Journal of Cardiac Failure Vol. 21 No. 2 2015
Editorial Comment
Cardiorenal Syndrome: Misgivings About Treatment Options, Clarity on Prognosis EUGENE S. CHUNG, MD,1 AND THEO E. MEYER, MD, DPhil2 Cincinnati, Ohio; and Worcester, Massachusetts
to be related to elevated central venous pressure (CVP),14 and that treatment with slow continuous ultrafiltration (SCUF) in diuretic-resistant AHF patients led to hemodialysis conversion in 59%, among whom in-hospital death or discharge to hospice occurred in 54%.15 In those publications, a favorable hemodynamic response was defined as a pulmonary artery occlusion pressure of #18 mm Hg, decrease in mean pulmonary arterial pressure by $20%, CVP #8 mm Hg, and cardiac index $2.2 L min1 m2, while maintaining mean arterial pressure O65 mm Hg. Although it is not clear what proportion of patients achieved all these targets, on average all of these parameters were significantly improved at the end of the 48-hour SCUF period.15 The disconnection between improved hemodynamics and poor outcomes raises the specter that the strategy of using hemodynamic goals for treating these advanced AHF patients may be too simplistic. In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial, hemodynamic guidance did not achieve significant advantage over usual management, either in the short term or in follow-up.16 Importantly, this lack of advantage was seen despite achieving significant improvements in all of the hemodynamic parameters recorded with invasive monitoring. Wehbe et al showed that low systolic perfusion pressure (systolic blood pressure [BP] CVP) was associated with poor outcomes and may represent a potential target for intervention. They observed an inflection point of 90 mm Hg, above which there was a linear decline in likelihood of progressing to dialysis. In fact, a perfusion pressure of 100 mm Hg is associated with one-half the peak risk. The relative values of systolic BP and CVP in determining risk of dialysis conversion are not clear, but clearly hypotension and elevated CVP both seem to increase risk of renal failure. Nonetheless, it is notable that when systolic BP is O105 mm Hg and CVP is !20 mm Hg, the risk of progressing to dialysis (and by inference, poor clinical outcomes) is significantly less. The authors also observed that baseline serum creatinine and blood urea nitrogen (BUN) were higher in those who progressed to dialysis and poor outcomes. These findings
To the Editor:
Decongestive therapy with loop diuretics remains the mainstay of therapy for acute heart failure (AHF) with volume overload. However, in a fair proportion of patients with advanced acute on chronic decompensated heart failure, loop diuretics do not achieve adequate decongestion. Investigations of other pharmacologic interventions have been invariably disappointing. These have included treatments to increase inotropy with milrinone1 and levosimendan,2 facilitate vasodilation with nesiritide3 and endothelin receptor inhibition,4,5 target hyponatremia with vasopressin inhibition,6 and reverse renal vasoconstriction with an adenosine A1-receptor inhibitor, rolofylline.7 A nonpharmacologic intervention, ultrafiltration with the use of mechanical volume removal, showed initial promise,8 but a more recent study did not confirm benefit in 188 patients with AHF complicated by the cardiorenal syndrome randomized to stepped pharmacologic therapy or ultrafiltration.9 The latter study attempted to address a particularly challenging subgroup of AHF patients (almost one-third) who develop worsening renal function related to the cardiorenal syndrome, during the course of their hospital stay.10 For this subgroup, the current European Society of Cardiology and American Heart Association/American College of Cardiology guidelines do not provide specific treatment recommendations.11,12 The study by Wehbe et al13 published in the current issue of the Journal of Cardiac Failure extends their previous work showing that development of cardiorenal syndrome appears
From the 1Christ Hospital, Cincinnati, Ohio and 2University of Massachusetts, Worcester, Massachusetts. Manuscript received November 18, 2014. Reprint requests: Eugene Sejin Chung, MD, The Lindner Center, The Christ Hospital, 2123 Auburn Ave, Ste 424, Cincinnati, OH 45219. Tel: þ1 513 585 1777; Fax: 513-585-4858. E-mail addresses: chunge@ ohioheart.org or [email protected] See page 117 for disclosure information. 1071-9164/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2014.11.011
116
Cardiorenal Syndrome
are consistent with the analysis of the Acute Decompensated Heart Failure National Registry (ADHERE) database that used systolic blood pressure, BUN, and creatinine to stratify risk of in-hospital death.17 These findings underscore the fact that although low cardiac output may be the central hemodynamic feature of certain AHF syndromes, the progressive interplay between systolic BP, central venous congestion, and renal function lies at the center of the perturbations that lead to worsening symptoms and mortality. It is sobering that ultrafiltration demonstrates no consistent benefit in this population with AHF and diuretic resistance. The Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) trial showed that ultrafiltration resulted in more effective volume removal than usual care, and even supported the notion that this intervention may reduce the 30-day readmission rate.8 Similar short-term outcomes are seen in clinical practice in patients with preserved ejection fraction.18 The divergent findings regarding the impact of ultrafiltration on outcomes in patients with the cardiorenal syndrome and AHF in the UNLOAD trial, the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS HF), and data from Wehbe et al may be due in part to differences in patient selection criteria as well as study protocol. The CARRESS HF trial recommended a diuretic therapy protocol that was aggressive and beyond usual care found in the community. Furthermore, some of the putative benefits of ultrafiltration, such as more sodium being removed (based on the isotonic nature of the ultrafiltrate versus hypotonic urine),19 are not always evident, because patients on ultrafiltration still produce significant amounts of very dilute urine.20 The current literature on the etiology and optimal treatment of the cardiorenal syndrome is incomplete; many unanswered questions remain. The essence of the uncertainty surrounding this clinical syndrome is the simple fact that worsening renal function in AHF occurs via more than 1 mechanism. Whereas some patients’ worsening renal failure is the direct consequence of AHF itself, many patients have intrinsic kidney disease caused by HF risk factors, such as hypertension and diabetes. In this regard, a more complete assessment of the severity intrinsic kidney disease, such as quantifying albuminuria, would be helpful to formulate a stepwise decongestive intervention which may include early introduction of renal replacement therapy. The data presented by Wehbe et al are not robust enough to be incorporated into practice guidelines yet. Nonetheless, they do lead one to conclude that (1) the outlook is poor and appropriate palliative care conversations should take place in many AHF patients with the cardiorenal syndrome, (2) hemodynamic surrogates of decongestion may not be appropriate therapeutic targets, and (3) strategies to improve systolic perfusion pressure without exacerbating pulmonary edema, venous congestion, and arrhythmias are worthy of further exploration.
Chung and Meyer
117
Disclosures Dr Chung has received research support from Boston Scientific, Medtronic, Otsuka, Gambro; and consults for Boston Scientific and Medtronic. Dr Meyer has no disclosures.
References 1. Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. J Am Med Assoc 2002;287:1541e7. 2. Packer M, Colucci W, Fisher L, Massie BM, Teerlink JR, Young J, et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail 2013;1:103e11. 3. O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32e43. 4. Kaluski E, Kobrin I, Zimlichman R, Marmor A, Krakov O, Milo O, et al. RITZ-5: Randomized Intravenous Tezosentan (an endothelinA/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study. J Am Coll Cardiol 2003;41:204e10. 5. O’Connor CM, Gattis WA, Adams KF Jr, Shah MR, Frey A, Gheorghiade M, et al. Tezosentan in patients with acute heart failure and acute coronary syndromes: design of the fourth Randomized Intravenous Tezosentan study (RITZ-4). Am Heart J 2003;145(2 Suppl):S58e9. 6. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. J Am Med Assoc 2007;297:1319e31. 7. Massie BM, O’Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363:1419e28. 8. Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA, Teerlink JR, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675e83. 9. Bart BA, Goldsmith SR, Lee KL, Givertz MM, O’Connor CM, Bull DA, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296e304. 10. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 2010;31:703e11. 11. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33:1787e847. 12. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147e239. 13. Wehbe E, Patarroyo M, Taliercio JJ, Starling RC, Nally JV, Tang WHW, et al. Renal failure requiring dialysis complicating slow continuous ultrafiltration in acute heart failure: Importance of systolic perfusion pressure. J Card Fail 2015;21:108e15. 14. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC, et al. Importance of venous congestion for worsening
118 Journal of Cardiac Failure Vol. 21 No. 2 February 2015 of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009;53:589e96. 15. Patarroyo M, Wehbe E, Hanna M, Taylor DO, Starling RC, Demirjian S, et al. Cardiorenal outcomes after slow continuous ultrafiltration therapy in refractory patients with advanced decompensated heart failure. J Am Coll Cardiol 2012;60:1906e12. 16. Binanay C, Califf RM, Hasselblad V, O’Connor CM, Shah MR, Sopko G, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. J Am Med Assoc 2005;294:1625e33. 17. Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ, et al, Adhere Scientific Advisory Committee SG. Risk stratification for
in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. J Am Med Assoc 2005;293: 572e80. 18. Jefferies JL, Bartone C, Menon S, Egnaczyk GF, O’Brien TM, Chung ES. Ultrafiltration in heart failure with preserved ejection fraction: comparison with systolic heart failure patients. Circ Heart Fail 2013;6:733e9. 19. Schrier RW. Role of diminished renal function in cardiovascular mortality: marker or pathogenetic factor? J Am Coll Cardiol 2006;47:1e8. 20. Chung ES, O’Brien TM, Menon S, Bartone C, Mazur W, Kereiakes DJ. A pilot study of target weight guided treatment in acute heart failure using ultrafiltration or usual care: effect on sodium removal. Korean Circ J 2014;44:156e61.
Editorial Comment
Cardiorenal Syndrome: Misgivings About Treatment Options, Clarity on Prognosis EUGENE S. CHUNG, MD,1 AND THEO E. MEYER, MD, DPhil2 Cincinnati, Ohio; and Worcester, Massachusetts
to be related to elevated central venous pressure (CVP),14 and that treatment with slow continuous ultrafiltration (SCUF) in diuretic-resistant AHF patients led to hemodialysis conversion in 59%, among whom in-hospital death or discharge to hospice occurred in 54%.15 In those publications, a favorable hemodynamic response was defined as a pulmonary artery occlusion pressure of #18 mm Hg, decrease in mean pulmonary arterial pressure by $20%, CVP #8 mm Hg, and cardiac index $2.2 L min1 m2, while maintaining mean arterial pressure O65 mm Hg. Although it is not clear what proportion of patients achieved all these targets, on average all of these parameters were significantly improved at the end of the 48-hour SCUF period.15 The disconnection between improved hemodynamics and poor outcomes raises the specter that the strategy of using hemodynamic goals for treating these advanced AHF patients may be too simplistic. In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial, hemodynamic guidance did not achieve significant advantage over usual management, either in the short term or in follow-up.16 Importantly, this lack of advantage was seen despite achieving significant improvements in all of the hemodynamic parameters recorded with invasive monitoring. Wehbe et al showed that low systolic perfusion pressure (systolic blood pressure [BP] CVP) was associated with poor outcomes and may represent a potential target for intervention. They observed an inflection point of 90 mm Hg, above which there was a linear decline in likelihood of progressing to dialysis. In fact, a perfusion pressure of 100 mm Hg is associated with one-half the peak risk. The relative values of systolic BP and CVP in determining risk of dialysis conversion are not clear, but clearly hypotension and elevated CVP both seem to increase risk of renal failure. Nonetheless, it is notable that when systolic BP is O105 mm Hg and CVP is !20 mm Hg, the risk of progressing to dialysis (and by inference, poor clinical outcomes) is significantly less. The authors also observed that baseline serum creatinine and blood urea nitrogen (BUN) were higher in those who progressed to dialysis and poor outcomes. These findings
To the Editor:
Decongestive therapy with loop diuretics remains the mainstay of therapy for acute heart failure (AHF) with volume overload. However, in a fair proportion of patients with advanced acute on chronic decompensated heart failure, loop diuretics do not achieve adequate decongestion. Investigations of other pharmacologic interventions have been invariably disappointing. These have included treatments to increase inotropy with milrinone1 and levosimendan,2 facilitate vasodilation with nesiritide3 and endothelin receptor inhibition,4,5 target hyponatremia with vasopressin inhibition,6 and reverse renal vasoconstriction with an adenosine A1-receptor inhibitor, rolofylline.7 A nonpharmacologic intervention, ultrafiltration with the use of mechanical volume removal, showed initial promise,8 but a more recent study did not confirm benefit in 188 patients with AHF complicated by the cardiorenal syndrome randomized to stepped pharmacologic therapy or ultrafiltration.9 The latter study attempted to address a particularly challenging subgroup of AHF patients (almost one-third) who develop worsening renal function related to the cardiorenal syndrome, during the course of their hospital stay.10 For this subgroup, the current European Society of Cardiology and American Heart Association/American College of Cardiology guidelines do not provide specific treatment recommendations.11,12 The study by Wehbe et al13 published in the current issue of the Journal of Cardiac Failure extends their previous work showing that development of cardiorenal syndrome appears
From the 1Christ Hospital, Cincinnati, Ohio and 2University of Massachusetts, Worcester, Massachusetts. Manuscript received November 18, 2014. Reprint requests: Eugene Sejin Chung, MD, The Lindner Center, The Christ Hospital, 2123 Auburn Ave, Ste 424, Cincinnati, OH 45219. Tel: þ1 513 585 1777; Fax: 513-585-4858. E-mail addresses: chunge@ ohioheart.org or [email protected] See page 117 for disclosure information. 1071-9164/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2014.11.011
116
Cardiorenal Syndrome
are consistent with the analysis of the Acute Decompensated Heart Failure National Registry (ADHERE) database that used systolic blood pressure, BUN, and creatinine to stratify risk of in-hospital death.17 These findings underscore the fact that although low cardiac output may be the central hemodynamic feature of certain AHF syndromes, the progressive interplay between systolic BP, central venous congestion, and renal function lies at the center of the perturbations that lead to worsening symptoms and mortality. It is sobering that ultrafiltration demonstrates no consistent benefit in this population with AHF and diuretic resistance. The Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) trial showed that ultrafiltration resulted in more effective volume removal than usual care, and even supported the notion that this intervention may reduce the 30-day readmission rate.8 Similar short-term outcomes are seen in clinical practice in patients with preserved ejection fraction.18 The divergent findings regarding the impact of ultrafiltration on outcomes in patients with the cardiorenal syndrome and AHF in the UNLOAD trial, the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS HF), and data from Wehbe et al may be due in part to differences in patient selection criteria as well as study protocol. The CARRESS HF trial recommended a diuretic therapy protocol that was aggressive and beyond usual care found in the community. Furthermore, some of the putative benefits of ultrafiltration, such as more sodium being removed (based on the isotonic nature of the ultrafiltrate versus hypotonic urine),19 are not always evident, because patients on ultrafiltration still produce significant amounts of very dilute urine.20 The current literature on the etiology and optimal treatment of the cardiorenal syndrome is incomplete; many unanswered questions remain. The essence of the uncertainty surrounding this clinical syndrome is the simple fact that worsening renal function in AHF occurs via more than 1 mechanism. Whereas some patients’ worsening renal failure is the direct consequence of AHF itself, many patients have intrinsic kidney disease caused by HF risk factors, such as hypertension and diabetes. In this regard, a more complete assessment of the severity intrinsic kidney disease, such as quantifying albuminuria, would be helpful to formulate a stepwise decongestive intervention which may include early introduction of renal replacement therapy. The data presented by Wehbe et al are not robust enough to be incorporated into practice guidelines yet. Nonetheless, they do lead one to conclude that (1) the outlook is poor and appropriate palliative care conversations should take place in many AHF patients with the cardiorenal syndrome, (2) hemodynamic surrogates of decongestion may not be appropriate therapeutic targets, and (3) strategies to improve systolic perfusion pressure without exacerbating pulmonary edema, venous congestion, and arrhythmias are worthy of further exploration.
Chung and Meyer
117
Disclosures Dr Chung has received research support from Boston Scientific, Medtronic, Otsuka, Gambro; and consults for Boston Scientific and Medtronic. Dr Meyer has no disclosures.
References 1. Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. J Am Med Assoc 2002;287:1541e7. 2. Packer M, Colucci W, Fisher L, Massie BM, Teerlink JR, Young J, et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail 2013;1:103e11. 3. O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32e43. 4. Kaluski E, Kobrin I, Zimlichman R, Marmor A, Krakov O, Milo O, et al. RITZ-5: Randomized Intravenous Tezosentan (an endothelinA/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study. J Am Coll Cardiol 2003;41:204e10. 5. O’Connor CM, Gattis WA, Adams KF Jr, Shah MR, Frey A, Gheorghiade M, et al. Tezosentan in patients with acute heart failure and acute coronary syndromes: design of the fourth Randomized Intravenous Tezosentan study (RITZ-4). Am Heart J 2003;145(2 Suppl):S58e9. 6. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. J Am Med Assoc 2007;297:1319e31. 7. Massie BM, O’Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363:1419e28. 8. Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA, Teerlink JR, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675e83. 9. Bart BA, Goldsmith SR, Lee KL, Givertz MM, O’Connor CM, Bull DA, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296e304. 10. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 2010;31:703e11. 11. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33:1787e847. 12. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147e239. 13. Wehbe E, Patarroyo M, Taliercio JJ, Starling RC, Nally JV, Tang WHW, et al. Renal failure requiring dialysis complicating slow continuous ultrafiltration in acute heart failure: Importance of systolic perfusion pressure. J Card Fail 2015;21:108e15. 14. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC, et al. Importance of venous congestion for worsening
118 Journal of Cardiac Failure Vol. 21 No. 2 February 2015 of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009;53:589e96. 15. Patarroyo M, Wehbe E, Hanna M, Taylor DO, Starling RC, Demirjian S, et al. Cardiorenal outcomes after slow continuous ultrafiltration therapy in refractory patients with advanced decompensated heart failure. J Am Coll Cardiol 2012;60:1906e12. 16. Binanay C, Califf RM, Hasselblad V, O’Connor CM, Shah MR, Sopko G, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. J Am Med Assoc 2005;294:1625e33. 17. Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ, et al, Adhere Scientific Advisory Committee SG. Risk stratification for
in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. J Am Med Assoc 2005;293: 572e80. 18. Jefferies JL, Bartone C, Menon S, Egnaczyk GF, O’Brien TM, Chung ES. Ultrafiltration in heart failure with preserved ejection fraction: comparison with systolic heart failure patients. Circ Heart Fail 2013;6:733e9. 19. Schrier RW. Role of diminished renal function in cardiovascular mortality: marker or pathogenetic factor? J Am Coll Cardiol 2006;47:1e8. 20. Chung ES, O’Brien TM, Menon S, Bartone C, Mazur W, Kereiakes DJ. A pilot study of target weight guided treatment in acute heart failure using ultrafiltration or usual care: effect on sodium removal. Korean Circ J 2014;44:156e61.
