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

December 2013 Phoenix Pulmonary Journal Club: Lung Cancer Screening

During this month’s pulmonary journal club we reviewed several of the sentinel studies looking at lung cancer screening. Since the National Lung Screening Research Team (NLSRT) (1) published the impressive results showing a 20% reduction in lung cancer mortality, the debate on when and if to initiate a national lung cancer screening program has been at the forefront of debate. The American Lung Association and American Cancer Society have issued statements that are not guidelines, but did offer insight on the price we pay for earlier lung cancer detection and reduction in mortality…which is the increased rates of false positives detected and increased rates of biopsies.

The US Task Force on Lung Cancer Screening has yet to decide on a screening program and have yielded a statement that neither supports nor refutes the current level of evidence. Prior to the NLSRT study there were others that showed conflicting results on lung cancer screening. The PLCO Cancer Screening Trial (2) was a large randomized prospective trial that recruited 77,464 patients and used chest X-rays at yearly intervals for 3 years in patients aged 55-74. This study included nonsmokers. The results are ongoing but the preliminary data showed that a total of 564 cancers were detected with 87% as non-small cell. Further data on outcomes will be reported in 2015.

The PANCAN and BCCA Study were 2 prospective cohort studies (3) done to see which CT detected incident nodules on more likely to be malignant. The results of the 2 combined studies showed that out of the 12029 incident nodules detected only 142 were biopsy proven malignant.  Nodules were more likely to be malignant if the size was greater than 1cm, spiculated, multiple nodules, and more upper lobe predominant. In addition a nodule along the perifissure region was highly unlikely to be cancer. The study also noted that biopsy of the largest nodule was often not the malignant nodule in 20% of cases. Subsequent image with volumetric imaging may help with this.

The results of the 2 year incidence screening results (4) demonstrated that the low dose CT screening was superior to chest radiography in detecting earlier stage cancers as well as showing lower incidence rates of lung cancer when the initial CT screening was negative. The highest rates of lung cancer were detected at the T2 interval screening due detection of enlarging nodules. Overall the 2 year incidence study showed that the use of CT screening was superior to chest Radiography in detecting earlier stage non-small cell lung cancers.

The review of the prior papers yielded a healthy discussion on where do we go as clinicians in offering lung cancer screening to patients. There was a consensus that nearly all curable lung cancers have been found incidentally, and that it makes sense to have a screening process. What this screening process should be is still uncertain.  By limiting the screening option to smokers with a significant 30 pack year history and limiting the initial screening age to 55 we have set initial targets to look at.  The price of CT screening will inevitably result in higher costs and higher rates of false positives. Future algorithms will need to be adjusted to limit rates of false positives by looking more at volumetric analysis and nodule characteristics to limit unnecessary biopsies.

Manoj Mathew, MD FCCP MCCM

References

1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. [CrossRef] [PubMed]
2. Hocking WG, Hu P, Oken MM, Winslow SD, Kvale PA, Prorok PC, Ragard LR, Commins J, Lynch DA, Andriole GL, Buys SS, Fouad MN, Fuhrman CR, Isaacs C, Yokochi LA, Riley TL, Pinsky PF, Gohagan JK, Berg CD; PLCO Project Team. Lung cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. J Natl Cancer Inst. 2010;102(10):722-31. [CrossRef] [PubMed]
3. McWilliams A, Tammemagi MC, Mayo JR, Roberts H, Liu G, Soghrati K, Yasufuku K, Martel S, Laberge F, Gingras M, Atkar-Khattra S, Berg CD, Evans K, Finley R, Yee J, English J, Nasute P, Goffin J, Puksa S, Stewart L, Tsai S, Johnston MR, Manos D, Nicholas G, Goss GD, Seely JM, Amjadi K, Tremblay A, Burrowes P, MacEachern P, Bhatia R, Tsao MS, Lam S. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med. 2013;369(10):910-9. [CrossRef] [PubMed]
4. Aberle DR, DeMello S, Berg CD, Black WC, Brewer B, Church TR, Clingan KL, Duan F, Fagerstrom RM, Gareen IF, Gatsonis CA, Gierada DS, Jain A, Jones GC, Mahon I, Marcus PM, Rathmell JM, Sicks J; National Lung Screening Trial Research Team. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med. 2013;369(10):920-31. [CrossRef] [PubMed] 

Reference as: Mathew M. December 2013 Phoenix pulmonary journal club: lung cancer screening. Southwest J Pulm Crit Care. 2013;7(6):363-4. doi: http://dx.doi.org/10.13175/swjpcc180-13 PDF

November 2013 Tucson Pulmonary Journal Club: Macitentan

Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-18. [CrossRef] [PubMed]

Treatment of pulmonary arterial hypertension (PAH) with endothelin receptor antagonists (ERA) has been shown to improve exercise capacity and functional status, but not mortality. A recent systematic review found uncertainty regarding ERAs’ effects on mortality (1). Macitentan, a new molecule structurally similar to bosentan, targets endothelin-A and endothelin-B receptors, offers greater tissue penetration, and has more sustained receptor binding.

SERAPHIN was an industry-sponsored, double-blinded, randomized controlled trial which examined the effect of long-term macitentan use on PAH morbidity and mortality. Between May 2008 and December 2009, 742 patients in 39 countries were randomized to placebo, macitentan 3 mg daily, or macitentan 10 mg daily. Participants had to be ≥12 years of age with Group 1 PAH confirmed by right heart catheterization and have WHO functional class II, III, or IV heart failure. Participants taking intravenous or subcutaneous prostanoids were excluded, but other concomitant treatments were allowed. The composite endpoint of worsening of PAH (initiation of intravenous or subcutaneous prostanoids, lung transplantation, or atrial septostomy) or death from any cause was the primary endpoint. Secondary outcomes included the composite outcome of hospitalization or death due to PAH, change in 6-minute walk (6MW), improvement in WHO functional class, and adverse events.

As compared to placebo, both the 3 mg and 10 mg daily dose of macitentan were found to reduce the composite endpoint of worsening PAH or death with hazard ratios of 0.70 (CI 95% 0.52-0.96) and 0.55 (CI 95% 0.32-0.76), respectively. Both also improved the composite endpoint of hospitalization or death due to PAH, 6MW and WHO functional class. The proportions of participants with elevated liver enzymes were comparable across the 3 groups (1-5%); however, participants in the 3 mg and 10 mg macitentan groups were more likely to experience anemia, 8.8% and 13.2%, respectively, than the 3.2% of participants in the placebo group.

Treatment with macitentan significantly decreased the composite endpoint of worsening PAH or death. The major driver of this reduction was fewer instances of worsening of PAH rather than fewer deaths. Similar to previous trials, SERAPHIN fails to clearly demonstrate that ERA use reduces all cause or PAH-specific mortality. While macitentan use did appear to result in meaningful reductions in symptom burden and hospitalization, the effect on 6MW is smaller than that previously reported for other ERAs (1). Macitentan use does appear to be safe with a slightly higher risk of anemia being observed. The incremental benefit of macitentan over existing treatments is unknown.

Candy Wong, MD; Cristine Berry, MD; Joe Gerald, PhD

University of Arizona

Tucson, AZ

Reference

1. Liu C, Chen J, Gao Y, Deng B, Liu K. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD004434. DOI: 10.1002/14651858.CD004434.pub5. [CrossRef] [PubMed]

Reference as: Wong C, Berry C, Gerald J. November 2013 Tucson pulmonary journal club: macitentan. Southwest J Pulm Crit Care. 2013;7(6):349-50. doi: http://dx.doi.org/10.13175/swjpcc174-13 PDF

October 2013 Tucson Pulmonary Journal Club: Tiotropium Respimat

Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, Dusser D, Joseph E, Kattenbeck S, Koenen-Bergmann M, Pledger G, Calverley P; TIOSPIR Investigators. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369(16):1491-501. [CrossRef] [PubMed]

Tiotropium, a long-acting inhaled anticholingeric bronchodilator, is commonly used to prevent COPD exacerbations (1).  Tiotropium is available as a dry powder (HandiHaler) or aqueous solution (Respimat).  Direct comparisons of the two formulations are lacking.  Prior post-hoc analyses suggest that that Respimat may be more efficacious than HandiHaler (2) but it may also increase the risk of death, particularly among those with cardiac dysrhythmias (3-6).  

The two were recently compared in a large randomized, double-blind, parallel trial of once daily treatment with Respimat (2.5 µg or 5 µg) or HandiHaler (18 µg).[add REF here]  Inclusion criteria included a COPD diagnosis, a 10 pack year smoking history, and post-bronchodilator FEV₁/FVC ratio ≤ 0.70 and FEV₁ ≤ 70% of predicted.  Major exclusion criteria included a myocardial infarction within past 6 months, hospitalization for Class III or IV heart failure, or unstable or life-threatening arrhythmia requiring new treatment within the previous 12 months.  The primary safety outcome was all cause mortality and the primary efficacy outcome was first COPD exacerbation.  Importantly, mortality was tested using a non-inferiority approach with a pre-specified non-inferiority margin of 1.25.

Approximately 17,000 participants (71% male) were followed for a median of 2.3 years.  Their mean age was 65 years, average FEV₁ was 48% of predicted, previous ischemic heart disease was present in 15%, and previous cardiac dysrhythmia was present in 10%.  During the study, 1302 (7.6%) deaths were recorded.  The hazard ratio for all-cause mortality comparing Respimat 5 µg versus HandiHaler 18 µg (referent) was 0.96 (CI_95% 0.84-1.09) indicating that Respimat was non-inferior to HandiHaler.  The hazard ratio for first exacerbation was 0.98 (CI _95% 0.93-1.03) indicating that Respimat was not superior to HandiHaler.  While mortality among participants with prior cardiac dysrhythmias was not higher in the Respimat group, HR 0.81 (CI_95% 0.58-1.12), myocardial infarctions among the Respimat group were marginally more frequent HR 1.41 (CI_95% 0.98-2.00; p=0.06).  

Notable strengths of the study included its large, prospective, head-to-head design with double-blinding of treatment assignment.  Follow-up was lengthy and well described; loss-to-follow-up was negligible.  The non-inferiority analysis of all-cause mortality provides convincing evidence that no meaningful difference in the risk of death is likely between the two Tiotropium formulations.

Without a placebo control, this study does not provide information with regard to the potential class effect of Tiotropium on all-cause or cardiac specific mortality.  The weak (p=0.06) signal suggesting a link between Respimat and increased risk of myocardial infarction was unexpected and remains unexplained.  During our discussion, we could not identify a mechanistic pathway that might account for a differential effect of the aqueous and dry powder Tiotropium formulations.   Without a credible link, the probability of a false positive signal is high.  Nevertheless, future analyses of secondary and/or claims data looking for evidence to support a link between Respimat and ischemic events may be warranted.

Abdulmagid Eddib MD

Joe Gerald MD PhD

Cristine Berry MD

University of Arizona

Tucson, Arizona

References

1. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093-103. [CrossRef] [PubMed]
2. Asakura Y, Nishimura N, Maezawa K, Terajima T, Kizu J, Chohnabayashi N. Effect of switching tiotropium HandiHaler® to Respimat® Soft Mist™ Inhaler in patients with COPD: the difference of adverse events and usability between inhaler devices. J Aerosol Med Pulm Drug Deliv. 2013 Feb;26(1):41-5. [CrossRef] [PubMed]
3. Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomized controlled trials. BMJ 2011;342:d3215. [CrossRef] [PubMed]
4. Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;7:CD009285. [CrossRef] [PubMed]
5. Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomized controlled trials. Thorax 2013;68:48-56. [CrossRef] [PubMed]
6. Loke YK, Singh S. Risks associated with tiotropium in chronic obstructive pulmonary disease: overview of the evidence to date. Ther Adv Drug Safe 2012;3:123-31. [CrossRef] 

Reference as: Eddib A, Gerald J, Berry C. October 2013 Tucson pulmonary journal club: tiotropium Respimat. Southwest J Pulm Crit Care. 2013;7(5):313-4. doi: http://dx.doi.org/10.13175/swjpcc170-13 PDF

August, 2011 Pulmonary Journal Club

Reference as: Mathew M. August 2011 pulmonary journal club. Southwest J Pulm Crit Care 2011;3:52-3. (Click here for a PDF version)

The National Lung Screening Research Team. Reduced lung cancer mortality with low dose computed tomographic screening. N Engl J Med 2011;365:395-409.

Lung cancer remains the number one cause of cancer related deaths among men and women. It is more fatal than colon, breast and prostate cancer combined. The poor prognosis is largely due to advanced cancer stage at the time of diagnosis. More than 75% of lung cancer cases are diagnosed with a stage 2 or higher and greater than 50% are diagnosed with stage 4. The best prognosis is early stage 1 with a 5 year survival of greater than 65%. Unfortunately the large bulk of early stage 1 cases come as incidental findings when patients receive either a chest x-ray or computerized tomography scan for an unrelated evaluation. Prior studies looking at lung cancer screening with chest x-rays and sputum cytology have not been shown to improve mortality due to poor sensitivity. Prior studies with low dose computed tomography (LDCT) show markedly improved sensitivity when compared to chest x-ray but failed to show improved mortality mainly due to lack of randomization and a control group (1-7). This study performed by the National Lung Screening Research Team was to date the largest randomized, controlled trial looking at low dose computed tomography as a lung cancer screening modality. The study performed from 2002 – 2007 was to determine whether screening with low LDCT improved lung cancer mortality. Inclusion criteria were age 55-74, smoking history of 30 pack/years and former smokers who have quit within the past 15 years. Patients with a prior history of lung cancer or had a LDCT scan within the past 18 months were excluded. A total 53,454 pts were enrolled and with 26732 received screening with a chest x-ray annually for 3 years and 26722 received screening with LDCT annually for 3 years. The results showed that there were significantly more abnormalities detected in the screening LDCT scan and this led to higher rates of evaluation and subsequently showed a 20% reduction in lung cancer mortality. The number needed to screen with LDCT to prevent 1 death from lung cancer was 320 patients. To put his into perspective the number of screening colonoscopies needed to prevent 1 death is 492 and the number of screening mammographies needed to prevent 1 death from breast cancer is 1224 (8). The study was well done and it did accomplish its primary objective. Although the results look promising additional validation is needed before a mass screening program is initiated. Several factors need to be addressed on subsequent studies, mainly who does the radiographic interpretation and a detailed cost analysis. A radiologist with a special interest in chest radiology may need to be designated before a screening program is released. Furthermore we still do not know the long term effects of even low dose radiation. In the accompanying editorial by Harold Sox it was well noted that patients seeking a screening LDCT may also need additional counseling on smoking cessation. Since lung cancer remains for the most part a preventable smoking related illness an equally aggressive (if not more aggressive) approach to smoking cessation needs to be implemented in conjunction with any screening program.

Manoj Mathew, MD, FCCP MCCM

Associate Editor, Pulmonary Journal Club

References

1. Sone S, Takashima S, Li F, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351:1242-5.
2. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99-105.
3. Swensen SJ, Jett JR, Sloan JA, et al. Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med 2002;165:508-13.
4. Nawa T, Nakagawa T, Kusano S, Kawasaki Y, Sugawara Y, Nakata H. Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies. Chest 2002;122:15-20.
5. Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile lowdose spiral computed tomography scanner. Br J Cancer 2001;84:25-32.
6. Jett JR. Spiral computed tomography screening for lung cancer is ready for prime time. Am J Respir Crit Care Med 2001;163:812, discussion 814-5.
7. Diederich S, Wormanns D, Semik M, et al. Screening for early lung cancer with low-dose spiral CT: prevalence in 817 asymptomatic smokers. Radiology 2002;222:773-81.
8. Humphrey LL. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task F