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How is acute kidney injury defined in pediatric patients?

How is acute kidney injury defined in pediatric patients?

Background

Acute kidney injury (AKI) is a term used to refer to the clinical continuum of kidney dysfunction. This dysfunction ranges from the biochemical changes that signal a decline in kidney function to complete anuric kidney failure.^1,2 Historically, acute renal failure (ARF) had been the term used to describe renal function decline. This definition was limiting as it referred to the discrete event of final kidney failure and did not allow for the characterization of declining renal function in the time prior to failure, where damage could be identified and potentially, prevented from further progression.¹ Identifying patients at risk for the development of AKI as well as those who are in its early stages may allow for interventions to reverse or prevent damage as well as signal the need to adjust doses of renally cleared medications and consider alternatives to nephrotoxic agents. In this review, the various definitions of AKI in the pediatric patient will be described.

Problems with historical definition of AKI

Diagnosis of AKI, identification of patients at risk, and exploration of the outcomes of patients who have experienced AKI has historically been limited by the lack of a consensus definition.^1,2 Traditionally, serum creatinine is used for adults to monitor renal function both acutely and chronically. The use of creatinine has various limitations in the pediatric population. Setting a baseline serum creatinine to compare to in a pediatric patient is difficult as a pre-illness serum creatinine is rarely available.³ Patients may present with no recent hospitalization or clinic visit. Estimating serum creatinine based on published norms for age ranges is possible but can also be inaccurate, as they are not normalized for height or weight. In the neonatal population, there are further confounders for the use of serum creatinine, such as the presence of the mother’s creatinine, especially in the early hours and days of life.⁴ The neonatal kidney also may not have developed the ability to reabsorb creatinine in the proximal tubule depending on the gestational age of the patient. This greatly hinders the ability of a clinician to rely solely on creatinine as a measure of renal function in the neonatal population.

Evolution of the definition of AKI

A more comprehensive screening method for AKI became necessary to reduce reliance on serum creatinine in isolation. The Risk for renal dysfunction, Injury to kidney, Failure of kidney function, Loss of kidney function, and End stage renal disease (RIFLE) criteria was originally developed to describe renal injury in critically ill adult patients based on serum creatinine or urine output changes.⁵ A modified version of this criteria, pediatric RIFLE (pRIFLE) was proposed as a tool tailored to the pediatric population. The main adjustment made in pRIFLE when compared to its original scoring tool was the departure from reliance on absolute changes in serum creatinine and instead, a focus on changes in creatinine clearance. The creatinine clearance included in the pRIFLE is calculated using the original Schwartz equation. The pRIFLE has been validated in various patient populations as a reliable predictor of renal damage and the outcomes associated to AKI.^5-7 The criteria, however, is not without its inherent flaws. The Schwartz formula used in the current pRIFLE criteria was modified in 2009 due to the original formula overestimating clearance because of changes in the assay for measuring creatinine.⁸ The pRIFLE criteria also still rely on creatinine and a comparison to baseline which limits its use in certain patient populations as described previously. The pRIFLE criteria has not been uniformly adopted in the neonatal intensive care unit (NICU) and its validation in this setting is limited.⁴

As a response to the original RIFLE criteria, the Acute Kidney Injury Network (AKIN) created a new set of criteria for definition of AKI for both adult and pediatric patients.⁹ These criteria limited the timeline of development of AKI to 48 hours. The authors defined AKI as an absolute increase of serum creatinine of ≥0.3 mg/dL or a 50% increase from baseline. They also included urine output and alternatively defined AKI as a reduction to less than 0.5 mL/kg/h for a sustained period greater than 6 hours. The use of this definition was limited by its strict timeline as patients may accumulate damage over more than 48 hours. The AKIN definition has also been validated but not as widely used as the pRIFLE criteria.¹⁰

The Kidney Disease Improving Global Outcomes (KDIGO) tool modified the AKIN definition to incorporate considerations from the pRIFLE criteria.² The KDIGO criteria incorporates the 48-hour timeline of the original AKIN definition which is specific to AKI but also has a 7-day criteria for patients who develop kidney injury through accumulation of damage over a slightly longer timespan. KDIGO also considers more than an absolute change in serum creatinine and classifies stages of injury by changes in creatinine clearance as well. This definition has been validated in critically ill pediatric patients and has performed well in comparison to the two previously discussed definitions.^10,11 The KDIGO definition has been further modified by neonatologists and pediatric nephrologists to better suit use in the NICU.⁴ The Table provides a description of the various methods used to define AKI in the pediatric patient.

Table. Definitions of AKI in the pediatric patient.^2,4,5,9

pRIFLE
Stage	Change in Estimated Creatinine Clearance*	Urine Output
Risk	Decrease by 25%	<0.5 mL/kg/h for 8 hours
Injury	Decrease by 50%	<0.5 mL/kg/h for 12 hours
Failure	Decrease by 75% or CrCl <35 mL/min/1.73m²	<0.3 mL/kg/h for 24 hours or anuria for 12 hours
Loss	Failure >4 weeks
End Stage	Failure >3 months
AKIN
Stage	Change in SCr^a	Urine Output
AKI – within 48 hours	Increase ≥0.3 mg/dL or SCr rise of 1.5 x reference	<0.5 mL/kg/h for >6 hours
KDIGO
Stage	Change in SCr	Urine Output
I	Increase 0.3 mg/dL during 48 hours or Increase of 150% to 200% within 7 days	<0.5 mL/kg/h for 8 hours
II	Increase of ≥200% to 300% within 7 days	<0.5 mL/kg/h for 16 hours
III	Increase of ≥300% within 7 days or SCr≥4 mg/dL or Dialysis or GFR <35 mL/min/1.73m²	<0.5 mL/kg/h for 24 hours or anuria for 12 hours
Neonatal KDIGO
Stage	Change in SCr	Urine output
0	No change or Increase <0.3 mg/dL	≥0.5 mL/kg/h
1	Increase of ≥0.3 mg/dL within 48 hours or SCr rise of 1.5 to 1.9 x reference within 7 days	<0.5 mL/kg/h for 6 to 12 hours
2	SCr rise of ≥ 2.0 to 2.9 x reference within 7 days	<0.5 mL/kg/h for ≥12 hours
3	SCr rise of ≥3 x reference within 7 days or SCr≥2.5 mg/dL or Dialysis	<0.3 mL/kg/h for ≥ 24 hours or anuria for ≥12 hours
*Original Schwartz equation: Creatinine clearance = (k x height)/SCr, where k is a constant dependent on age and gender ^aFor AKIN, SCr change is the absolute change in SCr while for KDIGO and neonatal KDIGO it is defined as change from the previous lowest SCr. Abbreviations: AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; CrCl, creatinine clearance; GFR, glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes; pRIFLE, pediatric Risk for renal dysfunction, Injury to kidney, Failure of kidney function, Loss of kidney function, and End stage renal disease criteria; SCr, serum creatinine.

Conclusion

All of the above definitions offer a more complete assessment of kidney function as they allow for identification of AKI by either a change in serum creatinine, creatinine clearance, or urine output. Moving forward, a unified definition for AKI is necessary for better description of not only the outcomes of the condition but also the patients in most need for intervention. Defining AKI in a standard way allows for prompt recognition and treatment, which can range from fluid resuscitation to discontinuation of nephrotoxic medications. A unified definition for AKI may also provide better guidance for pediatric pharmacists as they adjust medication doses based on renal function. Patients with renal injury are likely to receive higher than the recommended dose of various medications due to the lack of recommendations for dosing during AKI as well as the general reduced clearance of medications.¹²The disparate definitions of AKI in the pediatric patient as well as the various ways renal function is monitored has possibly limited the development of concrete dosing recommendations for medications frequently given to critically ill pediatric patients in the setting of reduced renal function. These recommendations are especially necessary for medications that have no therapeutic drug monitoring parameters. Assessing the trend of changes in serum creatinine remains the most widely used method of kidney function monitoring despite its flaws. However, standardized recommendations for use of one or more of the above definitions are still needed to allow early AKI identification, management, and proper medication dosing.

References:

Devarajan P. Pediatric acute kidney injury: different from acute renal failure but how and why. Curr Pediatr Rep. 2013;1(1):34-40.
Selewski DT, Symons JM. Acute kidney injury. Pediatr Rev. 2014;35(1):30-41.
Zappitelli M, Parikh CR, Akcan-arikan A, Washburn KK, Moffett BS, Goldstein SL. Ascertainment and epidemiology of acute kidney injury varies with definition interpretation. Clin J Am Soc Nephrol. 2008;3(4):948-954.
Selewski DT, Charlton JR, Jetton JG, et al. Neonatal acute kidney injury. Pediatrics. 2015;136(2):e463-e473.
Akcan-arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int. 2007;71(10):1028-1035.
Kavaz A, Ozçakar ZB, Kendirli T, Oztürk BB, Ekim M, Yalçinkaya F. Acute kidney injury in a paediatric intensive care unit: comparison of the pRIFLE and AKIN criteria. Acta Paediatr. 2012;101(3):e126-e129.
Plötz FB, Bouma AB, Van wijk JA, Kneyber MC, Bökenkamp A. Pediatric acute kidney injury in the ICU: an independent evaluation of pRIFLE criteria. Intensive Care Med. 2008;34(9):1713-1717.
Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629-637.
Mehta RL, Kellum JA, Shah SV, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31.
Sutherland SM, Byrnes JJ, Kothari M, et al. AKI in hospitalized children: comparing the pRIFLE, AKIN, and KDIGO definitions. Clin J Am Soc Nephrol. 2015;10(4):554-561.
Selewski DT, Cornell TT, Heung M, et al. Validation of the KDIGO acute kidney injury criteria in a pediatric critical care population. Intensive Care Med. 2014;40(10):1481-1488.
Awdishu L, Bouchard J. How to optimize drug delivery in renal replacement therapy. Semin Dial. 2011;24(2):176-182.

Prepared by:

Sana Said, PharmD

PGY2 Pediatric Resident

College of Pharmacy

University of Illinois at Chicago

September 2017

The information presented is current as of August 1, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What data are available on use of N-acetylcysteine in the management of non-acetaminophen drug-induced liver injury?

What data are available on use of N-acetylcysteine in the management of non-acetaminophen drug-induced liver injury?

Introduction

Approximately 11% of acute liver failure cases in the United States are caused by idiosyncratic drug-induced liver injury (DILI).¹ Drug-induced liver injury refers to damage to the liver due to a medication, herbal product, or dietary supplement.² Damage can range from elevated liver enzymes to acute liver failure, which is characterized by abnormal coagulation (international normalized ratio ≥ 1.5) and encephalopathy lasting < 26 weeks in patients without cirrhosis.^2,3 Acetaminophen differs from many other causes of DILI because acetaminophen causes intrinsic DILI, meaning the liver injury is predictable when given in high doses and has the potential to affect everyone.⁴ In contrast, many other medications cause idiosyncratic DILI, meaning the injury is unpredictable, not clearly dose-related, and affects those who are susceptible. The most common implicated agents in idiosyncratic or non-acetaminophen DILI are antibiotics and antiepileptic agents.

N-acetylcysteine

N-acetylcysteine, administered orally or intravenously, is approved by the Food and Drug Administration for the treatment of acetaminophen overdose.^5,6 When used for acetaminophen toxicity, N-acetylcysteine works to restore depleted glutathione concentrations or detoxifies the reactive metabolite of acetaminophen. The role of N-acetylcysteine for treatment of non-acetaminophen DILI is less clear.^3,4 Although the mechanism of N-acetylcysteine in non-acetaminophen DILI is not well understood, the antioxidant and vasodilating actions of N-acetylcysteine are hypothesized to help with the oxygen depletion in tissues.⁷

Management of Drug-Induced Liver Injury

Management of non-acetaminophen DILI is difficult due to a number of factors, including the large number of causative agents, varied presentation, and lack of a definitive antidote.⁴ In patients with suspected non-acetaminophen DILI, the first step is to immediately discontinue the offending agent.^3,4 The 2014 American College of Gastroenterology (ACG) guideline on the diagnosis and management of idiosyncratic DILI recognizes the lack of definitive treatments for idiosyncratic DILI, but recommends considering N-acetylcysteine in adults with early acute liver failure (conditional recommendation; low evidence level).⁴ However, the ACG does not recommend the use of N-acetylcysteine in pediatric patients with severe DILI (strong recommendation; low evidence level). The 2011 update to the American Association for the Study of Liver Diseases (AASLD) position paper on the management of acute liver failure states N-acetylcysteine may be beneficial in patients with DILI (grade I recommendation based on a randomized controlled trial).³ More recently, the 2017 American Gastroenterological Association (AGA) guideline for diagnosis and management of acute liver failure recommends treating patients with non-acetaminophen acute liver failure with N-acetylcysteine only in the context of clinical trials.⁸

Literature Review

There are limited data evaluating the use of N-acetylcysteine in non-acetaminophen DILI. Hu et al conducted a meta-analysis of 4 clinical studies of 331 patients who received N-acetylcysteine compared to 285 patients who did not for non-acetaminophen acute liver failure.⁹ While there was no difference in the primary endpoint of overall survival between groups, survival without transplantation was significantly higher with use of N-acetylcysteine (41%) compared to the control group (30%; odds ratio [OR], 1.61; 95% confidence interval [CI], 1.11 to 2.34; p=0.01). Survival after transplantation was also higher with use of N-acetylcysteine (85.7%) compared to the control group (71.4%; OR, 2.44; 95% CI, 1.11 to 5.37; p=0.03). Common adverse events associated with N-acetylcysteine included nausea, vomiting, diarrhea, and constipation. Other adverse events included rash, bronchospasm, and arrhythmia. The studies included in the meta-analysis are summarized in the following tables.^10-13 Table 1 includes studies in adults and Table 2 includes pediatric studies. Since the publication of the meta-analysis, 2 new trials in adults have been published on the use of N-acetylcysteine for non-acetaminophen acute liver failure; they are also summarized in Table 1 below.^14,15

Table 1. Studies evaluating NAC for use in non-acetaminophen ALF in adults.^10,11,14,15

Study Design

Subjects

Interventions

Results

Darweesh 2017¹⁴

MC, prospective, observational study

155 adults with NAI-ALF

DILI was etiology of ALF in 36.7% of patients treated with NAC and 40% of controls

IV NAC 150 mg/kg over 30 min, then 70 mg/kg over 4 h, then 70 mg/kg over 16 h. Continuous infusion of 150 mg/kg over 24 h was continued until two consecutive INRs < 1.3 with improving LFTs. The patient was then switched to oral NAC 600 mg/day (n=85)

Historical control (n=70)

Transplant-free survival: 96.4% with NAC vs. 23.3% of controls (p<0.01)

LOS was reduced with NAC (10.1 ± 3.8 days) vs. controls (28 ± 5.3 days; p<0.01)

Rate of encephalopathy was lower with NAC (33.3%) vs. controls (63.3%; p=0.02)

Bleeding tendency was lower with NAC (23.3%) vs. controls (66.7%; p<0.01)

AEs determined to be related to NAC included prolonged cholestasis (96.4%), fever and allergic reaction (10%), and dyspepsia (13.3%)

Nabi 2017¹⁵

Randomized, case control study

80 adults with NAI-ALF

DILI was etiology of ALF in 25% of patients treated with NAC and 12.5% of controls

IV NAC 150 mg/kg for 1 h, then 12.5 mg/kg/h for 4 h, then 6.25 mg/kg/h continuous infusion for 67 h (n=40)

Placebo (n=40)

Mortality was lower with NAC (27.5%) vs. placebo (52.5%; p=0.023)

Mean LOS was shorter with NAC (8.241 ± 2.115 days) vs. control (10.737 ± 3.106 days; p=0.002)

When stratified by etiology of ALF, survival was higher with NAC (100%) vs. placebo (60%; p=0.049) in patients with DILI

No AEs related to NAC were observed

Lee 2009¹⁰

DB, MC, PC, RCT

173 adults with NAI-ALF

DILI was etiology of ALF in 45 patients

IV NAC 150 mg/kg/h for 1h, then 12.5 mg/kg/h for 4 h, and then 6.25 mg/kg/h as a continuous infusion for 67 h (n=81)

Placebo (n=92)

No difference in overall survival at 3 weeks with NAC vs. placebo (70% vs. 66%, respectively; p=NS)

Transplant-free survival: 40% with NAC vs. 27% with placebo (p=0.043)

Transplant-free survival when stratified by coma grades:

Coma grades 1 to 2: 52% with NAC vs. 30% with placebo (p=0.01)
Coma grades 3 to 4: no difference between groups (p=NS)

Transplant-free survival in patients with DILI: 58% with NAC vs. 27% in placebo (p=NS)

AEs that occurred with higher frequency with NAC vs. placebo were nausea and vomiting (14% vs. 4%, respectively; p=0.031)

One patient in each group experienced bronchospasm

Mumtaz 2009¹¹

Retrospective cohort study

91 adults with NAI-ALF

DILI was etiology of ALF in 6.4% of patients treated with NAC and 18.2% of controls

Oral NAC was administered every 4 h at an initial dose of 140 mg/kg, then 70 mg/kg for 17 total doses (n=47)

Historical controls (n=44)

47% of patients in the NAC group survived compared to 27% in the control group (p=0.05)

AEs in the NAC group were nonspecific maculopapular rash (n=2), transient bronchospasm (n=1), and vomiting (n=4)

Abbreviations: AE(s)=adverse events; ALF=acute liver failure; DB=double-blind; DILI=drug-induced liver injury; INR=international normalized ratio; IV=intravenous; LFT(s)=liver function tests; LOS=length of stay; MC=multi-center; NAC=N-acetylcysteine; NAI-ALF=non-acetaminophen-induced acute liver failure; NS=not significant; PC=placebo-controlled; RCT=randomized controlled trial.

Table 2. Pediatric studies evaluating NAC for use in non-acetaminophen ALF.^12,13

Study Design

Subjects

Interventions

Results

Squires 2013¹²

PC, RCT

184 pediatric patients with NAI-ALF

None of the causes of ALF in the NAC group were secondary to DILI

IV NAC 150 mg/kg/day for 7 days (n=92)

Placebo (n=92)

Use of NAC did not improve survival at 1 year compared to placebo (73% vs. 82%, respectively; p=NS)

A lower rate of transplant-free survival at 1 year occurred with NAC vs. placebo (35% vs. 53%, respectively; p=0.03)

No significant differences in rates of AEs between groups were observed

Kortsalioudaki 2008¹³

Retrospective study

170 pediatric patients with NAI-ALF

DILI was the etiology of ALF in 6% of patients treated with NAC and 7% of controls

NAC 100 mg/kg/24 h continuous infusion until INR < 1.4, liver transplantation, or death (n=111)

Control (n=59)

Survival without liver transplantation occurred in 43% of patients with NAC vs. 22% in control group (p=0.005)

Of those who underwent liver transplantation, death occurred in 16% of patients with NAC vs. 39% of patients in the control group (p=0.02).

Rate of admission to intensive care and length of intensive care stay were not different between groups (p=NS)

LOS was 19 days with NAC vs. 25 days in control group (p=0.05)

NAC was discontinued in 1 patient due to an allergic reaction of bronchospasm and maculopapular rash

Abbreviations: AE(s)=adverse events; ALF=acute liver failure; DILI=drug-induced liver injury; INR=international normalized ratio; IV=intravenous; LOS=length of stay; NAC=N-acetylcysteine; NAI-ALF=non-acetaminophen-induced acute liver failure; NS=not significant; PC=placebo-controlled; RCT=randomized clinical trial.

Conclusion

Overall, evidence supporting the use of N-acetylcysteine in non-acetaminophen DILI is limited. A 2015 meta-analysis found that N-acetylcysteine is beneficial for the treatment of acute liver failure, but the analysis was not specific to acute liver failure secondary to DILI. The meta-analysis was based on the results of 4 studies. One of the included studies was a prospective study in adults by Lee et al that showed N-acetylcysteine improved transplant-free survival in patients with acute liver failure and grades 1 to 2 coma. Other studies included in the meta-analysis in adult and pediatric patients are limited by a small number of patients who experienced acute liver failure secondary to DILI. Since the publication of the meta-analysis, 2 additional studies were published in adults that found N-acetylcysteine beneficial for non-acetaminophen acute liver failure. Based on the data from the studies conducted in adults, N-acetylcysteine may benefit adults with DILI who are in early stages of acute liver failure.

There are currently not enough data to support use of N-acetylcysteine in pediatric patients; in fact, one study found lower transplant-free survival after use of N-acetylcysteine. However, it is important to note that none of the patients in the N-acetylcysteine group in the study experienced acute liver failure due to DILI. Despite this, the study is cited by the 2014 ACG guideline which does not recommend the use of N-acetylcysteine in pediatric patients with severe DILI causing acute liver failure.

References

1. Reuben A, Koch D, Lee W. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52(6):2065-2076.

2. Leise M, Poterucha J, Talwalkar J. Drug-induced liver injury. Mayo Clin Proc. 2014;89(1):95-106.

3. Lee WM, Larson AM, Stravitz RT. AASLD position paper: the management of acute liver failure: update 2011. American Association for the Study of Liver Diseases website. http://www.aasld.org/sites/default/files/guideline_documents/alfenhanced.pdf. Accessed August 20, 2017.

4. Chalasani N, Hayashi P, Bonkovsky H, Navarro V, Lee W, Fontana R. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109(7):950-966.

5. Acetylcysteine injection [package insert]. Lake Forest, IL: Akorn, Inc.; 2017.

6. Acetylcysteine solution [package insert]. Lake Forest, IL: Hospira, Inc.; 2015.

7. Sales I, Dzierba A, Smithburger P, Rowe D, Kane-Gill S. Use of acetylcysteine for non-acetaminophen-induced acute liver failure. Ann Hepatol. 2013;12(1):6-10.

8. Flamm SL, Yang YX, Singh S, Falck-Ytter YT; AGA Institute Clinical Guidelines Committee. American Gastroenterological Association Institute guidelines for the diagnosis and management of acute liver failure. Gastroenterology. 2017;152(3):644-647.

9. Hu J, Zhang Q, Ren X, Sun Z, Quan Q. Efficacy and safety of acetylcysteine in "non-acetaminophen" acute liver failure: a meta-analysis of prospective clinical trials. Clin Res Hepatol Gastroenterol. 2015;39(5):594-599.

10. Lee W, Hynan L, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009;137(3):856-864.

11. Mumtaz K, Azam Z, Hamid S, et al. Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center without the facility of liver transplantation. Hepatol Int. 2009;3(4):563-570.

12. Squires R, Dhawan A, Alonso E, et al. Intravenous N-acetylcysteine in pediatric patients with non-acetaminophen acute liver failure: a placebo-controlled clinical trial. Hepatology. 2013;57(4):1542-1549.

13. Kortsalioudaki C, Taylor R, Cheeseman P, Bansal S, Mieli-Vergani G, Dhawan A. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transpl. 2008;14(1):25-30.

14. Darweesh SK, Ibrahim MF, El-Tahawy MA. Effect of N-acetylcysteine on mortality and liver transplantation rate in non-acetaminophen-induced acute liver failure: a multicenter study. Clin Drug Investig. 2017;37(5):473-482.

15. Nabi T, Nabi S, Rafiq N, Shah A. Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: A prospective study. Saudi J Gastroenterol. 2017;23(3):169-175.

September 2017

The information presented is current as August 20, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What are the new data regarding risk of sudden death in heart failure?

What are the new data regarding risk of sudden death in heart failure?

Introduction

According to the World Health Organization (WHO), sudden cardiac death is defined as a “sudden, unexpected death either within 1 hour of symptom onset (event witnessed) or within 24 hours of having been observed alive and symptom free (un-witnessed).”¹ In the overall population, sudden death remains an important public health concern with an estimated incidence ranging from 184,000 to > 400,000 events annually. For patients with heart failure (HF), the risk of sudden death is particularly worrisome. Sudden cardiac death occurs 6 to 9 times more frequently in this patient population as compared to the general population. In fact, >80% of reported deaths among patients with HF are cardiovascular in nature with the majority caused by progressive pump failure or sudden death.² The pathophysiology of sudden cardiac death in HF is complex and usually involves a random interaction between a transient event (eg., acute myocardial ischemia) and an underlying pathologic issue, such as a preexisting cardiac structural abnormality.

There are various pharmacologic and nonpharmacologic interventions used to reduce the risk and potentially prevent sudden cardiac death. With regard to pharmacologic options, published studies involving many of the currently recommended medications for HF with reduced ejection fraction [angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and aldosterone antagonists (eg., spironolactone and eplerenone)] reveal a reduction in sudden death risk with therapy.^2,3 In general, patients with HF should not receive antiarrhythmics; however, amiodarone may reduce sudden cardiac death risk after myocardial infarction and may be an option in select patients.² In the nonpharmacologic arena, coronary revascularization, wearable and implantable cardioverter defibrillators (ICDs), and cardiac resynchronization therapy reduce sudden death risk in certain patient populations and settings.

Declining Risk of Sudden Death in HF

Per the 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America update of the HF management guideline, the cornerstone of pharmacologic therapy for patients with HF remains the use of an ACE inhibitor or ARB in combination with a beta-blocker and, potentially, an aldosterone antagonist.⁴ These treatments have a high quality of evidence from multiple randomized controlled trials supporting their use and clinicians have increased their prescribing of these agents in HF over time. As noted prior, an additional benefit of administering these agents in HF is a reduction in sudden death risk; however, how significantly have these medications reduced this risk over time? Shen and colleagues investigated this question in a recent analysis in the July issue of the New England Journal of Medicine.³

The analysis included 40,195 patients with symptomatic HF, a reduced ejection fraction (≤ 40%), and no ICD who were enrolled in 12 randomized, controlled trials from 1995 to 2014.³ The main outcome of interest was occurrence of sudden death, which was adjudicated by an independent committee in a blinded fashion with prespecified criteria. Additionally, the investigators evaluated the effects of baseline variables on the risk of sudden death including age, sex, ejection fraction, New York Heart Association (NYHA) class, HF cause (ischemic vs. nonischemic), prior myocardial infarction, and history of certain disease states such as hypertension or diabetes.

Results of the analysis revealed an overall sudden death rate of 8.9% (n=3,583 patients) in this study population.³ Baseline variables that were positively associated with sudden death included older age, male sex, a reduced ejection fraction, lower systolic blood pressure, increased heart rate, worse HF symptoms, an ischemic etiology of HF, and a history of myocardial infarction, diabetes, or renal dysfunction. With regard to death rate over time, the occurrence of sudden death fell significantly from 6.5% in the RALES trial (finished in 1998) to 3.3% in the PARADIGM-HF trial (completed in 2014; p value for trend = 0.02). Table 1 provides more information on mortality-related outcomes in the 12 clinical trials evaluated in the analysis. The cumulative 90-day rate of sudden death ranged from 2.4% in the RALES trial to 1.0% in the PARADIGM-HF. Additionally, the cumulative mortality at 1 year ranged from 6.7% to 3.7%, respectively, and mortality at 3 years decreased from 13.4% to 8.8%.

Table 1. Mortality-related outcomes.³

Trial	Patients with sudden death (n)	Patients with death from any cause (n)	Sudden deaths in total mortality (%)	Annual rate of sudden death per 100 patient-years (95% CI)
RALES	192	670	28.7	6.5 (5.6 to 7.4)
BEST	294	839	35	5.6 (5.0 to 6.3)
CIBIS-II	131	384	34.1	3.8 (3.2 to 4.5)
MERIT-HF	211	362	58.3	5.3 (4.6 to 6.1)
Val-HeFT	442	979	45.1	4.7 (4.3 to 5.2)
SCD-HeFT	168	484	34.7	3.0 (2.6 to 3.5)
CHARM-Alternative	186	540	34.4	3.7 (3.2 to 4.2)
CHARM-Added	311	762	40.8	4.3 (3.8 to 4.8)
CORONA*	631	1452	43.5	5.2 (4.8 to 5.6)
GISSI-HF	367	1055	34.8	2.7 (2.5 to 3.0)
EMPHASIS-HF	125	342	36.5	2.9 (2.4 to 3.4)
PARADIGM-HF	525	1344	39.1	3.3 (3.1 to 3.6)
CI=confidence interval. *Excluding the CORONA trial results from the analysis revealed an even steeper trend line for sudden death over time. The CORONA trial enrolled patients ≥ 60 years of age with an ischemic cause of HF only.

Based on these results, the investigators concluded that sudden death rates decreased significantly over time among patients with HF and a reduced ejection fraction who were enrolled in the 12 clinical trials.³ This significant reduction in sudden death paralleled an increase in the administration of evidence-based pharmacologic therapies for HF, which are known to reduce the occurrence of sudden death and are often used in combination. Additionally, these results suggest, “it may be difficult to show a significant benefit of ICD implantation for primary prevention in most patients with HF with reduced ejection fraction in the current era” per the investigators. In fact, future investigators may need to conduct more studies in order to identify those high-risk patients who would benefit most from ICD implantation since the rates of sudden death are currently quite low with appropriate pharmacologic therapy.

References

1. Obadah Al Chekakie M. Traditional heart failure medications and sudden cardiac death prevention: a review. J Cardiovasc Pharmacol Ther. 2012;18(5):412-426.

2. Klein L, Hsia H. Sudden cardiac death in heart failure. Cardiol Clin. 2014;32(1):135-144.

3. Shen L, Jhund PS, Petrie MC, et al. Declining risk of sudden death in heart failure. N Engl J Med. 2017;377(1):41-51.

4. Yancy CW, Jessup M, Bozkurt J, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure. A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161.

September 2017

The information presented is current as of August 1, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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