Week 22 – RALES

“The effect of spironolactone on morbidity and mortality in patients with severe heart failure”

by the Randomized Aldactone Evaluation Study Investigators

N Engl J Med. 1999 Sep 2;341(10):709-17. [free full text]

Inhibition of the renin-angiotensin-aldosterone system (RAAS) is a tenet of the treatment of heart failure with reduced ejection fraction (see post from Week 6 – SOLVD). However, physiologic evidence exists that suggests ACEis only partially inhibit aldosterone production. It had been hypothesized that aldosterone receptor blockade (e.g. with spironolactone) in conjunction with ACE inhibition could synergistically improve RAAS blockade; however, there was substantial clinician concern about the risk of hyperkalemia. In 1996, the RALES investigators demonstrated that the addition of spironolactone 12.5 or 25mg daily in combination with ACEi resulted in laboratory evidence of increased RAAS inhibition at 12 weeks with an acceptable increased risk of hyperkalemia. The 1999 RALES study was thus designed to evaluate prospectively the mortality benefit and safety of the addition of relatively low-dose aldosterone treatment to the standard HFrEF treatment regimen.

The study enrolled patients with severe HFrEF (LVEF ≤ 35% and NYHA class IV symptoms within the past 6 months and class III or IV symptoms at enrollment) currently being treated with an ACEi (if tolerated) and a loop diuretic. Patients were randomized to the addition of spironolactone 25mg PO daily or placebo. (The dose could be increased at 8 weeks to 50mg PO daily if the patient showed signs or symptoms of progression of CHF without evidence of hyperkalemia.) The primary outcome was all-cause mortality. Secondary outcomes included death from cardiac causes, hospitalization for cardiac causes, change in NYHA functional class, and incidence of hyperkalemia.

1663 patients were randomized. The trial was stopped early (mean follow-up of 24 months) due to the marked improvement in mortality among the spironolactone group. Among the placebo group, 386 (46%) patients died, whereas only 284 (35%) patients among the spironolactone group died (RR 0.70, 95% CI 0.60 to 0.82, p < 0.001; NNT = 8.8). See the dramatic Kaplan-Meier curve in Figure 1. Relative to placebo, spironolactone treatment reduced deaths secondary to cardiac causes by 31% and hospitalizations for cardiac causes by 30% (p < 0.001 for both). In placebo patients, NYHA class improved in 33% of cases, was unchanged in 18%, and worsened in 48% of patients; in spironolactone patients, the NYHA class improved in 41%, was unchanged in 21%, and worsened in 38% of patients (p < 0.001 for group difference by Wilcoxon test). “Serious hyperkalemia” occurred in 10 (1%) of placebo patients and 14 (2%) of spironolactone patients (p = 0.42). Treatment discontinuation rates were similar among the two groups.

Among patients with severe HFrEF, the addition of spironolactone improved mortality, reduced hospitalizations for cardiac causes, and improved symptoms without conferring an increased risk of serious hyperkalemia. The authors hypothesized that spironolactone “can prevent progressive heart failure by averting sodium retention and myocardial fibrosis” and can “prevent sudden death from cardiac causes by averting potassium loss and by increasing the myocardial uptake of norepinephrine.” Myocardial fibrosis is thought to be reduced via blocking the role aldosterone plays in collagen formation. Overall, this was a well-designed double-blind RCT that built upon the safety data of the safe-dose-finding 1996 RALES trial and ushered in the era of routine use of aldosterone receptor blockade in severe HFrEF. In 2003, the EPHESUS trial trial demonstrated a mortality benefit of aldosterone antagonism (with eplerenone) among patients with LV dysfunction following acute MI, and in 2011, the EMPHASIS-HF trial demonstrated a reduction in CV death or HF hospitalization with eplerenone use among patients with EF ≤ 35% and NYHA class II symptoms (and notably among patients with a much higher prevalence of beta-blocker use than those of the mid-1990s RALES cohort). The 2014 TOPCAT trial demonstrated that, among patients with HFpEF, spironolactone does not reduce a composite endpoint of CV mortality, aborted cardiac arrest, or HF hospitalizations.

The 2013 ACCF/AHA Guideline for the Management of Heart Failure recommends the use of aldosterone receptor antagonists in patients with NYHA class II-IV symptoms with LVEF ≤ 35% and following an acute MI in patients with LVEF ≤ 40% with symptomatic HF or with a history of diabetes mellitus. Contraindications include Cr ≥ 2.5 or K ≥ 5.0.

Further Reading/References:
1. “Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]).” American Journal of Cardiology, 1996.
2. RALES @ Wiki Journal Club
3. RALES @ 2 Minute Medicine
4. EPHESUS @ Wiki Journal Club
5. EMPHASIS-HF @ Wiki Journal Club
6. TOPCAT @ Wiki Journal Club
7. 2013 ACCF/AHA Guideline for the Management of Heart Failure

Summary by Duncan F. Moore, MD

Image Credit: Spirono, CC0 1.0, via Wikimedia Commons

Week 21 – EINSTEIN-PE

“Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism”

by the EINSTEIN-PE Investigators

N Engl J Med. 2012 Apr 5;366(14):1287-97. [free full text]

Prior to the introduction of DOACs, the standard of care for treatment of acute VTE was treatment with a vitamin K antagonist (VKA, e.g. warfarin) bridged with LMWH. In 2010, the EINSTEIN-DVT study demonstrated the non-inferiority of rivaroxaban (Xarelto) versus VKA with an enoxaparin bridge in patients with acute DVT in the prevention of recurrent VTE. Subsequently, in this 2012 study, EINSTEIN-PE, the EINSTEIN investigators examined the potential role for rivaroxaban in the treatment of acute PE.

This open-label RCT compared treatment of acute PE (± DVT) with rivaroxaban (15mg PO BID x21 days, followed by 20mg PO daily) versus VKA with an enoxaparin 1mg/kg bridge until the INR was therapeutic for 2+ days and the patient had received at least 5 days of enoxaparin. Patients with cancer were not excluded if they had a life expectancy of ≥ 3 months, but they comprised only ~4.5% of the patient population. Treatment duration was determined by the discretion of the treating physician and was decided prior to randomization. Duration was also a stratifying factor in the randomization. The primary outcome was symptomatic recurrent VTE (fatal or nonfatal). The pre-specified noninferiority margin was 2.0 for the upper limit of the 95% confidence interval of the hazard ratio. The primary safety outcome was “clinically relevant bleeding.”

4833 patients were randomized. In the conventional-therapy group, the INR was in the therapeutic range 62.7% of the time. Symptomatic recurrent VTE occurred in 2.1% of patients in the rivaroxaban group and 1.8% of patients in the conventional-therapy group (HR 1.12, 95% CI 0.75–1.68, p = 0.003 for noninferiority). The p value for superiority of conventional therapy over rivaroxaban was 0.57. A first episode of “clinically relevant bleeding” occurred in 10.3% of the rivaroxaban group versus 11.4% of the conventional-therapy group (HR 0.90, 95% CI 0.76-1.07, p = 0.23).

In a large, open-label RCT, rivaroxaban was shown to be noninferior to standard therapy with a VKA + enoxaparin bridge in the treatment of acute PE. This was the first major RCT to demonstrate the safety and efficacy of a DOAC in the treatment of PE and led to FDA approval of rivaroxaban for the treatment of PE that same year. The following year, the AMPLIFY trial demonstrated that apixaban was noninferior to VKA + LMWH bridge in the prevention of recurrent VTE, and apixaban was also approved by the FDA for the treatment of PE. The 2016 Chest guidelines for Antithrombotic Therapy for VTE Disease recommend the DOACs rivaroxaban, apixaban, dabigatran, or edoxaban over VKA therapy in VTE not associated with cancer. In cancer-associated VTE, LMWH remains the recommended initial agent. (See the Week 10 – CLOT post.) As noted previously, a study earlier this year in NEJM demonstrated the noninferiority of edoxaban over LMWH in the treatment of cancer-associated VTE.

Further Reading/References:
1. EINSTEIN-DVT @ NEJM
2. EINSTEIN-PE @ Wiki Journal Club
3. EINSTEIN-PE @ 2 Minute Medicine
4. AMPLIFY @ Wiki Journal Club
5. “Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism” NEJM 2018

Summary by Duncan F. Moore, MD

Image Credit: James Heilman, MD / CC BY-SA 4.0 / via WikiMedia Commons

Week 20 – Omeprazole for Bleeding Peptic Ulcers

“Effect of Intravenous Omeprazole on Recurrent Bleeding After Endoscopic Treatment of Bleeding Peptic Ulcers”

N Engl J Med. 2000 Aug 3;343(5):310-6. [free full text]

Intravenous proton-pump inhibitor (PPI) therapy is a cornerstone of modern therapy for bleeding peptic ulcers. However, prior to this 2000 study by Lau et al., the role of PPIs in the prevention of recurrent bleeding after endoscopic treatment was unclear. At the time, re-bleeding rates after endoscopic treatment were noted to be approximately 15-20%. Although other studies had approached this question, no high-quality, large, blinded RCT had examined adjuvant PPI use immediately following endoscopic treatment.

The study enrolled patients who had a bleeding gastroduodenal ulcer visualized on endoscopy and in whom hemostasis was achieved following epinephrine injection and thermocoagulation. Enrollees were randomized to treatment with either omeprazole 80mg IV bolus followed by 8mg/hr infusion x72 hours then followed by omeprazole 20mg PO x8 weeks or to placebo bolus + drip x72 hours followed by omeprazole 20mg PO x8 weeks. The primary outcome was recurrent bleeding within 30 days. Secondary outcomes included recurrent bleeding within 72 hours, amount of blood transfused by day 30, hospitalization duration, and all-cause 30-day mortality.

120 patients were randomized to each arm. The trial was terminated early due to the finding on interim analysis of a significantly lower recurrent bleeding rate in the omeprazole arm. Bleeding re-occurred within 30 days in 8 (6.7%) omeprazole patients versus 27 (22.5%) placebo patients (HR 3.9, 95% CI 1.7-9.0; NNT 6.3). A Cox proportional-hazards model, when adjusted for size and location of ulcers, presence/absence of coexisting illness, and history of ulcer disease, revealed a similar hazard ratio (HR 3.9, 95% CI 1.7-9.1). Recurrent bleeding was most common during the first 72 hrs (4.2% of the omeprazole group versus 20% of the placebo group, RR 4.80, 95% CI 1.89-12.2, p<0.001). For a nice visualization of the early separation of re-bleeding rates, see the Kaplan-Meier curve in Figure 1. The mean number of units of blood transfused within 30 days was 2.7 ± 2.5 in the omeprazole group versus 3.5 ± 3.8 in the placebo group (p = 0.04). Regarding duration of hospitalization, 46.7% of omeprazole patients were admitted for < 5 days versus 31.7% of placebo patients (p = 0.02). Median stay was 4 days in the omeprazole group versus 5 days in the placebo group (p = 0.006). 4.2% of the omeprazole patients died within 30 days, whereas 10% of the placebo patients died (p = 0.13).

Treatment with intravenous omeprazole immediately following endoscopic intervention for bleeding peptic ulcer significantly reduced the rate of recurrent bleeding. This effect was most prominent within the first 3 days of therapy. This intervention also reduced blood transfusion requirements and shortened hospital stays. The presumed mechanism of action is increased gastric pH facilitating platelet aggregation. In 2018, the benefit of this intervention seems so obvious based on its description alone that one would not imagine that such a trial would be funded or published in such a high-profile journal. However, the annals of medicine are littered with now-discarded interventions that made sense from a theoretical or mechanistic perspective but were demonstrated to be ineffective or even harmful (e.g. pharmacologic suppression of ventricular arrhythmias post-MI or renal denervation for refractory HTN).

Today, bleeding peptic ulcers are treated with an IV PPI twice daily. Per UpToDate, meta-analyses have not shown a benefit of continuous PPI infusion over this IV BID dosing. However, per 2012 guidelines in the American Journal of Gastroenterology, patients with active bleeding or non-bleeding visible vessels should receive both endoscopic intervention and IV PPI bolus followed by infusion.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Overview of the Treatment of Bleeding Peptic Ulcers”
4. Laine L, Jensen DM. “Management of patients with ulcer bleeding.” Am J Gastroenterol. 2012

Summary by Duncan F. Moore, MD

Image credit: Wesalius, CC BY 4.0, via Wikimedia Commons

Week 19 – COPERNICUS

“Effect of carvedilol on survival in severe chronic heart failure”

by the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group

N Engl J Med. 2001 May 31;344(22):1651-8. [free full text]

We are all familiar with the role of beta-blockers in the management of heart failure with reduced ejection fraction. In the late 1990s, a growing body of excellent RCTs demonstrated that metoprolol succinate, bisoprolol, and carvedilol improved morbidity and mortality in patients with mild to moderate HFrEF. However, the only trial of beta-blockade (with bucindolol) in patients with severe HFrEF failed to demonstrate a mortality benefit. In 2001, the COPERNICUS trial further elucidated the mortality benefit of carvedilol in patients with severe HFrEF.

The study enrolled patients with severe CHF (NYHA class III-IV symptoms and LVEF < 25%) despite “appropriate conventional therapy” and randomized them to treatment with carvedilol with protocolized uptitration (in addition to pt’s usual meds) or placebo with protocolized uptitration (in addition to pt’s usual meds). The major outcomes measured were all-cause mortality and the combined risk of death or hospitalization for any cause.

2289 patients were randomized before the trial was stopped early due to higher than expected survival benefit in the carvedilol arm. Mean follow-up was 10.4 months. Regarding mortality, 190 (16.8%) of placebo patients died, while only 130 (11.2%) of carvedilol patients died (p = 0.0014) (NNT = 17.9). Regarding mortality or hospitalization, 507 (44.7%) of placebo patients died or were hospitalized, but only 425 (36.8%) of carvedilol patients died or were hospitalized (NNT = 12.6). Both outcomes were found to be of similar directions and magnitudes in subgroup analyses (age, sex, LVEF < 20% or >20%, ischemic vs. non-ischemic CHF, study site location, and no CHF hospitalization within year preceding randomization).

Implication/Discussion:
In severe HFrEF, carvedilol significantly reduces mortality and hospitalization risk.

This was a straightforward, well-designed, double-blind RCT with a compelling conclusion. In addition, the dropout rate was higher in the placebo arm than the carvedilol arm! Despite longstanding clinician fears that beta-blockade would be ineffective or even harmful in patients with already advanced (but compensated) HFrEF, this trial definitively established the role for beta-blockade in such patients.

Per the 2013 ACCF/AHA guidelines, “use of one of the three beta blockers proven to reduce mortality (e.g. bisoprolol, carvedilol, and sustained-release metoprolol succinate) is recommended for all patients with current or prior symptoms of HFrEF, unless contraindicated.”

Please note that there are two COPERNICUS trials. This is the first reported study (NEJM 2001) which reports only the mortality and mortality + hospitalization results, again in the context of a highly anticipated trial that was terminated early due to mortality benefit. A year later, the full results were published in Circulation, which described findings such as a decreased number of hospitalizations, fewer total hospitalization days, fewer days hospitalized for CHF, improved subjective scores, and fewer serious adverse events (e.g. sudden death, cardiogenic shock, VT) in the carvedilol arm.

Further Reading/References:
1. 2013 ACCF/AHA Guideline for the Management of Heart Failure
2. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure
3. COPERNICUS, 2002 Circulation version
4. Wiki Journal Club (describes 2001 NEJM, cites 2002 Circulation)
5. 2 Minute Medicine (describes and cites 2002 Circulation)

Summary by Duncan F. Moore, MD

Week 18 – Early Palliative Care in NSCLC

“Early Palliative Care for Patients with Metastatic Non-Small-Cell Lung Cancer”

N Engl J Med. 2010 Aug 19;363(8):733-42 [free full text]

Ideally, palliative care improves a patient’s quality of life while facilitating appropriate usage of healthcare resources. However, initiating palliative care late in a disease course or in the inpatient setting may limit these beneficial effects. This 2010 study by Temel et al. sought to demonstrate benefits of early integrated palliative care on patient-reported quality-of-life (QoL) outcomes and resource utilization.

The study enrolled outpatients with metastatic NSCLC diagnosed < 8 weeks ago and ECOG performance status 0-2 and randomized them to either “early palliative care” (met with palliative MD/ARNP within 3 weeks of enrollment and at least monthly afterward) or to standard oncologic care. The primary outcome was the change in Trial Outcome Index (TOI) from baseline to 12 weeks.

TOI = sum of the lung cancer, physical well-being, and functional well-being subscales of the Functional Assessment of Cancer Therapy­–Lung (FACT-L) scale (scale range 0-84, higher score = better function)

Secondary outcomes included:

  1. change in FACT-L score at 12 weeks (scale range 0-136)
  2. change in lung cancer subscale of FACT-L at 12 weeks (scale range 0-28)
  3. “aggressive care,” meaning one of the following: chemo within 14 days before death, lack of hospice care, or admission to hospice ≤ 3 days before death
  4. documentation of resuscitation preference in outpatient records
  5. prevalence of depression at 12 weeks per HADS and PHQ-9
  6. median survival

151 patients were randomized. Palliative-care patients (n=77) had a mean TOI increase of 2.3 points vs. a 2.3-point decrease in the standard-care group (n=73) (p=0.04). Median survival was 11.6 months in the palliative group vs. 8.9 months in the standard group (p=0.02). (See Figure 3 on page 741 for the Kaplan-Meier curve.) Prevalence of depression at 12 weeks per PHQ-9 was 4% in palliative patients vs. 17% in standard patients (p = 0.04). Aggressive end-of-life care was received in 33% of palliative patients vs. 53% of standard patients (p=0.05). Resuscitation preferences were documented in 53% of palliative patients vs. 28% of standard patients (p=0.05). There was no significant change in FACT-L score or lung cancer subscale score at 12 weeks.

Implication/Discussion:
Early palliative care in patients with metastatic non-small cell lung cancer improved quality of life and mood, decreased aggressive end-of-life care, and improved survival. This is a landmark study, both for its quantification of the QoL benefits of palliative intervention and for its seemingly counterintuitive finding that early palliative care actually improved survival.

The authors hypothesized that the demonstrated QoL and mood improvements may have led to the increased survival, as prior studies had associated lower QoL and depressed mood with decreased survival. However, I find more compelling their hypotheses that “the integration of palliative care with standard oncologic care may facilitate the optimal and appropriate administration of anticancer therapy, especially during the final months of life” and earlier referral to a hospice program may result in “better management of symptoms, leading to stabilization of [the patient’s] condition and prolonged survival.”

In practice, this study and those that followed have further spurred the integration of palliative care into many standard outpatient oncology workflows, including features such as co-located palliative care teams and palliative-focused checklists/algorithms for primary oncology providers. Of note, in the inpatient setting, a recent meta-analysis concluded that early hospital palliative care consultation was associated with a $3200 reduction in direct hospital costs ($4250 in subgroup of patients with cancer).

Further Reading/References:
1. ClinicalTrials.gov
2. Wiki Journal Club
3. Profile of first author Dr. Temel
4. “Economics of Palliative Care for Hospitalized Adults with Serious Illness: A Meta-analysis” JAMA Internal Medicine (2018)
5. UpToDate, “Benefits, services, and models of subspecialty palliative care”

Summary by Duncan F. Moore, MD

Week 17 – 4S

“Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)”

Lancet. 1994 Nov 19;344(8934):1383-9 [free full text]

Statins are an integral part of modern primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Hypercholesterolemia is regarded as a major contributory factor to the development of atherosclerosis, and in the 1980s, a handful of clinical trials demonstrated reduction in MI/CAD incidence with cholesterol-lowering agents, such as cholestyramine and gemfibrozil. However, neither drug demonstrated a mortality benefit. By the late 1980s, there was much hope that the emerging drug class of HMG-CoA reductase inhibitors (statins) would confer a mortality benefit, given their previously demonstrated LDL-lowering effects. The 1994 Scandinavian Simvastatin Survival Study was the first large clinical trial to assess this hypothesis.

4444 adults ages 35-70 with a history of angina pectoris or MI and elevated serum total cholesterol (212 – 309 mg/dL) were recruited from 94 clinical centers in Scandinavia (and in Finland, which is technically a Nordic country but not a Scandinavian country…) and randomized to treatment with either simvastatin 20mg PO qPM or placebo. Dosage was increased at 12 weeks and 6 months to target a serum total cholesterol of 124 to 201 mg/dL. (Placebo patients were randomly uptitrated as well.) The primary endpoint was all-cause mortality. The secondary endpoint was time to first “major coronary event,” which included coronary deaths, nonfatal MI, resuscitated cardiac arrest, and definite silent MI per EKG.

The study was stopped early in 1994 after an interim analysis demonstrated a significant survival benefit in the treatment arm. At a mean 5.4 years of follow-up, 256 (12%) in the placebo group versus 182 (8%) in the simvastatin group had died (RR 0.70, 95% CI 0.58-0.85, p=0.0003, NNT = 30.1). The mortality benefit was driven exclusively by a reduction in coronary deaths. Dropout rates were similar (13% of placebo group and 10% of simvastatin group). The secondary endpoint, occurrence of a major coronary event, occurred in 622 (28%) of the placebo group and 431 (19%) of the simvastatin group (RR 0.66, 95% CI 0.59-0.75, p < 0.00001). Subgroup analyses of women and patients aged 60+ demonstrated similar findings for the primary and secondary outcomes. Over the entire course of the study, the average changes in lipid values from baseline in the simvastatin group were -25% total cholesterol, -35% LDL, +8% HDL, and -10% triglycerides. The corresponding percent changes from baseline in the placebo group were +1%, +1%, +1%, and +7%, respectively.

In conclusion, simvastatin therapy reduced mortality in patients with known CAD and hypercholesterolemia via reduction of major coronary events. This was a large, well-designed, double-blind RCT that ushered in the era of widespread statin use for secondary, and eventually, primary prevention of ASCVD. For further information about modern guidelines for the use of statins, please see the 2013 “ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults” and the 2016 USPSTF guideline “Statin use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication”.

Finally, for history buffs interested in a brief history of the discovery and development of this drug class, please see this paper by Akira Endo.

References / Additional Reading:
1. 4S @ Wiki JournalClub
2. “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults”
3. “Statin use for the Primary Prevention of Cardiovascular Disease in Adults: Preventive Medication” (2016)
4. UpToDate, “Society guideline links: Lipid disorders in adults”
5. “A historical perspective on the discovery of statins” (2010)

Summary by Duncan F. Moore, MD

Image Credit: Siol, CC BY-SA 3.0, via Wikimedia Commons

Week 16 – MELD

“A Model to Predict Survival in Patients With End-Stage Liver Disease”

Hepatology. 2001 Feb;33(2):464-70. [free full text]

Prior to the adoption of the Model for End-Stage Liver Disease (MELD) score for the allocation of liver transplants, the determination of medical urgency was dependent on the Child-Pugh score. The Child-Pugh score was limited by the inclusion of two subjective variables (severity of ascites and severity of encephalopathy), limited discriminatory ability, and a ceiling effect of laboratory abnormalities. Stakeholders sought an objective, continuous, generalizable index that more accurately and reliably represented disease severity. The MELD score had originally been developed in 2000 to estimate the survival of patients undergoing TIPS. The authors of this 2001 study hypothesized that the MELD score would accurately estimate short-term survival in a wide range of severities and etiologies of liver dysfunction and thus serve as a suitable replacement measure for the Child-Pugh score in the determination of medical urgency in transplant allocation.

This study reported a series of four retrospective validation cohorts for the use of MELD in prediction of mortality in advanced liver disease. The index MELD score was calculated for each patient. Death during follow-up was assessed by chart review.

MELD score = 3.8*ln([bilirubin])+11.2*ln(INR)+9.6*ln([Cr])+6.4*(etiology: 0 if cholestatic or alcoholic, 1 otherwise)

The primary study outcome was the concordance c-statistic between MELD score and 3-month survival. The c-statistic is equivalent to the area under receiver operating characteristic (AUROC). Per the authors, “a c-statistic between 0.8 and 0.9 indicates excellent diagnostic accuracy and a c-statistic greater than 0.7 is generally considered as a useful test.” (See page 455 for further explanation.) There was no reliable comparison statistic (e.g. c-statistic of MELD vs. that of Child-Pugh in all groups).

C-statistic for 3-month survival in the four cohorts ranged from 0.78 to 0.87 (no 95% CIs exceeded 1.0). There was minimal improvement in the c-statistics for 3-month survival with the individual addition of spontaneous bacterial peritonitis, variceal bleed, ascites, and encephalopathy to the MELD score (see Table 4, highest increase in c-statistic was 0.03). When the etiology of liver disease was excluded from the MELD score, there was minimal change in the c-statistics (see Table 5, all paired CIs overlap). C-statistics for 1-week mortality ranged from 0.80 to 0.95.

In conclusion, the MELD score is an excellent predictor of short-term mortality in patients with end-stage liver disease of diverse etiology and severity. Despite the retrospective nature of this study, this study represented a significant improvement upon the Child-Pugh score in determining medical urgency in patients who require liver transplant. In 2002, the United Network for Organ Sharing (UNOS) adopted a modified version of the MELD score for the prioritization of deceased-donor liver transplants in cirrhosis. Concurrent with the 2001 publication of this study, Wiesner et al. performed a prospective validation of the use of MELD in the allocation of liver transplantation. When published in 2003, it demonstrated that MELD score accurately predicted 3-month mortality among patients with chronic liver disease on the waitlist. The MELD score has also been validated in other conditions such as alcoholic hepatitis, hepatorenal syndrome, and acute liver failure (see UpToDate). Subsequent additions to the MELD score have come out over the years. In 2006, the MELD Exception Guidelines offered extra points for severe comorbidities (e.g HCC, hepatopulmonary syndrome). In January 2016, the MELDNa score was adopted and is now used for liver transplant prioritization.

References and Further Reading:
1. “A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts” (2000)
2. MDCalc “MELD Score”
3. Wiesner et al. “Model for end-stage liver disease (MELD) and allocation of donor livers” (2003)
4. Freeman Jr. et al. “MELD exception guidelines” (2006)
5. 2 Minute Medicine
6. UpToDate “Model for End-stage Liver Disease (MELD)”

Image Credit: Ed Uthman, CC-BY-2.0, via WikiMedia Commons

Week 14 – CURB-65

“Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study”

Thorax. 2003 May;58(5):377-82. [free full text]

Community-acquired pneumonia (CAP) is frequently encountered by the admitting medicine team. Ideally, the patient’s severity at presentation and risk for further decompensation should determine the appropriate setting for further care, whether as an outpatient, on an inpatient ward, or in the ICU. At the time of this 2003 study, the predominant decision aid was the 20-variable Pneumonia Severity Index. The authors of this study sought to develop a simpler decision aid for determining the appropriate level of care at presentation.

The study examined the 30-day mortality rates of adults admitted for CAP via the ED at three non-US academic medical centers (data from three previous CAP cohort studies). 80% of the dataset was analyzed as a derivation cohort – meaning it was used to identify statistically significant, clinically relevant prognostic factors that allowed for mortality risk stratification. The resulting model was applied to the remaining 20% of the dataset (the validation cohort) in order to assess the accuracy of its predictive ability.

The following variables were integrated into the final model (CURB-65):

  1. Confusion
  2. Urea > 19mg/dL (7 mmol/L)
  3. Respiratory rate ≥ 30 breaths/min
  4. low Blood pressure (systolic BP < 90 mmHg or diastolic BP < 60 mmHg)
  5. age ≥ 65

1068 patients were analyzed. 821 (77%) were in the derivation cohort. 86% of patients received IV antibiotics, 5% were admitted to the ICU, and 4% were intubated. 30-day mortality was 9%. 9 of 11 clinical features examined in univariate analysis were statistically significant (see Table 2).

Ultimately, using the above-described CURB-65 model, in which 1 point is assigned for each clinical characteristic, patients with a CURB-65 score of 0 or 1 had 1.5% mortality, patients with a score of 2 had 9.2% mortality, and patients with a score of 3 or more had 22% mortality. Similar values were demonstrated in the validation cohort. Table 5 summarizes the sensitivity, specificity, PPVs, and NPVs of each CURB-65 score for 30-day mortality in both cohorts. As we would expect from a good predictive model, the sensitivity starts out very high and decreases with increasing score, while the specificity starts out very low and increases with increasing score. For the clinical application of their model, the authors selected the cut points of 1, 2, and 3 (see Figure 2).

In conclusion, CURB-65 is a simple 5-variable decision aid that is helpful in the initial stratification of mortality risk in patients with CAP.

The wide range of specificities and sensitivities at different values of the CURB-65 score makes it a robust tool for risk stratification. The authors felt that patients with a score of 0-1 were “likely suitable for home treatment,” patients with a score of 2 should have “hospital-supervised treatment,” and patients with score of  ≥ 3 had “severe pneumonia” and should be admitted (with consideration of ICU admission if score of 4 or 5).

Following the publication of the CURB-65 Score, the author of the Pneumonia Severity Index (PSI) published a prospective cohort study of CAP that examined the discriminatory power (area under the receiver operating characteristic curve) of the PSI vs. CURB-65. His study found that the PSI “has a higher discriminatory power for short-term mortality, defines a greater proportion of patients at low risk, and is slightly more accurate in identifying patients at low risk” than the CURB-65 score.

Expert opinion at UpToDate prefers the PSI over the CURB-65 score based on its more robust base of confirmatory evidence. Of note, the author of the PSI is one of the authors of the relevant UpToDate article. In an important contrast from the CURB-65 authors, these experts suggest that patients with a CURB-65 score of 0 be managed as outpatients, while patients with a score of 1 and above “should generally be admitted.”

Further Reading/References:
1. Original publication of the PSI, NEJM (1997)
2. PSI vs. CURB-65 (2005)
3. Wiki Journal Club
4. 2 Minute Medicine
5. UpToDate, “CAP in adults: assessing severity and determining the appropriate level of care”

Summary by Duncan F. Moore, MD

Image Credit: by Christaras A, CC BY-SA 3.0

Week 13 – Sepsis-3

“The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)”

JAMA. 2016 Feb 23;315(8):801-10. [free full text]

In practice, we recognize sepsis as a potentially life-threatening condition that arises secondary to infection. Because the SIRS criteria were of limited sensitivity and specificity in identifying sepsis and because our understanding of the pathophysiology of sepsis had purportedly advanced significantly during the interval since the last sepsis definition, an international task force of 19 experts was convened to define and prognosticate sepsis more effectively. The resulting 2016 Sepsis-3 definition was the subject of immediate and sustained controversy.

In the words of Sepsis-3, sepsis simply “is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.” The paper further defines organ dysfunction in terms of a threshold change in the SOFA score by 2+ points. However, the authors state that “the SOFA score is not intended to be used as a tool for patient management but as a means to clinically characterize a septic patient.” The authors note that qSOFA, an easier tool introduced in this paper, can identify promptly at the bedside patients “with suspected infection who are likely to have a prolonged ICU stay or die in the hospital.” A positive screen on qSOFA is identified as 2+ of the following: AMS, SBP ≤ 100, or respiratory rate ≥ 22. At the time of this endorsement of qSOFA, the tool had not been validated prospectively. Finally, septic shock was defined as sepsis with persistent hypotension requiring vasopressors to maintain MAP ≥ 65 and with a serum lactate > 2 despite adequate volume resuscitation.

As noted contemporaneously in the excellent PulmCrit blog post “Top ten problems with the new sepsis definition,” Sepsis-3 was not endorsed by the American College of Chest Physicians, the IDSA, any emergency medicine society, or any hospital medicine society. On behalf of the American College of Chest Physicians, Dr. Simpson published a scathing rejection of Sepsis-3 in Chest in May 2016. He noted “there is still no known precise pathophysiological feature that defines sepsis.” He went on to state “it is not clear to us that readjusting the sepsis criteria to be more specific for mortality is an exercise that benefits patients,” and said “to abandon one system of recognizing sepsis [SIRS] because it is imperfect and not yet in universal use for another system that is used even less seems unwise without prospective validation of that new system’s utility.”

In fact, the later validation of qSOFA demonstrated that the SIRS criteria had superior sensitivity for predicting in-hospital mortality while qSOFA had higher specificity. See the following posts at PulmCrit for further discussion: [https://emcrit.org/isepsis/isepsis-sepsis-3-0-much-nothing/] [https://emcrit.org/isepsis/isepsis-sepsis-3-0-flogging-dead-horse/].

At UpToDate, authors note that “data of the value of qSOFA is conflicting,” and because of this, “we believe that further studies that demonstrate improved clinically meaningful outcomes due to the use of qSOFA compared to clinical judgement are warranted before it can be routinely used to predict those at risk of death from sepsis.”

Additional Reading:
1. PulmCCM, “Simple qSOFA score predicts sepsis as well as anything else”
2. 2 Minute Medicine

Summary by Duncan F. Moore, MD

Image Credit: By Mark Oniffrey – Own work, CC BY-SA 4.0

Week 12 – Rivers Trial

“Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock”

N Engl J Med. 2001 Nov 8;345(19):1368-77. [free full text]

Sepsis is common and, in its more severe manifestations, confers a high mortality risk. Fundamentally, sepsis is a global mismatch between oxygen demand and delivery. Around the time of this seminal study by Rivers et al., there was increasing recognition of the concept of the “golden hour” in sepsis management – “where definitive recognition and treatment provide maximal benefit in terms of outcome” (1368). Rivers and his team created a “bundle” of early sepsis interventions that targeted preload, afterload, and contractility, dubbed early goal-directed therapy (EGDT). They evaluated this bundle’s effect on mortality and end-organ dysfunction.

The “Rivers trial” randomized adults presenting to a single US academic center ED with ≥ 2 SIRS criteria and either SBP ≤ 90 after a crystalloid challenge of 20-30ml/kg over 30min or lactate > 4mmol/L to either treatment with the EGDT bundle or to the standard of care.

Intervention: early goal-directed therapy (EGDT)

  • Received a central venous catheter with continuous central venous O2 saturation (ScvO2) measurement
  • Treated according to EGDT protocol (see Figure 2, or below) in ED for at least six hours
    • 500ml bolus of crystalloid q30min to achieve CVP 8-12mm
    • Vasopressors to achieve MAP ≥ 65
    • Vasodilators to achieve MAP ≤ 90
    • If ScvO2 < 70%, transfuse RBCs to achieve Hct ≥ 30
    • If, after CVP, MAP, and Hct were optimized as above and ScvO2 remained < 70%, dobutamine was added and uptitrated to achieve ScvO2 ≥ 70 or until max dose 20 μg/kg/min
      • dobutamine was de-escalated if MAP < 65 or HR > 120
    • Patients in whom hemodynamics could not be optimized were intubated and sedated, in order to decrease oxygen consumption
  • Patients were transferred to inpatient ICU bed as soon as able, and upon transfer ScvO2 measurement was discontinued
  • Inpatient team was blinded to treatment group assignment

The primary outcome was in-hospital mortality. Secondary endpoints included: resuscitation end points, organ-dysfunction scores, coagulation-related variables, administered treatments, and consumption of healthcare resources.

130 patients were randomized to EGDT, and 133 to standard therapy. There were no differences in baseline characteristics. There was no group difference in the prevalence of antibiotics given within the first 6 hours. Standard-therapy patients spent 6.3 ± 3.2 hours in the ED, whereas EGDT patients spent 8.0 ± 2.1 (p < 0.001).

In-hospital mortality was 46.5% in the standard-therapy group, and 30.5% in the EGDT group (p = 0.009, NNT 6.25). 28-day and 60-day mortalities were also improved in the EGDT group. See Table 3.

During the initial six hours of resuscitation, there was no significant group difference in mean heart rate or CVP. MAP was higher in the EGDT group (p < 0.001), but all patients in both groups reached a MAP ≥ 65. ScvO2 ≥ 70% was met by 60.2% of standard-therapy patients and 94.9% of EGDT patients (p < 0.001). A combination endpoint of achievement of CVP, MAP, and UOP (≥ 0.5cc/kg/hr) goals was met by 86.1% of standard-therapy patients and 99.2% of EGDT patients (p < 0.001). Standard-therapy patients had lower ScvO2 and greater base deficit, while lactate and pH values were similar in both groups.

During the period of 7 to 72 hours, the organ-dysfunction scores of APACHE II, SAPS II, and MODS were higher in the standard-therapy group (see Table 2). The prothrombin time, fibrin-split products concentration, and d-dimer concentrations were higher in the standard-therapy group, while PTT, fibrinogen concentration, and platelet counts were similar.

During the initial six hours, EGDT patients received significantly more fluids, pRBCs, and inotropic support than standard-therapy patients. Rates of vasopressor use and mechanical ventilation were similar. During the period of 7 to 72 hours, standard-therapy patients received more fluids, pRBCs, and vasopressors than the EGDT group, and they were more likely to be intubated and to have pulmonary-artery catheterization. Rates of inotrope use were similar. Overall, during the first 72 hrs, standard-therapy patients were more likely to receive vasopressors, be intubated, and undergo pulmonary-artery catheterization. EGDT patients were more likely to receive pRBC transfusion. There was no group difference in total volume of fluid administration or inotrope use. Regarding utilization, there were no group differences in mean duration of vasopressor therapy, mechanical ventilation, or length of stay. Among patients who survived to discharge, standard-therapy patients spent longer in the hospital than EGDT patients (18.4 ± 15.0 vs. 14.6 ± 14.5 days, respectively, p = 0.04).

In conclusion, early goal-directed therapy reduced in-hospital mortality in patients presenting to the ED with severe sepsis or septic shock when compared with usual care. In their discussion, the authors note that “when early therapy is not comprehensive, the progression to severe disease may be well under way at the time of admission to the intensive care unit” (1376).

The Rivers trial has been cited over 10,500 times. It has been widely discussed and dissected for decades. Most importantly, it helped catalyze a then-ongoing paradigm shift of what “usual care” in sepsis is. As noted by our own Drs. Sonti and Vinayak and in their Georgetown Critical Care Top 40: “Though we do not use the ‘Rivers protocol’ as written, concepts (timely resuscitation) have certainly infiltrated our ‘standard of care’ approach.” The Rivers trial evaluated the effect of a bundle (multiple interventions). It was a relatively complex protocol, and it has been recognized that the transfusion of blood to Hgb > 10 may have caused significant harm. In aggregate, the most critical elements of the modern initial resuscitation in sepsis are early administration of antibiotics (notably not protocolized by Rivers) within the first hour and the aggressive administration of IV fluids (now usually 30cc/kg of crystalloid within the first 3 hours of presentation).

More recently, there have been three large RCTs of EGDT versus usual care and/or protocols that used some of the EGDT targets: ProCESS (2014, USA), ARISE (2014, Australia), and ProMISe (2015, UK). In general terms, EGDT provided no mortality benefit compared to usual care. Prospectively, the authors of these three trials planned a meta-analysis – the 2017 PRISM study – which concluded that “EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics.” Despite patients in the Rivers trial being sicker than those of ProCESS/ARISE/ProMISe, it was not found in the subgroup analysis of PRISM that EGDT was more beneficial in sicker patients. Overall, the PRISM authors noted that “it remains possible that general advances in the provision of care for sepsis and septic shock, to the benefit of all patients, explain part or all of the difference in findings between the trial by Rivers et al. and the more recent trials.”

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. Life in The Fast Lane
4. Georgetown Critical Care Top 40
5. “A randomized trial of protocol-based care for early septic shock” (ProCESS). NEJM 2014.
6. “Goal-directed resuscitation for patients with early septic shock” (ARISE). NEJM 2014.
7. “Trial of early, goal-directed resuscitation for septic shock” (ProMISe). NEJM 2015.
8. “Early, Goal-Directed Therapy for Septic Shock – A Patient-level Meta-Analysis” PRISM. NEJM 2017.
9. Surviving Sepsis Campaign
10. UpToDate, “Evaluation and management of suspected sepsis and septic shock in adults”

Summary by Duncan F. Moore, MD

Image Credit: By Clinical_Cases, [CC BY-SA 2.5] via Wikimedia Commons