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

Week 36 – HAS-BLED

“A Novel User-Friendly Score (HAS-BLED) To Assess 1-Year Risk of Major Bleeding in Patients with Atrial Fibrillation”

Chest. 2010 Nov;138(5):1093-100 [free full text]

Atrial fibrillation (AF) is a well-known risk factor for ischemic stroke. Stroke risk is further increased by individual comorbidities, such as CHF, HTN, and DM, and can be stratified with scores, such as CHADS2 and CHA2DS2VASC. Patients with intermediate stroke risk are recommended to be treated with oral anticoagulation (OAC). However, stroke risk is often also closely related to bleeding risk, and the benefits of anticoagulation for stroke need to be weighed against the added risk of bleeding. At the time of this study, there were no validated and user-friendly bleeding risk-stratification schemes. This study aimed to develop a practical risk score to estimate the 1-year risk of major bleeding (as defined in the study) in a contemporary, real world cohort of patients with AF.

The study enrolled adults with an EKG or Holter-proven diagnosis of AF. (Patients with mitral valve stenosis or previous valvular surgery were excluded.) No experiment was performed in this retrospective cohort study.

In a derivation cohort, the authors retrospectively performed univariate analyses to identify a range of clinical features associated with major bleeding (p < 0.10). Based on systematic reviews, they added additional risk factors for major bleeding. Ultimately, what resulted was a list of comprehensive risk factors deemed HAS-BLED:

H – Hypertension (> 160 mmHg systolic)
A – Abnormal renal (HD, transplant, Cr > 2.26 mg/dL) and liver function (cirrhosis, bilirubin > 2x normal w/ AST/ALT/ALP > 3x normal) – 1 pt each for abnormal renal or liver function
S – Stroke

B – Bleeding (prior major bleed or predisposition to bleed)
L – Labile INRs (time in therapeutic range < 60%)
E – Elderly (age > 65)
D – Drugs (i.e. ASA, clopidogrel, NSAIDs) or alcohol use (> 8 units per week) concomitantly – 1 pt each for use of either

Each risk factor was equivalent to one point. The HAS-BLED score was then compared to the HEMORR2HAGES scheme [https://www.mdcalc.com/hemorr2hages-score-major-bleeding-risk], a prior tool for estimating bleeding risk.

Outcomes:

      • incidence of major bleeding within 1 year, overall
      • bleeds per 100 patient-years, by HAS-BLED score
      • c-statistic for the HAS-BLED score in predicting the risk of bleeding

Definitions:

      • major bleeding = bleeding causing hospitalization, Hgb drop >2 g/L, or requiring blood transfusion, that was not a hemorrhagic stroke
      • hemorrhagic stroke = focal neurologic deficit of sudden onset, diagnosed by a neurologist, lasting >24h and caused by bleeding

Results:
3,456 patients with AF without mitral valve stenosis or valve surgery who completed their 1-year follow-up were analyzed retrospectively. 64.8% (2242) of these patients were on OAC (12.8% of whom on concurrent antiplatelet therapy), 24% (828) were on antiplatelet therapy alone, and 10.2% (352) received no antithrombotic therapy. 1.5% (53) of patients experienced a major bleed during the first year, with 17% (9) of these patients sustaining intracerebral hemorrhage.

HAS-BLED Score       Bleeds per 100-patient years
0                                        1.13
1                                         1.02
2                                        1.88
3                                        3.74
4                                        8.70
5                                        12.50
6*                                     0.0                   *(n = 2 patients at risk, neither bled)

Patients were given a HAS-BLED score and a HEMORR2HAGES score. C-statistics were then used to determine the predictive accuracy of each model overall as well as within patient subgroups (OAC alone, OAC + antiplatelet, antiplatelet alone, no antithrombotic therapy).

C statistics for HAS-BLED were as follows: for overall cohort, 0.72 (95%CI 0.65-0.79); for OAC alone, 0.69 (95%CI 0.59-0.80); for OAC + antiplatelet, 0.78 (95%CI 0.65-0.91); for antiplatelet alone, 0.91 (95%CI 0.83-1.00); and for those on no antithrombotic therapy, 0.85 (95%CI 0.00-1.00).

C statistics for HEMORR2HAGES were as follows: for overall cohort, 0.66 (95%CI 0.57-0.74); for OAC alone, 0.64 (95%CI 0.53-0.75); for OAC + antiplatelet, 0.83 (95%CI 0.74-0.91); for antiplatelet alone, 0.83 (95%CI 0.68-0.98); and for those without antithrombotic therapy, 0.81 (95%CI 0.00-1.00).

Implication/Discussion:
This study helped to establish a practical and user-friendly assessment of bleeding risk in AF. HAS-BLED is superior to its predecessor HEMORR2HAGES in that it has an easier-to-remember acronym and is quicker and simpler to perform. All of its risk factors are readily available from the clinical history or are routinely tested. Both stratification tools had a broadly similar c-statistics for the overall cohort – 0.72 for HAS-BLED versus 0.66 for HEMORR2HAGES respectively. However, HAS-BLED was particularly useful when looking at antiplatelet therapy alone or no antithrombotic therapy at all (0.91 and 0.85, respectively).

This study is useful because it provides evidence-based, easily-calculable, and actionable risk stratification in assessing bleeding risk in AF. In prior studies, such as ACTIVE-A (ASA + clopidogrel versus ASA alone for patients with AF deemed unsuitable for OAC), almost half of all patients (n= ~3500) were given a classification of “unsuitable for OAC,” which was based solely on physician clinical judgement alone without a predefined objective scoring. Now, physicians have an objective way to assess bleed risk rather than “gut feeling” or wanting to avoid iatrogenic insult.

The RE-LY trial used the HAS-BLED score to decide which patients with AF should get the standard dabigatran dose (150mg BID) versus a lower dose (110mg BID) for anticoagulation. This risk-stratified dosing resulted in a significant reduction in major bleeding compared with warfarin and maintained a similar reduction in stroke risk.

Furthermore, the HAS-BLED score could allow the physician to be more confident when deciding which patients may be appropriate for referral for a left atrial appendage occlusion device (e.g. Watchman).

Limitations:
The study had a limited number of major bleeds and a short follow-up period, and thus it is possible that other important risk factors for bleeding were not identified. Also, there were large numbers of patients lost to 1-year follow-up. These patients were likely to have had more comorbidities and may have transferred to nursing homes or even have died – which may have led to an underestimate of bleeding rates. Furthermore, the study had a modest number of very elderly patients (i.e. 75-84 and ≥85), who are likely to represent the greatest bleeding risk.

Bottom Line:
HAS-BLED provides an easy, practical tool to assess the individual bleeding risk of patients with AF. Oral anticoagulation should be considered for scores of 3 or less. HAS-BLED scores are ≥4, it is reasonable to think about alternatives to oral anticoagulation.

Further Reading/References:
1. HAS-BLED @ 2 Minute Medicine
2. ACTIVE-A trial
3. RE-LY trial:
4. RE-LY @ Wiki Journal Club
5. HAS-BLED Calculator
6. HEMORR2HAGES Calculator
7. CHADS2 Calculator
8. CHA2DS2VASC Calculator
9. Watchman (for Healthcare Professionals)

Summary by Patrick Miller, MD

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

Week 35 – CORTICUS

“Hydrocortisone Therapy for Patients with Septic Shock”

N Engl J Med. 2008 Jan 10;358(2):111-24. [free full text]

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 [https://emcrit.org/emnerd/cc-nerd-case-relative-insufficiency/] 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