Month: September 2017

Week 13 – 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.

Population: adults admitted for CAP via the ED at three non-US academic medical centers

Intervention/Comparison: none

Outcome: 30-day mortality

Additional details about methodology: This study analyzed the aggregate 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

Results:
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).


Implication/Discussion:
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

Week 12 – 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 outcomes and resource utilization.

Population: outpatients with metastatic NSCLC diagnosed < 8 weeks ago and ECOG performance status 0-2

Intervention: “early palliative care” – met with palliative MD/ARNP within 3 weeks of enrollment and at least monthly afterward

Comparison: standard oncologic care

Outcome:

Primary – 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

  • change in FACT-L score at 12 weeks (scale range 0-136)
  • change in lung-cancer subscale of FACT-L at 12 weeks (scale range 0-28)
  • “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
  • documentation of resuscitation preference in outpatient records
  • prevalence of depression at 12 weeks per HADS and PHQ-9
  • median survival

Results:
151 patients were randomized. There were no significant difference in baseline characteristics among the two groups. Palliative-care patients (n=77) had a mean TOI increase of 2.3 points, versus a 2.3-point decrease in the standard-care group (n=73) (p=0.04).

Secondary outcomes:

  • ∆ FACT-L score at 12 weeks: +4.2± 13.8 in the palliative group vs. -0.4 ±13.8 in the standard group (p=0.09 for difference between the two groups)
  • ∆ lung-cancer subscale at 12 weeks: +0.8±3.6 in palliative vs. +0.3±4.0 in standard (p=0.50)
  • 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)
  • depression at 12 weeks per PHQ-9 was 4% in palliative patients vs. 17% in standard patients (p = 0.04)
  • median survival was 11.6 months in the palliative group versus 8.9 months in the standard group (p=0.02). (See Figure 3 on page 741 for the Kaplan-Meier curve.)

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 quality-of-life (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.

Limitations of this study: 1) a complex subjective primary endpoint, 2) non-blinded, 3) single-center, minimally diverse patient population.

Further Reading/References:
1. ClinicalTrials.gov
2. Wiki Journal Club
3. Profile of first author Dr. Temel
4. UpToDate, “Benefits, services, and models of subspecialty palliative care”

Summary by Duncan F. Moore, MD

Week 11 – CAST

“Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo”

The Cardiac Arrhythmia Suppression Trial (CAST) [free full text]

N Engl J Med. 1991 Mar 21;324(12):781-8.
—

Ventricular arrhythmias are common following MI, and studies have demonstrated that PVCs and other arrhythmias such as non-sustained ventricular tachycardia (NSVT) are independent risk factors for cardiac mortality following MI. As such, by the late 1980s, many patients with PVCs post-MI were treated with antiarrhythmic drugs in an attempt to reduce mortality. The 1991 CAST trial sought to prove what predecessor trials had failed to prove – that suppression of such rhythms post-MI would improve survival.

Population:     

·       post-MI patients with ≥ 6 asymptomatic PVCs per hour and no runs of VT ≥ 15 beats, LVEF < 55% if within 90 days of MI, or LVEF < 40% if greater than 90 days since MI

o   patients were further selected by an open-label titration period in which patients were assigned to treatment with encainide, flecainide, or moricizine

o   “responders” had at least 80% suppression of PVCs and 90% suppression of runs of VT

Intervention: continuation of antiarrhythmic drug assigned during titration period

Comparison: transition from titration antiarrhythmic drug to placebo

Outcome:

Primary – death or cardiac arrest with resuscitation “either of which was due to arrhythmia”

Secondary
1. all-cause mortality or cardiac arrest
2. cardiac death or cardiac arrest due to any cardiac cause
3. VT ≥ 15 or more beats at rate ≥ 120 bpm
4. syncope
5. permanent pacemaker implantation
6. recurrent MI
7. CHF
8. angina pectoris
9. coronary artery revascularization

Results:
The trial was terminated early due to increased mortality in the encainide and flecainide treatment groups. 1498 patients were randomized following successful titration during the open-label period, and they were reported in this paper. The results of the moricizine arm were reported later in a different paper (CAST-II).

RR of death or cardiac arrest due to arrhythmia was 2.64 (95% CI 1.60–4.36). The number needed to harm was 28.2. See Figure 1 on page 783 for a striking Kaplan-Meier curve.

RR of death or cardiac arrest due to all causes was 2.38 (95% CI 1.59–3.57). The number needed to harm was 20.6. See Figure 2 on page 784 for the relevant Kaplan-Meier curve.

Regarding the other secondary outcomes, cardiac death/arrest due to any cardiac cause was similarly elevated in the treatment group, and there were no significant differences in non-lethal endpoints among the treatment and placebo arms.

Implication/Discussion:
Treatment of asymptomatic ventricular arrhythmias with encainide and flecainide in patients with LV dysfunction following MI results in increased mortality.

This study is a classic example of how a treatment that is thought to make intuitive sense based on observational data (i.e. PVCs and NSVT are associated with cardiac death post-MI, thus reducing these arrhythmias will reduce death) can be easily and definitively disproven with a placebo-controlled trial with hard endpoints (e.g. death). Correlation does not equal causation.

Modern expert opinion at UpToDate notes no role for suppression of asymptomatic PVCs or NSVT in the peri-infarct period. Indeed such suppression may increase mortality. As noted on Wiki Journal Club, modern ACC/AHA guidelines “do not comment on the use of antiarrhythmic medications in ACS care.”

Further Reading:
1. CAST-I Trial at ClinicalTrials.gov
2. CAST-II trial publication, NEJM (1992)
3. Wiki Journal Club
4. 2 Minute Medicine
5. UpToDate “Clinical features and treatment of ventricular arrhythmias during acute myocardial infarction”

Summary by Duncan F. Moore, MD

Week 10 – 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, 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 retrospective validation cohorts for the use of MELD in prediction of mortality in advanced liver disease.

Methods:

Populations:

  1. cirrhotic inpatients, Mayo Clinic, 1994-1999, n = 282 (see exclusion criteria)
  2. ambulatory patients with noncholestatic cirrhosis, newly-diagnosed, single-center in Italy, 1981-1984, n = 491 consecutive patients
  3. ambulatory patients with primary biliary cirrhosis, Mayo Clinic, 1973-1984, n = 326 (92 lacked all necessary variables for calculation of MELD)
  4. cirrhotic patients, Mayo Clinic, 1984-1988, n = 1179 patients with sufficient follow-up (≥ 3 months) and laboratory data

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)

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. Child-Pugh in all groups).

Results:

Primary:

  • hospitalized Mayo patients (late 1990s): c-statistic for prediction of 3-month survival = 0.87 (95% CI 0.82-0.92)
  • ambulatory, non-cholestatic Italian patients: c-statistic for 3-month survival = 0.80 (95% CI 0.69-0.90)
  • ambulatory PBC patients at Mayo: c-statistic for 3-month survival = 0.87 (95% CI 0.83-0.99)
  • cirrhotic patients at Mayo (1980s): c-statistic for 3-month survival = 0.78 (95% CI 0.74-0.81)

Secondary:

  • There was minimal improvement in the c-statistics for 3-month survival with the individual addition of SBP, 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.

Implication/Discussion:
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)”

Summary by Duncan F. Moore, MD