From Heart Failure to Renal Failure - The Myth

Motivation: Ever since the week on heart failure in second year of medical school, I have been thinking about congestive heart failure (CHF) as consisting of "backup" symptoms like dyspnea and edema or "forward flow" symptoms like somnolence and fatigue.  One of the CHF exacerbation symptoms that I usually categorize under forward flow  is renal failure.  The presumed explanation for renal failure is relative renal hypoperfusion from decreased cardiac output in acute CHF exacerbation.  Recently, I learnt about some trials that challenged this view.  Here is one of the trials:

Paper: Nohria, A., et. al. Cardiorenal Interactions: Insights From the ESCAPE Trial. J. Am. Coll. Cardiol.(2008) 51: 1268-74.  http://content.onlinejacc.org/cgi/content/full/51/13/1268

Methods: The ESCAPE trial was a randomized trial comparing pulmonary artery catheter versus clinical volume assessment based treatment for acute heart failure exacerbation.  Included patients had LVEF<30% with SBP<125 mmHg with signs and symptoms of acute heart failure.  Patients with baseline creatinine >3.5 mg/dL  were excluded.  The current paper was an ad hoc analysis of baseline hemodynamic parameters from pulmonary artery catheter measurements and serum creatinine.

Results:
Subjects: In general, the mean age of the patient group was 56 with serum creatinine of 1.5.  Most of the patients were getting an ACE-I/ARB and beta-blocker.

Hemodyamic Correlation: There was no correlation between baseline serum creatinine or estimated GFR and cardiac index, systemic vascular resistance, or wedge pressure!  There was a weak but significant correlation between baseline serum creatinine and right atrial pressure (r = 0.165, p = 0.03).  Similar correlation was found between baseline estimated GFR and right atrial pressure (r = -0.195, p = 0.01), meaning higher right atrial pressures were correlated with decreased GFR.

Discussion: This paper clearly calls into question the assumption that renal dysfunction from acute heart failure is directly linked to renal hypoperfusion.  Renal failure seen in acute heart failure is being increasingly called the "cardiorenal syndrome" in recognition of the more complex pathophysiology.  Rather than renal arterial hypoperfusion, this trial along with other evidence suggests that elevated venous pressures may directly compromise renal function.  One of the problems in extrapolating from trials like this is the complexity of interacting factors.  The patients in this trial were sick and being treated with multiple agents like beta-blockers and ACE-I/ARB that also affect the renal vasculature.  But, these pharmacologic confounders would be expected to affect vascular tone, and no correlation was found between  systemic vascular resistance and renal dysfunction either.  Besides the effects of elevated venous pressure, other possible explanations for renal dysfunction include undefined direct toxic effects of therapeutic agents.  Also, many processes that worsen CHF, like HTN and diabetes, also have pathologic effects on the kidneys.  In the coming years, we will likely learn more about the complex pathophysiology of cardiorenal syndrome!  

Maddrey, Lille, and Alcohol

Motivation: Compared to hospitals in Baltimore, hospitals in Boston - in my brief experience- appear to get fewer patients with poly-drug abuse but just about the same number of patients with alcohol abuse.  In particular, over the past few months, I have met many patients with alcoholic hepatitis.  Some have died while others have walked out of the hospital against medical advice to the nearest bar.  To distinguish who is likely to get very ill, the Maddrey's Discriminant Function is generally used with severe alcoholic hepatitis defined as a score more than 32 or presence of encephalopathy.  Patients with severe alcoholic hepatitis have significant mortality benefit from early steroid treatment.  Recently, a French group developed a scoring system called the Lille Model, which seeks to better identify patients with poor prognosis even after steroid treatment.  How good is the French system?

Paper: Louvet, A. et. al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology (2007) 45: 1348-54.

Methods: To identify prognosis in patients with severe alcoholic hepatitis, the study was carried out in two stages.  In the "exploratory" stage, patients with severe alcoholic hepatitis were treated with prednisone 40 mg or IV 32 mg methylprednisolone for 28 days and followed for 6 months.  Severe alcoholic hepatitis was defined as discriminant function [4.6*(pt's PT-control PT) + Tbili] >=32 or presence of encephalopathy.  The derived model was verified on another "validation" cohort with severe alcoholic hepatitis treated with steroids.

Results:
Survival: In total, 320 patients with severe alcoholic hepatitis were included in the "exploratory" cohort.  Survival at one, two, and six months were 86%, 77%, and 65%.  The mean Maddrey Discriminant Function score was 47.5.

Relevant Parameters: In univariate analysis, parameters which are predictive of worse survival outcome after six months are: 1) Age (lower is better), 2) albumin (higher is better), 3) renal insufficiency, 4) difference in bilirubin levels between day 0 and day 7 of treatment, 5) PT time, 6) bilirubin at day 0.  These parameters were then incorporated into a complicated formula called the Lille Model that gives a score between 0 and 1 with higher scores indicating increased probability of death.

Validation and Comparison: 118 patients with severe alcoholic hepatitis requiring corticosteroids were enrolled and followed.  The validity of the model was measured in terms of area under the receiver operating characteristic (AUROC), which is a measure of the performance of the test (basically tests sensitivity versus specificity under varying cutoff scores).  The Lille Model, when compared to other models as indicator of survival at six months, was a better predictor of survival than Discriminant Function or MELD score at presentation.

Number to Remember: The authors next identified a Lille Model score that had the most predictive value for death at six months (optimum balance between sensitivity and specificity).  The optimum value is obtained at Lille Model score of 0.45. Patient with Lille score more than 0.45 had average 6 month survival of 25% compared to average six month survival of 85% for those with scores under 0.45.

Discussion: The Lille Model takes the prediction algorithms one step further.  Currently, the discriminant function just identifies who has severe alcoholic hepatitis and who does not.  With the Lille Model, the likely clinical trajectory of the patient can be more accurately predicted.  Patients with Lille scores above 0.45 have a very high mortality rate that is at times hard to recognize early on!  Hopefully, adjunctive therapies in these patients (like pentoxyfillene) can make a difference.   To me, the most important lesson from the paper is that patients with severe alcoholic hepatitis are potentially very sick.  Even with corticosteroid treatment, about a third will die in six months.  So, recognition of the disease severity and timely treatment are key. 

SIADH and Uric Acid

Motivation: In my brief experience as an intern, most patients predictably have two conditions.  One is a mild anemia (which implies, of course, that you need to have ordered iron, ferritin, folate, and B12 before morning rounds).  The second condition is hyponatremia.  I am not talking about sodium level of 120 but rather about the sodium level of 131.  Since the causes of hyponatremia are so many, there is often no good reflex testing to click.  I was recently told that uric acid is often low in hyponatremia from SIADH.  How sensitive is hypourecemia for hyponatremia?

Paper: Beck, Laurence, "Hypouricemia in the Syndrome of Inappropriate Secretion of Antidiuretic Hormone".  NEJM (1979) 301: 528-30.

Methods: A single person review of records of patients examined by the author (in the grand old tradition).  Over a period of 18 months, patients with hyponatremia (defined as less than 130 mM) without renal failure (Cr<2.0) and not on diuretics were included in the study.  Patients were labeled as having SIADH if they had serum osmolality less than 270 mOsm with urine osmolality greater than 250 mOsm.  Also excluded were patients who were overtly hypervolemic (judged by edema), hypovolemic, or had signs of glucocorticoid deficiency.

Results:
Subjects: In the 18 month period, 49 patients were evaluated for hyponatremia. 19 patients were excluded for lack of uric acid measurement. Seventeen patients met criteria for SIADH wile the remaining 13 patients had euvolemic hyponatremia without SIADH.

Uric Acid Levels: The mean uric acid level in patients with SIADH was 2.9 mg/dL while the patients in the other group had mean level of 7.7 mg/dL (p<0.001).  Only one patient with SIADH had uric acid level greater than 4 mg/dL.  All patients without SIADH had uric acid concentration greater than 5 mg/dL.  In seven patients with SIADH, when fluid restricted, uric acid levels rose to a mean level of 5.2 mg/dL from previous mean of 2.8 mg/dL.

Clearance of Uric Acid: In three patients, clearance of uric acid was measured by 24 hour urine collection.  During periods of hyponatremia from SIADH, the uric acid clearance was increased compared to period after water restriction indicating that overexcretion rather than underproduction was the cause of hypouricemia.

Discussion: The paper is old with many weaknesses like few subjects and lack of testing for hypothyroidism, but this is one of the original papers showing the utility of uric acid measurement in distinguishing SIADH.  One of the key points is that in both hypovolemic and hypervolemic hyponatremia, uric acid is generally expected to be normal or higher than normal.  This paper showed that in euvolemic hyponatremia, SIADH can generally be distinguished from other causes (the paper does not investigate the "other" etiologies) by measuring uric acid levels.  What was so remarkable was the degree of difference in mean uric acid levels among patients with SIADH (mean of 2.9 mg/dL) and those with other causes (7.7 mg/dL).  These findings have been replicated in some subsequent studies (though none have very large number of subjects).  From now on, I think that uric acid level is a great test to send overnight to investigate euvolemic hyponatremia.  

Beta-Blockers in Acute Heart Failure

Motivation: When a patient is admitted with acute heart failure and laboring to breathe, I often debate whether or not to continue the home metoprolol.  In chronic heart failure, I understand the bit about beta-blockade having protective effects.  But, acutely, beta-blockers decrease heart inotropy resulting in decreased cardiac output and elevated left ventricular filling pressures - effects that are not helpful in acute heart failure.  Like so many things in cardiology, it turns out that there has been a randomized trial with a nice acronym (B-CONVINCED) that examines this issue.

Paper:  "B-CONVINCED: Beta-blocker CONtinuation Vs. INterruption in patients with Congestive heart failue hospitalizED for a decompensation episode." Jondeau, G. et. al. European Heart Journal (2009) 30: 2186-2192.

Methods: Randomized, controlled, open-labelled trial conducted in 36 centres in France.  Eligible patients were older than 18 on chronic beta-blocker therapy hospitalized for acute heart failure (including pulmonary edema) with left ventricular ejection fraction less than 40%.  Patients were excluded if found to have STEMI, bradycardia, or second-third degree heart block.  Patients who were initially judged to need dobutamine therapy were also excluded.  Intervention was continuation of home-dose beta-blocker therapy or discontinuation of beta-blocker for at least 3 days.  Primary endpoint was the general health and dyspnea at 3 days of hospitalization. 

Results:
Subjects: Analysis was performed in 147 patients (69 on BB therapy and 78 without BB).  There were no significant differences between groups including age, etiology (ischemic vs non-ischemic), ejection fraction, prevalence of atrial fibrillation, or home CHF treatment regimen.  The most common cause for acute exacerbation was non-adherence to therapy.  The beta-blockers most commonly used were bisoprolol (beta-1 blocker) 70%, carvedilol 11%, and atenolol 10%.  In the group on beta-blocker therapy, beta-blockers were stopped in four patients (three needed dobutamine and one had bronchospasm).

Hospital Courses: There were no significant differences in clinical features of heart failure (dyspnea, pulmonary rales, lower extremity edema, JVD, hepatomegaly) on the first 8 days of hospitalization (including day 3) between the two groups.  Patients without BB had higher heart rates :)  There were no differences in blood pressure during the course of hospitalization in the two groups.  No differences were observed in BNP levels either.  One death occurred in the BB group while two deaths occurred in the BB stopped group (difference not significant).

Long-term Follow-up: At 3 months, death rate and re-hospitalization rate were similar in both groups.  After 3 months, patients who were continued on beta-blockers were more likely to be receiving beta-blockers (90%) than those who had beta-blockers stopped (76%, p=0.04). 

Discussion: This paper shows that even during acute heart failure exacerbations, beta-blockers can be safely continued without adversely affecting rate of recovery.  On the other side of the fence, one can also say that this paper shows beta-blockers can be discontinued during hospitalization without affecting rate of recovery.  Between these two varying viewpoints, I would favor continuing beta-blockers since beta-blockers decrease myocardial ischemia and have proven anti-arrhythmic effect.  Also, as shown in the paper, once beta-blockers are discontinued upon hospitalization, the risk of beta-blockers not being restarted upon discharge increases.

While the paper demonstrates non-inferiority of continuing beta-blockers during acute heart failure, this trial has some important limitations.  First, the study was underpowered to detect potential benefit of beta-blockers in preventing arrhythmias during heart failure.  That part of the benefit of beta-blockers in acute heart failure remains speculative.  Also, in the study, the beta-blocker dosage was not standardized.  It is unclear if beta-blocker titrated to, for example, heart rate is beneficial in one dosage but detrimental at higher doses.   

Azithromycin for COPD

Motivation: During the first couple of months of internship, I have often taken care of patients with COPD, and in the morning presentations, the conversation inevitably turns towards the benefits of adding an antibiotic to the steroid regimen.  Macrolide antibiotics are thought to have additional anti-inflammatory benefits beyond the standard anti-microbial effects.  Recently, this hypothesis was extended further to test for beneficial effects of azithromycin in COPD patients as a standing drug in-between flares.

Paper: "Azithromycin for Prevention of Exacerbations of COPD", Albert, R.K. et. al. NEJM (2011) 365: 689-698.

Methods: A multi-centered, randomized controlled trial.  The trial included patients over 40 with a history of COPD (>10 pack year of smoking, FEV1/FVC<70%, and FEV1<80% of predicted value).  To the included in the study, the patients had to have either used systemic steroids or required ED/hospital care in the past 12 months.  Patients could also be included if using home oxygen.  The exclusion criteria were tachycardia, prolonged QTc, and hearing impairment.  The intervention was daily dose of 250 mg of azithromycin.  The primary outcome was the time to first acute exacerbation of COPD.  The follow-up period was one year.

Results: 
Patient Recruitment: Overall, 558 patients were in the treatment arm, and 559 patients were in the placebo group.  The completion rate was 89% in the treatment arm and 90% in the placebo group.  The treatment and placebo group did not differ significantly in terms of age, gender, race, disease severity, or home treatment regimens.

COPD Exacerbation: The median time to acute exacerbation was 266 days in the azithromycin group vs. 174 days in the placebo group (p<0.001).  A total of 741 exacerbations among 558 patients occurred in the azithromycin group while 900 exacerbations occurred in the placebo group (p=0.01).  The number needed to treat to prevent one acute exacerbation of COPD was 2.86.

Secondary Outcomes: There was not a statistically significant difference between the azithromycin and placebo groups in hospitalizations related to COPD (156 vs. 200, p =0.15), exacerbations requiring intubations (11 vs. 16, p=0.56), or hospitalization for any cause (323 vs. 329, p=0.52).  There was a trend towards decreased ED or urgent care visit (199 vs 257, p=0.09).

Adverse Effects: The rate of death was 3% in the azithromycin group and 4% in the placebo group (difference not significant).  The only adverse effect that occurred more frequently in the azithromycin group was audiogram confirmed hearing decrease (25% vs 20%, p=0.04).  At the end of the one year study, patients receiving azithromycin were also more likely to be colonized in the nasopharynx with azithromycin resistant organisms.

Discussion: The trial demonstrates that a daily standing regimen of azithromycin results in decreased number of total exacerbations.  While there is evidence that increased number of exacerbations results in increased morbidity and mortality, the trial was not sufficiently powered and did not have a long-enough follow-up time to demonstrate mortality benefits or decreased hospitalizations.  I think that showing a mortality benefit or showing decreased hospital stays would have made this trial much more significant.  There was an interesting side effect of increased hearing loss in a sizable minority of patients.  The data presented in the paper though is unclear about the magnitude of hearing loss.  A little bit might be tolerable while total deafness is likely not.

In summary, if a patient keeps coming back with repeated exacerbations of COPD, a standing regimen of azithromycin might be the next medicine for them!

Magnesium for Torsades

Motivation: The standard ACLS catechism is that: "If you see torsades de pointes, give magnesium."  During the ACLS protocol, torsades is, I think, the only point where magnesium enters into the algorithm.  While supplementing someone with mag the other day, I wondered what the evidence was for use of magnesium in torsades and other rhythms.  I was a bit surprised to learn that the ACLS guideline for torsades is based mostly on two (quoted from the official ACLS publication) observational studies.  The major study in Circulation appeared in 1988 and is reviewed here:

Paper: "Treatment of torsade de pointes with magnesium sulfate" Tzivoni, D. et. al. Circulation (1988), 77: 392-397.

Methods: An unblinded, uncontrolled study in which 12 consecutive patients who developed torsades de pointes (TdP) with QT prolongation were treated with magnesium (2g IV bolus over 1 to 2 minutes followed in most patients with a continuous infusion).  Five additional patients with polymorphic ventricular tachycardia with normal QT interval were also treated with magnesium.

Results:
Patients: Of 12 patients with TdP (10 men and 2 women) and prolonged QT, six had ischemic heart disease, two had valvular rheumatic heart disease, two had atrial arrhythmia, and two did not have known heart disease.  Nine of the twelve patients were also on antiarrhythmic therapy.  The mean corrected QTc was 640 msec.  The five patients with polymorphic VT with normal QT interval who received magnesium all had chronic ischemic heart disease.

Patients with prolonged QTc: In nine of the twelve patients, a single bolus of magnesium stopped TdP.  In the other three patients, TdP was stopped after second Mag bolus.  In eight of 12 patients, potassium levels were below 3.5, which was repleted with oral and intravenous potassium.  The mean QTc did not change after magnesium bolus.  Magnesium levels were available in eight patients, and all were normal.

Patients without prolonged QTc: In the five patients with polymorphic ventricular tachycardia, none responded to multiple boluses of magnesium.

Discussion: One of the major points of the paper for me is that sometimes amazing results trump poorly designed studies.  Most of the patients had multiple confounders, including hypokalemia and concurrent anti-arrhythmic administration, but achieving a 100% response rate really makes this paper landmark.  And, really since the publication of the paper, magnesium has become the standard therapy of choice for TdP.  There were a couple of other interesting points in the paper as well.  The first is that not every polymorphic ventricular tachycardia responds to magnesium - only polymorphic v-tach in patient with prolonged QTc can be properly called TdP.  Also, while magnesium bolus is key, the precipitating factor for TdP is not hypomagnesemia since magnesium levels were normal.  Finally, repleting potassium and other electrolytes are pretty important too! 

The Flutter-Fibrillation Spectrum

Motivation: Every time I encounter a patient with atrial flutter and hard to control ventricular rates, I wonder why the patient is on the floor and not in an electrophysiology suite. I mean, why should we spend time titrating diltiazem when the ablation procedure (ablation of cavo-tricuspid isthmus) has more than 90% success rate.  In fact, general guidelines state that in contrast to a-fib, for patients with recurrent atrial flutter, ablation should be the first-line approach rather than rate control.  Ablation, however, is not a good long-term fix if patients with atrial flutter also develop atrial fibrillation, which does not respond well to ablation.  I have at times heard of the "flutter fibrillation spectrum." But, how often do patients with atrial flutter actually develop atrial fibrillation in the future?

Paper: "Risk of Stroke in Patients with Atrial Flutter", Biblo, L.A. et. al. Am. J. of Card. (2001) 87: 346-349.  http://www.ncbi.nlm.nih.gov/pubmed?term=11165976%20

Methods: In this large retrospective study, the authors scanned Medicare inpatient files in 1984 for patients older than 65 who were diagnosed with atrial flutter or atrial fibrillation without stroke.  For control, a 5% random sample of other hospitalized patients were chosen without atrial flutter or fibrillation.  Patients were followed for 8 years.  The primary endpoints assessed were incidence of stroke and incidence of atrial fibrillation in patients with atrial flutter.

Results:
Subjects: The study followed 17,413 patients with atrial flutter, 337,428 with atrial fibrillation, and 395,147 controls.

Atrial Flutter to Fibrillation Incidence: Patients with atrial flutter developed atrial fibrillation in an almost linear fashion over the 8 year follow-up period.  By about 6.5 years of follow-up, half of the initial group of patients with atrial flutter had developed an episode of atrial fibrillation.  The top three factors which predicted which patients would develop fibrillation were rheumatic heart disease (Risk Ratio: 1.464, CI: 1.250-1.715)., systemic hypertension (RR: 1.333, CI: 1.267-1.402), and congestive heart failure (RR: 1.243, CI: 1.174-1.316).

Stroke Risk: After adjusting for known risk factors like hypertension, CHF, rheumatic heart disease, DM, and MI, the stroke risk in patients with atrial flutter was greater than controls (RR: 1.406, p < 0.0001).  The adjusted stroke risk in patients with atrial fibrillation (RR: 1.642, p < 0.0001) was greater than those with atrial flutter.  Importantly, the stroke risk for patients initially with atrial flutter with new onset atrial fibrillation was not significantly different from the stroke risk in patients with atrial fibrillation.

Discussion: I think that this paper nicely illustrates why it is hard to manage atrial flutter.  Patients with atrial flutter are at significant risk for atrial fibrillation (about half have atrial fibrillation by about 6.5 years of follow-up).  In these patients, going through ablation is questionable since a-fib requires rate-control and anti-coagulation regardless.  On the other hand, for the half of patients who do not develop a-fib by seven years, conversion to sinus rhythm through ablation would save them many years of hazards of warfarin anti-coagulation.  I think that it is still unclear exactly which subgroup benefits most from ablation.  Likely as suggested by the paper, patients with additional risk factors like HTN, CHF, and rheumatic heart disease are likely to go on to develop a-fib.  Another point underscored by the paper is that while both atrial flutter and fibrillation have elevated stroke risk, patients with atrial fibrillation are at higher risk than those with flutter.   Finally, while the paper is impressive in the large number of subjects tracked, the paper is retrospective in nature and only examines patients older than 65.   Also, I have some doubts about how accurately atrial flutter/fibrillation is coded during hospitalizations (!).