September 2014 Tucson Pulmonary Journal Club: PANTHEON Study

Zheng JP, Wen FQ, Bai CX, Wan HY, Kang J, Chen P et al. for the PANTHEON study group. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomized, double-blind placebo-controlled trial. Lancet Respir Med. 2014; 2(3):187-94. [CrossRef] [PubMed]

Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity, mortality, and healthcare utilization. Oxidative stress is thought to be important in COPD pathogenesis, and thus antioxidant therapy has been of great interest, including N-Acetylcysteine (NAC). However, prior studies of NAC in COPD patients have shown varied results. The PANTHEON study was designed to examine the effects of NAC on exacerbation rate in Chinese patients with COPD using a daily dose that is twice as high as that previously studied.

PANTHEON was a randomized double-blinded placebo-controlled trial that enrolled patients aged 40-80 years with GOLD class II, III and IV COPD from 34 academic pulmonary clinics in China. Patients with asthma, oxygen dependence, or poor compliance were excluded. The primary outcome was the COPD exacerbation rate following one year of observation. Exacerbations were defined using the Anthonisen instrument which relies on daily diary reporting. Important secondary outcomes included time to first exacerbation, time to subsequent exacerbations, number of patients requiring antibiotics or steroids, and number of patients requiring hospitalization. The enrollment goal was 1250 patients which would have provided have 95% power to detect a 20% reduction in the exacerbation; however, only 1006 patients were actually randomized. Nevertheless, the study was adequately powered for the primary outcome.

More than 80% of the patients were males; 46% had GOLD II severity, 53% had GOLD III severity, and 1% had GOLD IV severity. Mean FEV1 was 1.2 L. Twenty-five percent were non-smokers; 48% were using both ICS and a long-acting bronchodilator at enrollment; and 27% were taking theophylline.

As compared to placebo, twice daily treatment with 600mg of NAC led to a significant reduction in the annual COPD exacerbation rate (RR 0.78, 95% CI 0.67–0.90; p=0.001) and the rate of steroid or antibiotic-requiring exacerbations (RR 0.83 95% CI 0.69-0.99; p=0.04) but not the annual rate of hospitalizations. Interestingly, the time to first exacerbation did not differ between the groups but the time to second and third exacerbations was longer in the NAC group.

This study suggests that NAC, a relatively inexpensive compound that is available over-the-counter, may reduce exacerbation risk among patients with COPD. Given that NAC is safe and the costs would be borne entirely by the patient, it is reasonable to advise patients of this potential treatment option. Patients should be cautioned that the data supporting the benefits of NAC are not conclusive and the magnitude of benefit is likely to be modest. The major limitation includes reliance on a Chinese population of COPD patients in whom the benefits may not be generalizable to US patients. Of unknown importance is the fact that treatment benefits were limited to self-reported outcomes rather than objective observation of hospitalizations. To the extent that the self-reported data is free of bias, the failure to detect differences in hospitalizations may not matter to patients.

Bhupinder Natt MD¹, Christine Berry MD¹, Joe K. Gerald MD, PhD²

¹Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Arizona Medical Center; Tucson, AZ

²College of Public Health, University of Arizona Medical Center; Tucson, AZ

Reference as: Natt B, Berry C, Gerald JK. September 2014 Tucson pulmonary journal club: PANTHEON study. Southwest J Pulm Crit Care. 2014;9(4):249-50. doi: http://dx.doi.org/10.13175/swjpcc144-14 PDF

December 2013 Tucson Pulmonary Journal Club: Hypothermia

Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369(23):2197-206. [CrossRef] [PubMed]

Therapeutic hypothermia is recommended by international resuscitation guidelines for unconscious patients who regain spontaneous circulation after cardiac arrest (1). Two randomized controlled trials in 2002 demonstrated that mild therapeutic hypothermia significantly improved neurologic outcomes and survival among patients who experienced cardiac arrests due to an initial shockable rhythm (2,3).  However, the optimal temperature target for therapeutic hypothermia has yet to be determined.

The Target Temperature Management (TTM-36) study was an international randomized control trial that investigated the benefits and harms of two temperature targets, 33°C and 36°C, among 950 participants who experienced out-of-hospital cardiac arrest. Participants were randomly assigned to receive 24 hours of therapeutic hypothermia at a temperature of 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial (180 days after the last participant was enrolled). Secondary outcomes included a composite of poor neurologic function or death at 180 days using both the Cerebral Performance Category (CPC) scale and the modified Rankin scale. Participants 18 years of age or older who were unconscious and had a score <8 on the Glasgow Coma on admission following out-of-hospital cardiac arrest were eligible. Eligible patients had more than 20 consecutive minutes of spontaneous circulation after resuscitation. The main exclusion criteria were an interval from the return of spontaneous circulation to screening of more than 240 minutes, unwitnessed arrest with asystole as the initial rhythm, suspected or known acute intracranial hemorrhage or stroke, and a body temperature of less than 30°C.

At the end of the trial, there was no significant difference in the number of  deaths between the two groups (hazard ratio in the 33°C group, 1.06; 95% confidence interval, 0.89 to 1.28; P = 0.51). No significant difference was found with respect to composite outcome of poor neurologic function or death at 180 days with the use of either the CPC or the modified Rankin scale score. The results were consistent in six predefined subgroups. No significant harm was found with targeted temperature of 33°C as compared to 36°C.

TTM-36 failed to demonstrate post-arrest therapeutic hypothermia at 33°C to be superior to post-arrest therapeutic hypothermia of 36°C.  Post-arrest therapeutic hypothermia at 33°C was not associated with any additional harm either.  TTM-36 provides evidence that lowering temperature below 36°C does not yield additional clinical benefit among patients surviving out-of-hospital cardiac arrest.  Given that the current treatment standard is 33°C, a non-inferiority design would have provided stronger evidence to support the safety of a higher temperature target (36°C). 

Aarthi Ganesh, MBBS; Cristine Berry, MD; Joe Gerald, PhD

University of Arizona

Tucson, AZ

References

1. Peberdy MA, Callaway CW, Neumar RW, et al.; American Heart Association. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S768-86. [CrossRef] [PubMed]
2. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-63. [CrossRef] [PubMed]
3. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-56. [CrossRef] [PubMed] 

Reference as: Ganesh A, Berry C, Gerald J. December 2013 Tucson pulmonary journal club: hypothermia. Southwest J Pulm Crit Care. 2014;8(1):44-45. doi: http://dx.doi.org/10.13175/swjpcc003-14 PDF