Week 28 – FACT

“Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout”

aka the Febuxostat versus Allopurinol Controlled Trial (FACT)

N Engl J Med. 2005 Dec 8;353(23):2450-61. [free full text]

Gout is thought to affect approximately 3% of the US population, and its prevalence appears to be rising. Gout occurs due to precipitation of monosodium urate crystals from supersaturated body fluids. Generally, the limit of solubility is 6.8 mg/dL, but local factors such as temperature, pH, and other solutes can lower this threshold. A critical element in the treatment of gout is the lowering of the serum urate concentration below the limit of solubility, and generally, the accepted target is 6.0 mg/dL. The xanthine oxidase inhibitor allopurinol is the most commonly used urate-lowering pharmacologic therapy. Allopurinol rarely can have severe or life-threatening side effects, particularly among patients with renal impairment. Thus drug companies have sought to bring to market other xanthine oxidase inhibitors such as febuxostat (trade name Uloric). In this chronic and increasingly burdensome disease, a more efficacious drug with fewer exclusion criteria and fewer side effects would be a blockbuster.

The study enrolled adults with gout and a serum urate concentration of ≥ 8.0 mg/dL. Exclusion criteria included serum Cr ≥ 1.5 mg/dL or eGFR < 50 ml/min (due to this being a relative contraindication for allopurinol use) as well as a the presence of various conditions or use of various drugs that would affect urate metabolism and/or clearance of the trial drugs. (Patients already on urate-lowering therapy were given a two week washout period prior to randomization.) Patients were randomized to treatment for 52 weeks with either febuxostat 80mg PO daily, febuxostat 120mg PO daily, or allopurinol 300mg PO daily. Because the initiation of urate-lowering therapy places patients at increased risk of gout flares, patients were placed on prophylaxis with either naproxen 250mg PO BID or colchicine 0.6mg PO daily for the first 8 weeks of the study. The primary endpoint was a serum urate level of < 6.0 mg/dL at weeks 44, 48, and 52. Selected secondary endpoints included percentage reduction in serum urate from baseline at each visit, percentage reduction in area of a selected tophus, and prevalence of acute gout flares weeks requiring treatment.

762 patients were randomized. Baseline characteristics were statistically similar among all three groups. A majority of the patients were white males age 50+ who drank alcohol. Average serum urate was slightly less than 10 mg/dL. The primary endpoint (urate < 6.0 at the last three monthly measurements) was achieved in 53% of patients taking febuxostat 80mg, 62% of patients taking febuxostat 120mg, and 21% of patients taking allopurinol 300mg (p < 0.001 for each febuxostat groups versus allopurinol). Regarding selected secondary endpoints:

1) The percent reduction in serum urate from baseline at the final visit was 44.73 ± 19.10 in the febuxostat 80mg group, 52.52 ± 19.91 in the febuxostat 120mg group, and 32.99 ± 15.33 in the allopurinol 300mg group (p < 0.001 for each febuxostat group versus allopurinol, and p < 0.001 for febuxostat 80mg versus 120mg). 2) The percentage reduction in area of a single selected tophus was assessed in 156 patients who had tophi at baseline. At week 52, the median percentage reduction in tophus area was 83% in febuxostat 80mg patients, 66% in febuxostat 120mg patients, and 50% in allopurinol patients (no statistical difference per authors, p values not reported). Additionally, there was no significant reduction in tophus count in any of the groups. 3) During weeks 1-8 (in which acute gout flare prophylaxis was scheduled), 36% of patients in the febuxostat 120mg sustained a flare, whereas only 22% of the febuxostat 80mg group and 21% of the allopurinol group sustained a flare (p < 0.001 for both pairwise comparisons versus febuxostat 120mg). During weeks 9-52 (in which acute gout flare prophylaxis was no longer scheduled), a similar proportion of patients in each treatment group sustained an acute flare of gout (64% in the febuxostat 80mg group, 70% in the febuxostat 120mg group, and 64% in the allopurinol group). Finally, the incidence of treatment-related adverse events was similar among all three groups (see Table 3). Treatment was most frequently discontinued in the febuxostat 120mg group (98 patients, versus 88 patients in the febuxostat 80mg group and 66 patients in the allopurinol group; p = 0.003 for comparison between febuxostat 120mg and allopurinol).

In summary, this large RCT of urate-lowering therapy among gout patients found that febuxostat, dosed at either 80mg or 120mg PO daily, was more efficacious than allopurinol 300mg in reducing serum urate to below 6.0 mg/dL. Febuxostat was not superior to allopurinol with respect to the tested clinical outcomes of tophus size reduction, tophus count, and acute gout flares. Safety profiles were similar among the three regimens.

The authors note that the incidence of gout flares during and after the prophylaxis phase of the study “calls attention to a well-described paradox with important implications for successful management of gout: the risk of acute gout flares is increased early in the course of urate-lowering treatment” and the authors suggest that there is “a role for more sustained prophylaxis during the initiation of urate-lowering therapy than was provided here” (2458).

A limitation of this study is that its comparator group, allopurinol 300mg PO daily, may not have represented optimal use of the drug. Allopurinol should be uptitrated q2-4 weeks to the minimum dose required to maintain the goal serum urate of < 6.0 mg/dL (< 5.0 if tophi are present). According to UpToDate, “a majority of gout patients require doses of allopurinol exceeding 300 mg/day in order to maintain serum urate < 6.0 mg/dL.” In the United States allopurinol has been approved for doses of up to 800 mg daily. The authors state that “titration of allopurinol would have compromised the blinding of the study” (2459) but this is not true – blinded protocolized titration of study or comparator drugs has been performed in numerous other RCTs and could have been achieved simply at greater cost to and effort from the study sponsor (which happens to be the drug company TAP Pharmaceuticals). The likelihood that such titration would have shifted the results toward a null effect does not go unnoted. Another limitation is the relatively short duration of the trial – follow-up may have been insufficient to establish superiority in clinical outcomes, given the chronic nature of the disease.

In the UK, the National Institute for Health and Care Excellence (NICE), the agency tasked with assessing cost-effectiveness of various medical therapies, recommended as of 2008 that febuxostat be used for the treatment of hyperuricemia in gout “only for people who are intolerant of allopurinol or for whom allopurinol is contraindicated.”

Of note, a recent study funded by Takeda Pharmaceuticals demonstrated the non-inferiority of febuxostat relative to allopurinol with respect to rates of adverse cardiovascular events in patient with gout and major pre-existing cardiovascular conditions.

Allopurinol started at 100mg PO daily and titrated gradually to goal serum urate is the current general practice in the US. However, patients of Chinese, Thai, Korean, or “another ethnicity with similarly increased frequency of HLA-B*5801” should be tested for HLA-B*5801 prior to initiation of allopurinol therapy, as those patients are at increased risk of a severe cutaneous adverse reaction to allopurinol.

Further Reading/References:
1. FACT @ ClinicalTrials.gov
2. UpToDate “Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout”
3. NICE: “Febuxostat for the management of hyperuricemia in people with gout”
4. “Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout.” N Engl J Med. 2018 Mar 29;378(13):1200-1210.

Summary by Duncan F. Moore, MD

Image Credit: James Gilray, US Public Domain, via Wikimedia Commons

Week 27 – ELITE-Symphony

“Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation”

by the Efficacy Limiting Toxicity Elimination (ELITE)-Symphony investigators

N Engl J Med. 2007 Dec 20;357(25):2562-75. [free full text]

A maintenance immunosuppressive regimen following kidney transplantation must balance the benefit of immune tolerance of the transplanted kidney against the adverse effects of the immunosuppressive regimen. Calcineurin inhibitors, such as cyclosporine (CsA) and tacrolimus, are nephrotoxic and can cause long-term renal dysfunction. They can also cause neurologic and infectious complications. At the time of this study, tacrolimus had been only recently introduced but already was appearing to be better than CsA at preventing acute rejection. Sirolimus, an mTOR inhibitor, is notable for causing delayed wound healing, among other adverse effects. The goal of the ELITE-Symphony study was to directly compare two different dosing regimens of CsA (standard- and low-dose) versus low-dose tacrolimus versus low-dose sirolimus, all while on background mycophenolate mofetil (MMF) and prednisone in order to determine which of these immunosuppressive regimens had the lowest nephrotoxicity, most efficacious prevention of rejection, and fewest other adverse effects.

The trial enrolled adults aged 18-75 scheduled to receive kidney transplants. There was a detailed set of exclusion criteria, including the need for treatment with immunosuppressants outside of the aforementioned regimens, specific poor prognostic factors regarding the allograft match or donor status, and specific comorbid or past medical conditions of the recipients. Patients were randomized open-label to one of four immunosuppressive treatment regimens in addition to MMF 2 gm daily and corticosteroids (“according to practice at the center” but with a pre-specified taper of minimum maintenance doses): 1) standard-dose CsA (target trough 150-300 ng/mL x3 months, then target trough 100-200 ng/mL), 2) daclizumab induction accompanied by low-dose cyclosporine (target trough 50-100 ng/mL), 3) daclizumab induction accompanied by low-dose tacrolimus (target trough 3-7 ng/mL), and 4) daclizumab induction accompanied by low-dose sirolimus (target trough 4-8 ng/mL). The primary endpoint was the eGFR at 12 months after transplantation. Secondary endpoints included acute rejection, incidence of delayed allograft function, and frequency of treatment failure (defined as use of additional immunosuppressive medication, discontinuation of any study medication for > 14 consecutive days or > 30 cumulative days, allograft loss, or death) within the first 12 months.

1645 patients were randomized. There were no significant differences in baseline characteristics among the four treatment groups. At 12 months following transplantation, mean eGFR differed among the four groups (p < 0.001). Low-dose tacrolimus patients had an eGFR of 65.4 ± 27.0 ml/min while standard-dose cyclosporine patients had an eGFR of 57.1 ± 25.1 ml/min (p < 0.001 for pairwise comparison with tacrolimus), low-dose cyclosporine patients had an eGFR of 59.4 ± 25.1 ml/min (p = 0.001 for pairwise comparison with tacrolimus), and low-dose sirolimus patients had an eGFR of 56.7 ± 26.9 ml/min (p < 0.001 for pairwise comparison with tacrolimus). The incidence of biopsy-proven acute rejection (excluding borderline values) at 6 months was only 11.3% in the low-dose tacrolimus group; however it was 24.0% in the standard-dose cyclosporine, 21.9% in the low-dose cyclosporine, and 35.3% in the low-dose sirolimus (p < 0.001 for each pairwise comparison with tacrolimus). Values were similar in magnitude and proportionality at 12-month follow-up. Delayed allograft function (among recipients of a deceased donor kidney) was lowest in the sirolimus group at 21.1% while it was 35.7% in the low-dose tacrolimus group (p = 0.001), 33.6% in the standard-dose cyclosporine group, and 32.4% (p = 0.73 for pairwise comparison with tacrolimus) in the low-dose cyclosporine group (p = 0.51 for pairwise comparison with tacrolimus). Treatment failure occurred in 12.2% of the low-dose tacrolimus group, 22.8% of the standard-dose cyclosporine group (p < 0.001 for pairwise comparison with tacrolimus), 20.1% of the low-dose cyclosporine group (p = 0.003 for pairwise comparison with tacrolimus), and in 35.8% of the low-dose sirolimus group (p < 0.001 for pairwise comparison with tacrolimus). Regarding safety events, the incidence of new-onset diabetes after transplantation (NODAT) at 12 months was highest among the low-dose tacrolimus group at 10.6% but only 6.4% among the standard-dose cyclosporine group, 4.7% among the low-dose cyclosporine group, and 7.8% among the low-dose sirolimus group (p = 0.02 for between-group difference per log-rank test). Opportunistic infections were most common in the standard-dose cyclosporine group at 33% (p = 0.03 for between-group difference per log-rank test).

In summary, the post-kidney transplant immunosuppression maintenance regimen with low-dose tacrolimus was superior to the standard- and low-dose cyclosporine regimens and sirolimus regimens with respect to renal function at 12 months, acute rejection at 6 and 12 months, and treatment failure during follow-up. However, this improved performance came at the cost of a higher rate of new-onset diabetes after transplantation. The findings of this study were integral to the 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients which recommends maintenance with a calcineurin inhibitor (tacrolimus first-line), and antiproliferative agent (MMF first-line), and corticosteroids (can consider discontinuation within 1 week in the relatively few patients at low immunologic risk for acute rejection, though expert opinion at UpToDate disagrees with this recommendation).

Further Reading/References:
1. ELITE-Symphony @ Wiki Journal Club
2. “The ELITE & the Rest in Kidney Transplantation.” Renal Fellow Network.
3. “HARMONY: Is it safe to withdraw steroids early after kidney transplant?” NephJC
4. 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients
5. “Maintenance immunosuppressive therapy in kidney transplantation in adults.” UpToDate

Summary by Duncan F. Moore, MD

Image Credit: Rmarlin, CC BY-SA 4.0, via Wikimedia Commons

Week 26 – ARISTOTLE

“Apixaban versus Warfarin in Patients with Atrial Fibrillation”

N Engl J Med. 2011 Sep 15;365(11):981-92. [free full text]

Prior to the development of the DOACs, warfarin was the standard of care for the reduction of risk of stroke in atrial fibrillation. Drawbacks of warfarin include a narrow therapeutic range, numerous drug and dietary interactions, the need for frequent monitoring, and elevated bleeding risk. Around 2010, the definitive RCTs for the oral direct thrombin inhibitor dabigatran (RE-LY) and the oral factor Xa inhibitor rivaroxaban (ROCKET AF) showed equivalence or superiority to warfarin. Shortly afterward, the ARISTOTLE trial demonstrated the superiority of the oral factor Xa inhibitor apixaban (Eliquis).

The trial enrolled patients with atrial fibrillation or flutter with at least one additional risk factor for stroke (age 75+, prior CVA/TIA, symptomatic CHF, or reduced LVEF). Notably, patients with Cr > 2.5 were excluded. Patients were randomized to treatment with either apixaban BID + placebo warfarin daily (reduced 2.5mg apixaban dose given in patients with 2 or more of the following: age 80+, weight < 60, Cr > 1.5) or to placebo apixaban BID + warfarin daily. The primary efficacy outcome was the incidence of stroke, and the primary safety outcome was “major bleeding” (clinically overt and accompanied by Hgb drop of ≥ 2, “occurring at a critical site,” or resulting in death). Secondary outcomes included all-cause mortality and a composite of major bleeding and “clinically-relevant non-major bleeding.”

9120 patients were assigned to the apixaban group, and 9081 were assigned to the warfarin group. Mean CHADS2 score was 2.1. Fewer patients in the apixaban group discontinued their assigned study drug. Median duration of follow-up was 1.8 years. The incidence of stroke was 1.27% per year in the apixaban group vs. 1.60% per year in the warfarin group (HR 0.79, 95% CI 0.66-0.95, p < 0.001). This reduction was consistent across all major subgroups (see Figure 2). Notably, the rate of hemorrhagic stroke was 49% lower in the apixaban group, and the rate of ischemic stroke was 8% lower in the apixaban group. All-cause mortality was 3.52% per year in the apixaban group vs. 3.94% per year in the warfarin group (HR 0.89, 95% CI 0.80-0.999, p = 0.047). The incidence of major bleeding was 2.13% per year in the apixaban group vs. 3.09% per year in the warfarin group (HR 0.69, 95% CI 0.60-0.80, p<0.001). The rate of intracranial hemorrhage was 0.33% per year in the apixaban group vs. 0.80% per year in the warfarin group (HR 0.42, 95% CI 0.30-0.58, p < 0.001). The rate of any bleeding was 18.1% per year in the apixaban group vs. 25.8% in the warfarin group (p <  0.001).

In patients with non-valvular atrial fibrillation and at least one other risk factor for stroke, anticoagulation with apixaban significantly reduced the risk of stroke, major bleeding, and all-cause mortality relative to anticoagulation with warfarin. This was a large RCT that was designed and powered to demonstrate non-inferiority but in fact was able to demonstrate the superiority of apixaban. Along with ROCKET AF and RE-LY, the ARISTOTLE trial ushered in the modern era of DOACs in atrial fibrillation. Apixaban was approved by the FDA for the treatment of non-valvular atrial fibrillation in 2012. Patient prescription cost is no longer a major barrier to prescription. These three major DOACs are all preferred in the DC Medicaid formulary (see page 13). To date, no trial has compared the various DOACs directly.

Further Reading/References:
1. ARISTOTLE @ Wiki Journal Club
2. ARISTOTLE @ 2 Minute Medicine
3. “Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost-effectiveness analysis,” BMJ 2017

Summary by Duncan F. Moore, MD

Week 25 – The Oregon Experiment

“The Oregon Experiment – Effects of Medicaid on Clinical Outcomes”

N Engl J Med. 2013 May 2;368(18):1713-22. [free full text]

Access to health insurance is not synonymous with access to healthcare. However, it has been generally assumed that increased access to insurance should improve healthcare outcomes among the newly insured. In 2008, Oregon expanded its Medicaid program by approximately 30,000 patients. These policies were lotteried among approximately 90,000 applicants. The authors of the Oregon Health Study Group sought to study the impact of this “randomized” intervention, and the results were hotly anticipated given the impending Medicaid expansion of the 2010 PPACA.

Population: Portland, Oregon residents who applied for the 2008 Medicaid expansion

Not all applicants were actually eligible.

Eligibility criteria: age 19-64, US citizen, Oregon resident, ineligible for other public insurance, uninsured for the previous 6 months, income below 100% of the federal poverty level, and assets < $2000.

Intervention: winning the Medicaid-expansion lottery

Comparison: The statistical analyses of clinical outcomes in this study do not actually compare winners to non-winners. Instead, they compare non-winners to winners who ultimately received Medicaid coverage. Winning the lottery increased the chance of being enrolled in Medicaid by about 25 percentage points. Given the assumption that “the lottery affected outcomes only by changing Medicaid enrollment, the effect of being enrolled in Medicaid was simply about 4 times…as high as the effect of being able to apply for Medicaid.” This allowed the authors to conclude causal inferences regarding the benefits of new Medicaid coverage.

Outcomes:
Values or point prevalence of the following at approximately 2 years post-lottery:

      1. blood pressure, diagnosis of hypertension
      2. cholesterol levels, diagnosis of hyperlipidemia
      3. HgbA1c, diagnosis of diabetes
      4. Framingham risk score for cardiovascular events
      5. positive depression screen, depression dx after lottery, antidepressant use
      6. health-related quality of life measures
      7. measures of financial hardship (e.g. catastrophic expenditures)
      8. measures of healthcare utilization (e.g. estimated total annual expenditure)

These outcomes were assessed via in-person interviews, assessment of blood pressure, and a blood draw for biomarkers.

Results:
The study population included 10,405 lottery winners and 10,340 non-winners. Interviews were performed ~25 months after the lottery. While there were no significant differences in baseline characteristics among winners and non-winners, “the subgroup of lottery winners who ultimately enrolled in Medicaid was not comparable to the overall group of persons ho did not win the lottery” (no demographic or other data provided).

At approximately 2 years following the lottery, there were no differences in blood pressure or prevalence of diagnosed hypertension between the lottery non-winners and those who enrolled in Medicaid. There were also no differences between the groups in cholesterol values, prevalence of diagnosis of hypercholesterolemia after the lottery, or use of medications for high cholesterol. While more Medicaid enrollees were diagnosed with diabetes after the lottery (absolute increase of 3.8 percentage points, 95% CI 1.93-5.73, p < 0.001; prevalence 1.1% in non-winners) and were more likely to be using medications for diabetes than the non-winners (absolute increase of 5.43 percentage points, 95% CI 1.39-9.48, p= 0.008), there was no statistically significant difference in HgbA1c values among the two groups. Medicaid coverage did not significantly alter 10-year Framingham cardiovascular event risk. At follow-up, fewer Medicaid-enrolled patients screened positive for depression (decrease of 9.15 percentage points, 95% CI -16.70 to -1.60,  p= 0.02), while more had formally been diagnosed with depression during the interval since the lottery (absolute increase of 3.81 percentage points, 95% CI 0.15-7.46, p= 0.04). There was no significant difference in prevalence of antidepressant use.

Medicaid-enrolled patients were more likely to report that their health was the same or better since 1 year prior (increase of 7.84 percentage points, 95% CI 1.45-14.23, p = 0.02). There were no significant differences in scores for quality of life related to physical health or in self-reported levels of pain or global happiness. As seen in Table 4, Medicaid enrollment was associated with decreased out-of-pocket spending (15% had a decrease, average decrease $215), decreased prevalence of medical debt, and a decreased prevalence of catastrophic expenditures (absolute decrease of 4.48 percentage points, 95% CI -8.26 to 0.69, p = 0.02).

Medicaid-enrolled patients were prescribed more drugs and had more office visits but no change in number of ED visits or hospital admissions. Medicaid coverage was estimated to increase total annual medical spending by $1,172 per person (an approximately 35% increase). Of note, patients enrolled in Medicaid were more likely to have received a pap smear or mammogram during the study period.

Implication/Discussion:
This study was the first major study to “randomize” health insurance coverage and study the health outcome effects of gaining insurance.

Overall, this study demonstrated that obtaining Medicaid coverage “increased overall health care utilization, improved self-reported health, and reduced financial strain.” However, its effects on patient-level health outcomes were much more muted. Medicaid coverage did not impact the prevalence or severity of hypertension or hyperlipidemia. Medicaid coverage appeared to aid in the detection of diabetes mellitus and use of antihyperglycemics but did not affect average A1c. Accordingly, there was no significant difference in Framingham risk score among the two groups.

The glaring limitation of this study was that its statistical analyses compared two groups with unequal baseline characteristics, despite the purported “randomization” of the lottery. Effectively, by comparing Medicaid enrollees (and not all lottery winners) to the lottery non-winners, the authors failed to perform an intention-to-treat analysis. This design engendered significant confounding, and it is remarkable that the authors did not even attempt to report baseline characteristics among the final two groups, let alone control for any such differences in their final analyses. Furthermore, the fact that not all reported analyses were pre-specified raises suspicion of post hoc data dredging for statistically significant results (“p-hacking”). Overall, power was limited in this study due to the low prevalence of the conditions studied.

Contemporary analysis of this study, both within medicine and within the political sphere, was widely divergent. Medicaid-expansion proponents noted that new access to Medicaid provided a critical financial buffer from potentially catastrophic medical expenditures and allowed increased access to care (as measured by clinic visits, medication use, etc.), while detractors noted that, despite this costly program expansion and fine-toothed analysis, little hard-outcome benefit was realized during the (admittedly limited) follow-up at two years.

Access to insurance is only the starting point in improving the health of the poor. The authors note that “the effects of Medicaid coverage may be limited by the multiple sources of slippage…[including] access to care, diagnosis of underlying conditions, prescription of appropriate medications, compliance with recommendations, and effectiveness of treatment in improving health.”

Further Reading/References:
1. Baicker et al. (2013), “The Impact of Medicaid on Labor Force Activity and Program Participation: Evidence from the Oregon Health Insurance Experiment”
2. Taubman et al. (2014), “Medicaid Increases Emergency-Department Use: Evidence from Oregon’s Health Insurance Experiment”
3. The Washington Post, “Here’s what the Oregon Medicaid study really said” (2013)
4. Michael Cannon, “Oregon Study Throws a Stop Sign in Front of ObamaCare’s Medicaid Expansion”
5. HealthAffairs Policy Brief, “The Oregon Health Insurance Experiment”
6. The Oregon Health Insurance Experiment

Summary by Duncan F. Moore, MD

Image Credit: Centers for Medicare and Medicaid Services, Public Domain, via Wikimedia Commons

Week 24 – CHOIR

“Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease”

by the Investigators in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)

N Engl J Med. 2006 Nov 16;355(20):2085-98. [free full text]

Anemia is a prevalent condition in CKD and ESRD. The anemia is largely attributable to the loss of erythropoietin production due to the damage of kidney parenchyma. Thus erythropoiesis-stimulating agents (ESAs) were introduced to improve this condition. Retrospective data and small interventional trials suggested that treatment to higher hemoglobin goals (such as > 12 g/dL) was associated with improved cardiovascular outcomes. However, in 1998, a prospective trial in ESRD patients on HD with a hematocrit treatment target of 42% versus 30% demonstrated a trend toward increased rates of non-fatal MI and death in the higher-target group. In an effort to clarify the hemoglobin goal in CKD patients, the 2006 CHOIR trial was designed. It was hypothesized that treatment of anemia in CKD to a target of 13.5 g/dL would lead to fewer cardiac events and reduced mortality when compared to a target of 11.3 g/dL.

The trial enrolled adults with CKD (eGFR 15-50 ml/min) and Hgb < 11.0 g/dL and notably excluded patients with active cancer. The patients were randomized to erythropoietin support regimens targeting a hemoglobin of either 13.5 g/dL or 11.3 g/dL. The primary outcome was a composite of death, MI, hospitalization for CHF, or stroke. Secondary outcomes included individual components of the primary outcome, need for renal replacement therapy, all-cause hospitalization, and various quality-of-life scores.

The study was terminated early due to an interim analysis revealing a < 5% chance that there would be a demonstrated benefit for the high-hemoglobin group by the scheduled end of the study. Results from 715 high-hemoglobin and 717 low-hemoglobin patients were analyzed. The mean change in hemoglobin was +2.5 g/dL in the high-hemoglobin group versus +1.2g/dL in the low-hemoglobin group (p < 0.001). The primary endpoint occurred in 125 of the high-hemoglobin patients (17.5%) versus 97 of the low-hemoglobin patients (13.5%) [HR 1.34, 95% CI 1.03-1.74, p = 0.03; number needed to harm = 25]. There were no significant group differences among the four components of the primary endpoint when analyzed as individual secondary outcomes, nor was there a difference in rates of renal replacement therapy. Any-cause hospitalization rates were 51.6% in the high-hemoglobin group versus 46.6% in the low-hemoglobin group (p = 0.03). Regarding quality-of-life scores, both groups demonstrated similar, statistically significant improvements from their respective baseline values.

In patients with anemia and CKD, treatment to a higher hemoglobin goal of 13.5 g/dL was associated with an increased incidence of a composite endpoint of death, MI, hospitalization for CHF, or stroke relative to a treatment goal of 11.3 g/dL. There were no differences between the two groups in hospitalization rates or progression to renal replacement therapy, and the improvement in quality of life was similar among the two treatment groups. Thus this study demonstrated no additional benefit and some harm with the higher treatment goal. The authors noted that “this study did not provide a mechanistic explanation for the poorer outcome with the use of a high target hemoglobin level.” Limitations of this trial included its non-blinded nature and relatively high patient withdrawal rates. Following this trial, the KDOQI clinical practice guidelines for the management of anemia in CKD were updated to recommend a Hgb target of 11.0-12.0 g/dL. However, this guideline was superseded by the 2012 KDIGO guidelines which, on the basis of further evidence, ultimately recommend initiating ESA therapy only in iron-replete CKD patients with Hgb < 10 g/dL with the goal of maintaining Hgb between 10 and 11.5 g/dL. Treatment should be individualized in patients with concurrent malignancy.

Further Reading/References:
1. Besarab et al. “The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin.” N Engl J Med. 1998 Aug 27;339(9):584-90.
2. CHOIR @ Wiki Journal Club
3. CHOIR @ 2 Minute Medicine
4. National Kidney Foundation Releases Anemia Guidelines Update (2007)
5. Pfeffer et al. “A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.” N Engl J Med. 2009;361(21):2019.
6. KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD

Summary by Duncan F. Moore, MD

Week 23 – Effect of Early vs. Deferred Therapy for HIV (NA-ACCORD)

“Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival”

N Engl J Med. 2009 Apr 30;360(18):1815-26. [free full text]

Until recently, the optimal timing of initiation of antiretroviral therapy (ART) in asymptomatic patients with HIV had been a subject of investigation since the advent of antiretrovirals. Guidelines in 1996 recommended starting ART for all HIV-infected patients with CD4 count < 500, but over time provider concerns regarding resistance, medication nonadherence, and adverse effects of medications led to more restrictive prescribing. In the mid-2000s, guidelines recommended ART initiation in asymptomatic HIV patients with CD4 < 350. However, contemporary subgroup analysis of RCT data and other limited observational data suggested that deferring initiation of ART increased rates of progression to AIDS and mortality. Thus the NA-ACCORD authors sought to retrospectively analyze their large dataset to investigate the mortality effect of early vs. deferred ART initiation.

The study examined the cases of treatment-naïve patients with HIV and no hx of AIDS-defining illness evaluated during 1996-2005. Two subpopulations were analyzed retrospectively: CD4 count 351-500 and CD4 count 500+. No intervention was undertaken. The primary outcome was, within each CD4 sub-population, mortality in patients treated with ART within 6 months after the first CD4 count within the range of interest vs. mortality in patients for whom ART was deferred until the CD4 count fell below the range of interest.

8362 eligible patients had a CD4 count of 351-500, and of these, 2084 (25%) initiated ART within 6 months, whereas 6278 (75%) patients deferred therapy until CD4 < 351. 9155 eligible patients had a CD4 count of 500+, and of these, 2220 (24%) initiated ART within 6 months, whereas 6935 (76%) patients deferred therapy until CD4 < 500. In both CD4 subpopulations, patients in the early-ART group were older, more likely to be white, more likely to be male, less likely to have HCV, and less likely to have a history of injection drug use. Cause-of-death information was obtained in only 16% of all deceased patients. The majority of these deaths in both the early- and deferred-therapy groups were from non-AIDS-defining conditions.

In the subpopulation with CD4 351-500, there were 137 deaths in the early-therapy group vs. 238 deaths in the deferred-therapy group. Relative risk of death for deferred therapy was 1.69 (95% CI 1.26-2.26, p < 0.001) per Cox regression stratified by year. After adjustment for history of injection drug use, RR = 1.28 (95% CI 0.85-1.93, p = 0.23). In an unadjusted analysis, HCV infection was a risk factor for mortality (RR 1.85, p= 0.03). After exclusion of patients with HCV infection, RR for deferred therapy = 1.52 (95% CI 1.01-2.28, p = 0.04).

In the subpopulation with CD4 500+, there were 113 deaths in the early-therapy group vs. 198 in the deferred-therapy group. Relative risk of death for deferred therapy was 1.94 (95% CI 1.37-2.79, p < 0.001). After adjustment for history of injection drug use, RR = 1.73 (95% CI 1.08-2.78, p = 0.02). Again, HCV infection was a risk factor for mortality (RR = 2.03, p < 0.001). After exclusion of patients with HCV infection, RR for deferred therapy = 1.90 (95% CI 1.14-3.18, p = 0.01).

Thus, in a large retrospective study, the deferred initiation of antiretrovirals in asymptomatic HIV infection was associated with higher mortality.

This was the first retrospective study of early initiation of ART in HIV that was large enough to power mortality as an endpoint while controlling for covariates. However, it is limited significantly by its observational, non-randomized design that introduced substantial unmeasured confounders. A notable example is the absence of socioeconomic confounders (e.g. insurance status). Perhaps early-initiation patients were more well-off, and their economic advantage was what drove the mortality benefit rather than the early initiation of ART. This study also made no mention of the tolerability of ART or adverse reactions to it.

In the years that followed this trial, NIH and WHO consensus guidelines shifted the trend toward earlier treatment of HIV. In 2015, the INSIGHT START trial (the first large RCT of immediate vs. deferred ART) showed a definitive mortality benefit of immediate initiation of ART in patients with CD4 500+. Since that time, the standard of care has been to treat essentially all HIV-infected patients with ART (with some considerations for specific subpopulations, such as delaying initiation of therapy in patients with cryptococcal meningoencephalitis due to risk of IRIS). See further discussion at UpToDate.

Further Reading/References:
1. NA-ACCORD @ Wiki Journal Club
2. NA-ACCORD @ 2 Minute Medicine
3. INSIGHT START (2015), Pubmed, NEJM PDF
4. UpToDate, “When to initiate antiretroviral therapy in HIV-infected patients”

Summary by Duncan F. Moore, MD

Image Credit: Sigve, CC0 1.0, via WikiMedia Commons

Week 20 – 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. MELD @ 2 Minute Medicine
6. UpToDate “Model for End-stage Liver Disease (MELD)”

Summary by Duncan F. Moore, MD

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

Week 19 – 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 12 – 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 18 – 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 11,000 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. Rivers trial @ Wiki Journal Club
2. Rivers trial @ 2 Minute Medicine
3. “Early Goal Directed Therapy in Septic Shock” @ 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. “Hour-1 Bundle,” 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

Week 17 – 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 creator 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. CURB-65 @ Wiki Journal Club
4. CURB-65 @ 2 Minute Medicine
5. UpToDate, “CAP in adults: assessing severity and determining the appropriate level of care”

Summary by Duncan F. Moore, MD