October 2013 Pulmonary Journal Club: Pulmonary Artery Hypertension

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]

The October pulmonary journal club was focused on pulmonary hypertension. We reviewed a total of 5 articles on pulmonary hypertension. The 2 articles on riociguat that appeared in the New England Journal of Medicine have been reviewed and summarized in the September Pulmonary Journal Club (1-3).

Current therapies in the treatment of pulmonary hypertension have been based on their efficacy in improving exercise tolerance and 6 minute walk time. Macitentan is a new endothelin receptor antagonist that has now been approved by the FDA for the treatment of Class I pulmonary hypertension. The trial was a multicenter double-blind, placebo-controlled study. A total of 742 patients were included and divided into 3 arms (placebo, 3mg, and 10mg). Inclusion criteria were Class I pulmonary hypertension, World Health Organization (WHO) class 2-4, and confirmation of pulmonary hypertension by right heart catheterization.  Patients were excluded if they were receiving subcutaneous or IV prostacyclin therapy. Composite primary endpoints were monitored for morbidity (decrease in 6 minute walk, increase in symptoms, need for additional therapy, septoplasty, lung transplantation) and mortality. The results showed that there was a reduction in composite endpoint for morbidity but this was largely due to an improvement in 6 minute walk time. There was no significant reduction in mortality. The studying initially looks exciting in that it was a large study and the first to look at morbidity and mortality. The problem however lies in using composite endpoints in defining morbidity. By using multiple variables as 1 composite endpoint it’s easier to report a significant effect when there really is not much of one. The study is promising and the medication does show an improved exercise tolerance.  A longer term study would be more fruitful in further evaluating mortality.  Our review yielded that we would consider using this medication, but were unsure as to what tier it would fall in. Cost will likely be a prohibitive factor especially since other less expensive endothelin receptor antagonists have similar efficacy.

Minai OA, Yared JP, Kaw R, Subramaniam K, Hill NS.Perioperative risk and management in patients with pulmonary hypertension. Chest. 2013;144(1):329-40. [CrossRef] [PubMed]

Kosarek L, Fox C, Baluch AR, Kaye AD. Pulmonary hypertension and current anesthetic implications. Middle East J Anesthesiol. 2009;20(3):337-46

The perioperative care of patients with pulmonary hypertension remains a challenge with no formal guidelines on management. The above 2 articles were a review on the physiology of pulmonary hypertension, and the rationale for use of certain medications. Our review of the articles led to the consensus that our current model of practice follows that of expert opinion. We often start a PDE5 inhibitor as first line therapy preoperatively and will delay surgery in high risk patients until pulmonary hypertension management has been optimized. The main differences we encountered were in the use of pulmonary artery catheters over continuous TEE probes and whether to initiate IV prostacyclin therapy based on echo findings alone. Our practice style has been to place pulmonary artery catheters preoperatively and leave them in during the post operative period for the first 24-48hrs while medications such as inhaled nitric oxide or IV prostacyclin infusions are in use.  Echocardiograms are often misleading in identifying the severity of pulmonary hypertension, but once you identified that that a severe pulmonary hypertension scenario is present, we advocate having an experienced cardiac anesthetist and/or pulmonologist experienced with inhaled nitric oxide, IV prostacyclin therapy on standby while undergoing moderate sedation or anesthesia, and this even includes the initial right heart catheterization. Much of the perioperative management is recognizing the potential needs of the patient and having the appropriate meds and personnel available. I think it goes without saying that these patients should be managed in specialized centers.

Manoj Mathew, MD FCCP

Associate Editor

Pulmonary Journal Club

References

1. Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319-29. [CrossRef] [PubMed]
2. Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-40. [CrossRef] [PubMed] 
3. Robbins RA. September 2013 pulmonary journal club: riociguat; pay the doctor. Southwest J Pulm Crit Care. 2013;7(3):190-2. [CrossRef]

Reference as: Mathew M. October 2013 pulmonary journal club: pulmonary artery hypertension. Southwest J Pulm Crit Care. 2013;7(4):267-8. doi: http://dx.doi.org/10.13175/swjpcc146-13 PDF

September 2013 Pulmonary Journal Club: Riociguat; Pay the Doctor

Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319-29. [CrossRef] [PubMed]

Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-40. [CrossRef] [PubMed] 

Bonderman D, Ghio S, Felix SB, Ghofrani HA, Michelakis E, Mitrovic V, Oudiz RJ, Boateng F, Scalise AV, Roessig L, Semigran MJ; Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial (LEPHT) Study Group. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation. 2013;128(5):502-11. [CrossRef] [PubMed]

Three articles appeared within the past month describing clinical trials with riociguat, a new therapy for pulmonary arterial hypertension (PAH). Riociguat is a soluble guanylate cyclase stimulator. Guanylate cyclase is the enzyme that is stimulated by nitric oxide which results in arterial smooth muscle relaxation. All three trials were phase 3, multicenter, randomized, placebo-controlled studies sponsored by Bayer, the manufacturer.

In the first trial, 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy were randomized to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety. By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (P<0.001). Pulmonary vascular resistance, NT-proBNP level and WHO functional class significantly improved with riociguat.

In the second trial, 443 patients with symptomatic pulmonary arterial hypertension were randomized to received placebo or riociguat in individually adjusted doses of up to 2.5 mg three times daily. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary endpoint and the secondary endpoints were the same as in the first trial and the results were also similar. Six minute walk, pulmonary vascular resistance, NT-proBNP level and WHO functional class all significantly improved with riociguat.

The third trial studied 201 patients with pulmonary hypertension caused by systolic left ventricular dysfunction.  Currently, no treatment is approved for this indication. The primary outcome in this trial was not the 6 minute walk but the mean pulmonary artery pressure. Although there was a decrease in mean pulmonary artery pressure with riociguat, the difference was not significantly different compared to placebo (P=0.10). However, the secondary end points cardiac and stroke volume index, pulmonary vascular resistance and the Minnesota Living with Heart Failure score all significantly improved with riociguat.

In all three trials the drug was well tolerated and the side-effects were those expected which can result from systemic peripheral vasodilatation-syncope, lightheadedness, and peripheral edema.

An FDA panel of outside experts voted unanimously to approve riociguat for PAH as well as chronic pulmonary thromboembolic hypertension. The FDA seems likely accept the panel’s recommendation. The drug will be sold as Adempas.

Although we have frequently warned about over-enthusiasm with the first publications on new therapies, the results with riociguat appear promising and realistic. However, it is unclear how this drug will fit into the ever expanding armamentarium of anti-PAH drugs. Will the drug be most effective when combined with other phosphodiesterase agonists such as sidenafil or tadalafil or combined with other drugs such as endothelin receptor antagonists such as bosentan?

Petersen LA, Simpson K, Pietz K, Urech TH, Hysong SJ, Profit J, Conrad DA, Dudley RA, Woodard LD. Effects of individual physician-level and practice-level financial incentives on hypertension care: a randomized trial. JAMA. 2013;310(10):1042-50. [CrossRef] [PubMed]

Pay for performance is intended to align incentives to promote high-quality care, but results have been contradictory. The authors randomized 83 Veterans Administration (VA) physicians and 42 nonphysician personnel (nurses, pharmacists, etc) to receive individual financial incentives, practice-level incentives, both, or none for adhering to guideline-recommended care. They found that the proportion of patients who had controlled hypertension or who (appropriately) had their treatment tweaked as a result of persistent hypertension increased in all of the groups where incentives were received, but not in the group without any financial incentives. The best-performing group, and the only group where the changes reached statistical significance, was the group receiving individual pay-for-performance payments. In none of the groups did financial incentives improve use of guideline-recommended medications compared with controls. There was no increase in hypotension among patients treated in the course of the study, suggesting that overtreatment (in the hopes of more financial rewards) was not a problem. The performance gains among physicians during the pay-for-performance period of the study did not tend to last during a "washout" period when the payments were stopped.

This is a small study where the measures for the most part did not reach statistical significance. Despite these limitations, this is a welcome investigation. Pay-for-performance initiatives are part of the US Affordable Care Act. It is also heartening that the VA, which was one of the first organizations to do pay for performance back in the 1990’s, is investigating the issue. The VA initiated a pay for performance model where incentives were paid to VA administrators, not physicians, for compliance with a number of chronic disease indicators (1). Although some of the indicators were evidence-based, the evidence supporting the three that improved the most (pneumococcal vaccination, advice to quit smoking and hospital discharge instructions) could generously be described as weak (2). This points to a danger to all pay-for-performance programs, i.e., who decides on the performance standards. If the performance standards are weak or non-evidence based, it is likely that pay-for-performance will not improve patient outcomes and are a waste of money. On the other hand, if the performance standards are supported by level 1 evidence (data from >1 properly randomized controlled trial) or better, pay-for-performance shows promise to improve patient care. This article suggests that paying physicians is the best way to improve performance.

Richard A. Robbins, MD

References

1. Jha AK, Perlin JB, Kizer KW, Dudley RA. Effect of the transformation of the Veterans Affairs Health Care System on the quality of care. N Engl J Med. 2003;348(22):2218-27. [CrossRef] [PubMed]
2. Robbins RA, Klotz SA. Quality of care in U.S. hospitals. N Engl J Med. 2005;353(17):1860-1. [CrossRef] [PubMed] 

Reference as: Robbins RA. September 2013 pulmonary journal club: riociguat; pay the doctor. Southwest J Pulm Crit Care. 2013;7(3):190-2. doi: http://dx.doi.org/10.13175/swjpcc116-13 PDF

August 2013 Pulmonary Journal Club: Pneumococcal Vaccine Déjà Vu

Griffin MR, Zhu Y, Moore MR, Whitney CG, Grijalva CG. U.S. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med. 2013;369(2):155-63. [CrossRef] [PubMed]

The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) into the U.S. childhood immunization schedule in 2000 has substantially reduced the incidence of vaccine-serotype invasive pneumococcal disease in young children and in unvaccinated older children and adults. By preventing the acquisition and carriage of pneumococcus in the nasopharynx of vaccinated children, PCV7 reduced the transmission of vaccine serotypes to the unvaccinated. The authors estimated the annual rates of hospitalization for pneumonia from any cause using the Nationwide Inpatient Sample database. Average annual rates of pneumonia-related hospitalizations from 1997 through 1999 (before the introduction of PCV7) and from 2007 through 2009 (well after its introduction) were used to estimate annual declines in hospitalizations due to pneumonia. The annual rate of hospitalization for pneumonia among children younger than 2 years of age declined by 551.1 per 100,000 children. The rate for adults 85 years of age or older also declined by 1300.8 per 100,000. Overall, the authors estimated an age-adjusted annual reduction of 54.8 per 100,000, or 168,000 fewer hospitalizations for pneumonia annually.

Taken at face value this article would appear to provide convincing evidence of the efficacy of PCV7. However, the same argument was made for the 23-polyvalent pneumococcal vaccine (PPV-23) in adults. Beginning in the mid-1990’s the Veterans Administration (VA) made a large effort to increase the rates of pneumococcal vaccination which was quite successful (Figure 1) (1).

Figure 1. Percent of VA patients vaccinated with PPV-23 by year (1).

The VA touted this increase in vaccination as responsible for a decrease in inpatient admissions for pneumonia (Figure 2) (2).

Figure 2. Hospital discharges per 1000 for pneumonia by year (2).

However, what was not cited was that hospital discharges for all groups were decreasing. Furthermore, there was an increase in outpatient visits for pneumonia (Figure 3) (3).

Figure 3. Risk-adjusted rates of clinic use in patients with pneumonia in the Veterans Administration 1994 through 1998 (3).

An increase in risk-adjusted one year survival occurred for pneumonia from 1994 through 1998 which was less than 1% (p=0.02) (3). However, the improvement in survival did not correlate with the increase in pneumococcal vaccination (r=0.19, p>0.05). Most of the improvement in survival occurred between 1994 and 1995 before the dramatic increase in PPV-23 vaccination rate occurred between 1995 and 1997. It would appear that the reduction in hospital admissions was part of a trend to increase outpatient therapy. There appeared to be no clinically significant impact on the incidence or mortality.

Determinants of hospitalization for pneumonia are many as the above illustrates. Since the introduction of PCV7 in 2000, there has been a 60% increase in the vaccination of adults 65 years of age or older with pneumococcal polysaccharide vaccine and an increase of 67% in influenza (4). During this same period, the percentage of adults who smoked fell to 24% (5). There has been increasing emphasis placed on outpatient therapy for pneumonia with assessment tools such as the pneumonia severity index and CURB-65 (6). 

Despite the similarity of arguments for a decline in hospitalizations from PCV7, there is an important difference. There is strong evidence that PCV7 works in children while the efficacy of PPV-23 in adults is suspect (7,8). There is considerable year-to-year variability in the incidence of pneumonia with <5% actually diagnosed with pneumococcal disease (1). The influence of these and other factors such as influenza vaccine and variability in hospital admissions further confuse the issue (9). It may be that the authors are correct, that PCV7 does prevent pneumonia in adults.  However, presenting only the hospital admission rates without accounting for at least some of the many confounding variables makes the overall level of evidence cited in this article unconvincing.

Richard A. Robbins, MD

References

1. Jha AK, Perlin JB, Kizer KW, Dudley RA. Effect of the transformation of the Veterans Affairs Health Care System on the quality of care. N Engl J Med. 2003;348(22):2218-27. [CrossRef] [PubMed]
2. Jha AK, Wright SM, Perlin JB. Performance measures, vaccinations, and pneumonia rates among high-risk patients in Veterans Administration health care. Am J Public Health. 2007;97(12):2167-72. [CrossRef] [PubMed]
3. Ashton CM, Souchek J, Petersen NJ, et al. Hospital use and survival among Veterans Affairs beneficiaries. N Engl J Med. 2003;349(17):1637-1646. [CrossRef] [PubMed]
4. Centers for Disease Control and Prevention. Seasonal influenza (flu): vaccination trends. Available at: http://www.cdc.gov/flu/fluvaxview/trends.htm (accessed 8/30/13).
5. U.S. smoking rate still coming down. Gallup. July 24, 2008. Available at : http://www.gallup.com/poll/109048/us-smoking-rate-stillcoming-down.aspx (accessed 8/30/13).
6. Varshochi M, Kianmehr P, Naghavi-Behzad M, Bayat-Makoo Z. Correspondence between hospital admission and the pneumonia severity index (PSI), CURB-65 criteria and comparison of their predictive value in mortality and hospital stay. Infez Med. 2013;21(2):103-10. [PubMed]
7. Black SB, Shinefield HR, Ling S, Hansen J, Fireman B, Spring D, Noyes J, Lewis E, Ray P, Lee J, Hackell J. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J. 2002;21(9):810-5. [CrossRef] [PubMed]
8. Huss A, Scott P, Stuck AE, Trotter C, Egger M. Efficacy of pneumococcal vaccination in adults: a meta-analysis. CMAJ. 2009;180(1):48-58. [CrossRef] [PubMed]
9. Centers for Disease Control and Prevention. Comparability between the rates for all-listed inpatient procedures using national hospital discharge survey and Medicare claims, 1999 and 2007. September 27, 2012. Available at: http://www.cdc.gov/nchs/data/nhsr/nhsr057.pdf (accessed 8/30/13).

Reference as: Robbins RA. August 2013 pulmonary journal club: pneumococcal vaccine déjà vu. Southwest J Pulm Crit Care. 2013;7(2):131-4. doi: http://dx.doi.org/10.13175/swjpcc115-13 PDF

July 2013 Pulmonary Journal Club

Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319-32. [CrossRef] [PubMed]

Chronic Thromboembolic Disease (CTED) leading to pulmonary hypertension has an incidence of 5000 cases per year. It is estimated that up to 3% of all patients with pulmonary embolism develop CTED within 2 years of initial pulmonary embolism event.

The diagnosis of CTED is made through a ventilation perfusion scan detecting chronic thromboembolic disease. Treatment of CTED centers on anticoagulation and surgical thromboendartectomy. Thromboendartectomy is a unique procedure offered only in a few specialized centers throughout the country. Pharmacologic agents in the treatment of CTED have been ineffective except for bosentan. Bosentan, an endothelin receptor antagonist, has been shown to decrease pulmonary vascular resistance but not improve 6 minute walk time. Riociguat is a soluble guanylate cyclase stimulator, which works by increasing levels of cyclic GMP levels, resulting in vasorelaxation.

This study is a randomized double blind placebo controlled 16 week phase 3 trial evaluating the efficacy and safety of riociguat. The study was performed between 2009 – 2012 within 26 countries and 89 centers. A total of 261 patients were included in the study. Patients were excluded if they were pharmacologic agents used in the treatment of pulmonary hypertension. The primary outcome of the study was the improvement in 6 minute walk distance. Secondary outcomes included changes in pulmonary vascular resistance, N terminal BNP levels, WHO functional classification, Dyspnea severity. Medication side effect profiles were also noted.

Patients were divided into 2 groups, 88 subjects in the placebo group and 173 subjects in the treatment group. The discrepancy in sample size was based on needing 173 subjects within the treatment arm to reach a power of 90%. The dose of riociguat was adjusted between 0.5 mg to 2.5mg three times a day based on tolerance to side effects. This dose adjustment was done over the first 8 weeks and then a stable dose maintained for the next 8 weeks. At the end of the 16 weeks outcomes and safety profiles were measured.

The results showed that riociguat improved 6 minute walk distance by a mean of 39 meters as opposed to a decline of 6 meters within placebo. Secondary outcomes were also favorable showing an improvement in cardiac output while decreasing the pulmonary vascular resistance and pulmonary pressures.

The side effects included right ventricular failure in 3% and syncope in 2% of the subjects, both of which were the same in the placebo group. Two percent of patients stopped the drug due to nausea, vomiting and headache and another 2% developed hemoptysis. Two patients died in the treatment arm secondary to drug related heart failure and acute renal failure.

The study demonstrated that riociguat may offer benefit in patients ineligible for thromboendartectomy. Further studies to evaluate longitudinal benefits and safety profiles are needed.

Manoj Mathew, MD FCCP MCCM

Reference as: Mathew M. July 2013 pulmonary journal club. Southwest J Pulm Crit Care. 2013;7(1):51-2. doi: http://dx.doi.org/10.13175/swjpcc097-13 PDF

June 2013 Pulmonary Journal Club

National Lung Screening Trial Research Team, Church TR, Black WC, Aberle DR, Berg CD, Clingan KL, Duan F, Fagerstrom RM, Gareen IF, Gierada DS, Jones GC, Mahon I, Marcus PM, Sicks JD, Jain A, Baum S. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013;368(21):1980-91. [CrossRef]  [PubMed]

This paper serves as a follow up on the results of the first round of testing using low dose computed tomography in screening for lung cancer.  A full review on the initial results can be referenced from the August 2011 Pulmonary Journal Club (1).

The study was performed at 33 centers from 2002 – 2004. A total of 53454 patients were enrolled. Inclusion criteria were age 55-74 and a 30 pack-year smoking history. All patients were randomized to receive either low dose screening CT scan (LDCT) or a chest x-ray.

The results of the first year of screening showed that the LDCT group had 7191 patients with a positive result. Out of these 7191 patients 270 patients (3.75%) were diagnosed with lung cancer. In the chest x-ray group a total of 2387 patients had a positive result and 136 patients (5.7%) were diagnosed with lung cancer. There were more stage 1A cancers diagnosed in the LDCT group (132 patients) compared to the chest x-ray group (46 patients).

The results of the study support that there is a higher prevalence in stage 1A lung cancer within the LDCT screening arm. However this comes at a cost of a substantial number of false positives which often result in additional tests, procedures and costs. In addition when we look at the overall prevalence of lung cancer between the LDCT and chest x-ray groups the difference is only 1% in the LDCT group compared to 0.7% in the chest x-ray group.  

Further information as the screening process continues will be needed to see if CT scanning is cost effective in screening for lung cancer.

Manoj Mathew, MD MCCM, FCCP

Reference

1. Mathew M. August 2011 pulmonary journal club. Southwest J Pulm Crit Care. 2011;3:52-3.

Reference as: Mathew M. June 2013 pulmonary journal club. Southwest J Pulm Crit Care. 2013;6(6):308. doi: http://dx.doi.org/10.13175/swjpcc086-13 PDF