CAPE COD

Published

Dequin PF, et al. "Hydrocortisone in severe community-acquired pneumonia". The New England Journal of Medicine. 2023. Epub 2023-03-21:1-11.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

Among patients with severe community acquired pneumonia requiring ICU or intermediate care unit admission, does hydrocortisone reduce the risk of all-cause mortality at 28 days when compared to placebo?

Bottom Line

Among patients with severe community acquired pneumonia requiring ICU or intermediate care unit admission, hydrocortisone lowers all-cause mortality at 28 days when compared to placebo.

Major Points

In the 2010s, the role of corticosteroids in treatment of severe community acquired pneumonia (CAP) was unclear. A 2011 Cochrane review including 6 trials with 437 participants concluded that corticosteroids improved time to symptom resolution, but the evidence was not high-quality enough to guide recommendations about its routine use. To address this knowledge gap, in 2015, the CAPE COD trial began recruiting a target of 1200 participants from 31 centers in France with severe CAP requiring ICU or intermediate care unit treatment. Participants were randomized to hydrocortisone 200 mg IV per day x4-7 days with 4-7 day taper or placebo. The trial halted enrollment at 800 participants recruited at the onset of the Covid-19 pandemic. A planned interim analysis at 800 participants did not occur for several years. At that delayed interim analysis, the decision was made to close the trial early. In the main results manuscript published in 2023, hydrocortisone therapy was associated with a significant reduction in all-cause mortality at 28 days (6.2% vs. 11.9%; P=0.006; NNT 17.5). Intubation and use of vasopressors was also less common in the hydrocortisone arm. The results of CAPE COD differ from the 2022 ESCAPe trial in the VA, which found no benefit of adding methylprednisolone 40 mg daily among 586 veterans with pneumonia. ESCAPe was underpowered, with target recruitment of 1,420 participants, and had a longer duration of time from admission to administration of the study medication at a median of ~1.5 to 2 days (vs. ~20 hours in CAPE COD). Finally, in contrast with CAPE COD's exclusion of patients on pressors, ESCAPe included ~13% patients on pressors.

Of note, an updated 2017 Cochrane review (published about 2 years after CAPE COD's initial enrollment) included 17 trials with 2,264 participants and found a significant reduction in mortality among persons with severe CAP (RR 0.58; 95% CI 0.40-0.84) based upon moderate quality evidence. This Cochrane review estimated the NNT of hydrocortisone to prevent 1 death from severe CAP was 18 patients, which was essentially identical to the observed NNT in CAPE COD. More recently, a non-Cochrane 2023 meta-analysis including results from CAPE COD and ESCAPe confirmed an overall mortality benefit with corticosteroids. When they broke down their analysis they found not a class effect but the benefit was more pronounced with hydrocortisone, and a dose response relationship with doses above 6mg dexamethasone equivalents (~160mg hydrocortisone).

Guidelines

As of April 2023, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, double-blind, parallel-group, randomized, controlled trial
• N=795 (stopped early)
  • Hydrocortisone (n=400)
  • Placebo (n=395)
• Setting: 31 centers in France
• Enrollment: 2015-2020
• Mean follow-up: 28 days
• Analysis: Per-protocol
• Primary outcome: All-cause mortality at 28 days

Population

Inclusion Criteria

From the supplemental appendix, which had some odd wording, presumably because this was a French trial and this was translated from a French document.

• Aged ≥18 years, participating in French social security (WJC ed: presumably, this means they have state-funded health insurance)
• Admitted to intensive care or intermediate care unit
• Diagnosis of community-acquired pneumonia in first 48 hours of admission, with ≥2 of the 4:
  • Cough
  • Purulent sputum
  • Chest pain
  • Dyspnea
• Radiological evidence with focal infiltrate or shadowing
• Study medication initiated within 24 hours after first severity criteria
• Severe disease with ≥1 of the following:
  • Fine class V/pneumonia Severity Index >130
  • On invasive or non-invasive ventilation for acute respiratory failure, with PEEP ≥5 cm H2O
  • HFNC ≥50% and PaO2:FiO2 <300 (note: this was originally <200 but was increased in Spring 2017 after 285 patients included)
  • On non-rebreather
• On antibiotics
• Informed consent

Exclusion Criteria

• Septic shock treated with vasopressors
• Aspiration as likely etiology
• Invasive ventilation in 2 weeks prior to admission
• On antibiotics treating a respiratory infection for >7 days at time of admission, unless an isolated pathogen is identified that is resistant to antibiotics
• CF, active TB, or active fungal infection
• Post-obstructive pneumonia
• Flu+ on PCR test
• Active viral hepatitis or infection with herpes virus
• Myelosuppression
• DNR
• Hypersensitivity to corticosteroids
• Needs corticosteroids or hydrocortisone for other reasons
• On prednisone ≥15 mg/day or equivalent dosing of other corticosteriods for >30 days
• Enrolled in another trial with mortality as an endpoint.
• Pregnant/breastfeeding
• Under guardianship

Baseline Characteristics

From the hydrocortisone group.

• Demographics: Age 67y, 70% men
• Medical problems: COPD 22%, asthma 6%, DM 24%, immunosuppression 6%
• Respiratory support type: Mechanical ventilation 45% (invasive 23%, noninvasive 22%), HFNC 42%, non-rebreather 13%
• Pulmonary severity index, median: 127
  • Class I 1%, class II 4%, class III 11%, class IV 38%, class V 46%
• SAPS score, median: 37
• SOFA score, median: 4
• Vasopressor treatment: 10%
• Labs, median: CRP 26.3 mg/dL (CRP >15 mg/dL 70%), procalcitonin 3.2 ng/mL, cortisol 302 nmol/L
• Duration of time: Hospital to ICU admission 5.5 hours, ICU admission to initiation of study drug 15 hours

Interventions

• Randomized to a group:
  • Hydrocortisone - 200 mg IV per day as a continuous infusion for 4-7 days, followed by a taper outlined in Figure s1 on page 10 of the supplemental appendix
  • Placebo
• Antibiotics were at discretion of treating team, and must have been started prior to inclusion
• Other treatments were allowed, including sedative agents, and severe ARDS rescue treatments
• Rescue corticosteroids were not allowed

Outcomes

Comparisons are hydrocortisone vs. placebo.

Primary Outcomes

All-cause mortality at 28 days

6.2% vs. 11.9% (difference -5.6; -9.6 to -1.7; P=0.006; NNT 17.5)

Secondary Outcomes

All-cause mortality at 90 days

9.3% vs. 14.7% (difference -5.4; 95% CI -9.9 to -0.8; NNT 18.5)

Ventilation at 28 days

Among those not requiring mechanical ventilation at enrollment

Endotracheal intubation: 18.0% vs. 29.5% (HR 0.59; 95% CI 0.40 to 0.86)

Noninvasive ventilation: 6.8% vs. 10.9% (HR 0.60; 95% CI 0.32 to 1.15)

Among those not requiring endotracheal intubation at enrollment

Endotracheal intubation: 19.5% vs. 27.7% (HR 0.69; 95% CI 0.50 to 0.94)

Vasopressors at 28 days, among those not receiving vasopressors at enrollment

15.3% vs. 25.0% (HR 0.59; 95% CI 0.43 to 0.82)

Other Outcomes

Median insulin dose by day 7 among those on insulin

35 vs. 20 units/day (median difference 8.7; 95% CI 4.0 to 13.8; P<0.001)

Median weight change from baseline to day 7

2 vs 1 kg (median difference 1 kg; 95% CI 0 to 2 kg; P=0.18)

Subgroup Analysis

See table S3 on page 12 of the supplemental appendix

The primary outcome was generally similar by mechanical ventilation status, whether a "germ" was isolated, age threshold of 65, sex, PSI threshold of 130, and CRP of 15 mg/dL.

Adverse Events

See table S6 on page 24 of the supplemental appendix

Serious adverse event

70 vs. 99 events

≥1: 16% vs. 22%

Hospital-acquired infections: 10% vs. 11% (HR 0.87; 95% CI 0.57 to 1.34; P=0.54)

Ventilator-associated pneumonia, among intubated patients: 21% vs. 22%

Blood stream infections: 1% vs. 2%

GI bleed: 2% vs. 3% (HR 0.68; 95% CI 0.29 to 1.59; P=0.38)

Peptic ulcerations: 2% vs. 1%

Stroke: 0 vs. 3 events

Mesenteric ischemia: 0 vs. 2 events

PE: 2 vs. 2 events

Unanticipated cardiac arrest: 0 vs 2 events

Symptomatic hypokalemia: 2 vs 0 events

Other serious adverse event: 10 vs 10 events

Criticisms

• Trial enrollment halted in March 2020 with the emergence of the Covid-19 pandemic after around 800 participants had been enrolled. (The study team used the CAPE COD protocol among patients with Covid-19 instead.) The authors had intended to do an interim analysis at around 800 participants enrolled but didn't get around to it until several years later. At that point (presumably without enrolling any additional patients since 2019), the decision was made to close the trial and report the results. The WJC editors are physicians and sympathize with the study group's workload that probably contributed to the delayed interim analysis. However, delaying the planned interim analysis several years is problematic since this trial's results are highly relevant to contemporary clinical practice.
• A 2017 Cochrane analysis concluded that corticosteroids lowered morbidity and mortality. This was released about 2 years after CAPE COD was started, so there was less clinical equipoise to support the trial's continuation. However, 2019 ATS/IDSA guidelines did not recommend routine treatment of persons with severe CAP with corticosteroids.
• Excluded persons on pressors.
• Lower-than-anticipated mortality
• No standardized use of antimicrobials
• Few patients who were immunocompromised
• Did not assess other side effects from steroids, including psychiatric and neuromuscular problems
• Used continuous infusion of hydrocortisone rather than bolus dosing
• In this trial that was conducted in France, the authors did not report demographic characteristics that are commonly reported in US-based trials (eg, race, ethnicity)

Funding

French Ministry of Health