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2 Nov | Categories : Cardiovascular Start a topic Comment Mail Share Download
European society of Cardiology released guidelines for diagnosis and management of patients with HF. Few excerpts to guide the doctors have been presented here.

MITRAL CLIP-FR trial concluded that in patients with severe secondary mitral regurgitation, ra.....

22 Sep | Categories : Cardiovascular Start a topic Comment Mail Share Download

Reference: Yao X, Tangri N, Gersh B et al. Renal outcomes in anticoagulated patients with atri.....

JACC 2017;70(21):2621-32



·         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


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.


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


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.


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.


  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.


Risk categories

Risk factors


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.


-Dr Akshay Mehta


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%.


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
- Dr Akshay Mehta

Source: Arya S, Khakharia A, Binney ZO, DeMartino RR, Brewster LP, Goodney PP,et al. Association of Statin Dose With Amputation and Survival in Patients With Peripheral Artery Disease. Circulation. 2018; 137:1435-1446

Key Points:

  1. In 155647 patients with incident PAD, identified from the national Veterans affairs data, it was found that high-intensity statins were underused.


  1. High-intensity statin use at the time of PAD diagnosis was associated with a significant reduction in limb loss and mortality in comparison with low-to-moderate–intensity statin users, and patients treated only with antiplatelet medications but not with statins.

Study Protocol:

Patients with incident PAD from 2003 to 2014 were identified from the national Veterans health administration data using a validated algorithm.

Statin use and dose/intensity (as defined by the 2013 ACC/AHA guidelines) by a veteran around their PAD diagnosis date (6 months before and after) was recorded.

The outcomes were

(1) Incident amputation (mid/hind foot, below- and above-knee amputations) and

(2) Death after PAD diagnosis during follow-up

A host of patient covariates was abstracted from the database.


 Out of 155647 patients with incident PAD, 28% were not on statins. High-intensity statin users were associated with lower amputation risk and mortality in comparison with antiplatelet therapy–only users (hazard ratio, 0.67; 95% confidence interval, 0.61–0.74 and hazard ratio, 0.74; 95% confidence interval, 0.70–0.77, respectively). Low-to-moderate–intensity statins also had significant reductions in the risk of amputation and mortality (hazard ratio amputation, 0.81; 95% confidence interval, 0.75– 0.86; hazard ratio death, 0.83; 95% confidence interval, 0.81–0.86) in comparison with no statins (antiplatelet therapy only), but effect was significantly weaker than the high-intensity statins (P<0.001). The results remained significant and robust in propensity score–matched, sensitivity, and subgroup analyses.


There is lack of optimal use of statins in patients with PAD. High-intensity statin use at the time of PAD diagnosis is associated with a significant reduction in limb loss and mortality in comparison with low-to-moderate–intensity statin users, and patients treated only with antiplatelet medications.

Critical Appraisal:

Although the 2013 the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults recommended that all patients with clinically apparent atherosclerotic cardiovascular disease should be initiated on high-intensity statins (3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors),  the level of evidence for PAD was low and based on data or risk estimates obtained from sub-cohorts of patients with CAD or isolated from population group estimates.

Hence, this largest and first of its kind study to examine the effect of statin use and intensity on mortality and amputation risk in a large cohort of patients with PAD assumes importance.

It shows that low-to-moderate–intensity statins were associated with a 17% reduction in mortality and a 19% reduction in amputation, whereas high-intensity statin therapy was associated with a 26% reduction in mortality and a 33% reduction in the risk of amputation in multivariable adjusted Cox regression models comparing statin users with the active comparator group.

To obviate the problem of residual confounding in this observational study, the investigators also performed a propensity score–matched analysis. In comparison with statin nonusers, high-intensity and low-to-moderate–intensity statin use were both associated with reductions in mortality (30% and 20%, respectively) and amputation (40% and 20%, respectively).

The study was limited by its observational design which raises doubts about additional unidentified confounders that account for the differences in clinical outcome between these groups. Also statin changes beyond the 1-year window used in the study is not known. Finally the results do not account for the initiation of additional therapies, such as smoking cessation or angiotensin-converting enzyme inhibitors, or clopidigrel use instead of aspirin use that could also explain some of the between-group differences.

Clinical Application:

As is evident from the study, there is still considerable underuse and recognition of the role of statins in patients with PAD, especially in those without coronary disease.

In patients with only PAD as their sole atherosclerotic disease process, about 42% were not on any statin medication and only 5.8% were on high-intensity statins.

The study shows that use of high-intensity statins early in peripheral artery disease (PAD) diagnosis is better in terms of decreasing the risk of amputation and death in patients with PAD.

Hence even if there is no evidence of disease in any other vascular territory, on diagnosis of PAD, a patient should be started on the highest intensity of statin that can be tolerated, to reduce their lifetime risk of amputation and death and this amplifies the need for education and dissemination among the medical fraternity caring for PAD.

Suggested readings:

  1. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 suppl 2):S1–S45
  2. Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004;363:757–767
  3. Aday AW and Brendan M. Everett. Statins in Peripheral Artery Disease. Circulation. 2018;137:1447-1449