Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD

From the Hospital of the Universities of Giessen and Marburg, Marburg (C.V.); Boehringer Ingelheim, Ingelheim (B.H., T.G., H.S.); and insaf Respiratory Research Institute, Wiesbaden (K.M.B.) — all in Germany; the Institute for Medical Technology Assessment (IMTA), Erasmus University, Rotterdam (M.P.M.H.R.-M.); and Leiden University Medical Center, Leiden (K.F.R.) — both in the Netherlands; and the University of Modena and Reggio Emilia, Modena, Italy (L.M.F.). Address reprint requests to Dr. Fabbri at the Section of Respiratory Diseases, Department of Oncology, Hematology, and Pulmonary Diseases, University of Modena and Reggio Emilia, Policlinico di Modena, Largo del Pozzo 71, I-41124 Modena, Italy, or at leonardo.fabbri@unimore.it.

acerbation occurred. The times to first exacerbation were 187 and 145 days in the tiotropium and salmeterol groups, respectively, which corresponded to a 17% reduction in risk with tiotropium. Compared with salmeterol, tiotropium reduced the risk of moderate and of severe exacerbations by 14% and 28%, respectively. It also reduced the risk of exacerbations that required treatment with systemic glucocorticoids by 23%, those leading to treatment with antibiotics by 15%, and those leading to treatment with both classes of drugs by 24%. The annual rates of exacerbations were 0.64 for tiotropium and 0.72 for salmeterol, that is, an 11% reduction in the rate with tiotropium, which also reduced the annual rate of moderate and severe exacerbations by 7% and 27%, respectively. The effects of tiotropium compared with salmeterol were consistent across prespecified subgroups based on age, sex, smoking status, severity of COPD, and use or not of inhaled glucocorticoids at baseline. A serious adverse event was reported by 545 patients (14.7%) and 606 patients (16.5%) in the tiotropium and salmeterol groups, respectively. The most common serious adverse event was an exacerbation of COPD, occurring in 270 patients (7.3%) receiving tiotropium and 335 (9.1%) given salmeterol. Seventy patients in the tiotropium group and 88 in the salmeterol group had radiologically confirmed pneumonia. Sixty-four patients in the tiotropium group and 78 patients in the salmeterol died during the 360 days of the study (including deaths among patients who had withdrawn from the study prematurely and whose status was known at 360 days).
Although long-term trials have shown that both drugs reduce the rate of exacerbations, this study showed that tiotropium substantially increased the time to the first moderate or severe exacerbation of COPD and decreased the annual rate of exacerbations among this cohort of patients. These data might offer clinicians information on which to base their choice of longacting bronchodilator therapy for patients needing maintenance treatment of COPD.

COMMENT
The Prevention of Exacerbations With Tiotropium in COPD trial was specifically designed to directly compare the effects of tiotropium with salmeterol on the risk of moderate and severe exacerbations. A placebo group was not included in the current study because there is substantial evidence for the superiority of both tiotropium and salmeterol over placebo.
In patients with persistent symptoms of COPD, long-acting bronchodilators provide more uniform relief than shorter-acting agent such as albuterol. Currently, there are 2 classes of longacting bronchodilators available: long-acting A 2 -agonists and long-acting anticholinergic agents of which salmeterol and tiotropium, respectively, are examples. The current results demonstrated that, in patients with moderate to very severe COPD (those with a forced expiratory volume in 1 second [FEV 1 ] of e70% of predicted), tiotropium is more effective than salmeterol in preventing exacerbations.
It is important to underscore, however, that this trial was not a direct comparison of a long-acting A 2 -agonist with a longacting anticholinergic agent because concomitant medications were allowed. 1 Indeed, more than 50% of the patients were regularly taking inhaled glucocorticoids to reduce exacerbations.
Moreover, there is no evidence for the superiority of tiotropium in patients with mild COPD (those with an FEV 1 970% of predicted) or symptomatic patients with moderate COPD but without a history of exacerbations. Indeed, in patients with progressive COPD, combinations of inhaled long-acting A 2 -agonists, long-acting anticholinergic agents, glucocorticoids, and new antiinf lammatory agents such as oral phosphodiesterase 4 inhibitors may be beneficial. Future studies should explore which therapies and combinations are optimal for which COPD phenotypes and disease severities to better manage this debilitating disease. C igarette smoking by surgical patients increases the risk of perioperative complications, and impending surgery offers clinicians a teachable moment to assist patients in quitting smoking. A telephone quitline that provides counseling support is efficacious in helping smokers quit, but most are currently underused. However, few patients receive smoking cessation interventions before undergoing surgery. This study developed and tested a clinician-delivered intervention to increase quitline use by adult patients scheduled for elective surgery.
Initially, a brief (È5-min) quitline intervention was developed and assessed by clinicians and a focus group of surgeons and anesthesiologists. From this, the prototype intervention was developed and included the following: advice to quit smoking for as long as possible before and after surgery, with emphasis on avoiding cigarettes the morning of surgery; a description of quitline services; and distribution of a brochure with pertinent information and telephone numbers. A control standard brief stop-smoking intervention was a comparator, with both interventions delivered by clinicians. These were evaluated in a randomized trial of 300 adults scheduled for elective surgery. The primary outcome was the rate of use of a quitline accessed through a dedicated toll-free number, with use defined as completing at least 1 full counseling session. Secondary outcomes included self-reported abstinence from cigarettes at 30 and 90 days postoperatively.
Of the 300 patients, 149 received the quitline, and 151 received the comparison intervention information in the Preoperative Evaluation Center (POE). All patients underwent the scheduled surgery. The groups did not differ in baseline characteristics. The median time from POE assessment to surgery was 1 day. At the baseline assessment in the POE, 109 (73.2%) in the quitline group and 111 (73.5%) in the control group were planning to abstain from cigarettes for some length of time after hospital discharge. A total of 258 patients had made at least 1 previous attempt to quit smoking. At the assessment the morning of surgery, the groups did not differ in the time from last cigarette to the assessment, the exhaled carbon monoxide concentration, or the proportion who reported abstinence since the baseline assessment. By 30 days postoperatively, 22 patients in the quitline group and 2 in the control group reported having received quitline counseling. At 90 days after surgery, 29 quitline patients (19.5%) and 4 control patients (2.6%) self-reported having received quitline counseling. Records from the quitline documented that 29 patients in the quitline group and 0 patients in the control group completed the first full counseling session, suggesting that control patients contacted a different quitline service or did not accurately report their experience. Satisfaction with quitline services was high; 87.1% of those who used it reported it as either excellent or very good, reported that it was a useful aid to help them quit smoking, and would recommend it to other surgical patients. At 30 and 90 days, no differences were found in the self-reported point prevalent and continuous abstinence rates between the groups, although rates tended to be higher in the patients in the quitline intervention group.
Clinicians can effectively increase quitline access by surgical patients preoperatively with this brief intervention. The feasibility of this approach could potentially aid patients in their efforts to quit smoking before and after surgery. Additional studies are needed to evaluate the efficacy of this approach regarding long-term abstinence from cigarette smoking.

COMMENT
In addition to its deleterious effects on long-term health, cigarette smoking by surgical patients increases the risk of such perioperative complications as wound infections, pneumonia, and respiratory failure. A surgical operation can be a highly motivating event in terms of offering an impetus to adopt safer health behaviors. Moreover, there are numerous opportunities for clinicians in the perioperative period to deliver tobacco interventions to their patients.
The current investigation showed that it is efficacious for clinicians to facilitate quitline use by surgical patients using a brief intervention, with approximately 1 in 5 smokers accessing quitline counseling services. Nevertheless, the authors appropriately underscore that their results are limited to patients seen in only 1 preoperative clinic 1 day before surgery. Hence, the results may not apply to other settings and circumstances. Another limitation was that the study was insufficiently powered to evaluate abstinence outcomes, and biochemical validation of smoking status was not performed. Clearly, additional work is needed to evaluate the effectiveness of the described approach in terms of long-term abstinence from cigarette smoking. C urrent perioperative management practices are unclear for children with sickle cell disease, who often undergo surgical procedures associated with acute exacerbations of the disease. An electronic survey was conducted of North American members of the Society for Pediatric Anesthesia in which respondents were asked about their perioperative management of the disease. The response rate to valid addresses was 25% (n = 510/2006). In 4 scenarios (a patient with mild disease undergoing a minor procedure, a patient with mild disease undergoing a more invasive procedure, a patient with severe disease undergoing a minor procedure, and a patient with severe disease undergoing a more invasive procedure), 80%, 38%, 27%, and 16% of respondents, respectively, would rely on oral f luids to hydrate patients during the perioperative fast, whereas 13%, 34%, 44%, and 59%, respectively, would use intravenous f luid. Using the same 4 scenarios, 64%, 28%, 33%, and 10%, respectively, would not transfuse patients in an effort to avert sickle cell exacerbations, and 17%, 49%, 36%, and 51%, respectively, would transfuse to a hemoglobin (Hgb) concentration of 10 g/dL. The likelihood of administering intravenous f luid and transfusing blood increased with the severity of the disease and the invasiveness of the procedure. Although 89% felt comfortable managing patients with sickle cell disease, 73% thought an advisory statement on optimal perioperative man-agement was needed. Management of children with sickle cell disease varies widely, and clinicians differentiate management on the basis of disease severity and type of procedure.

COMMENT
The perioperative management of pediatric patients with sickle cell disease remains a challenge. Variability in disease severity, procedural risk, and clinical practice leaves numerous unanswered questions. Just to name a fewVwhat is the optimal Hgb? To what extent should disease severity and procedural complexity determine the optimal Hgb and perioperative management? How should surgeons, anesthesiologists, and hematologists weigh the risks of blood transfusion against sickle cell crisis and perioperative morbidity? Firth et al present an interesting survey on perioperative management of sickle cell disease that intentionally asks more questions than it answers.
The authors sent questionnaires to members of the Society for Pediatric Anesthesia to determine relationships involving sickle cell disease severity, procedural complexity, and perioperative management in terms of transfusion threshold, f luid management, and postprocedural care. They found that aggressive intravenous hydration and blood transfusion (Hgb 910 mg/dL) correlated with both increasing sickle cell disease severity and procedural complexity. Despite these correlations, the authors acknowledge considerable variability in clinical practice among respondents. When confronted with a severe sickle cell patient scheduled for an invasive procedure, 51% of respondents would transfuse to an Hgb of 10 mg/dL, whereas the remaining 49% would defer transfusion. The authors astutely mention the large randomized trial in Britain underway that randomizes sickle cell patients to aggressive versus conservative preoperative transfusion regimens. A randomized trial could potentially answer many questions; however, generalizing the results may prove challenging in light of the diversity of management strategies for sickle cell disease. Quite possibly, answering these questions will require a multicenter international trialVor at least adherence to previously established guidelines for management of sickle cell disease.

Comment by Christopher Stemland, MD
Disclosure: The author declares no conf lict of interest.