Month: March 2020

Week 40 – 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]
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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 prior 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:

      • 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

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 39 – Early TIPS in Cirrhosis with Variceal Bleeding

“Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding”

N Engl J Med. 2010 Jun 24;362(25):2370-9. [free full text]
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Variceal bleeding is a major cause of morbidity and mortality in decompensated cirrhosis. The standard of care for an acute variceal bleed includes a combination of vasoactive drugs, prophylactic antibiotics, and endoscopic techniques (e.g. banding). Transjugular intrahepatic portosystemic shunt (TIPS) can be used to treat refractory bleeding. This 2010 trial sought to determine the utility of early TIPS during the initial bleed in high-risk patients when compared to standard therapy.

The trial enrolled cirrhotic patients (Child-Pugh class B or C with score ≤ 13) with acute esophageal variceal bleeding. All patients received endoscopic band ligation (EBL) or endoscopic injection sclerotherapy (EIS) at the time of diagnostic endoscopy. All patients also received vasoactive drugs (terlipressin, somatostatin, or octreotide). Patients were randomized to either TIPS performed within 72 hours after diagnostic endoscopy or to “standard therapy” by 1) treatment with vasoactive drugs with transition to nonselective beta blocker when patients were free of bleeding followed by 2) addition of isosorbide mononitrate to maximum tolerated dose, and 3) a second session of EBL at 7-14 days after the initial session (repeated q10-14 days until variceal eradication was achieved). The primary outcome was a composite of failure to control acute bleeding or failure to prevent “clinically significant” variceal bleeding (requiring hospital admission or transfusion) at 1 year after enrollment. Selected secondary outcomes included 1-year mortality, development of hepatic encephalopathy (HE), ICU days, and hospital LOS.

359 patients were screened for inclusion, but ultimately only 63 were randomized. Baseline characteristics were similar among the two groups except that the early TIPS group had a higher rate of patients with previous hepatic encephalopathy. The primary composite endpoint of failure to control acute bleeding or rebleeding within 1 year occurred in 14 of 31 (45%) patients in the pharmacotherapy-EBL group and in only 1 of 32 (3%) of the early TIPS group (p = 0.001). The 1-year actuarial probability of remaining free of the primary outcome was 97% in the early TIPS group vs. 50% in the pharmacotherapy-EBL group (ARR 47 percentage points, 95% CI 25-69 percentage points, NNT 2.1). Regarding mortality, at one year, 12 of 31 (39%) patients in the pharmacotherapy-EBL group had died, while only 4 of 32 (13%) in the early TIPS group had died (p = 0.001, NNT = 4.0). There were no group differences in prevalence of HE at one year (28% in the early TIPS group vs. 40% in the pharmacotherapy-EBL group, p = 0.13). Additionally, there were no group differences in 1-year actuarial probability of new or worsening ascites. There were also no differences in length of ICU stay or hospitalization duration.

Early TIPS in acute esophageal variceal bleeding, when compared to standard pharmacotherapy and endoscopic band ligation, improved control of index bleeding, reduced recurrent variceal bleeding at 1 year, and reduced all-cause mortality. Prior studies had demonstrated that TIPS reduced the rebleeding rate but increased the rate of hepatic encephalopathy without improving survival. As such, TIPS had only been recommended as a rescue therapy. In contrast, this study presents compelling data that challenge these paradigms. The authors note that in “patients with Child-Pugh class C or in class B with active variceal bleeding, failure to initially control the bleeding or early rebleeding contributes to further deterioration in liver function, which in turn worsens the prognosis and may preclude the use of rescue TIPS.” Despite this, today, TIPS remains primarily a salvage therapy for use in cases of recurrent bleeding despite standard pharmacotherapy and EBL. There may be a subset of patients in whom early TIPS is the ideal strategy, but further trials will be required to identify this subset.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Prevention of recurrent variceal hemorrhage in patients with cirrhosis”

Summary by Duncan F. Moore, MD

Week 38 – ACCORD

“Effects of Intensive Glucose Lowering in Type 2 Diabetes”

by the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group

N Engl J Med. 2008 Jun 12;358(24):2545-59. [free full text]
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We all treat type 2 diabetes mellitus (T2DM) on a daily basis, and we understand that untreated T2DM places patients at increased risk for adverse micro- and macrovascular outcomes. Prior to the 2008 ACCORD study, prospective epidemiological studies had noted a direct correlation between increased hemoglobin A1c values and increased risk of cardiovascular events. This correlation implied that treating T2DM to lower A1c levels would result in the reduction of cardiovascular risk. The ACCORD trial was the first large RCT to evaluate this specific hypothesis through comparison of events in two treatment groups – aggressive and less aggressive glucose management.

The trial enrolled patients with T2DM with A1c ≥ 7.5% and either age 40-79 with prior cardiovascular disease or age 55-79 with “anatomical evidence of significant atherosclerosis,” albuminuria, LVH, or ≥ 2 additional risk factors for cardiovascular disease (dyslipidemia, HTN, current smoker, or obesity). Notable exclusion criteria included “frequent or recent serious hypoglycemic events,” an unwillingness to inject insulin, BMI > 45, Cr > 1.5, or “other serious illness.” Patients were randomized to either intensive therapy targeting A1c to < 6.0% or to standard therapy targeting A1c 7.0-7.9%. The primary outcome was a composite first nonfatal MI or nonfatal stroke and death from cardiovascular causes. Reported secondary outcomes included all-cause mortality, severe hypoglycemia, heart failure, motor vehicle accidents in which the patient was the driver, fluid retention, and weight gain.

10,251 patients were randomized. The average age was 62, the average duration of T2DM was 10 years, and the average A1c was 8.1%. Both groups lowered their median A1c quickly, and median A1c values of the two groups separated rapidly within the first four months. (See Figure 1.) The intensive-therapy group had more exposure to antihyperglycemics of all classes. See Table 2.) Drugs were more frequently added, removed, or titrated in the intensive-therapy group (4.4 times per year versus 2.0 times per year in the standard-therapy group). At one year, the intensive-therapy group had a median A1c of 6.4% versus 7.5% in the standard-therapy group.

The primary outcome of MI/stroke/cardiovascular death occurred in 352 (6.9%) intensive-therapy patients versus 371 (7.2%) standard-therapy patients (HR 0.90, 95% CI 0.78-1.04, p = 0.16).  The trial was stopped early at a mean follow-up of 3.5 years due to increased all-cause mortality in the intensive-therapy group. 257 (5.0%) of the intensive-therapy patients died, but only 203 (4.0%) of the standard-therapy patients died (HR 1.22, 95% CI 1.01-1.46, p = 0.04). For every 95 patients treated with intensive therapy for 3.5 years, one extra patient died. Death from cardiovascular causes was also increased in the intensive-therapy group (HR 1.35, 95% CI 1.04-1.76, p = 0.02). Regarding additional secondary outcomes, the intensive-therapy group had higher rates of hypoglycemia, weight gain, and fluid retention than the standard-therapy group. (See Table 3.) There were no group differences in rates of heart failure or motor vehicle accidents in which the patient was the driver.

Intensive glucose control of T2DM increased all-cause mortality and did not alter the risk of cardiovascular events. This harm was previously unrecognized. The authors performed sensitivities analyses, including non-prespecified analyses, such as group differences in use of drugs like rosiglitazone, and they were unable to find an explanation for this increased mortality.

The target A1c level in T2DM remains a nuanced, patient-specific goal. Aggressive management may lead to improved microvascular outcomes, but it must be weighed against the risk of hypoglycemia. As summarized by UpToDate, while long-term data from the UKPDS suggests there may be a macrovascular benefit to aggressive glucose management early in the course of T2DM, the data from ACCORD suggest strongly that, in patients with longstanding T2DM and additional risk factors for cardiovascular disease, such management increases mortality.

The 2019 American Diabetes Association guidelines suggest that “a reasonable A1c goal for many nonpregnant adults is < 7%.” More stringent goals (< 6.5%) may be appropriate if they can be achieved without significant hypoglycemia or polypharmacy, and less stringent goals (< 8%) may be appropriate for patients “with a severe history of hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications…”

Of note, ACCORD also simultaneously cross-enrolled its patients in studies of intensive blood pressure management and adjunctive lipid management with fenofibrate. See this 2010 NIH press release and the links below for more information.

Further Reading/References:
1. ACCORD @ Wiki Journal Club
2. ACCORD @ 2 Minute Medicine
3. American Diabetes Association – “Glycemic Targets.” Diabetes Care (2019).
4. “Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.” Lancet (2010).

Summary by Duncan F. Moore, MD

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

Week 37 – AFFIRM

“A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation”

by the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Investigators

N Engl J Med. 2002 Dec 5;347(23):1825-33. [free full text]
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It seems like the majority of patients with atrial fibrillation that we encounter today in the inpatient setting are being treated with a rate-control strategy, as opposed to a rhythm-control strategy. There was a time when both approaches were considered acceptable, and perhaps rhythm control was even the preferred initial strategy. The AFFIRM trial was the landmark study to address this debate.

The trial randomized patients with atrial fibrillation (judged “likely to be recurrent”) aged 65 or older “or who had other risk factors for stroke or death” to either 1) a rhythm-control strategy with one or more drugs from a pre-specified list and/or cardioversion to achieve sinus rhythm or 2) a rate-control strategy with beta-blockers, CCBs, and/or digoxin to a target resting HR ≤ 80 and a six-minute walk test HR ≤ 110. The primary endpoint was death during follow-up. The major secondary endpoint was a composite of death, disabling stroke, disabling anoxic encephalopathy, major bleeding, and cardiac arrest.

4060 patients were randomized. Death occurred in 26.7% of rhythm-control patients versus 25.9% of rate-control patients (HR 1.15, 95% CI 0.99 – 1.34, p = 0.08). The composite secondary endpoint occurred in 32.0% of rhythm control-patients versus 32.7% of rate-control patients (p = 0.33). Rhythm-control strategy was associated with a higher risk of death among patients older than 65 and patients with CAD (see Figure 2). Additionally, rhythm-control patients were more likely to be hospitalized during follow-up (80.1% vs. 73.0%, p < 0.001) and to develop torsades de pointes (0.8% vs. 0.2%, p = 0.007).

This trial demonstrated that a rhythm-control strategy in atrial fibrillation offers no mortality benefit over a rate-control strategy. At the time of publication, the authors wrote that rate control was an “accepted, though often secondary alternative” to rhythm control. Their study clearly demonstrated that there was no significant mortality benefit to either strategy and that hospitalizations were greater in the rhythm-control group. In subgroup analysis that rhythm control led to higher mortality among the elderly and those with CAD. Notably, 37.5% of rhythm-control patients had crossed over to rate control strategy by 5 years of follow-up, whereas only 14.9% of rate-control patients had switched over to rhythm control.

But what does this study mean for our practice today? Generally speaking, rate control is preferred in most patients, particularly the elderly and patients with CHF, whereas rhythm control may be pursued in patients with persistent symptoms despite rate control, patients unable to achieve rate control on AV nodal agents alone, and patients younger than 65. Both the AHA/ACC (2014) and the European Society of Cardiology (2016) guidelines have extensive recommendations that detail specific patient scenarios.

Further Reading / References:
1. Cardiologytrials.org
2. AFFIRM @ Wiki Journal Club
3. AFFIRM @ 2 Minute Medicine
4. Visual abstract @ Visualmed

Summary by Duncan F. Moore, MD

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

Week 36 – CORTICUS

“Hydrocortisone Therapy for Patients with Septic Shock”

N Engl J Med. 2008 Jan 10;358(2):111-24. [free full text]
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Steroid therapy in septic shock has been a hotly debated topic since the 1980s. The Annane trial in 2002 suggested that there was a mortality benefit to early steroid therapy and so for almost a decade this became standard of care. In 2008, the CORTICUS trial was performed suggesting otherwise.

The trial enrolled ICU patients with septic shock onset with past 72 hrs (defined as SBP < 90 despite fluids or need for vasopressors and hypoperfusion or organ dysfunction from sepsis). Excluded patients included those with an “underlying disease with a poor prognosis,” life expectancy < 24hrs, immunosuppression, and recent corticosteroid use. Patients were randomized to hydrocortisone 50mg IV q6h x5 days plus taper or to placebo injections q6h x5 days plus taper. The primary outcome was 28-day mortality among patients who did not have a response to ACTH stim test (cortisol rise < 9mcg/dL). Secondary outcomes included 28-day mortality in patients who had a positive response to ACTH stim test, 28-day mortality in all patients, reversal of shock (defined as SBP ≥ 90 for at least 24hrs without vasopressors) in all patients and time to reversal of shock in all patients.

In ACTH non-responders (n = 233), intervention vs. control 28-day mortality was 39.2% vs. 36.1%, respectively (p = 0.69). In ACTH responders (n = 254), intervention vs. control 28-day mortality was 28.8% vs. 28.7% respectively (p = 1.00). Reversal of was shock 84.7%% vs. 76.5% (p = 0.13). Among all patients, intervention vs. control 28-day mortality was 34.3% vs. 31.5% (p = 0.51) and reversal of shock 79.7% vs. 74.2% (p = 0.18). The duration of time to reversal of shock was significantly shorter among patients receiving hydrocortisone (per Kaplan-Meier analysis, p<0.001; see Figure 2) with median time to of reversal 3.3 days vs. 5.8 days (95% CI 5.2 – 6.9).

In conclusion, the CORTICUS trial demonstrated no mortality benefit of steroid therapy in septic shock regardless of a patient’s response to ACTH. Despite the lack of mortality benefit, it demonstrated an earlier resolution of shock with steroids. This lack of mortality benefit sharply contrasted with the previous Annane 2002 study. Several reasons have been posited for this difference including poor powering of the CORTICUS study (which did not reach the desired n = 800), inclusion starting within 72 hrs of septic shock vs. Annane starting within 8 hrs, and the overall sicker nature of Annane patients (who were all mechanically ventilated). Subsequent meta-analyses disagree about the mortality benefit of steroids, but meta-regression analyses suggest benefit among the sickest patients. All studies agree about the improvement in shock reversal. The 2016 Surviving Sepsis Campaign guidelines recommend IV hydrocortisone in septic shock in patients who continue to be hemodynamically unstable despite adequate fluid resuscitation and vasopressor therapy.

Per Drs. Sonti and Vinayak of the GUH MICU (excepted from their excellent Georgetown Critical Care Top 40): “Practically, we use steroids when reaching for a second pressor or if there is multiorgan system dysfunction. Our liver patients may have deficient cortisol production due to inadequate precursor lipid production; use of corticosteroids in these patients represents physiologic replacement rather than adjunct supplement.”

The ANZICS collaborative group published the ADRENAL trial in NEJM in 2018 – which demonstrated that “among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo.” The authors did note “a more rapid resolution of shock and a lower incidence of blood transfusion” among patients receiving hydrocortisone. The folks at EmCrit argued that this was essentially a negative study, and thus in the existing context of CORTICUS, the results of the ADRENAL trial do not change our management of refractory septic shock.

Finally, the 2018 APPROCCHSS trial (also by Annane) evaluated the survival benefit hydrocortisone plus fludocortisone vs. placebo in patients with septic shock and found that this intervention reduced 90-day all-cause mortality. At this time, it is difficult truly discern the added information of this trial given its timeframe, sample size, and severity of underlying illness. See the excellent discussion in the following links: WikiJournal Club, PulmCrit, PulmCCM, and UpToDate.

References / Additional Reading:
1. CORTICUS @ Wiki Journal Club
2. CORTICUS @ Minute Medicine
3. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock (2016), section “Corticosteroids”
4. Annane trial (2002) full text
5. PulmCCM, “Corticosteroids do help in sepsis: ADRENAL trial”
6. UpToDate, “Glucocorticoid therapy in septic shock”

Post by Gordon Pelegrin, MD

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