide (BNP) as a guide to determine the presence of fluid retention and the quantification of diuretic therapy. The manufacturers of BNP testing equipment make no claim that it is a surrogate for blood or plasma volume measurements. Since BNP is predominantly released by the ventricular myocytes in response to stretch or increases in wall tension caused by intrinsic myocardial abnormalities, its common use as a surrogate marker for fluid retention and/or decisions regarding the need for diuretic adjustments therapy, requires careful re-examination. The correlation between time-related venous BNP and Iodine-131 labeled Albumin measurement of blood volume (BVA-100, Daxor, NY) was made in 151 patients admitted to the heart failure service of a community hospital over the past 2.5 years. The patients entered in the study had ejection fractions by echocardiography, MUGA, or cardiac MRI that varied from 10% to 80%. There were 65 females and 86 males enrolled and the ages of the patients ranged from 38 to 94. There was no exclusion of patients or correction of the data for intrinsic renal function or body mass index. The results indicated that there was no significant correlation between serum BNP and Total Blood Volume measurement expressed either as a % deviation from Ideal Blood Volume or as the Absolute Blood Volume meassurement. In addition, there was no correlation between serum BNP measurements and Total Blood Volume or the % deviation from Ideal Blood Volume when the data was straified by gender or age. Over 60% of the patients enrolled had measured reductions in Red Cell Volumes of greater than 10% from the Ideal Red Cell Volume indicating the high prevalence of anemia in these patients. These data represent the largest study to date correlating serum BNP to Iodine-131 labeled Albumin blood volume measurements. Previous studies have shown a lack of correlation between BNP and Blood Volume in acutely ill post-surgical patients and in a small cohort of patients undergoing pulmonary artery catheterization. In both studies, hemodynamics correlated significantly with Blood Volume measurements. These findings lend new credence to the use of Blood Volume measurements in conjunction with clinical assessment to guide diuretic therapy or other forms of renal replacement therapy in heart failure patients.

As of 2010 Coronary Artery Disease, remains the number 1 cause of death for people of all ages in the United States. 1 in 3 women will die from coronary artery disease, yet research and diagnostic techniques have traditionally focused on men, leading to a significant gender gap in knowledge and diagnostic accuracy. Premier heart’s Multifunction Cardiogram (MCG) technology represents the best available noninvasive, stress, radiation and drug free approach to detecting CAD ischemia without any gender bias. MCG has been validated in multiple prospective clinical trial comparing MCG results to the invasive coronary angiography as the gold standard for CAD diagnosis for the ability to detect and quantify ischemia resulting from CAD earlier, cheaper with the highest accuracy available.

The STICH trial was designed to compare coronary bypass (CABG) alone vs. CABG plus surgical ventricular reconstruction (SVR) in patients with left ventricular (LV) dysfunction and akinetic or dyskinetic LV segments from prior anterior wall myocardial infarction (MI). It reported1 that adding SVR to coronary bypass CABG was not associated with a greater improvement in symptoms, exercise tolerance, or reduced intermediate mortality. This trial was federally funded to provide evidence-based methodology for this comparison, but its implementation was faulty in many ways. Surgical ventricular reconstruction treats congestive heart failure (CHF) by reducing LV volume, perhaps the most powerful predictor of mortality in dilated cardiomyopathy and more predictive than ejection fraction (EF)2–4 (Figures 1 and 2). The 490 patients who underwent SVR in STICH was predicated on favourable reports of recovery in over 5000 patients worldwide and registry data from approximately 1200 patients that decreased LV end-systolic volume index (LVESVI) ∼40% (ranging 30–58%, Table 1),5–8 but had different results. Is SVR an improper concept or was the STICH trial improperly executed? Eligibility for STICH required that 'all patients will be evaluated further for appropriateness of SVR indicated by evidence of absent viability in the anterior ventricle by nuclear scan determination, LVESVI ≥60 ml/m2, and akinesia ≥35% of the anterior wall' (http://clinicaltrials.gov/archine/NTC00023595/2005_06_23). Echocardiography was specifically excluded for measuring LV volume because of its inaccuracy when regional asynergy is present.9 Selection of STICH centres was based on capability to measure volume by cardiac magnetic resonance (CMR) imaging (Excerpt 1). However, STICH enrolled a quite different group of patients, namely those with NYHA Class II–IV CHF (within 3 months of entry), coronary artery disease that was amenable to CABG, an EF ≤35% [defined by echocardiogram, left ventriculogram, CMR, or gated single photon (SPECT) studies], and 'dominant anterior left ventricular dysfunction'. Accurate viability and LV volume were not done in all patients as planned. STICH required that all patients have dyskinesia or akinesia with evidence of non-viability in 35% of the anterior ventricular wall (Excerpt 2). Dyskinesia is caused by no reperfusion of the LV after infarction. Akinesia accompanies early thrombolysis or angioplasty and results in a dilated but thick LV. STICH, however, reports that only half of patients had akinesia or dyskinesia and 13% had no prior history of infarction. Surgical ventricular reconstruction has never been reported or recommended in patients with regional dysfunction alone and absent scar.5,7 The STICH surgical therapy committee specifically defined SVR as 'any ventricular reconstruction method that consistently results in a low operative mortality, an average EF increase of ≥10%, and an average LVESVI decrease of ≥30% as assessed on the four-month post-operative CMR measurement' (Excerpt 3). STICH, however, measured LVESVI in only 212 of 490 patients (43%) in the CABG-only group and in 161 of 490 patients (33%) in the CABG plus SVR group by echocardiography. The number of CMR measurements is not given. STICH reported that SVR lowered LVESVI an average of only 19%. Patients should be excluded from the analysis if the originally defined goals were not met. Patients in the SVR trial underwent SVR based on qualitative rather than quantitative assessment. Perhaps they had hibernation of ischaemic areas or post-infarction stunning, both of which are clearly not indications for SVR. Surgeons cannot know when SVR should be performed without accurate viability and volume information. The STICH patients cannot be compared with previously reported patients with SVR. Dor's5,7 1000 patients and the 1198 patients in the RESTORE group had prior history of MI, akinesia, or dyskinesia involving ≥35% of the LV, reduced EF, and LVESVI ≥60 mL/m2. Furthermore, only 49% of patients in STICH had NYHA class III or IV CHF vs. >66% in the RESTORE registry.5 STICH trial original protocol deviations can be viewed in 'history of changes' on: http://clinicaltrials.gov/show/NCT00023595. Why was accurate LVESVI by CMR or nuclear study retracted? The principal investigator may change the protocol, but only with approval from the NIH grant administration officer. Though it does not require approval from other trial participants, the grant administrator must assume the responsibility for investigational review board (IRB) notification of changes for all trial participants. The STICH publication does not report changes during the trial. The 50 original STICH centres expanded to 127 in 26 countries (Excerpt 4). A total of 489 patients underwent CABG plus SVR, an average of only four operations per site done by surgeons whose only certification was an operative mortality of 5% or less in 25 patients who underwent CABG with EF ≤40% with 'consistent post-operative decrease in LV volume in five consecutive patients who survived the operation'. STICH surgeons did not meet the benchmark reduction in LVESVI of ≥30%, as the average decrease in volume was only 19%. Were the operations in the STICH trial true SVR operations, consistent with those described in multiple publications, or merely small LV plications or limited intracavitary reconstructions? Originally, eligible patients for SVR in STICH were those with discreet scar, an asynergic area of ≥35%, and LVESVI ≥60 mL/m2. This volume was also chosen because progressive ventricular remodelling is not prevented after aortic or mitral valve replacement if the LVESVI ≥60 mL/m2.2,10 An analysis of STICH SVR patients with preoperative LVESVI ≥60 mL/m2 and accurate post-operative LV reduction of >30% should be reported, as these are the patients who benefit from SVR according to all published series. We conclude that the STICH trial is misleading because SVR procedures were not uniformly or effectively performed in properly selected patients. STICH has failed to meet the goals expected from an evidence-based study. Internists and cardiologists must be aware of the extensive registry data that confirms the long-term efficacy of SVR in a select group of patients operated on by experienced surgeons who can reliably exclude scarred LV segments, thereby reducing volume and reshaping the chamber. Extensive worldwide application of SVR confirms its beneficial effect on remote muscle function, regional wall synchronicity, and global systolic function. Surgical ventricular reconstruction reduces neurohormonal activators and improves the functional status of CHF patients.11 Such findings cannot be ignored on the basis of a single flawed study. Surgical ventricular reconstruction is an effective operation when performed by properly trained surgeons in correctly selected patients. An accurately executed trial with evidence-based methodology is required to refine the indications of SVR in subgroups of CHF patients. Excerpt 1 Initial evaluation of patients for eligibility for randomization in specified stratum Therefore, a two-step process is proposed. The first step uses the best available LV assessment by either a contrast, gated SPECT, or CMR ventriculogram read at the clinical sites or a resting echocardiogram read by the Echo Laboratory. This first step will identify patients meeting LVEF entry criteria and characterize the extent of anterior LV wall dysfunction needed to evaluate SVR eligibility After completion of the first step, patients will be approached for informed consent for randomization The second step to confirm the accuracy of these criteria by CMR or RN LV assessment proceeds only in consenting patients 'Unpublished information from funded STICH Grant document, that is "publicly available" through the Freedom of Information Act'. Bold type added by authors Excerpt 2 B.3. Rationale for noninvasive cardiac imaging studies The common clinical practice of not offering CABG to patients with LV dysfunction in regions found to be non-viable on noninvasive studies is not justified by published data The STICH trial proposes to use core laboratories for cardiac magnetic resonance (CMR), echocardiography (ECHO), and radionuclide (RN) studies to insure standardization of testing practices and of data analysis for operational use of these studies in the STICH trial 'Unpublished information from funded STICH Grant document, that is "publicly available" through the Freedom of Information Act'. Bold type added by authors Excerpt 3 CABG + SVR definition. The two criteria used by the Surgical Therapy Committee to define the acceptable range of specific operative manoeuvres essential to be considered an acceptable technical SVR operation for the STICH trial will be any ventricular reconstruction method that consistently results in: (i) a low operative mortality; and (ii) an average EF increase of 10% and average LVESVI decrease of 30% as assessed on the 4-month postoperative CMR measurement 'Unpublished information from funded STICH Grant document, that is "publicly available" through the Freedom of Information Act'. Bold type added by authors Excerpt 4 Over 3 years, 50 clinical sites will recruit 2800 patients with heart failure, left ventricular ejection fraction less than 0.35, and CAD amenable to CABG From http://clinicaltrials.gov/show/NCT00023595 Conflict of interest: C.L.A. and G.D.B. are co-holders of a left ventricular reconstruction device patent. This device is not commercially produced.

OBJECTIVE:Hypertension affects 73 million Americans and costs the US healthcare system over $73 billion annually. Despite increasing awareness of the consequences of uncontrolled hypertension, numerous antihypertensive pharmacologic clinical studies and consistent updates to hypertension guidelines, control rates are suboptimal and have not met national goals. Among treated hypertensives, only 45% of women and 51% of men have reached blood pressure (BP) levels below 140/90 mmHg. Individualization of antihypertensive regimens with hemodynamic information from impedance cardiography (ICG) has been advocated to further improve hypertension control rates. We therefore undertook a quantitative analysis of the trials evaluating the role of ICG as an adjunct to therapeutic decision-making in the treatment of hypertension and the attainment of BP control.METHODS:Five studies comprising a total population of 759 patients met the inclusion criteria. Two randomized controlled trials (RCTs) involving a total of 268 patients and three single-arm prospective trials with 491 patients were evaluated using ICG data to guide therapeutic decision-making in the treatment of hypertensive patients.RESULTS:Significant benefit was found in both RCTs for ICG-guided BP treatment. The combined odds ratio for the two trials was 2.41 (95% CI = 1.44-4.05, p = 0.0008), in favor of ICG treatment, meaning that it was more than twice as likely to achieve BP success when using ICG than if ICG was not used. Success attainment of goal BP of <140/90 mmHg was 67% in the ICG-guided arms of the combined randomized trials. Overall success in the single-arm prospective trials of ICG-guided BP treatment was a similar 68%.CONCLUSION:The results of this meta-analysis confirm the value of using ICG-derived hemodynamic data as an adjunct to therapeutic decision-making in the treatment of hypertension. The data reviewed here demonstrate that ICG-based approaches are in keeping with previously advocated strategies incorporating patient-individualized drug regimens, evidence-based medicine, and practical, easy to apply, cost-effective principles to further improve hypertension control rates.