Source:

Januzzi JL Jr, Chen-Tournoux AA, Christenson RH, et al. N-Terminal Pro–B-Type Natriuretic Peptide in the Emergency Department: The ICON-RELOADED Study.  J Am Coll Cardiol 2018;71:1191-1200

Key Points:

1. To prospectively validate the use of NT-proBNP cutoffs to aid in the diagnosis or exclusion of HF, in patients who presented to an emergency department (ED) with dyspnea.
2. Results of the study indicate excellent performance of NT-proBNP to identify or exclude acute HF using the mentioned age-stratified rule-in NT-proBNP levels and age-independent rule-out NT-proBNP levels.

Study Protocol:

This was a prospective, multicenter trial in the United States and Canada enrolling subjects who presented to an emergency deparment (ED) with dyspnea. The cut off points tested were the positive predictive value (PPV) of age-specific rule-in values  of 450, 900, and 1,800 pg/ml for ages <50, 50-75, and >75 years, respectively for acute HF, and the negative predictive value (NPV) of the rule-out, age-independent value of 300 pg/ml. Receiver-operating characteristic (ROC) curves were constructed relative to the gold-standard diagnosis, and multivariable logistic regression analyses were used to evaluate the significance of age-adjusted NT-proBNP values.

Study results:

After exclusions, 1,461 subjects were available for the final analysis. Using the mentioned age-dependent cutoff values, NT-proBNP had a positive predictive value (PPV) of 53.6% and sensitivity of 85.7% (age <50 years); PPV 58.4% and sensitivity 79.3% (age 50-75 years), and PPV 62.0% and sensitivity 75.9% (age >75 years). In multivariable logistic regression, an elevated age-adjusted NT-proBNP had the highest odds ratio for HF of all variables retained (including prior HF, interstitial edema on chest radiography, rales on examination, and peripheral edema). The age-independent cutoff level of NT-proBNP <300 pg/ml had a NPV of 98% and specificity of 71.7%.

Conclusion:

Results of the study support the utility of the widely-used age-stratified levels of NT proBNP to identify and an age independent value to exclude acute HF in the ED.

Critical Appraisal:

Using a cut off value of 300 pg/ml, guidelines advocate the use of NT pro BNP for ruling-out HF, but not to establish the diagnosis. This is the first study to prospectively validate in a North American cohort the age-stratified NT-proBNP rule-in cut point strategy for diagnosis of acute HF and age-independent rule-out cut point to exclude acute HF.

Strength of the study is

The diverse range of patient groups, with approximately

• 50% women and
• More than 40% nonwhite patients

Also, the test performance remained accurate in a variety of patient subgroups, including those with

• Abnormal renal function
• Obesity and
• Atrial fibrillation

Limitations of the study are:

1. Lack of generalizability of the findings as this study was conducted only in the United States and Canada.
2. Low PPV probably due to low prevalence of HF in the population studied. (likelihood ratio would have been a more useful parameter)  

Clinical Application:

Early and accurate diagnosis of patients with acute dyspnea in the ED is essential to prevent the increased mortality associated with delayed treatment for acute HF. 

For patients presenting to the ED with acute dyspnea categorized by age <50, 50 to 75, and ≥75 years, accurate diagnosis of HF may be based on NT-proBNP cutoff levels of 450, 900, and 1,800 pg/ml, respectively, and acute HF is largely excluded when the level is below 300 pg/ml.

What remains to be studied is the generalizability of these cutoff values to patients in other care settings and other populations.

Suggested readings:

1. Yancy C.W., Jessup M., Bozkurt B., et al. (2013) 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 62:e147–e239
2. Januzzi J.L. Jr.., Camargo C.A., Anwaruddin S., et al. (2005) The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol 95:948–954
3. Piotr Ponikowski, Adriaan A. Voors etal : 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Heart Journal (2016) 37, 2129–2200

Risk categories

Risk factors

Points

Predisposing conditions

• Marfan syndrome or other connective tissue disease
• Family history of aortic disease
• Known aortic valve disease
• Known thoracic aortic aneurysm
• Recent aortic manipulation

1 if any of these present

Pain features

• Abrupt pain
• Severe pain
• Ripping or tearing pain

1 if any of these present

Physical findings

• Pulse asymmetry or systolic blood pressure differential
• Focal neurological deficit
• New diastolic murmur of aortic insufficiency
• Shock state or hypotension

1 if any of these present

Suggested Readings: 

1. Rogers AM, Hermann LK, Booher AM, Nienaber CA, Williams DM, Kazerooni EA, et al. Sensitivity of the aortic dissection detection risk score, a novel guideline-based tool for identification of acute aortic dissection at initial presentation: results from the International Registry of Acute Aortic Dissection. Circulation. 2011;123:2213–2218.
2. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr., et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of Task Force on Practice Guidelines, Circulation. 2010;121:e266–e369.
3. Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, et al. ESC Committee for Practice Guidelines. 2014 ESC guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult: the Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014;35:2873–2926.

KEY MESSAGES:

·         Decline in renal function is commonly observed in patients with atrial fibrillation (AF) treated with anticoagulants

·         The risk of decline is lower in patients treated with dabigatran and rivaroxaban as compared to Vitamin K antagonists (VKA)

·         Dabigatran and Rivaroxaban (but not apixaban) are linked with fewer adverse renal outcomes

·         High INR values are associated with greater degree of nephropathy

INTRODUCTION:

Current guidelines recommend oral anticoagulants for patients with non-valvular AF to prevent stroke.  With the availability of novel oral anticoagulants (NOACs) most of the physicians prefer to treat them with NOACs rather than with VKA if the economics permit. In developing countries it is estimated that approximately 50% patients are treated with NOACs and rest with VKA. Physicians tend to avoid prescribing NOACs in patients with renal dysfunction. Patients with eGFR<30 are prescribed VKA, perceiving it to be less nephrotoxic than NOACs. The comparative risk of renal dysfunction with currently available 3 NOACs versus VKA has not been studied in great detail.

OBJECTIVES:

 To compare the effect of 4 oral anticoagulant agents’ apixaban, dabigatran, rivaroxaban and warfarin on renal functions.

METHODS:

This study included 9769 patients who were treated with oral anticoagulants for prevention of stroke in AF. The average on treatment follow up was 10.7 ± 9.9 months study that evaluated 4 renal parameters:

1.      ≥than 30% decline in eGFR

2.      Rise in serum creatinine by 100%

3.      Acute kidney injury

4.      Kidney failure

The overall risk of adverse kidney outcomes seen at the end of 2 years were-

a)     30% decline in eGFR: 24.4%

b)     Doubling of serum creatinine: 4%

c)      Acute Renal injury: 14.8%

d)     Renal failure: 1.7%

With 3 NOACs combined there was statistically significant reduction in risk of all 4 kidney injury parameters studied as compared to VKA. Individually evaluated dabigatran was associated with lower risk of decline in eGFR and AKI. Rivaroxaban carried a lower risk of fall in eGFR, doubling of creatinine and AKI as compared to VKA.

As compared to rivaroxaban and dabigatran, apixaban did not have significant relationship with decreased adverse renal outcomes when compared to VKA.

CLINICAL RELEVANCE:

Patients with renal failure and AF pose therapeutic challenge since it is perceived that use of NOACs in these patients would lead to extensive bleeding.  Comparative effects of NOACs and warfarin on kidney function were lacking. Patients with AF have several co morbidities like diabetes, hypertension, pre- existing renal dysfunction and coronary artery disease propelling them to further kidney injury. Choice of anticoagulant is therefore of paramount importance.  Warfarin inhibits Vitamin K dependent protein matrix leading to damage to the renal vessels while NOVACs because of their effect on inhibiting factor Xa and thrombin could reduce vascular inflammation. The study further highlights the evidence that very high INR values are associated with greater renal damage.  The therapeutic relevance of the study is that it defies the earlier assumptions of NOVACs being more injurious to kidney as compared to Warfarin. Dabigatran and rivaroxaban could be a better alternative to warfarin to reduce the chances of kidney damage.

 SUGGESTED READINGS

1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–51.
2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883–91.
3.  Yao X, Abraham NS, Sangaralingham LR, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc 2016; 5: e003725.
4. Böhm M, Ezekowitz MD, Connolly SJ, et al. Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY Trial. J Am CollCardiol 2015; 65: 2481–93.
5. Fordyce CB, Hellkamp AS, Lokhnygina Y, et al. On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin: insights from ROCKET AF. Circulation 2016; 134: 37–47.
6. Chatrou ML, Winckers K, Hackeng TM, Reutelingsperger CP, Schurgers LJ. Vascular calcification: the price to pay for anticoagulation therapy with vitamin K-antagonists. Blood Rev 2012; 26: 155–66.
7. Schurgers LJ, Joosen IA, Laufer EM, et al. Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype. PloS One 2012;7: e43229.
8. Chan YH, Yeh YH, See LC, et al. Acute kidney injury in Asians with atrial fibrillation treated with dabigatran or warfarin. JACC, 2016;68: 2272–83.

 http://www.cardiositeindia.com/Content.aspx?CatID=2&ID=1129