[Black Square] SILDENAFIL TO IMPROVE RESPIRATORY REHABILITATION OUTCOMES IN COPD: A CONTROLLED TRIAL
Blanco I, Santos S, Gea J, et al
ERJ Express. Published online first March 21, 2013, doi:10.1183/09031936.00176312.
Rationale: Pulmonary hypertension is a serious complication of COPD that currently has no established pharmacological treatment.
Objective: To assess whether concomitant treatment with sildenafil would enhance the results of pulmonary rehabilitation in patients with COPD and increased pulmonary arterial pressure (PAP).
Methods: Double-blind, randomised, controlled trial. Patients received 20 mg sildenafil or placebo t.i.d. and underwent pulmonary rehabilitation for 3 months. The primary endpoint was the gain in the cycle endurance time at a constant work-rate. Secondary endpoints included performance in the incremental exercise test, six-minute walk distance and quality of life.
Results: 63 patients with severe COPD and moderately increased PAP were randomised. Cycle endurance time increased by 149 seconds (95% CI, 26-518) in the sildenafil group and by 169 seconds (95%CI, 0-768) in the placebo group (median change difference, -7 seconds (95%CI, -540-244; p = 0.77). Gains in the incremental exercise test, six-minute walk distance and quality of life at the end of the study did not differ between groups. Measurements of arterial oxygenation and adverse events were similar in both groups.
Conclusions: In patients with severe COPD and moderately increased PAP, concomitant treatment with sildenafil does not improve the results of pulmonary rehabilitation in exercise tolerance.
Editor's Comment: The presence of pulmonary arterial hypertension (PAH) is considered both common and important in patients with chronic obstructive pulmonary disease (COPD). Whether it is merely a consequence of the lung disease or has an independent component is somewhat unclear, and there is certainly a group of patients who have pulmonary arterial pressures that are disproportionately worse than the severity of COPD may predict. In these patients there may be a rational basis for targeting the PAH, but in the usual patient, with moderate/severe COPD and mild/moderate PAH, treatment directed at reducing pulmonary pressures may be on less firm physiological footing. In fact, and this has been observed, some patients will have a worsening in their oxygenation on treatment, a not surprising consequence of trying to override hypoxic pulmonary vasoconstriction.
The present study reports on the effects on the exercise performance of patients with moderate/severe COPD and moderate PAH, when treatment with sildenafil, a commonly used and usually well tolerated agent, is added to a pulmonary rehabilitation program. The first observation is that echocardiographic (or right heart catheterization) pulmonary hypertension was present in just under a third of screened patients (92 with PAH from a total of 289 screened). The 63 who were eventually randomized to sildenafil or placebo were well matched in COPD and PAH severity. After 3 months of treatment with sildenafil or placebo, and 36 sessions of pulmonary rehabilitation, there was no meaningful difference between the groups in either the primary endpoint-cycle endurance time-or in any of the other ones-6 minute walk distance, incremental exercise test, and quality of life measures. No oxygenation issues arose in those on the active drug, and the overall side effect profile was as expected. Importantly, no reassessment of pulmonary arterial pressures was repeated.
In a limited way, this establishes a lack of benefit from using sildenafil in such patients. However, this does not address the possibility that more severe PAH may behave differently (and based on clinical anecdotes, this may be for better or worse) and also fails to establish whether there may be a dose-effect relationship that a fixed dosing of 20 mg three times a day may miss. Since the impact on the primary target of the drug, pulmonary arterial pressure, was not assessed at study end, there is no way of saying whether the PAH was adequately treated; this leaves unanswered the question of whether that was the reason for the lack of difference between the 2 groups.-SK
[Black Square] SYSTEMATIC REVIEW OF SUPERVISED EXERCISE PROGRAMS AFTER PULMONARY REHABILITATION IN INDIVIDUALS WITH COPD
Beauchamp MK, Evans R, Janaudis-Ferreira T, et al
Chest. Published online first February 21, 2013, doi:10.1378/chest.12-2421.
Background: The success of pulmonary rehabilitation (PR) is established, but how to sustain benefits over the long-term is less clear. The aim of this systematic review was to determine the effect of supervised exercise programs after primary PR on exercise capacity and health-related quality of life (HRQL) in individuals with COPD.
Methods: Randomized controlled trials (RCTs) of post-rehabilitation supervised exercise programs versus usual care for individuals with COPD were identified after searches of six databases and reference lists of appropriate studies. Two reviewers independently assessed study quality. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated using a fixed-effect model for measures of exercise capacity and HRQL.
Results: Seven RCTs, with a total of 619 individuals with moderate to severe COPD, met the inclusion criteria. At 6-months follow-up there was a significant difference in exercise capacity in favor of the post-rehabilitation interventions (SMD -0.20, 95%CI - 0.39 to -0.01), which was not sustained at 12 months (SMD -0.09 95%CI -0.29 to 0.11). There was no difference between post-rehabilitation interventions and usual care with respect to HRQL at any time-point.
Conclusions: Supervised exercise programs after primary PR appear to be more effective than usual care for preserving exercise capacity in the medium-term but not the long-term. In this review, there was no effect on HRQL. The small number of studies precludes a definitive conclusion as to the impact of post rehabilitation exercise maintenance on longer term benefits in individuals with COPD.
Editor's Comment: The issue of sustaining the benefits of pulmonary rehabilitation (PR) beyond the duration of the program itself remains vexatious. Several studies have shown that primary PR gains usually tend to dissipate by 6 months, although some have reported effects for somewhat longer. Keeping patients committed to a lifestyle that includes regular exercise has been difficult, and the real-life benefit of such maintenance exercise programs has been hard to prove. Randomized, controlled data are sparse and the present report is a systematic review of studies looking at PR maintenance programs that included at least 1 session a month of supervised exercise for >= 6 months. Only 7 trials were found to satisfy even this low exercise frequency threshold. They included 619 subjects with moderate to severe chronic obstructive pulmonary disease and showed that extended PR did provide some exercise advantage out to 6 months. Beyond that, and this may be a study design issue more than anything else, there was little to show in terms of exercise performance or health related quality of life.
Rather than see this as a disappointing outcome, I think the correct interpretation has to hinge on the nature of extended interventions after primary PR is completed. Once a month interventions for 6 months are predictably unlikely to produce a measurable impact and meaningful interventions likely have to contain much more. The problem in implementing longer term programs is of course one of resource constraint; perhaps the future lies in programs that can find cost-effective interventions that motivate and enable patients to exercise, perhaps with remotely delivered encouragement coupled with monitoring.-SK
[Black Square] 21ST-CENTURY HAZARDS OF SMOKING AND BENEFITS OF CESSATION IN THE UNITED STATES
Jha P, Ramasundarahettige C, Landsman V, et al
N Engl J Med. 2013;368(4):341-350.
Background: Extrapolation from studies in the 1980s suggests that smoking causes 25% of deaths among women and men 35 to 69 years of age in the United States. Nationally representative measurements of the current risks of smoking and the benefits of cessation at various ages are unavailable.
Methods: We obtained smoking and smoking-cessation histories from 113,752 women and 88,496 men 25 years of age or older who were interviewed between 1997 and 2004 in the U.S. National Health Interview Survey and related these data to the causes of deaths that occurred by December 31, 2006 (8236 deaths in women and 7479 in men). Hazard ratios for death among current smokers, as compared with those who had never smoked, were adjusted for age, educational level, adiposity, and alcohol consumption.
Results: For participants who were 25 to 79 years of age, the rate of death from any cause among current smokers was about three times that among those who had never smoked (hazard ratio for women, 3.0; 99% confidence interval [CI], 2.7 to 3.3; hazard ratio for men, 2.8; 99% CI, 2.4 to 3.1). Most of the excess mortality among smokers was due to neoplastic, vascular, respiratory, and other diseases that can be caused by smoking. The probability of surviving from 25 to 79 years of age was about twice as great in those who had never smoked as in current smokers (70% vs. 38% among women and 61% vs. 26% among men). Life expectancy was shortened by more than 10 years among the current smokers, as compared with those who had never smoked. Adults who had quit smoking at 25 to 34, 35 to 44, or 45 to 54 years of age gained about 10, 9, and 6 years of life, respectively, as compared with those who continued to smoke.
Conclusions: Smokers lose at least one decade of life expectancy, as compared with those who have never smoked. Cessation before the age of 40 years reduces the risk of death associated with continued smoking by about 90%.
[Black Square] 50-YEAR TRENDS IN SMOKING-RELATED MORTALITY IN THE UNITED STATES
Thun MJ, Carter BD, Feskanich D, et al
N Engl J Med. 2013;368(4):351-364.
Background: The disease risks from cigarette smoking increased in the United States over most of the 20th century, first among male smokers and later among female smokers. Whether these risks have continued to increase during the past 20 years is unclear.
Methods: We measured temporal trends in mortality across three time periods (1959-1965, 1982-1988, and 2000-2010), comparing absolute and relative risks according to sex and self-reported smoking status in two historical cohort studies and in five pooled contemporary cohort studies, among participants who became 55 years of age or older during follow-up.
Results: For women who were current smokers, as compared with women who had never smoked, the relative risks of death from lung cancer were 2.73, 12.65, and 25.66 in the 1960s, 1980s, and contemporary cohorts, respectively; corresponding relative risks for male current smokers, as compared with men who had never smoked, were 12.22, 23.81, and 24.97. In the contemporary cohorts, male and female current smokers also had similar relative risks for death from chronic obstructive pulmonary disease (COPD) (25.61 for men and 22.35 for women), ischemic heart disease (2.50 for men and 2.86 for women), any type of stroke (1.92 for men and 2.10 for women), and all causes combined (2.80 for men and 2.76 for women). Mortality from COPD among male smokers continued to increase in the contemporary cohorts in nearly all the age groups represented in the study and within each stratum of duration and intensity of smoking. Among men 55 to 74 years of age and women 60 to 74 years of age, all-cause mortality was at least three times as high among current smokers as among those who had never smoked. Smoking cessation at any age dramatically reduced death rates.
Conclusions: The risk of death from cigarette smoking continues to increase among women and the increased risks are now nearly identical for men and women, as compared with persons who have never smoked. Among men, the risks associated with smoking have plateaued at the high levels seen in the 1980s, except for a continuing, unexplained increase in mortality from COPD.
[Black Square] BUPROPION FOR SMOKING CESSATION IN PATIENTS HOSPITALIZED WITH ACUTE MYOCARDIAL INFARCTION: A RANDOMIZED, PLACEBO-CONTROLLED TRIAL
Eisenberg MJ, Grandi SM, Gervais A, et al
J Am Coll Cardiol. 2013;61(5):524-532.
Objectives: The purpose of this study was to examine smoking cessation rates among smokers with AMI to determine whether bupropion, started in-hospital, is safe and can improve cessation rates at 1 year.
Background: Bupropion doubles quit rates in otherwise healthy smokers and patients with stable cardiovascular disease. Although 2 previous trials examined the use of bupropion in patients hospitalized with acute cardiovascular disease, these studies have been inconclusive with respect to its safety and efficacy in patients with acute myocardial infarction (AMI).
Methods: We conducted a multicenter, double-blind, placebo-controlled, randomized trial in smokers hospitalized with AMI. Participants received bupropion or placebo for 9 weeks and were followed for 12 months. Both groups received low-intensity counseling. Point prevalence abstinence was assessed by 7-day recall and biochemical validation of expired carbon monoxide.
Results: A total of 392 patients were randomized (mean age 53.9 +/-10.3 years); 83.5% were male; 64.9% had ST-segment elevation myocardial infarction). Patients smoked a mean of 23.2 +/- 10.6 cigarettes/day for a mean of 32.9 +/- 12.4 years. At 12 months, point prevalence abstinence rates were 37.2% in the bupropion group and 32.0% in the placebo group (p = 0.33;% difference after adjusting for between center differences 3.9%). Continuous abstinence rates were 26.8% and 22.2%, respectively (p = 0.34). Major adverse cardiac event rates were similar (13.0% vs. 11.0%, respectively; p = 0.64).
[Black Square] EDITORIAL COMMENT: SMOKING CESSATION AFTER ACUTE MYOCARDIAL INFARCTION
Benowitz NL, Prochaska JJ
J Am Coll Cardiol. 2013;61(5):533-535.
[Black Square] PUBLIC HEALTH: THE BENEFITS AND CHALLENGES OF SMOKING CESSATION
Cully, M
Nat Rev Cardiol. 2013;10(3):117, doi:10.1038/nrcardio.2013.17.
Editor's Comment: I have included a more-than-usual 3 abstracts and 2 editorials in this month's column. The 3 research articles are dense with data and research methodology and are worth reading. The 2 editorials summarize the state of the research literature on smoking cessation (and smoking, for that matter) and provide the practitioner with practical, "doable" advice on smoking cessation for patients in outpatient cardiac rehabilitation programs. My hope is that you will read the editorials and that it will make you go to the articles and read them too. The first editorial (only by chronology) is the one published in the Journal of the American College of Cardiology by Benowitz and Prochaska, 2 prominent names from the research literature on nicotine addiction and behavior change science, as well as prominent voices in public health policy making in those specialties as they relate to public health policy. The authors conclude with 4 recommendations that seem sound and doable.
1. Effective counseling in the hospital for all smokers, and not just the minority who are ready to quit. Hospital-based cessation treatment needs to be proactive, tailored to readiness to quit, progressive in use of nicotine replacement for the management of withdrawal symptoms, and focused on gaining buy-in and building rapport for continued treatment and patient adherence posthospitalization.
2. Effective transition from inpatient to outpatient smoking cessation treatment, with a minimum of 1-month followup and preferably longer.
3. Personalized prescription of medication, intended to relieve withdrawal symptoms in all patients and to support long-term cessation in patients motivated to quit.
4. Management of co-occurring mental health conditions, such as depression, that are known to be triggers for smoking relapse and predictive of mortality after cardiovascular events.
It is clear that smoking cessation is an extremely complex behavioral and biochemical milieu. It is difficult for patients and professionals to deal with effectively, and the habit has a long history of being resistant to change. Long-term (>1 year) recidivism rates have been reported to be in excess of 80% to 90%, which confirms the difficulties involved a health habit that is chemically and behaviorally addictive; thus, there is little chance that a single mode of therapy will work. There is much to learn about how we can encourage smoking cessation, when to do so, what kinds of assistance should be tailored to smokers, how to asses those needs, and what the missing pieces to the puzzle are. Though the job is nowhere near complete, the editorials (particularly) will help health care professionals to better understand the problem and offer practical strategies that may enhance efficacy.-JR