LOS ANGELES – Hang a do-not-disturb sign on brain arteriovenous malformations.

Patients who underwent invasive interventions to repair an unruptured arteriovenous malformation (AVM) in their brain faced a greater than two-fold increased rate of death or stroke during an average 4 years of follow-up, compared with patients who received medical treatment only with no active intervention, Dr. Christian Stapf reported at the International Stroke Conference.

When analyzed on an intention-to-treat basis, for every five AVM patients treated by endovascular surgery, conventional surgery, or radiotherapy, one additional patient died or had a stroke, compared with the death or stroke rate among control patients who received only medical management. When analyzed based on the treatments that patients actually received, the number-needed-to-harm fell to one excess death or stroke for every three AVM patients who underwent an invasive procedure, compared with control patients, reported Dr. Stapf, a professor in the department of neurosciences at the University of Montreal.

The results from A Randomized Trial of Unruptured Brain AVMs (ARUBA) “show us that we clearly have not been as good as we thought in helping patients against their stroke risk,” said Dr. Stapf in a video interview during the meeting. “Given that the risk of death or stroke was reduced three- to fivefold with no [invasive] treatment and leaving the AVM alone makes us think that we can’t recommend preventive intervention with currently-used techniques. Living with the AVM seems like the far better option.”

The ARUBA study, run at 39 centers in nine countries including 13 U.S. centers, randomized 226 patients with unruptured AVMs before the study’s data safety and monitoring board stopped study enrollment prematurely in April 2013. The study group included 110 patients randomized to receive medical interventions only and 116 randomized to medical intervention plus “best possible” AVM eradication. The exact type of eradication for each patient was left up to local clinicians, who tailored the intervention to address the size, location, and anatomy of each AVM. Medical management included steps such as treatment with antiepileptic drugs to treat seizures, various treatments for headaches, and physiotherapy for patients with neurologic deficits.

The study’s primary endpoint was the combined rate of death or stroke, which occurred in 41 of the 116 patients (35%) randomized to receive an invasive intervention and in 15 of the 110 (14%) randomized to medical treatment only during an average follow-up of 50 months, with many patients followed for 5 years.

When analyzed by the treatment patients actually received, 106 underwent an invasive intervention and 43 of these patients (41%) died or had a stroke, and 120 patients received medical treatments only, of whom 13 (11%) died or had a stroke.

A secondary endpoint was the rate of death or disability after 5-year follow-up, with disability defined as a modified Rankin Scale score of 2 or more. This occurred in 38% of the 45 patients who underwent AVM eradication and had this follow-up available, and in 18% of 51 patients who had medial treatment only and received this follow-up.

Interim results from the study came out 2 years ago, with an average follow-up of 33 months (Lancet. 2014 Feb 15;383[9917]:614-21), but the trial was designed to have 5-year follow-up, largely accomplished in the new data reported by Dr. Stapf.

Many clinicians had already abandoned invasive interventions to treat brain AVMs following release of the interim results, and Dr. Stapf predicted that this trend will further strengthen now that the final results are in and confirm the earlier indication of hazard. Until the ARUBA results became available, clinicians had presumed invasive interventions to resolve or minimize malformations were beneficial based on intuition. ARUBA is the first systematic comparison of procedures versus a hands-off approach for brain AVMs, he said.

“Neurologists will now be less likely to refer patients for intervention, and interventionalists will be less enthusiastic to perform procedures,” Dr. Stapf said during the meeting, sponsored by the American Heart Association. In addition, anyone now performing an intervention in routine practice would need to consider the possible legal implications if the patient were to have a bad outcome. Dr. Stapf also noted that some professional societies are now considering recommendations against routine interventions. He conceded that some invasive interventions might still occur for selected cases on an investigational basis, but the ARUBA results “set the bar very high against performing any new interventions,” he concluded.

Approximately 3,000 patients annually are newly diagnosed with an unruptured brain AVM in the United States and Canada, he estimated.

ARUBA received no commercial support. Dr. Stapf had no disclosures.

[email protected]

On Twitter @mitchelzoler

LOS ANGELES – Hang a do-not-disturb sign on brain arteriovenous malformations.

Patients who underwent invasive interventions to repair an unruptured arteriovenous malformation (AVM) in their brain faced a greater than two-fold increased rate of death or stroke during an average 4 years of follow-up, compared with patients who received medical treatment only with no active intervention, Dr. Christian Stapf reported at the International Stroke Conference.

When analyzed on an intention-to-treat basis, for every five AVM patients treated by endovascular surgery, conventional surgery, or radiotherapy, one additional patient died or had a stroke, compared with the death or stroke rate among control patients who received only medical management. When analyzed based on the treatments that patients actually received, the number-needed-to-harm fell to one excess death or stroke for every three AVM patients who underwent an invasive procedure, compared with control patients, reported Dr. Stapf, a professor in the department of neurosciences at the University of Montreal.

The results from A Randomized Trial of Unruptured Brain AVMs (ARUBA) “show us that we clearly have not been as good as we thought in helping patients against their stroke risk,” said Dr. Stapf in a video interview during the meeting. “Given that the risk of death or stroke was reduced three- to fivefold with no [invasive] treatment and leaving the AVM alone makes us think that we can’t recommend preventive intervention with currently-used techniques. Living with the AVM seems like the far better option.”

The ARUBA study, run at 39 centers in nine countries including 13 U.S. centers, randomized 226 patients with unruptured AVMs before the study’s data safety and monitoring board stopped study enrollment prematurely in April 2013. The study group included 110 patients randomized to receive medical interventions only and 116 randomized to medical intervention plus “best possible” AVM eradication. The exact type of eradication for each patient was left up to local clinicians, who tailored the intervention to address the size, location, and anatomy of each AVM. Medical management included steps such as treatment with antiepileptic drugs to treat seizures, various treatments for headaches, and physiotherapy for patients with neurologic deficits.

The study’s primary endpoint was the combined rate of death or stroke, which occurred in 41 of the 116 patients (35%) randomized to receive an invasive intervention and in 15 of the 110 (14%) randomized to medical treatment only during an average follow-up of 50 months, with many patients followed for 5 years.

When analyzed by the treatment patients actually received, 106 underwent an invasive intervention and 43 of these patients (41%) died or had a stroke, and 120 patients received medical treatments only, of whom 13 (11%) died or had a stroke.

A secondary endpoint was the rate of death or disability after 5-year follow-up, with disability defined as a modified Rankin Scale score of 2 or more. This occurred in 38% of the 45 patients who underwent AVM eradication and had this follow-up available, and in 18% of 51 patients who had medial treatment only and received this follow-up.

Interim results from the study came out 2 years ago, with an average follow-up of 33 months (Lancet. 2014 Feb 15;383[9917]:614-21), but the trial was designed to have 5-year follow-up, largely accomplished in the new data reported by Dr. Stapf.

Many clinicians had already abandoned invasive interventions to treat brain AVMs following release of the interim results, and Dr. Stapf predicted that this trend will further strengthen now that the final results are in and confirm the earlier indication of hazard. Until the ARUBA results became available, clinicians had presumed invasive interventions to resolve or minimize malformations were beneficial based on intuition. ARUBA is the first systematic comparison of procedures versus a hands-off approach for brain AVMs, he said.

“Neurologists will now be less likely to refer patients for intervention, and interventionalists will be less enthusiastic to perform procedures,” Dr. Stapf said during the meeting, sponsored by the American Heart Association. In addition, anyone now performing an intervention in routine practice would need to consider the possible legal implications if the patient were to have a bad outcome. Dr. Stapf also noted that some professional societies are now considering recommendations against routine interventions. He conceded that some invasive interventions might still occur for selected cases on an investigational basis, but the ARUBA results “set the bar very high against performing any new interventions,” he concluded.

Approximately 3,000 patients annually are newly diagnosed with an unruptured brain AVM in the United States and Canada, he estimated.

ARUBA received no commercial support. Dr. Stapf had no disclosures.

[email protected]

On Twitter @mitchelzoler

LOS ANGELES – Hang a do-not-disturb sign on brain arteriovenous malformations.

Patients who underwent invasive interventions to repair an unruptured arteriovenous malformation (AVM) in their brain faced a greater than two-fold increased rate of death or stroke during an average 4 years of follow-up, compared with patients who received medical treatment only with no active intervention, Dr. Christian Stapf reported at the International Stroke Conference.

When analyzed on an intention-to-treat basis, for every five AVM patients treated by endovascular surgery, conventional surgery, or radiotherapy, one additional patient died or had a stroke, compared with the death or stroke rate among control patients who received only medical management. When analyzed based on the treatments that patients actually received, the number-needed-to-harm fell to one excess death or stroke for every three AVM patients who underwent an invasive procedure, compared with control patients, reported Dr. Stapf, a professor in the department of neurosciences at the University of Montreal.

The results from A Randomized Trial of Unruptured Brain AVMs (ARUBA) “show us that we clearly have not been as good as we thought in helping patients against their stroke risk,” said Dr. Stapf in a video interview during the meeting. “Given that the risk of death or stroke was reduced three- to fivefold with no [invasive] treatment and leaving the AVM alone makes us think that we can’t recommend preventive intervention with currently-used techniques. Living with the AVM seems like the far better option.”

The ARUBA study, run at 39 centers in nine countries including 13 U.S. centers, randomized 226 patients with unruptured AVMs before the study’s data safety and monitoring board stopped study enrollment prematurely in April 2013. The study group included 110 patients randomized to receive medical interventions only and 116 randomized to medical intervention plus “best possible” AVM eradication. The exact type of eradication for each patient was left up to local clinicians, who tailored the intervention to address the size, location, and anatomy of each AVM. Medical management included steps such as treatment with antiepileptic drugs to treat seizures, various treatments for headaches, and physiotherapy for patients with neurologic deficits.

The study’s primary endpoint was the combined rate of death or stroke, which occurred in 41 of the 116 patients (35%) randomized to receive an invasive intervention and in 15 of the 110 (14%) randomized to medical treatment only during an average follow-up of 50 months, with many patients followed for 5 years.

When analyzed by the treatment patients actually received, 106 underwent an invasive intervention and 43 of these patients (41%) died or had a stroke, and 120 patients received medical treatments only, of whom 13 (11%) died or had a stroke.

A secondary endpoint was the rate of death or disability after 5-year follow-up, with disability defined as a modified Rankin Scale score of 2 or more. This occurred in 38% of the 45 patients who underwent AVM eradication and had this follow-up available, and in 18% of 51 patients who had medial treatment only and received this follow-up.

Interim results from the study came out 2 years ago, with an average follow-up of 33 months (Lancet. 2014 Feb 15;383[9917]:614-21), but the trial was designed to have 5-year follow-up, largely accomplished in the new data reported by Dr. Stapf.

Many clinicians had already abandoned invasive interventions to treat brain AVMs following release of the interim results, and Dr. Stapf predicted that this trend will further strengthen now that the final results are in and confirm the earlier indication of hazard. Until the ARUBA results became available, clinicians had presumed invasive interventions to resolve or minimize malformations were beneficial based on intuition. ARUBA is the first systematic comparison of procedures versus a hands-off approach for brain AVMs, he said.

“Neurologists will now be less likely to refer patients for intervention, and interventionalists will be less enthusiastic to perform procedures,” Dr. Stapf said during the meeting, sponsored by the American Heart Association. In addition, anyone now performing an intervention in routine practice would need to consider the possible legal implications if the patient were to have a bad outcome. Dr. Stapf also noted that some professional societies are now considering recommendations against routine interventions. He conceded that some invasive interventions might still occur for selected cases on an investigational basis, but the ARUBA results “set the bar very high against performing any new interventions,” he concluded.

Approximately 3,000 patients annually are newly diagnosed with an unruptured brain AVM in the United States and Canada, he estimated.

ARUBA received no commercial support. Dr. Stapf had no disclosures.

[email protected]

On Twitter @mitchelzoler

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

Abstract

• Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
• Methods: Review of the literature.
• Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
• Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m² vs 1.8 ± 0.4 L/min/m²; P = 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; P = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; P = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

Diuretic Responsiveness

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl₂-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, [email protected].

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

Abstract

• Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
• Methods: Review of the literature.
• Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
• Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m² vs 1.8 ± 0.4 L/min/m²; P = 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; P = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; P = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

Diuretic Responsiveness

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl₂-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, [email protected].

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

Abstract

• Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
• Methods: Review of the literature.
• Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
• Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m² vs 1.8 ± 0.4 L/min/m²; P = 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; P = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; P = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

Diuretic Responsiveness

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl₂-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, [email protected].

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

VAGINAL/RECTAL PROBES FOR LAPAROSCOPYBanyan Medical’s Vaginal/Rectal Probes are low-cost reusable instruments used to enhance accurate anatomical visualization during gynecologic surgery. They are designed to be easily positioned to maximize anatomical visualization during excision of lesions from the posterior vagina, rectum, and cul-de-sac. According to the manufacturer, use of one of their probes ensures maximum accuracy; assists in opening the rectovaginal pouch and mapping of the cul-de-sac; can be used to help identify open vessels and other injuries; and acts as a mobilizer when dissecting, cauterizing, and suturing.

Banyan Medical assures that its vaginal/rectal probes are easy to sterilize and ergonomic. Probes have color-coded handles, surgical-grade stainless steel shafts, and atraumatic tips made of high-grade polymer.

FOR MORE INFORMATION, VISIT: http://banyanmedllc.com

ONLINE EDUCATIONAL VIDEO RESOURCEDoctablet is an online educational video resource that offers animated narratives in English and Spanish that describe medical conditions to patients. Jose M. Taveras, MD, a cardiologist at Montefiore Center for Heart and Vascular Care in New York and Christopher R. Palmeiro, MD, chairman of endocrinology at HealthAlliance of the Hudson Valley in Kingston, New York, have developed this free educational platform, which they describe as easily accessible, comprehensive, and entertaining.

Drs. Taveras and Palmeiro note that they created Doctablet to educate people about crucial health issues. They cite the pressures of shrinking budgets and the fact that physicians have less time for individualized care and education and that all too often a patient leaves her physician’s office without clear and direct crucial information.

“I’ve found myself telling little simple stories to my patients to illustrate various heart conditions. They’ve really helped—I’ve seen people quit smoking and seen people become proactive in taking their medication,” says Dr. Taveras. “The way to seriously impact patients, and reduce the need for procedures, is to change the way people live. You do that through taking the time to educate them in a way that makes sense to them.”

The patient-oriented videos are “jargon-free,” approximately 3 minutes in length, and cover health topics such as prediabetes and diabetes, nutrition, and cardiac care and heart attacks.

FOR MORE INFORMATION, VISIT: www.doctablet.com

FERTILITY-FRIENDLY LUBRICANTPre-Seed^® Fertility-Friendly Lubricant is specially formulated for couples trying to conceive. Pre-Seed was invented by a sperm physiologist who discovered that many couples were using lubricants that killed sperm. The National Institutes of Health funded research to develop Pre-Seed’s patented sperm-safe lubricant formula. In a January 2014 clinical study published in The Journal of Assisted Reproduction and Genetics, Mowat and colleagues analyzed the effects of 9 lubricants on sperm motility, vitality, and DNA fragmentation. The study authors named Pre-Seed as the leading lubricant of choice for couples who are trying to get pregnant.

Pre-Seed’s design mimics fertile cervical mucus in its pH, ion concentration, and consistency, says its inventor. In addition, Pre-Seed is glycerin-free to allow sperm to swim freely and formulated with antioxidants to help support sperm on their journey to fertilize the egg. Pre-Seed is available nationally at major drug and discount stores, and is offered by select regional and Internet retailers.

FOR MORE INFORMATION, VISIT: www.preseed.com

SONOHYSTEROGRAPHY DEVICECrossBay Medical Inc.™ offers SonoSure™, a single-use, disposable device to access the uterine cavity for saline infusion sonohysterography (SIS) and endometrial sampling. The product is designed to assist in the evaluation of a patient with abnormal uterine bleeding (AUB) or heavy menstrual periods.

CrossBay says that SonoSure is meant for single-handed use during concurrent ultrasonography. The device features a built-in deployed endometrial sampling brush, a low profile malleable insertion catheter, a repositionable cervical sealing mechanism for uterine distension designed to not obscure the lower uterine segment, and a 50-cc refillable fluid injection bag.

During SIS, the shapeable catheter with soft acorn tip can be used with anteversion or retroversion placement and provides uterine distention upon infusion and release for draining without the use of forceps. The echogenic tip and brush allow for visualization during insertion and placement. The blunt tip is designed to avoid uterine perforation.

FOR MORE INFORMATION, VISIT: http://crossbaymedicalinc.com/products/crossbay-women/sonosure

VAGINAL/RECTAL PROBES FOR LAPAROSCOPYBanyan Medical’s Vaginal/Rectal Probes are low-cost reusable instruments used to enhance accurate anatomical visualization during gynecologic surgery. They are designed to be easily positioned to maximize anatomical visualization during excision of lesions from the posterior vagina, rectum, and cul-de-sac. According to the manufacturer, use of one of their probes ensures maximum accuracy; assists in opening the rectovaginal pouch and mapping of the cul-de-sac; can be used to help identify open vessels and other injuries; and acts as a mobilizer when dissecting, cauterizing, and suturing.

Banyan Medical assures that its vaginal/rectal probes are easy to sterilize and ergonomic. Probes have color-coded handles, surgical-grade stainless steel shafts, and atraumatic tips made of high-grade polymer.

FOR MORE INFORMATION, VISIT: http://banyanmedllc.com

ONLINE EDUCATIONAL VIDEO RESOURCEDoctablet is an online educational video resource that offers animated narratives in English and Spanish that describe medical conditions to patients. Jose M. Taveras, MD, a cardiologist at Montefiore Center for Heart and Vascular Care in New York and Christopher R. Palmeiro, MD, chairman of endocrinology at HealthAlliance of the Hudson Valley in Kingston, New York, have developed this free educational platform, which they describe as easily accessible, comprehensive, and entertaining.

Drs. Taveras and Palmeiro note that they created Doctablet to educate people about crucial health issues. They cite the pressures of shrinking budgets and the fact that physicians have less time for individualized care and education and that all too often a patient leaves her physician’s office without clear and direct crucial information.

“I’ve found myself telling little simple stories to my patients to illustrate various heart conditions. They’ve really helped—I’ve seen people quit smoking and seen people become proactive in taking their medication,” says Dr. Taveras. “The way to seriously impact patients, and reduce the need for procedures, is to change the way people live. You do that through taking the time to educate them in a way that makes sense to them.”

The patient-oriented videos are “jargon-free,” approximately 3 minutes in length, and cover health topics such as prediabetes and diabetes, nutrition, and cardiac care and heart attacks.

FOR MORE INFORMATION, VISIT: www.doctablet.com

FERTILITY-FRIENDLY LUBRICANTPre-Seed^® Fertility-Friendly Lubricant is specially formulated for couples trying to conceive. Pre-Seed was invented by a sperm physiologist who discovered that many couples were using lubricants that killed sperm. The National Institutes of Health funded research to develop Pre-Seed’s patented sperm-safe lubricant formula. In a January 2014 clinical study published in The Journal of Assisted Reproduction and Genetics, Mowat and colleagues analyzed the effects of 9 lubricants on sperm motility, vitality, and DNA fragmentation. The study authors named Pre-Seed as the leading lubricant of choice for couples who are trying to get pregnant.

Pre-Seed’s design mimics fertile cervical mucus in its pH, ion concentration, and consistency, says its inventor. In addition, Pre-Seed is glycerin-free to allow sperm to swim freely and formulated with antioxidants to help support sperm on their journey to fertilize the egg. Pre-Seed is available nationally at major drug and discount stores, and is offered by select regional and Internet retailers.

FOR MORE INFORMATION, VISIT: www.preseed.com

SONOHYSTEROGRAPHY DEVICECrossBay Medical Inc.™ offers SonoSure™, a single-use, disposable device to access the uterine cavity for saline infusion sonohysterography (SIS) and endometrial sampling. The product is designed to assist in the evaluation of a patient with abnormal uterine bleeding (AUB) or heavy menstrual periods.

CrossBay says that SonoSure is meant for single-handed use during concurrent ultrasonography. The device features a built-in deployed endometrial sampling brush, a low profile malleable insertion catheter, a repositionable cervical sealing mechanism for uterine distension designed to not obscure the lower uterine segment, and a 50-cc refillable fluid injection bag.

During SIS, the shapeable catheter with soft acorn tip can be used with anteversion or retroversion placement and provides uterine distention upon infusion and release for draining without the use of forceps. The echogenic tip and brush allow for visualization during insertion and placement. The blunt tip is designed to avoid uterine perforation.

FOR MORE INFORMATION, VISIT: http://crossbaymedicalinc.com/products/crossbay-women/sonosure

VAGINAL/RECTAL PROBES FOR LAPAROSCOPYBanyan Medical’s Vaginal/Rectal Probes are low-cost reusable instruments used to enhance accurate anatomical visualization during gynecologic surgery. They are designed to be easily positioned to maximize anatomical visualization during excision of lesions from the posterior vagina, rectum, and cul-de-sac. According to the manufacturer, use of one of their probes ensures maximum accuracy; assists in opening the rectovaginal pouch and mapping of the cul-de-sac; can be used to help identify open vessels and other injuries; and acts as a mobilizer when dissecting, cauterizing, and suturing.

Banyan Medical assures that its vaginal/rectal probes are easy to sterilize and ergonomic. Probes have color-coded handles, surgical-grade stainless steel shafts, and atraumatic tips made of high-grade polymer.

FOR MORE INFORMATION, VISIT: http://banyanmedllc.com

ONLINE EDUCATIONAL VIDEO RESOURCEDoctablet is an online educational video resource that offers animated narratives in English and Spanish that describe medical conditions to patients. Jose M. Taveras, MD, a cardiologist at Montefiore Center for Heart and Vascular Care in New York and Christopher R. Palmeiro, MD, chairman of endocrinology at HealthAlliance of the Hudson Valley in Kingston, New York, have developed this free educational platform, which they describe as easily accessible, comprehensive, and entertaining.

Drs. Taveras and Palmeiro note that they created Doctablet to educate people about crucial health issues. They cite the pressures of shrinking budgets and the fact that physicians have less time for individualized care and education and that all too often a patient leaves her physician’s office without clear and direct crucial information.

“I’ve found myself telling little simple stories to my patients to illustrate various heart conditions. They’ve really helped—I’ve seen people quit smoking and seen people become proactive in taking their medication,” says Dr. Taveras. “The way to seriously impact patients, and reduce the need for procedures, is to change the way people live. You do that through taking the time to educate them in a way that makes sense to them.”

The patient-oriented videos are “jargon-free,” approximately 3 minutes in length, and cover health topics such as prediabetes and diabetes, nutrition, and cardiac care and heart attacks.

FOR MORE INFORMATION, VISIT: www.doctablet.com

FERTILITY-FRIENDLY LUBRICANTPre-Seed^® Fertility-Friendly Lubricant is specially formulated for couples trying to conceive. Pre-Seed was invented by a sperm physiologist who discovered that many couples were using lubricants that killed sperm. The National Institutes of Health funded research to develop Pre-Seed’s patented sperm-safe lubricant formula. In a January 2014 clinical study published in The Journal of Assisted Reproduction and Genetics, Mowat and colleagues analyzed the effects of 9 lubricants on sperm motility, vitality, and DNA fragmentation. The study authors named Pre-Seed as the leading lubricant of choice for couples who are trying to get pregnant.

Pre-Seed’s design mimics fertile cervical mucus in its pH, ion concentration, and consistency, says its inventor. In addition, Pre-Seed is glycerin-free to allow sperm to swim freely and formulated with antioxidants to help support sperm on their journey to fertilize the egg. Pre-Seed is available nationally at major drug and discount stores, and is offered by select regional and Internet retailers.

FOR MORE INFORMATION, VISIT: www.preseed.com

SONOHYSTEROGRAPHY DEVICECrossBay Medical Inc.™ offers SonoSure™, a single-use, disposable device to access the uterine cavity for saline infusion sonohysterography (SIS) and endometrial sampling. The product is designed to assist in the evaluation of a patient with abnormal uterine bleeding (AUB) or heavy menstrual periods.

CrossBay says that SonoSure is meant for single-handed use during concurrent ultrasonography. The device features a built-in deployed endometrial sampling brush, a low profile malleable insertion catheter, a repositionable cervical sealing mechanism for uterine distension designed to not obscure the lower uterine segment, and a 50-cc refillable fluid injection bag.

During SIS, the shapeable catheter with soft acorn tip can be used with anteversion or retroversion placement and provides uterine distention upon infusion and release for draining without the use of forceps. The echogenic tip and brush allow for visualization during insertion and placement. The blunt tip is designed to avoid uterine perforation.

FOR MORE INFORMATION, VISIT: http://crossbaymedicalinc.com/products/crossbay-women/sonosure

In 2016, the conversation over the safety of duodenoscopes has continued to evolve. Here’s what you need to know:

1. On Jan. 15, 2016, FDA approved a modified version of Olympus’ duodenoscope (TJF-Q180V), which has been redesigned to create a tighter seal and reduce the potential for leakage of patient fluids and tissue into the scope’s closed elevator channel. The previous reprocessing instructions remain in place; FDA urges facilities to continue to follow the validated manual reprocessing procedures outlined in the March 26, 2015, Safety Communication when reprocessing Olympus TJF-Q180V duodenoscopes.

2. Following FDA’s approval of its redesign, Olympus announced that it would recall all 4,400 of its TJF-Q180V model duodenoscopes in use around the country and replace the existing elevator mechanism with one designed to be less vulnerable to contamination.

3. Meanwhile, Senate minority staff have issued a report highlighting the need for additional oversight of medical devices, noting that the outbreak of antibiotic-resistant infections from duodenoscopes demonstrates the importance of multiple checks.

4. FDA has developed a web page specifically highlighting automated endoscope reprocessors (AERs), which provides a list of the companies whose AERs have passed the agency’s validation testing for reprocessing and decontaminating duodenoscopes.

Michael L. Kochman, M.D., AGAF, FASGE, chair of the AGA Center for GI Innovation and Technology, offers his comments on this news: “The recent announcements from Congress, FDA, and Olympus are welcomed. These announcements demonstrate that “Getting to Zero” is a priority for all parties to ensure that we are using the safest possible devices for our patients. It is reassuring that modifications to existing devices are being developed and that the responsible agencies are proactively adjusting recommendations in view of new data and findings. We anticipate additional changes to the devices and reprocessing recommendations and our members should stay tuned and be vigilant.”

AGA will continue to keep you updated on this important issue. As always, our goal is to ensure patients continue to have access to this medically necessary procedure, while removing any risk of device-transmitted infections.

In 2016, the conversation over the safety of duodenoscopes has continued to evolve. Here’s what you need to know:

1. On Jan. 15, 2016, FDA approved a modified version of Olympus’ duodenoscope (TJF-Q180V), which has been redesigned to create a tighter seal and reduce the potential for leakage of patient fluids and tissue into the scope’s closed elevator channel. The previous reprocessing instructions remain in place; FDA urges facilities to continue to follow the validated manual reprocessing procedures outlined in the March 26, 2015, Safety Communication when reprocessing Olympus TJF-Q180V duodenoscopes.

2. Following FDA’s approval of its redesign, Olympus announced that it would recall all 4,400 of its TJF-Q180V model duodenoscopes in use around the country and replace the existing elevator mechanism with one designed to be less vulnerable to contamination.

3. Meanwhile, Senate minority staff have issued a report highlighting the need for additional oversight of medical devices, noting that the outbreak of antibiotic-resistant infections from duodenoscopes demonstrates the importance of multiple checks.

4. FDA has developed a web page specifically highlighting automated endoscope reprocessors (AERs), which provides a list of the companies whose AERs have passed the agency’s validation testing for reprocessing and decontaminating duodenoscopes.

Michael L. Kochman, M.D., AGAF, FASGE, chair of the AGA Center for GI Innovation and Technology, offers his comments on this news: “The recent announcements from Congress, FDA, and Olympus are welcomed. These announcements demonstrate that “Getting to Zero” is a priority for all parties to ensure that we are using the safest possible devices for our patients. It is reassuring that modifications to existing devices are being developed and that the responsible agencies are proactively adjusting recommendations in view of new data and findings. We anticipate additional changes to the devices and reprocessing recommendations and our members should stay tuned and be vigilant.”

AGA will continue to keep you updated on this important issue. As always, our goal is to ensure patients continue to have access to this medically necessary procedure, while removing any risk of device-transmitted infections.

In 2016, the conversation over the safety of duodenoscopes has continued to evolve. Here’s what you need to know:

1. On Jan. 15, 2016, FDA approved a modified version of Olympus’ duodenoscope (TJF-Q180V), which has been redesigned to create a tighter seal and reduce the potential for leakage of patient fluids and tissue into the scope’s closed elevator channel. The previous reprocessing instructions remain in place; FDA urges facilities to continue to follow the validated manual reprocessing procedures outlined in the March 26, 2015, Safety Communication when reprocessing Olympus TJF-Q180V duodenoscopes.

2. Following FDA’s approval of its redesign, Olympus announced that it would recall all 4,400 of its TJF-Q180V model duodenoscopes in use around the country and replace the existing elevator mechanism with one designed to be less vulnerable to contamination.

3. Meanwhile, Senate minority staff have issued a report highlighting the need for additional oversight of medical devices, noting that the outbreak of antibiotic-resistant infections from duodenoscopes demonstrates the importance of multiple checks.

4. FDA has developed a web page specifically highlighting automated endoscope reprocessors (AERs), which provides a list of the companies whose AERs have passed the agency’s validation testing for reprocessing and decontaminating duodenoscopes.

Michael L. Kochman, M.D., AGAF, FASGE, chair of the AGA Center for GI Innovation and Technology, offers his comments on this news: “The recent announcements from Congress, FDA, and Olympus are welcomed. These announcements demonstrate that “Getting to Zero” is a priority for all parties to ensure that we are using the safest possible devices for our patients. It is reassuring that modifications to existing devices are being developed and that the responsible agencies are proactively adjusting recommendations in view of new data and findings. We anticipate additional changes to the devices and reprocessing recommendations and our members should stay tuned and be vigilant.”

AGA will continue to keep you updated on this important issue. As always, our goal is to ensure patients continue to have access to this medically necessary procedure, while removing any risk of device-transmitted infections.

Blood in bags and vials

Photo by Daniel Gay

Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.

Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.

But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.

So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.

To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.

The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).

Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).

The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.

However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).

On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).

The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.

However, such a strategy might impact other important neonatal outcomes, so further study is needed.

Blood in bags and vials

Photo by Daniel Gay

Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.

Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.

But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.

So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.

To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.

The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).

Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).

The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.

However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).

On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).

The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.

However, such a strategy might impact other important neonatal outcomes, so further study is needed.

Blood in bags and vials

Photo by Daniel Gay

Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.

Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.

But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.

So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.

To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.

The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).

Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).

The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.

However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).

On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).

The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.

However, such a strategy might impact other important neonatal outcomes, so further study is needed.

Early in 2015, SHM published the updated edition of the “Key Principles and Characteristics of an Effective Hospital Medicine Group,” which is a free download via the SHM website. Every hospitalist group should use this comprehensive list of attributes as one important frame of reference to guide ongoing improvement efforts and long-range planning.

In this column and the next two, I’ll split the difference between the very brief list of top success factors for hospitalist groups I wrote about in my March 2011 column and the very comprehensive “Key Characteristics” document. I think these attributes are among the most important to support a high-performing group, yet they are sometimes overlooked or implemented poorly. They are of roughly equal importance and are listed in no particular order.

Deliberately Cultivating a Culture (or Mindset) of Practice Ownership

It’s easy for hospitalists to think of themselves as employees who just work shifts but have no need or opportunity to attend to the bigger picture of the practice or the hospital in which they operate. After all, being a good doctor for your patients is an awfully big job itself, and lots of recruitment ads tell you doctoring is all that will be expected of you. Someone else will handle everything necessary to ensure your practice is successful.

This line of thinking will limit the success of your group.

Your group will perform much better and you’re likely to find your career much more rewarding if you and your hospitalist colleagues think of yourselves as owning your practice and take an active role in managing it. You’ll still need others to manage day-to-day business affairs, but at least a portion of the hospitalists in the group should be actively involved in planning and making decisions about the group’s operations and future evolution.

I encounter hospitalist groups that have become convinced they don’t even have the opportunity to shape or influence their practice. “No one ever listens,” they say. “The hospital executives just do what they want regardless of what we say.” But in nearly every case, that is an exaggeration. Most administrative leaders desperately want hospitalist engagement and thoughtful participation in planning and decision making.

I wrote additional thoughts about the importance of a culture, or mindset, of practice ownership in August 2008. The print version of that column included a short list of questions you could ask yourself to assess whether your own group has such a culture, but it is missing from the web version and can be found at nelsonflores.com/html/quiz.html.

A Formal System of Group ‘Governance’

So many hospitalist groups rely almost entirely on consensus to make decisions. This might work well enough for a very small group (e.g., four or five doctors), but for large groups, it means just one or two dissenters can block a decision and nothing much gets done.

Disagreements about practice operations and future direction are common, so every group should commit to writing some method of how votes will be taken in the absence of consensus. For example, the group might be divided about whether to adopt unit-based assignments or change the hours of an evening (“swing”) shift, and a formal vote might be the only way to make a decision. It’s best if you have decided in advance issues such as what constitutes a quorum, who is eligible to vote, and whether the winning vote requires a simple or super-majority. And a formalized system of voting helps support a culture ownership.

I wrote about this originally in December 2007 and provided sample bylaws your group could modify as needed. Of course, you should keep in mind that if you are indeed employed by a larger entity such as a hospital or staffing company, you don’t have the ability to make all decisions by a vote of the group. Pay raises, staff additions, and similar decisions require support of the employer, and while a vote in support of them might influence what actually happens, it still requires the support of the employer. But there are lots of things, like the work schedule, system of allocating patients across providers, etc., that are usually best made by the group itself, and sometimes they might come down to a vote of the group.

Never Stop Recruiting and Ensure Hospitalists Themselves Are Actively Engaged in Recruiting

I wrote about recruiting originally in July 2008 when there was a shortage of hospitalists everywhere. Since then, the supply of doctors seeking work as a hospitalist has caught up with demand in many major metropolitan areas like Minneapolis and Washington, D.C.

But outside of large markets—that is, in most of the country—demand for hospitalists still far exceeds supply, and groups face ongoing staffing deficits that come with the need for existing doctors to work extra shifts and use locum tenens or other forms of temporary staffing. The potential excess supply of hospitalists in major markets may eventually trickle out and ease the shortages elsewhere, but that hasn’t happened in a big way yet. So for these places, it is crucial to devote a lot of energy and resources to recruiting.

A vital component of successful recruiting is participation in the effort by the hospitalists themselves. I think the best mindset for the hospitalists is to think of themselves as leading recruitment efforts assisted by recruiters rather than the other way around. For example, the lead hospitalist or some other designated doctor should try to respond by phone (if that’s impractical, then respond by email) to every reasonable inquiry from a new candidate within 24 hours and serve as the candidate’s principle point of communication throughout the recruitment process. The recruiter can handle details of things like arranging travel for an interview, but a hospitalist in the group should be the main source of information regarding things like the work schedule, patient volume, compensation, etc. And a hospitalist should serve as the main host during a candidate’s on-site interview.

More to Come …

Next month, I’ll address things like a written policy and procedure manual, clear reporting relationships for the hospitalist group, and roles for advanced practice clinicians (NPs and PAs). TH

Early in 2015, SHM published the updated edition of the “Key Principles and Characteristics of an Effective Hospital Medicine Group,” which is a free download via the SHM website. Every hospitalist group should use this comprehensive list of attributes as one important frame of reference to guide ongoing improvement efforts and long-range planning.

In this column and the next two, I’ll split the difference between the very brief list of top success factors for hospitalist groups I wrote about in my March 2011 column and the very comprehensive “Key Characteristics” document. I think these attributes are among the most important to support a high-performing group, yet they are sometimes overlooked or implemented poorly. They are of roughly equal importance and are listed in no particular order.

Deliberately Cultivating a Culture (or Mindset) of Practice Ownership

It’s easy for hospitalists to think of themselves as employees who just work shifts but have no need or opportunity to attend to the bigger picture of the practice or the hospital in which they operate. After all, being a good doctor for your patients is an awfully big job itself, and lots of recruitment ads tell you doctoring is all that will be expected of you. Someone else will handle everything necessary to ensure your practice is successful.

This line of thinking will limit the success of your group.

Your group will perform much better and you’re likely to find your career much more rewarding if you and your hospitalist colleagues think of yourselves as owning your practice and take an active role in managing it. You’ll still need others to manage day-to-day business affairs, but at least a portion of the hospitalists in the group should be actively involved in planning and making decisions about the group’s operations and future evolution.

I encounter hospitalist groups that have become convinced they don’t even have the opportunity to shape or influence their practice. “No one ever listens,” they say. “The hospital executives just do what they want regardless of what we say.” But in nearly every case, that is an exaggeration. Most administrative leaders desperately want hospitalist engagement and thoughtful participation in planning and decision making.

I wrote additional thoughts about the importance of a culture, or mindset, of practice ownership in August 2008. The print version of that column included a short list of questions you could ask yourself to assess whether your own group has such a culture, but it is missing from the web version and can be found at nelsonflores.com/html/quiz.html.

A Formal System of Group ‘Governance’

So many hospitalist groups rely almost entirely on consensus to make decisions. This might work well enough for a very small group (e.g., four or five doctors), but for large groups, it means just one or two dissenters can block a decision and nothing much gets done.

Disagreements about practice operations and future direction are common, so every group should commit to writing some method of how votes will be taken in the absence of consensus. For example, the group might be divided about whether to adopt unit-based assignments or change the hours of an evening (“swing”) shift, and a formal vote might be the only way to make a decision. It’s best if you have decided in advance issues such as what constitutes a quorum, who is eligible to vote, and whether the winning vote requires a simple or super-majority. And a formalized system of voting helps support a culture ownership.

I wrote about this originally in December 2007 and provided sample bylaws your group could modify as needed. Of course, you should keep in mind that if you are indeed employed by a larger entity such as a hospital or staffing company, you don’t have the ability to make all decisions by a vote of the group. Pay raises, staff additions, and similar decisions require support of the employer, and while a vote in support of them might influence what actually happens, it still requires the support of the employer. But there are lots of things, like the work schedule, system of allocating patients across providers, etc., that are usually best made by the group itself, and sometimes they might come down to a vote of the group.

Never Stop Recruiting and Ensure Hospitalists Themselves Are Actively Engaged in Recruiting

I wrote about recruiting originally in July 2008 when there was a shortage of hospitalists everywhere. Since then, the supply of doctors seeking work as a hospitalist has caught up with demand in many major metropolitan areas like Minneapolis and Washington, D.C.

But outside of large markets—that is, in most of the country—demand for hospitalists still far exceeds supply, and groups face ongoing staffing deficits that come with the need for existing doctors to work extra shifts and use locum tenens or other forms of temporary staffing. The potential excess supply of hospitalists in major markets may eventually trickle out and ease the shortages elsewhere, but that hasn’t happened in a big way yet. So for these places, it is crucial to devote a lot of energy and resources to recruiting.

A vital component of successful recruiting is participation in the effort by the hospitalists themselves. I think the best mindset for the hospitalists is to think of themselves as leading recruitment efforts assisted by recruiters rather than the other way around. For example, the lead hospitalist or some other designated doctor should try to respond by phone (if that’s impractical, then respond by email) to every reasonable inquiry from a new candidate within 24 hours and serve as the candidate’s principle point of communication throughout the recruitment process. The recruiter can handle details of things like arranging travel for an interview, but a hospitalist in the group should be the main source of information regarding things like the work schedule, patient volume, compensation, etc. And a hospitalist should serve as the main host during a candidate’s on-site interview.

More to Come …

Next month, I’ll address things like a written policy and procedure manual, clear reporting relationships for the hospitalist group, and roles for advanced practice clinicians (NPs and PAs). TH

Early in 2015, SHM published the updated edition of the “Key Principles and Characteristics of an Effective Hospital Medicine Group,” which is a free download via the SHM website. Every hospitalist group should use this comprehensive list of attributes as one important frame of reference to guide ongoing improvement efforts and long-range planning.

In this column and the next two, I’ll split the difference between the very brief list of top success factors for hospitalist groups I wrote about in my March 2011 column and the very comprehensive “Key Characteristics” document. I think these attributes are among the most important to support a high-performing group, yet they are sometimes overlooked or implemented poorly. They are of roughly equal importance and are listed in no particular order.

Deliberately Cultivating a Culture (or Mindset) of Practice Ownership

It’s easy for hospitalists to think of themselves as employees who just work shifts but have no need or opportunity to attend to the bigger picture of the practice or the hospital in which they operate. After all, being a good doctor for your patients is an awfully big job itself, and lots of recruitment ads tell you doctoring is all that will be expected of you. Someone else will handle everything necessary to ensure your practice is successful.

This line of thinking will limit the success of your group.

Your group will perform much better and you’re likely to find your career much more rewarding if you and your hospitalist colleagues think of yourselves as owning your practice and take an active role in managing it. You’ll still need others to manage day-to-day business affairs, but at least a portion of the hospitalists in the group should be actively involved in planning and making decisions about the group’s operations and future evolution.

I encounter hospitalist groups that have become convinced they don’t even have the opportunity to shape or influence their practice. “No one ever listens,” they say. “The hospital executives just do what they want regardless of what we say.” But in nearly every case, that is an exaggeration. Most administrative leaders desperately want hospitalist engagement and thoughtful participation in planning and decision making.

I wrote additional thoughts about the importance of a culture, or mindset, of practice ownership in August 2008. The print version of that column included a short list of questions you could ask yourself to assess whether your own group has such a culture, but it is missing from the web version and can be found at nelsonflores.com/html/quiz.html.

A Formal System of Group ‘Governance’

So many hospitalist groups rely almost entirely on consensus to make decisions. This might work well enough for a very small group (e.g., four or five doctors), but for large groups, it means just one or two dissenters can block a decision and nothing much gets done.

Disagreements about practice operations and future direction are common, so every group should commit to writing some method of how votes will be taken in the absence of consensus. For example, the group might be divided about whether to adopt unit-based assignments or change the hours of an evening (“swing”) shift, and a formal vote might be the only way to make a decision. It’s best if you have decided in advance issues such as what constitutes a quorum, who is eligible to vote, and whether the winning vote requires a simple or super-majority. And a formalized system of voting helps support a culture ownership.

I wrote about this originally in December 2007 and provided sample bylaws your group could modify as needed. Of course, you should keep in mind that if you are indeed employed by a larger entity such as a hospital or staffing company, you don’t have the ability to make all decisions by a vote of the group. Pay raises, staff additions, and similar decisions require support of the employer, and while a vote in support of them might influence what actually happens, it still requires the support of the employer. But there are lots of things, like the work schedule, system of allocating patients across providers, etc., that are usually best made by the group itself, and sometimes they might come down to a vote of the group.

Never Stop Recruiting and Ensure Hospitalists Themselves Are Actively Engaged in Recruiting

I wrote about recruiting originally in July 2008 when there was a shortage of hospitalists everywhere. Since then, the supply of doctors seeking work as a hospitalist has caught up with demand in many major metropolitan areas like Minneapolis and Washington, D.C.

But outside of large markets—that is, in most of the country—demand for hospitalists still far exceeds supply, and groups face ongoing staffing deficits that come with the need for existing doctors to work extra shifts and use locum tenens or other forms of temporary staffing. The potential excess supply of hospitalists in major markets may eventually trickle out and ease the shortages elsewhere, but that hasn’t happened in a big way yet. So for these places, it is crucial to devote a lot of energy and resources to recruiting.

A vital component of successful recruiting is participation in the effort by the hospitalists themselves. I think the best mindset for the hospitalists is to think of themselves as leading recruitment efforts assisted by recruiters rather than the other way around. For example, the lead hospitalist or some other designated doctor should try to respond by phone (if that’s impractical, then respond by email) to every reasonable inquiry from a new candidate within 24 hours and serve as the candidate’s principle point of communication throughout the recruitment process. The recruiter can handle details of things like arranging travel for an interview, but a hospitalist in the group should be the main source of information regarding things like the work schedule, patient volume, compensation, etc. And a hospitalist should serve as the main host during a candidate’s on-site interview.

More to Come …

Next month, I’ll address things like a written policy and procedure manual, clear reporting relationships for the hospitalist group, and roles for advanced practice clinicians (NPs and PAs). TH

NEW YORK (Reuters Health) - Opioid modulation with the combination of buprenorphine and samidorphan (ALKS 5461) improves symptoms in patients whose depression has not responded adequately to antidepressant treatment, researchers report.

"If the findings are confirmed in phase 3 studies, ALKS 5461 could be used as an augmenting agent in patients not responding to standard antidepressant therapies as an alternative to the atypical antipsychotic agents currently approved for the treatment of this population," Dr. Maurizio Fava, from Massachusetts General Hospital and Harvard Medical School, Boston, told Reuters Health by email.

Buprenorphine is a mu- and kappa-opioid partial agonist, and samidorphan blocks the mu agonist effects of buprenorphine associated with its abuse and addictive potential. A growing body of evidence implicates dysregulation of the endogenous mu- and kappa-opioid system in mood disorders.

Dr. Fava and colleagues at 31 sites in the U.S. used a sequential parallel comparison design to investigate the efficacy of buprenorphine/samidorphan (2 mg/2 mg or 8 mg/8 mg) in 142 patients with major depression inadequately responsive to antidepressant therapy.

At the end of four weeks of treatment, patients in the ALKS 5461 2 mg/2 mg group showed significantly greater improvements in Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression severity scores, compared with patients in the placebo group. The ALKS 5461 8 mg/8 mg group showed smaller, nonsignificant improvements.

"The overall effect sizes for the 2/2 dosage were 0.50 for HAM-D and 0.54 for MADRS," the researchers noted. "The result compares favorably with results from a meta-analysis of 14 studies with atypical antipsychotics as adjunctive therapy for major depression, with reported effect sizes of 0.35 to 0.48 for individual drugs."

Treatment response rates according to HAM-D and MADRS (at least 50% reduction in scores) were highest with ALKS 5461 2 mg/2 mg treatment group, according to the February 12 onlinereport in the American Journal of Psychiatry.

Two patients (1.6%) in the placebo group and 17 patients (19.3%) in the ALKS 5461 groups discontinued because of treatment-emergent adverse events, but there was no evidence of opioid withdrawal in any patient.

"When depressed patients do not respond to standard monoamine-based therapies for depression, consider the use of an augmenting agent that modulates other systems, such as the opioid one," Dr. Fava concluded.

Dr. Jeffrey F. Scherrer, from Saint Louis University School of Medicine, St. Louis, Missouri, recently examined the association between opioid use and increased depression rates. He told Reuters Health by email, "Our analysis of opioid use and depression did not include buprenorphine among the opioid exposure variable. Therefore, it is difficult to extrapolate our results to a trial of buprenorphine/samidorphan and major depression."

"As the authors noted, the clinical trial was of short duration and the risks of depression that we have observed appears to be greatest among those patients remaining on opioids for more than 90 days," he explained. "Additional work is currently being done to determine if some opioid medications have a greater depressogenic effect than others, which further limits direct comparison of our findings to the current study."

"I will say that it is unlikely for oxycodone, codeine, and hydrocodone (which together account for more than 90% of prescribed opioids) would help depressed patients and be more likely to worsen their depression with chronic treatment," Dr. Scherrer concluded.

Alkermes sponsored the trial, employed seven coauthors, and had various relationships with the other four coauthors.

NEW YORK (Reuters Health) - Opioid modulation with the combination of buprenorphine and samidorphan (ALKS 5461) improves symptoms in patients whose depression has not responded adequately to antidepressant treatment, researchers report.

"If the findings are confirmed in phase 3 studies, ALKS 5461 could be used as an augmenting agent in patients not responding to standard antidepressant therapies as an alternative to the atypical antipsychotic agents currently approved for the treatment of this population," Dr. Maurizio Fava, from Massachusetts General Hospital and Harvard Medical School, Boston, told Reuters Health by email.

Buprenorphine is a mu- and kappa-opioid partial agonist, and samidorphan blocks the mu agonist effects of buprenorphine associated with its abuse and addictive potential. A growing body of evidence implicates dysregulation of the endogenous mu- and kappa-opioid system in mood disorders.

Dr. Fava and colleagues at 31 sites in the U.S. used a sequential parallel comparison design to investigate the efficacy of buprenorphine/samidorphan (2 mg/2 mg or 8 mg/8 mg) in 142 patients with major depression inadequately responsive to antidepressant therapy.

At the end of four weeks of treatment, patients in the ALKS 5461 2 mg/2 mg group showed significantly greater improvements in Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression severity scores, compared with patients in the placebo group. The ALKS 5461 8 mg/8 mg group showed smaller, nonsignificant improvements.

"The overall effect sizes for the 2/2 dosage were 0.50 for HAM-D and 0.54 for MADRS," the researchers noted. "The result compares favorably with results from a meta-analysis of 14 studies with atypical antipsychotics as adjunctive therapy for major depression, with reported effect sizes of 0.35 to 0.48 for individual drugs."

Treatment response rates according to HAM-D and MADRS (at least 50% reduction in scores) were highest with ALKS 5461 2 mg/2 mg treatment group, according to the February 12 onlinereport in the American Journal of Psychiatry.

Two patients (1.6%) in the placebo group and 17 patients (19.3%) in the ALKS 5461 groups discontinued because of treatment-emergent adverse events, but there was no evidence of opioid withdrawal in any patient.

"When depressed patients do not respond to standard monoamine-based therapies for depression, consider the use of an augmenting agent that modulates other systems, such as the opioid one," Dr. Fava concluded.

Dr. Jeffrey F. Scherrer, from Saint Louis University School of Medicine, St. Louis, Missouri, recently examined the association between opioid use and increased depression rates. He told Reuters Health by email, "Our analysis of opioid use and depression did not include buprenorphine among the opioid exposure variable. Therefore, it is difficult to extrapolate our results to a trial of buprenorphine/samidorphan and major depression."

"As the authors noted, the clinical trial was of short duration and the risks of depression that we have observed appears to be greatest among those patients remaining on opioids for more than 90 days," he explained. "Additional work is currently being done to determine if some opioid medications have a greater depressogenic effect than others, which further limits direct comparison of our findings to the current study."

"I will say that it is unlikely for oxycodone, codeine, and hydrocodone (which together account for more than 90% of prescribed opioids) would help depressed patients and be more likely to worsen their depression with chronic treatment," Dr. Scherrer concluded.

Alkermes sponsored the trial, employed seven coauthors, and had various relationships with the other four coauthors.

NEW YORK (Reuters Health) - Opioid modulation with the combination of buprenorphine and samidorphan (ALKS 5461) improves symptoms in patients whose depression has not responded adequately to antidepressant treatment, researchers report.

"If the findings are confirmed in phase 3 studies, ALKS 5461 could be used as an augmenting agent in patients not responding to standard antidepressant therapies as an alternative to the atypical antipsychotic agents currently approved for the treatment of this population," Dr. Maurizio Fava, from Massachusetts General Hospital and Harvard Medical School, Boston, told Reuters Health by email.

Buprenorphine is a mu- and kappa-opioid partial agonist, and samidorphan blocks the mu agonist effects of buprenorphine associated with its abuse and addictive potential. A growing body of evidence implicates dysregulation of the endogenous mu- and kappa-opioid system in mood disorders.

Dr. Fava and colleagues at 31 sites in the U.S. used a sequential parallel comparison design to investigate the efficacy of buprenorphine/samidorphan (2 mg/2 mg or 8 mg/8 mg) in 142 patients with major depression inadequately responsive to antidepressant therapy.

At the end of four weeks of treatment, patients in the ALKS 5461 2 mg/2 mg group showed significantly greater improvements in Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression severity scores, compared with patients in the placebo group. The ALKS 5461 8 mg/8 mg group showed smaller, nonsignificant improvements.

"The overall effect sizes for the 2/2 dosage were 0.50 for HAM-D and 0.54 for MADRS," the researchers noted. "The result compares favorably with results from a meta-analysis of 14 studies with atypical antipsychotics as adjunctive therapy for major depression, with reported effect sizes of 0.35 to 0.48 for individual drugs."

Treatment response rates according to HAM-D and MADRS (at least 50% reduction in scores) were highest with ALKS 5461 2 mg/2 mg treatment group, according to the February 12 onlinereport in the American Journal of Psychiatry.

Two patients (1.6%) in the placebo group and 17 patients (19.3%) in the ALKS 5461 groups discontinued because of treatment-emergent adverse events, but there was no evidence of opioid withdrawal in any patient.

"When depressed patients do not respond to standard monoamine-based therapies for depression, consider the use of an augmenting agent that modulates other systems, such as the opioid one," Dr. Fava concluded.

Dr. Jeffrey F. Scherrer, from Saint Louis University School of Medicine, St. Louis, Missouri, recently examined the association between opioid use and increased depression rates. He told Reuters Health by email, "Our analysis of opioid use and depression did not include buprenorphine among the opioid exposure variable. Therefore, it is difficult to extrapolate our results to a trial of buprenorphine/samidorphan and major depression."

"As the authors noted, the clinical trial was of short duration and the risks of depression that we have observed appears to be greatest among those patients remaining on opioids for more than 90 days," he explained. "Additional work is currently being done to determine if some opioid medications have a greater depressogenic effect than others, which further limits direct comparison of our findings to the current study."

"I will say that it is unlikely for oxycodone, codeine, and hydrocodone (which together account for more than 90% of prescribed opioids) would help depressed patients and be more likely to worsen their depression with chronic treatment," Dr. Scherrer concluded.

Alkermes sponsored the trial, employed seven coauthors, and had various relationships with the other four coauthors.

Researchers in the lab

Photo by Rhoda Baer

Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).

Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.

The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.

And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.

To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.

HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.

“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.

“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”

The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.

Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).

“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”

Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.

“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”

Researchers in the lab

Photo by Rhoda Baer

Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).

Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.

The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.

And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.

To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.

HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.

“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.

“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”

The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.

Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).

“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”

Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.

“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”

Researchers in the lab

Photo by Rhoda Baer

Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).

Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.

The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.

And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.

To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.

HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.

“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.

“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”

The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.

Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).

“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”

Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.

“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”

Red blood cells

The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).

The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.

Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.

The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.

Phase 3 trials

The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.

Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.

The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).

The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.

The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.

AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.

“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.

“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’

Red blood cells

The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).

The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.

Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.

The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.

Phase 3 trials

The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.

Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.

The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).

The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.

The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.

AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.

“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.

“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’

Red blood cells

The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).

The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.

Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.

The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.

Phase 3 trials

The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.

Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.

The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).

The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.

The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.

AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.

“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.

“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’

Cells infected with

Plasmodium vivax

Image by Mae Melvin

Results of a phase 1 trial suggest a vaccine candidate does not prevent Plasmodium vivax malaria.

The vaccine, VMP001/AS01_B, did not prevent malaria in any of the 30 subjects tested, although it did significantly delay parasitemia in 59% of subjects.

Lieutenant Colonel Jason W. Bennett, of the Walter Reed Army Institute

of Research (WRAIR) in Silver Spring, Maryland, and his colleagues reported these results in PLOS Neglected Tropical Diseases.

The vaccine antigen VMP001 is an Escherichia coli-produced, synthetic, chimeric, recombinant protein that incorporates the 3 major domains of circumsporozoite protein but is distinct from the native molecule. The VMP001 antigen was adjuvanted with AS01_B, a proprietary liposome-based adjuvant system from GlaxoSmithKline.

For this phase 1 study, the investigators tested VMP001/AS01_B in 30 healthy volunteers. The subjects received 3 intramuscular injections of VMP001 at 15 μg (n=10), 30 μg (n=10), or 60 μg (n=10), respectively, all formulated in 500 μL of AS01_B at each immunization.

Fourteen days after the third immunization, the subjects were exposed to mosquitoes carrying P vivax. Six non-vaccinated control subjects were exposed to the mosquitoes as well.

The investigators said VMP001/AS01_B was well tolerated and generated robust immune responses. However, it did not protect the subjects from malaria infection.

Still, the vaccine induced a “small but significant” delay in time to parasitemia in 59% of vaccinated subjects, when compared to controls.

Colonel Robert Paris, director of the US Military Malaria Research Program at WRAIR, believes the investigators can use the results of this study to design a better vaccine for P vivax malaria.

“Findings from the analysis of the immune response of vaccinated subjects have given us clues to improve vaccine candidates,” he said. “[S]tudies are now underway at WRAIR to develop next-generation vivax vaccines.”

Cells infected with

Plasmodium vivax

Image by Mae Melvin

Results of a phase 1 trial suggest a vaccine candidate does not prevent Plasmodium vivax malaria.

The vaccine, VMP001/AS01_B, did not prevent malaria in any of the 30 subjects tested, although it did significantly delay parasitemia in 59% of subjects.

Lieutenant Colonel Jason W. Bennett, of the Walter Reed Army Institute

of Research (WRAIR) in Silver Spring, Maryland, and his colleagues reported these results in PLOS Neglected Tropical Diseases.

The vaccine antigen VMP001 is an Escherichia coli-produced, synthetic, chimeric, recombinant protein that incorporates the 3 major domains of circumsporozoite protein but is distinct from the native molecule. The VMP001 antigen was adjuvanted with AS01_B, a proprietary liposome-based adjuvant system from GlaxoSmithKline.

For this phase 1 study, the investigators tested VMP001/AS01_B in 30 healthy volunteers. The subjects received 3 intramuscular injections of VMP001 at 15 μg (n=10), 30 μg (n=10), or 60 μg (n=10), respectively, all formulated in 500 μL of AS01_B at each immunization.

Fourteen days after the third immunization, the subjects were exposed to mosquitoes carrying P vivax. Six non-vaccinated control subjects were exposed to the mosquitoes as well.

The investigators said VMP001/AS01_B was well tolerated and generated robust immune responses. However, it did not protect the subjects from malaria infection.

Still, the vaccine induced a “small but significant” delay in time to parasitemia in 59% of vaccinated subjects, when compared to controls.

Colonel Robert Paris, director of the US Military Malaria Research Program at WRAIR, believes the investigators can use the results of this study to design a better vaccine for P vivax malaria.

“Findings from the analysis of the immune response of vaccinated subjects have given us clues to improve vaccine candidates,” he said. “[S]tudies are now underway at WRAIR to develop next-generation vivax vaccines.”

Cells infected with

Plasmodium vivax

Image by Mae Melvin

Results of a phase 1 trial suggest a vaccine candidate does not prevent Plasmodium vivax malaria.

The vaccine, VMP001/AS01_B, did not prevent malaria in any of the 30 subjects tested, although it did significantly delay parasitemia in 59% of subjects.

Lieutenant Colonel Jason W. Bennett, of the Walter Reed Army Institute

of Research (WRAIR) in Silver Spring, Maryland, and his colleagues reported these results in PLOS Neglected Tropical Diseases.

The vaccine antigen VMP001 is an Escherichia coli-produced, synthetic, chimeric, recombinant protein that incorporates the 3 major domains of circumsporozoite protein but is distinct from the native molecule. The VMP001 antigen was adjuvanted with AS01_B, a proprietary liposome-based adjuvant system from GlaxoSmithKline.

For this phase 1 study, the investigators tested VMP001/AS01_B in 30 healthy volunteers. The subjects received 3 intramuscular injections of VMP001 at 15 μg (n=10), 30 μg (n=10), or 60 μg (n=10), respectively, all formulated in 500 μL of AS01_B at each immunization.

Fourteen days after the third immunization, the subjects were exposed to mosquitoes carrying P vivax. Six non-vaccinated control subjects were exposed to the mosquitoes as well.

The investigators said VMP001/AS01_B was well tolerated and generated robust immune responses. However, it did not protect the subjects from malaria infection.

Still, the vaccine induced a “small but significant” delay in time to parasitemia in 59% of vaccinated subjects, when compared to controls.

Colonel Robert Paris, director of the US Military Malaria Research Program at WRAIR, believes the investigators can use the results of this study to design a better vaccine for P vivax malaria.

“Findings from the analysis of the immune response of vaccinated subjects have given us clues to improve vaccine candidates,” he said. “[S]tudies are now underway at WRAIR to develop next-generation vivax vaccines.”