Week 46 – 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]

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.

ACCORD Blood Pressure – NEJM, Wiki Journal Club

ACCORD Lipids – NEJM, Wiki Journal Club

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

Week 45 – COURAGE

“Optimal Medical Therapy with or without PCI for Stable Coronary Disease”

by the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Research Group

N Engl J Med. 2007 Apr 12;356(15):1503-16 [free full text]

The optimal medical management of stable coronary artery disease has been well-described. However, prior to the 2007 COURAGE trial, the role of percutaneous coronary intervention (PCI) in the initial management of stable coronary artery disease was unclear. It was known that PCI improved angina symptoms and short-term exercise performance in stable disease, but its mortality benefit and reduction of future myocardial infarction and ACS were unknown.

The trial recruited patients with stable coronary artery disease. (See paper for inclusion/exclusion criteria. Disease had to be sufficiently and objectively severe, but not too severe, and symptoms could not be sustained at the highest CCS grade.) Patients were randomized to either optimal medical management (including antiplatelet, anti-anginal, ACEi/ARB, and cholesterol-lowering therapy) and PCI or to optimal medical management alone. The primary outcome was a composite of all-cause mortality and non-fatal MI.

2287 patients were randomized. Both groups had similar baseline characteristics with the exception of a higher prevalence of proximal LAD disease in the medical-therapy group. Median duration of follow-up was 4.6 years in both groups. Death or non-fatal MI occurred in 18.4% of the PCI group and in 17.8% of the medical-therapy group (p = 0.62). Death, non-fatal MI, or stroke occurred in 20.0% of the PCI group and 19.5% of the medical-therapy group (p = 0.62). Hospitalization for ACS occurred in 12.4% of the PCI group and 11.8% of the medical-therapy group (p = 0.56). Revascularization during follow-up was performed in 21.1% of the PCI group but in 32.6% of the medical-therapy group (HR 0.60, 95% CI 0.51–0.71, p < 0.001). Finally, 66% of PCI patients were free of angina at 1-year follow-up compared with 58% of medical-therapy patients (p < 0.001). Rates were 72% and 67% at 3 years (p = 0.02) and 72% and 74% at five years (not significant).

Thus, in the initial management of stable coronary artery disease, PCI in addition to optimal medical management provided no mortality benefit over optimal medical management alone. However, initial management with PCI did provide a time-limited improvement in angina symptoms.

As the authors of COURAGE nicely summarize on page 1512, the atherosclerotic plaques of ACS and stable CAD are different. Vulnerable, ACS-prone plaques have thin caps and spread outward along the wall of the coronary artery, as opposed to stable CAD plaques, which have thick fibrous caps and are associated with inward-directed remodeling that narrows the artery lumen (and cause reliable angina symptoms and luminal narrowing on coronary angiography).

Notable limitations of this study:

      • Generalizability was limited due to the population, which was largely male, white, and 42% came from VA hospitals.
      • Drug-eluting stents were not clinically available until the last 6 months of the study, so most stents placed were bare metal.

Later meta-analyses were weakly suggestive of an association of PCI with improved all-cause mortality. It is thought that there may be a subset of patients with stable CAD who achieve a mortality benefit from PCI.

The 2017 ORBITA trial made headlines and caused sustained controversy when it demonstrated in a randomized trial that, in the context of optimal medical therapy, PCI did not increase exercise time more than did a sham PCI. Take note of the relatively savage author’s reply to commentary regarding the trial. See blog discussion here. The ORBITA-2 trial is currently underway.

The ongoing ISCHEMIA trial is both eagerly awaited and involved in a degree of controversy after a recent change in endpoints.

It is important to note that all of the above discussions assume that the patient does not have specific coronary artery anatomy (e.g. left main disease, multi-vessel disease with decreased LVEF) in which initial CABG would provide a mortality benefit. Finally, PCI should be considered in patients whose physical activity is limited by angina symptoms despite optimal medical therapy.

Further Reading:
1. COURAGE @ Wiki Journal Club
2. COURAGE @ 2 Minute Medicine
3. Canadian Cardiovascular Society grading of angina pectoris
4. ORBITA-2 @ ClinicalTrials.gov
5. ISCHEMIA @ ClinicalTrials.gov
6. Discussion re: ISCHEMIA trial changes @ CardioBrief

Summary by Duncan F. Moore, MD

Image Credit: National Institutes of Health, US Public Domain, via Wikimedia Commons

Week 44 – National Lung Screening Trial (NLST)

“Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening”

by the National Lung Cancer Screening Trial (NLST) Research Team

N Engl J Med. 2011 Aug 4;365(5):395-409 [free full text]

Despite a reduction in smoking rates in the United States, lung cancer remains the number one cause of cancer death in the United States as well as worldwide. Earlier studies of plain chest radiography for lung cancer screening demonstrated no benefit, and in 2002 the National Lung Screening Trial (NLST) was undertaken to determine whether then recent advances in CT technology could lead to an effective lung cancer screening method.

The study enrolled adults age 55-74 with 30+ pack-years of smoking (if former smokers, they must have quit within the past 15 years). Patients were randomized to either the intervention of three annual screenings for lung cancer with low-dose CT or to the comparator/control group to receive three annual screenings for lung cancer with PA chest radiograph. The primary outcome was mortality from lung cancer. Notable secondary outcomes were all-cause mortality and the incidence of lung cancer.

53,454 patients were randomized, and both groups had similar baseline characteristics. The low-dose CT group sustained 247 deaths from lung cancer per 100,000 person-years, whereas the radiography group sustained 309 deaths per 100,000 person-years. A relative reduction in rate of death by 20.0% was seen in the CT group (95% CI 6.8 – 26.7%, p = 0.004). The number needed to screen with CT to prevent one lung cancer death was 320. There were 1877 deaths from any cause in the CT group and 2000 deaths in the radiography group, so CT screening demonstrated a risk reduction of death from any cause of 6.7% (95% CI 1.2% – 13.6%, p = 0.02). Incidence of lung cancer in the CT group was 645 per 100,000 person-years and 941 per 100,000 person-years in the radiography group (RR 1.13, 95% CI 1.03 – 1.23).

Lung cancer screening with low-dose CT scan in high-risk patients provides a significant mortality benefit. This trial was stopped early because the mortality benefit was so high. The benefit was driven by the reduction in deaths attributed to lung cancer, and when deaths from lung cancer were excluded from the overall mortality analysis, there was no significant difference among the two arms. Largely on the basis of this study, the 2013 USPSTF guidelines for lung cancer screening recommend annual low-dose CT scan in patients who meet NLST inclusion criteria. However, it must be noted that, even in the “ideal” circumstances of this trial performed at experienced centers, 96% of abnormal CT screening results in this trial were actually false positives. Of all positive results, 11% led to invasive studies.

Per UpToDate, since NSLT, there have been several European low-dose CT screening trials published. However, all but one (NELSON) appear to be underpowered to demonstrate a possible mortality reduction. Meta-analysis of all such RCTs could allow for further refinement in risk stratification, frequency of screening, and management of positive screening findings.

No randomized trial has ever demonstrated a mortality benefit of plain chest radiography for lung cancer screening. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial tested this modality vs. “community care,” and because the PLCO trial was ongoing at the time of creation of the NSLT, the NSLT authors trial decided to compare their intervention (CT) to plain chest radiography in case the results of plain chest radiography in PLCO were positive. Ultimately, they were not.

Further Reading:
1. USPSTF Guidelines for Lung Cancer Screening (2013)
2. NLST @ ClinicalTrials.gov
3. NLST @ Wiki Journal Club
4. NLST @ 2 Minute Medicine
5. UpToDate, “Screening for lung cancer”

Summary by Duncan F. Moore, MD

Image Credit: Yale Rosen, CC BY-SA 2.0, via Wikimedia Commons

Week 43 – FREEDOM

“Strategies for Multivessel Revascularization in Patients with Diabetes”

by the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) Trial investigators

N Engl J Med. 2012 Dec 20;367(25):2375-84. [free full text]

Previous studies, such as the 1996 BARI trial), have demonstrated that patients who have multivessel coronary artery disease (CAD) and diabetes mellitus (DM) and who received coronary artery bypass grafting (CABG) surgery lived longer than patients undergoing balloon angioplasty. However, since that publication, percutaneous coronary intervention (PCI) technology advanced significantly. Prior to the publication of FREEDOM in 2012, there had only been small, underpowered studies comparing PCI with drug-eluting stent (DES) to CABG. FREEDOM was powered appropriately to discover superiority of revascularization strategy (PCI with DES vs. CABG) in patients with DM and multivessel CAD.

Population:

Inclusion criteria:

      • 18 years or older
      • Diabetes mellitus – defined by American Diabetes Association
      • Multivessel Coronary Artery Disease
        • > 70% stenosis (angiographically confirmed)
        • 2 or more epicardial vessels
        • 2 or more coronary-artery territories

Selected exclusion criteria:

      • NYHA Class III-IV heart failure
      • Prior CABG, valve surgery, or PCI (< 6 months)
      • Prior significant bleed (< 6 months)
      • Left main stenosis ≥ 50%

 

Design:
Patients meeting criteria were assigned 1:1 into PCI with first-generation paclitaxel-eluting stent (51%) or sirolimus-eluting stent (43%) versus CABG. The PCI group was placed on aspirin and clopidogrel for dual antiplatelet therapy (DAPT) for at least 12 months. For the CABG group, arterial revascularization was encouraged. The mean SYNTAX score (tool used to score complexity of CAD) was 26.2 and did not significantly differ between groups. Guideline-driven targets for lowering medical risk factors were used: LDL <70, BP <130/80, HgbA1c <7. Minimum follow-up was 2 years.


Outcomes:

Primary: Composite of death from any cause, non-fatal myocardial infarction (MI), and non-fatal stroke

Secondary

      1. Rate of major adverse cardiovascular and cerebrovascular events at 30 days and 12 months
      2. Repeat revascularization
      3. Annual all-cause mortality
      4. Annual cardiovascular mortality


Results:
953 patients and 947 patients were randomized into the PCI and CABG groups, respectively. At 5 years, the primary outcome (combined death, MI, or stroke) occurred in 200 of the PCI group and 146 of the CABG group (26.6% vs 18.7%, p = 0.005). The curves started diverging at 2 years. All-cause mortality was higher in the PCI group versus the CABG group (16.3% vs 10.9%, p = 0.049). Regarding secondary outcomes, 13.9% of patients in the PCI group had a repeat MI versus 6.0% in the CABG group (p < 0.001). There were fewer strokes in the PCI group than in the CABG group (2.4% vs 5.2%, p = 0.03). There was no statistically significant difference between study groups regarding cardiovascular death (10.9% vs 6.8%, p = 0.12).

At 5 years, the analysis of outcomes according to category of SYNTAX score (≤ 22, 23 to 32, ≥ 33) showed no significant subgroup interaction (p = 0.58).

Regarding safety, major bleeding between the two groups at 30 days was 0.02% for PCI vs 0.04% for CABG (p = 0.13). The incidence of acute renal failure requiring hemodialysis was observed in one patient in the PCI group and eight patients in the CABG group (p = 0.02)

Implication/Discussion:
The BARI Trial (1996) was the first trial to show that patients with DM and multivessel CAD derive mortality benefit from bypass grafting over PCI with balloon angioplasty. Furthermore, the BARI 2D (2009) trial demonstrated this benefit of bypass grafting over PCI with bare metal stents (BMS). At the time of the FREEDOM Trial, there had not been a randomized comparison of CABG versus PCI with newer technology and first-generation paclitaxel/sirolimus DES. In this study, CABG showed a 5.3% absolute reduction in all-cause mortality over PCI as well decreased rates of MI and repeat revascularization. CABG was associated with a mild absolute increase in stroke (2.8%). However, this mild increased stroke risk is consistent with most other comparative trials of the two treatment strategies. There was no statistical difference in major bleeding between the two groups.

CABG is likely better than PCI for various reasons. For one, diabetic arteries are affected diffusely and tend to have more extensive atherosclerotic disease compared to those without diabetes, so the likelihood of successful PCI alone is low. Many suspected that with advancement in PCI (i.e. DES) that the BARI data would become irrelevant. However, CABG continued to show benefit despite the technological advancements of drug-eluting stents and PCI. Improvement in surgical technique as well as the use of arterial revascularization (i.e. internal mammary artery) helped maintain superior outcomes with CABG compared to PCI.

The study was limited by the fact that due to low numbers, the subgroup analysis (i.e. SYNTAX scores) was not appropriately powered for statistical significance. Further, the study was not blinded, and patients may have been treated differently on the basis of their surgical procedure. Also, there was variability of STYNAX scores between the study groups, but this circumstance was thought to reflect real world heterogeneity.

Bottom Line:
CABG was superior to PCI with DES in patients with DM and multivessel CAD in that it significantly reduced rates of death and MI despite a small increased risk of stroke.

Further Reading/References:
1. BARI Trial @ NEJM
2. BARI 2D Trial @ NEJM
3. ACCF/AHA 2011 Guideline for Coronary Artery Bypass Graft Surgery
4. FREEDOM @ Wiki Journal Club
5. FREEDOM @ 2 Minute Medicine
5. FREEDOM @ Visualmed

Summary by Patrick Miller, MD.

Image Credit: Jerry Hecht, US Public Domain, via Wikimedia Commons

Week 42 – BeSt

“Clinical and Radiographic Outcomes of Four Different Treatment Strategies in Patients with Early Rheumatoid Arthritis (the BeSt Study).”

Arthritis & Rheumatism. 2005 Nov;52(11):3381-3390. [free full text]

Rheumatoid arthritis (RA) is among the most prevalent of the rheumatic diseases with a lifetime prevalence of 3.6% in women and 1.7% in men [1]. It is a chronic, systemic, inflammatory autoimmune disease of variable clinical course that can severely impact physical functional status and even mortality. Over the past 30 years, as the armamentarium of therapies for RA has exploded, there has been increased debate about the ideal initial therapy. The BeSt (Dutch: Behandel-Strategieën “treatment strategies”) trial was designed to compare, according to the authors, four of “the most frequently used and discussed strategies.” Regimens incorporating traditional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and newer therapies, such as TNF-alpha inhibitors, were compared directly.

The trial enrolled 508 DMARD-naïve patients with early rheumatoid arthritis. Pertinent exclusion criteria included history of cancer and pre-existing laboratory abnormalities or comorbidities (e.g. elevated creatinine or ALT, alcohol abuse, pregnancy or desire to conceive, etc.) that would preclude the use of various DMARDs. Patients were randomized to one of four treatment groups. Within each regimen, the Disease Activity Score in 44 joints (DAS-44) was assessed q3 months, and, if > 2.4, the medication regimen was uptitrated to the next step within the treatment group.

Four Treatment Groups

  1. Sequential monotherapy: methotrexate (MTX) 15mg/week, uptitrated PRN to 25-30mg/week. If insufficient control, the following sequence was pursued: sulfasalazine (SSZ) monotherapy, leflunomide monotherapy, MTX + infliximab, gold with methylprednisolone, MTX + cyclosporin A (CSA) + prednisone
  2. Step-up combination therapy: MTX 15mg/week, uptitrated PRN to 25-30mg/week. If insufficient control, SSZ was added, followed by hydroxychloroquine (HCQ), followed by prednisone. If patients failed to respond to those four drugs, they were switched to MTX + infliximab, then MTX + CSA + prednisone, and finally to leflunomide.
  3. Initial combination therapy with tapered high-dose prednisone: MTX 7.5 mg/week + SSZ 2000 mg/day + prednisone 60mg/day (tapered in 7 weeks to 7.5 mg/day). If insufficient control, MTX was uptitrated to 25-30 mg/week. Next, combination would be switched to MTX + CSA + prednisone, then MTX + infliximab, then leflunomide monotherapy, gold with methylprednisolone, and finally azathioprine with prednisone.
  4. Initial combination therapy with infliximab: MTX 25-30 mg/week + infliximab 3 mg/kg at weeks 0, 2, 6, and q8 weeks thereafter. There was a protocol for infliximab-dose uptitration starting at 3 months. If insufficient control on MTX and infliximab 10 mg/kg, patients were switched to SSZ, then leflunomide, then MTX + CSA + prednisone, then gold + methylprednisolone, and finally AZA with prednisone.

Once clinical response was adequate for at least 6 months, there was a protocol for tapering the drug regimen.

The primary endpoints were: 1) functional ability per the Dutch version of the Health Assessment Questionnaire (D-HAQ), collected by a blinded research nurse q3 months and 2) radiographic joint damage per the modified Sharp/Van der Heijde score (SHS). Pertinent secondary outcomes included DAS-44 score and laboratory evidence of treatment toxicity.

At randomization, enrolled RA patients had a median duration of symptoms of 23 weeks and median duration since diagnosis of RA of 2 weeks. Mean DAS-44 was 4.4 ± 0.9. 72% of patients had erosive disease. Mean D-HAQ score at 3 months was 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (p < 0.001 for groups 1 and 2 vs. groups 3 and 4; paired tests otherwise insignificant). Mean D-HAQ at 1 year was 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (p = 0.010 for group 1 vs. group 3, p = 0.003 for group 1 vs. group 4; paired tests otherwise insignificant). At 1 year, patients in group 3 or 4 had less radiographic progression in joint damage per SHS than patients in group 1 or 2. Median increases in SHS were 2.0, 2.5., 1.0, and 0.5 in groups 1-4, respectively (p = 0.003 for group 1 vs. group 3, p < 0.001 for group 1 versus group 4, p = 0.007 for group 2 vs. group 3, p < 0.001 for group 2 vs. group 4). Regarding DAS-44 score: low disease activity (DAS-44 ≤ 2.4) at 1 year was reached in 53%, 64%, 71%, 74% of groups 1-4, respectively (p = 0.004 for group 1 vs. group 3, p = 0.001 for group 1 vs. group 4, p not significant for other comparisons). There were no group differences in prevalence of adverse effects.

Overall, among patients with early RA, initial combination therapy that included either prednisone (group 3) or infliximab (group 4) resulted in better functional and radiographic improvement than did initial therapy with sequential monotherapy (group 1) or step-up combination therapy (group 2). In the discussion, the authors note that given the treatment group differences in radiographic progression of disease, “starting therapy with a single DMARD would be a missed opportunity in a considerable number of patients.” Contemporary commentary by Weisman notes that “the authors describe both an argument and a counterargument arising from their observations: aggressive treatment with combinations of expensive drugs would ‘overtreat’ a large proportion of patients, yet early suppression of disease activity may have an important influence on subsequent long‐term disability and damage.”

Fourteen years later, it is a bit difficult to place the specific results of this trial in our current practice. Its trial design is absolutely byzantine and compares the 1-year experience of a variety of complex protocols that theoretically have substantial eventual potential overlap. Furthermore, it is difficult to assess if the relatively small group differences in symptom (D-HAQ) and radiographic (SHS) scales were truly clinically significant even if they were statistically significant. The American College of Rheumatology 2015 Guideline for the Treatment of Rheumatoid Arthritis synthesized the immense body of literature that came before and after the BeSt study and ultimately gave a variety of conditional statements about the “best practice” treatment of symptomatic early RA. (See Table 2 on page 8.) The recommendations emphasized DMARD monotherapy as the initial strategy but in the specific setting of a treat-to-target strategy. They also recommended escalation to combination DMARDs or biologics in patients with moderate or high disease activity despite DMARD monotherapy.

References / Additional Reading:
1. “The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases.” Arthritis Rheum. 2011 Mar;63(3):633-9. [https://www.ncbi.nlm.nih.gov/pubmed/21360492]
2. BeSt @ Wiki Journal Club
3. “Progress toward the cure of rheumatoid arthritis? The BeSt study.” Arthritis Rheum. 2005 Nov;52(11):3326-32.
4. “Review: treat to target in rheumatoid arthritis: fact, fiction, or hypothesis?” Arthritis Rheumatol. 2014 Apr;66(4):775-82. [https://www.ncbi.nlm.nih.gov/pubmed/24757129]
5. “2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis” Arthritis Rheumatol. 2016 Jan;68(1):1-26
6. RheumDAS calculator

Summary by Duncan F. Moore, MD

Image Credit: Braegel, CC BY 3.0, via Wikimedia Commons

Week 41 – Transfusion Strategies for Upper GI Bleeding

“Transfusion Strategies for Acute Upper Gastrointestinal Bleeding”

N Engl J Med. 2013 Jan 3;368(1):11-21. [free full text]

A restrictive transfusion strategy of 7 gm/dL was established following the previously discussed 1999 TRICC trial. Notably, both TRICC and its derivative study TRISS excluded patients who had an active bleed. In 2013, Villanueva et al. performed a study to establish whether there was benefit to a restrictive transfusion strategy in patients with acute upper GI bleeding.

The study enrolled consecutive adults presenting to a single center in Spain with hematemesis (or bloody nasogastric aspirate), melena, or both. Notable exclusion criteria included: a clinical Rockall score* of 0 with a hemoglobin level higher than 12g/dL, massive exsanguinating bleeding, lower GIB, patient refusal of blood transfusion, ACS, stroke/TIA, transfusion within 90 days, recent trauma or surgery

*The Rockall score is a system to assess risk for further bleeding or death on a scale from 0-11. Higher scores (3-11) indicate higher risk. Of the 648 patients excluded, the most common reason for exclusion (n = 329) was low risk of bleeding.

Intervention: restrictive transfusion strategy (transfusion threshold Hgb = 7.0 gm/dL) [n = 444]

Comparison: liberal transfusion strategy (transfusion threshold Hgb = 9.0 gm/dL) [n = 445]

During randomization, patients were stratified by presence or absence of cirrhosis.

As part of the study design, all patients underwent emergent EGD within 6 hours and received relevant hemostatic intervention depending on the cause of bleeding.

 

Outcome:
Primary outcome: 45-day mortality

Secondary outcomes, selected:

      • Incidence of further bleeding associated with hemodynamic instability or hemoglobin drop > 2 gm/dL in 6 hours
      • Incidence and number of RBC transfusions
      • Other products and fluids transfused
      • Hgb level at nadir, discharge, and 45 days

Subgroup analyses: Patients were stratified by presence of cirrhosis and corresponding Child-Pugh class, variceal bleeding, and peptic ulcer bleeding. An additional subgroup analysis was performed to evaluate changes in hepatic venous pressure gradient between the two strategies.

Results:
The primary outcome of 45-day mortality was lower in the restrictive strategy (5% vs. 9%; HR 0.55, 95% CI 0.33-0.92; p = 0.02; NNT = 24.8). In subgroup analysis, this finding remained consistent for patients who had Child-Pugh class A or B but was not statistically significant among patients who had Class C. Further stratification for variceal bleeding and peptic ulcer disease did not make a difference in mortality.

Secondary outcomes:
Rates of further bleeding events and RBC transfusion, as well as number of products transfused, were lower in the restrictive strategy. Subgroup analysis demonstrated that rates of re-bleeding were lower in Child-Pugh class A and B but not in C. As expected, the restrictive strategy also resulted in the lowest hemoglobin levels at 24 hours. Hemoglobin levels among patients in the restrictive strategy were lower at discharge but were not significantly different from the liberal strategy at 45 days. There was no group difference in amount of non-RBC blood products or colloid/crystalloid transfused. Patients in the restrictive strategy experienced fewer adverse events, particularly transfusion reactions such as transfusion-associated circulatory overload and cardiac complications. Patients in the liberal-transfusion group had significant post-transfusion increases in mean hepatic venous pressure gradient following transfusion. Such increases were not seen in the restrictive-strategy patients.

Implication/Discussion:
In patients with acute upper GI bleeds, a restrictive strategy with a transfusion threshold 7 gm/dL reduces 45-day mortality, the rate and frequency of transfusions, and the rate of adverse reactions, relative to a liberal strategy with a transfusion threshold of 9 gm/dL.

In their discussion, the authors hypothesize that the “harmful effects of transfusion may be related to an impairment of hemostasis. Transfusion may counteract the splanchnic vasoconstrictive response caused by hypovolemia, inducing an increase in splanchnic blood flow and pressure that may impair the formation of clots. Transfusion may also induce abnormalities in coagulation properties.”

Subgroup analysis suggests that the benefit of the restrictive strategy is less pronounced in patients with more severe hepatic dysfunction. These findings align with prior studies in transfusion thresholds for critically ill patients. However, the authors note that the results conflict with studies in other clinical circumstances, specifically in the pediatric ICU and in hip surgery for high-risk patients.

There are several limitations to this study. First, its exclusion criteria limit its generalizability. Excluding patients with massive exsanguination is understandable given lack of clinical equipoise; however, this choice allows too much discretion with respect to the definition of a massive bleed. (Note that those excluded due to exsanguination comprised only 39 of 648.) Lack of blinding was a second limitation. Potential bias was mitigated by well-defined transfusion protocols. Additionally, there a higher incidence of transfusion-protocol violations in the restrictive group, which probably biased results toward the null. Overall, deviations from the protocol occurred in fewer than 10% of cases.

Further Reading/References:
1. Transfusion Strategies for Acute Upper GI Bleeding @ Wiki Journal Club
2. Transfusion Strategies for Acute Upper GI Bleeding @ 2 Minute Medicine
3. TRISS @ Wiki Journal Club

Summary by Gordon Pelegrin, MD

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

Week 40 – PROSEVA

Prone Positioning in Severe Acute Respiratory Distress Syndrome
by the PROSEVA Study Group

N Engl J Med. 2013 June 6; 368(23):2159-2168 [free full text]

Prone positioning had been used for many years in ICU patients with ARDS in order to improve oxygenation. Per Dr. Sonti’s Georgetown Critical Care Top 40, the physiologic basis for benefit with proning lies in the idea that atelectatic regions of lung typically occur in the most dependent portion of an ARDS patient, with hyperinflation affecting the remaining lung. Periodic reversal of these regions via moving the patient from supine to prone and vice versa ensures no one region of the lung will have extended exposure to either atelectasis or overdistention. Although the oxygenation benefits have been long noted, the PROSEVA trial established mortality benefit.

Study patients were selected from 26 ICUs in France and 1 in Spain which had daily practice with prone positioning for at least 5 years. Inclusion criteria: ARDS patients intubated and ventilated <36hr with severe ARDS (defined as PaO2:FiO2 ratio <150, PEEP>5, and TV of about 6ml/kg of predicted body weight). (NB: by the Berlin definition for ARDS, severe ARDS is defined as PaO2:FiO2 ratio <100.) Patients were either randomized to the intervention of proning within 36 hours of mechanical ventilation for at least 16 consecutive hours (N=237) or to the control of being left in a semirecumbent (supine) position (N=229). The primary outcome was mortality at day 28. Secondary outcomes included mortality at day 90, rate of successful extubation (no reintubation or use of noninvasive ventilation x48hr), time to successful extubation, length of stay in the ICU, complications, use of noninvasive ventilation, tracheotomy rate, number of days free from organ dysfunction, ventilator settings, measurements of ABG, and respiratory system mechanics during the first week after randomization.

At the time of randomization in the study, the majority of characteristics were similar between the two groups, although the authors noted differences in the SOFA score and the use of neuromuscular blockers and vasopressors. The supine group at baseline had a higher SOFA score indicating more severe organ failure, and also had higher rate of vasopressor usage. The prone group had a higher rate of usage of neuromuscular blockade. The primary outcome of 28 day mortality was significantly lower in the prone group than in the supine group, at 16.0% vs 32.8% (p < 0.001, NNT = 6.0). This mortality decrease was still statistically significant when adjusted for the SOFA score. Secondary outcomes were notable for a significantly higher rate of successful extubation in the prone group (hazard ratio 0.45; 95% CI 0.29-0.7, p < 0.001). Additionally, the PaO2:FiO2 ratio was significantly higher in the supine group, whereas the PEEP and FiO2 were significantly lower. The remainder of secondary outcomes were statistically similar.

PROSEVA showed a significant mortality benefit with early use of prone positioning in severe ARDS. This mortality benefit was considerably larger than that seen in past meta-analyses, which was likely due to this study selecting specifically for patients with severe disease as well as specifying longer prone-positioning sessions than employed in prior studies. Critics have noted the unexpected difference in baseline characteristics between the two arms of the study. While these critiques are reasonable, the authors mitigate at least some of these complaints by adjusting the mortality for the statistically significant differences. With such a radical mortality benefit it might be surprising that more patients are not proned at our institution. One reason is that relatively few of our patients have severe ARDS. Additionally, proning places a high demand on resources and requires a coordinated effort of multiple staff. All treatment centers in this study had specially-trained staff that had been performing proning on a daily basis for at least 5 years, and thus were very familiar with the process. With this in mind, we consider the use of proning in patients meeting criteria for severe ARDS.

References and further reading:
1. PROSEVA @ 2 Minute Medicine
2. PROSEVA @ Wiki Journal Club
3. PROSEVA @ Georgetown Critical Care Top 40, pages 8-9
4. Life in the Fastlane, Critical Care Compendium, “Prone Position and Mechanical Ventilation”
5. PulmCCM.org, “ICU Physiology in 1000 Words: The Hemodynamics of Prone”

Summary by Gordon Pelegrin, MD

Image Credit: by James Heilman, MD, CC BY-SA 3.0, via Wikimedia Commons

Week 39 – POISE

“Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery: a randomised controlled trial”

Lancet. 2008 May 31;371(9627):1839-47. [free full text]

Non-cardiac surgery is commonly associated with major cardiovascular complications. It has been hypothesized that perioperative beta blockade would reduce such events by attenuating the effects of the intraoperative increases in catecholamine levels. Prior to the 2008 POISE trial, small- and moderate-sized trials had revealed inconsistent results, alternately demonstrating benefit and non-benefit with perioperative beta blockade. The POISE trial was a large RCT designed to assess the benefit of extended-release metoprolol succinate (vs. placebo) in reducing major cardiovascular events in patients of elevated cardiovascular risk.

The trial enrolled patients age 45+ undergoing non-cardiac surgery with estimated LOS 24+ hrs and elevated risk of cardiac disease, meaning: either 1) hx of CAD, 2) peripheral vascular disease, 3) hospitalization for CHF within past 3 years, 4) undergoing major vascular surgery, 5) or any three of the following seven risk criteria: undergoing intrathoracic or intraperitoneal surgery, hx CHF, hx TIA, hx DM, Cr > 2.0, age 70+, or undergoing urgent/emergent surgery.

Notable exclusion criteria: HR < 50, 2nd or 3rd degree heart block, asthma, already on beta blocker, prior intolerance of beta blocker, hx CABG within 5 years and no cardiac ischemia since

Intervention: metoprolol succinate (extended-release) 100mg PO starting 2-4 hrs before surgery, additional 100mg at 6-12 hrs postoperatively, followed by 200mg daily for 30 days. (Patients unable to take PO meds postoperatively were given metoprolol infusion.)

Comparison: placebo PO / IV at same frequency as metoprolol arm

Outcome:
Primary – composite of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest at 30 days

Secondary (at 30 days)

        • cardiovascular death
        • non-fatal MI
        • non-fatal cardiac arrest
        • all-cause mortality
        • non-cardiovascular death
        • MI
        • cardiac revascularization
        • stroke
        • non-fatal stroke
        • CHF
        • new, clinically significant atrial fibrillation
        • clinically significant hypotension
        • clinically significant bradycardia

Pre-specified subgroup analyses of primary outcome:

Results:
9298 patients were randomized. However, fraudulent activity was detected at participating sites in Iran and Colombia, and thus 947 patients from these sites were excluded from the final analyses. Ultimately, 4174 were randomized to the metoprolol group, and 4177 were randomized to the placebo group. There were no significant differences in baseline characteristics, pre-operative cardiac medications, surgery type, or anesthesia type between the two groups (see Table 1).

Regarding the primary outcome, metoprolol patients were less likely than placebo patients to experience the primary composite endpoint of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest (HR 0.84, 95% CI 0.70-0.99, p = 0.0399). See Figure 2A for the relevant Kaplan-Meier curve. Note that the curves separate distinctly within the first several days.

Regarding selected secondary outcomes (see Table 3 for full list), metoprolol patients were more likely to die from any cause (HR 1.33, 95% CI 1.03-1.74, p = 0.0317). See Figure 2D for the Kaplan-Meier curve for all-cause mortality. Note that the curves start to separate around day 10. Cause of death was analyzed, and the only group difference in attributable cause was an increased number of deaths due to sepsis or infection in the metoprolol group (data not shown). Metoprolol patients were more likely to sustain a stroke (HR 2.17, 95% CI 1.26-3.74, p = 0.0053) or a non-fatal stroke (HR 1.94, 95% CI 1.01-3.69, p = 0.0450). Of all patients who sustained a non-fatal stroke, only 15-20% made a full recovery. Metoprolol patients were less likely to sustain new-onset atrial fibrillation (HR 0.76, 95% CI 0.58-0.99, p = 0.0435) and less likely to sustain a non-fatal MI (HR 0.70, 95% CI 0.57-0.86, p = 0.0008). There were no group differences in risk of cardiovascular death or non-fatal cardiac arrest. Metoprolol patients were more likely to sustain clinically significant hypotension (HR 1.55, 95% CI 1.38-1.74, P < 0.0001) and clinically significant bradycardia (HR 2.74, 95% CI 2.19-3.43, p < 0.0001).

Subgroup analysis did not reveal any significant interaction with the primary outcome by RCRI, sex, type of surgery, or anesthesia type.

Implication/Discussion:
In patients with cardiovascular risk factors undergoing non-cardiac surgery, the perioperative initiation of beta blockade decreased the composite risk of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest and increased the overall mortality risk and risk of stroke.

This study affirms its central hypothesis – that blunting the catecholamine surge of surgery is beneficial from a cardiac standpoint. (Most patients in this study had an RCRI of 1 or 2.) However, the attendant increase in all-cause mortality is dramatic. The increased mortality is thought to result from delayed recognition of sepsis due to masking of tachycardia. Beta blockade may also limit the physiologic hemodynamic response necessary to successfully fight a serious infection. In retrospective analyses mentioned in the discussion, the investigators state that they cannot fully explain the increased risk of stroke in the metoprolol group. However, hypotension attributable to beta blockade explains about half of the increased number of strokes.

Overall, the authors conclude that “patients are unlikely to accept the risks associated with perioperative extended-release metoprolol.”

A major limitation of this study is the fact that 10% of enrolled patients were discarded in analysis due to fraudulent activity at selected investigation sites. In terms of generalizability, it is important to remember that POISE excluded patients who were already on beta blockers.

Currently, per expert opinion at UpToDate, it is not recommended to initiate beta blockers preoperatively in order improve perioperative outcomes. POISE is an important piece of evidence underpinning the 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery, which includes the following recommendations regarding beta blockers:

      • Beta blocker therapy should not be started on the day of surgery (Class III – Harm, Level B)
      • Continue beta blockers in patients who are on beta blockers chronically (Class I, Level B)
      • In patients with intermediate- or high-risk preoperative tests, it may be reasonable to begin beta blockers
      • In patients with ≥ 3 RCRI risk factors, it may be reasonable to begin beta blockers before surgery
      • Initiating beta blockers in the perioperative setting as an approach to reduce perioperative risk is of uncertain benefit in those with a long-term indication but no other RCRI risk factors
      • It may be reasonable to begin perioperative beta blockers long enough in advance to assess safety and tolerability, preferably > 1 day before surgery

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Management of cardiac risk for noncardiac surgery”
4. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines.

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

Summary by Duncan F. Moore, MD

Week 38 – 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]

The optimal timing of initiation of antiretroviral therapy (ART) in asymptomatic patients with HIV has 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, per UpToDate, the standard of care has been to treat “essentially all” HIV-infected patients with ART.

Further Reading/References:
1. Wiki Journal Club
2. 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 37 – LOTT

“A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation”

by the Long-Term Oxygen Treatment Trial (LOTT) Research Group

N Engl J Med. 2016 Oct 27;375(17):1617-1627. [free full text]

The long-term treatment of severe resting hypoxemia (SpO2 < 89%) in COPD with supplemental oxygen has been a cornerstone of modern outpatient COPD management since its mortality benefit was demonstrated circa 1980. Subsequently, the utility of supplemental oxygen in COPD patients with moderate resting daytime hypoxemia (SpO2 89-93%) was investigated in trials in the 1990s; however, such trials were underpowered to assess mortality benefit. Ultimately, the LOTT trial was funded by the NIH and Centers for Medicare and Medicaid Services (CMS) primarily to determine if there was a mortality benefit to supplemental oxygen in COPD patients with moderate hypoxemia as well to analyze as numerous other secondary outcomes, such as hospitalization rates and exercise performance.

The LOTT trial was originally planned to enroll 3500 patients. However, after 7 months the trial had randomized only 34 patients, and mortality had been lower than anticipated. Thus in late 2009 the trial was redesigned to include broader inclusion criteria (now patients with exercise-induced hypoxemia could qualify) and the primary endpoint was broadened from mortality to a composite of time to first hospitalization or death.

The revised LOTT trial enrolled COPD patients with moderate resting hypoxemia (SpO2 89-93%) or moderate exercise-induced desaturation during the 6-minute walk test (SpO2 ≥ 80% for ≥ 5 minutes and < 90% for ≥ 10 seconds). Patients were randomized to either supplemental oxygen (24-hour oxygen if resting SpO2 89-93%, otherwise oxygen only during sleep and exercise if the desaturation occurred only during exercise) or to usual care without supplemental oxygen. Supplemental oxygen flow rate was 2 liters per minute and could be uptitrated by protocol among patients with exercise-induced hypoxemia. The primary outcome was time to composite of first hospitalization or death. Secondary outcomes included hospitalization rates, lung function, performance on 6-minute walk test, and quality of life.

368 patients were randomized to the supplemental-oxygen group and 370 to the no-supplemental-oxygen group. Of the supplemental-oxygen group, 220 patients were prescribed 24-hour oxygen support, and 148 were prescribed oxygen for use during exercise and sleep only. Median duration of follow-up was 18.4 months. Regarding the primary outcome, there was no group difference in time to death or first hospitalization (p = 0.52 by log-rank test). See Figure 1A. Furthermore, there were no treatment-group differences in the primary outcome among patients of the following pre-specified subgroups: type of oxygen prescription, “desaturation profile,” race, sex, smoking status, SpO2 nadir during 6-minute walk, FEV1, BODE  index, SF-36 physical-component score, BMI, or history of anemia. Patients with a COPD exacerbation in the 1-2 months prior to enrollment, age 71+ at enrollment, and those with lower Quality of Well-Being Scale score at enrollment all demonstrated benefit from supplemental O2, but none of these subgroup treatment effects were sustained when the analyses were adjusted for multiple comparisons. Regarding secondary outcomes, there were no treatment-group differences in rates of all-cause hospitalizations, COPD-related hospitalizations, or non-COPD-related hospitalizations, and there were no differences in change from baseline measures of quality of life, anxiety, depression, lung function, and distance achieved in 6-minute walk.

The LOTT trial presents compelling evidence that there is no significant benefit, mortality or otherwise, of oxygen supplementation in patients with COPD and either moderate hypoxemia at rest (SpO2 > 88%) or exercise-induced hypoxemia. Although this trial’s substantial redesign in its early course is noted, the trial still is our best evidence to date about the benefit (or lack thereof) of oxygen in this patient group. As acknowledged by the authors, the trial may have had significant selection bias in referral. (Many physicians did not refer specific patients for enrollment because “they were too ill or [were believed to have benefited] from oxygen.”) Another notable limitation of this study is that nocturnal oxygen saturation was not evaluated. The authors do note that “some patients with COPD and severe nocturnal desaturation might benefit from nocturnal oxygen supplementation.”

For further contemporary contextualization of the study, please see the excellent post at PulmCCM from 11/2016. Included in that post is a link to an overview and Q&A from the NIH regarding the LOTT study.

References / Additional Reading:
1. PulmCCM, “Long-term oxygen brought no benefits for moderate hypoxemia in COPD”
2. LOTT @ 2 Minute Medicine
3. LOTT @ ClinicalTrials.gov
4. McDonald, J.H. 2014. Handbook of Biological Statistics (3rd ed.). Sparky House Publishing, Baltimore, Maryland.
5. Centers for Medicare and Medicaid Services, “Certificate of Medical Necessity CMS-484– Oxygen”
6. Ann Am Thorac Soc. 2018 Dec;15(12):1369-1381. “Optimizing Home Oxygen Therapy. An Official American Thoracic Society Workshop Report.”

Summary by Duncan F. Moore, MD

Image Credit: Patrick McAleer, CC BY-SA 2.0 UK, via Wikimedia Commons