Harold S. Nelson, M.D.. National Jewish ... Wechsler ME, Lehman E, Lazarus SC, Lemanske RF Jr, Boushey HA,. Deykin A .... Bradley TD, Floras JS. Obstructive ...
650
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
vided support for ATS activities. A.H.E. is a full-time employee of GlaxoSmithKline; she holds $1,001–$5,000 of GlaxoSmithKline stock. H.G.O. is a full-time employee of GlaxoSmithKline; he owns $10,001–$50,000 in GlaxoSmithKline stock.
3.
Eugene R. Bleecker, M.D. Wake Forest University Health Sciences Winston Salem, North Carolina Harold S. Nelson, M.D. National Jewish Health Denver, Colorado
4.
Monica Kraft, M.D. Duke University Medical Center Durham, North Carolina
5.
Jonathan Corren, M.D. Allergy Medical Clinic, Inc. Los Angeles, California
6.
7.
Deborah A. Meyers, Ph.D. Wake Forest University Health Sciences Winston Salem, North Carolina Steven W. Yancey, M.S. Wayne H. Anderson, Ph.D. Amanda H. Emmett, M.S. Hector A. Ortega, M.D., Sc.D. GlaxoSmithKline Research Triangle Park, North Carolina
8.
9.
10.
References 1. Martinez FD, Fabbri LM. Genetics, ethics, and the use of long-acting b-adrenergics to treat asthma. Am J Respir Crit Care Med 2010;181: 647–648. 2. Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM, Cooper DM, Fahy JV, Fish JE, Ford JG, et al. The effect of polymorphisms of the b2-adrenergic receptor on the re-
11.
VOL 181
2010
sponse to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000;162:75–80. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, Deykin A, Fagan JK, Fahy JV, Fish J, et al.; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;364:1505– 1512. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term beta agonist use: influence of b(2) adrenoceptor polymorphism. Thorax 2000;55: 762–767. Joos L, Sandford AJ. Genotype predictors of response to asthma medications. Curr Opin Pulm Med 2002;8:9–15. Lipworth BJ, Hall IP, Aziz I, Tan KS, Wheatley A. b2-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting b2-agonist therapy. Clin Sci 1999;96:253– 259. Wechsler ME, Lehman E, Lazarus SC, Lemanske RF Jr, Boushey HA, Deykin A, Fahy JV, Sorkness CA, Chinchilli VM, Craig TJ, et al.; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. b-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006;173:519– 526. Bleecker ER, Yancey SW, Baitinger LA, Edwards LD, Klotsman M, Anderson WH, Dorinsky PM. Salmeterol response is not affected by b2-adrenergic receptor genotype in subjects with persistent asthma. J Allergy Clin Immunol 2006;18:809–816. Bleecker ER, Postma DS, Lawrence RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to longacting b2-agonists therapy: a pharmacogenetic analysis of two randomised studies. Lancet 2007;370:2118–2125. Taylor DR, Hall IP. ADRB2 polymorphisms and b2 agonists. Lancet 2007;370:2075–2076. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15–26.
DOI: 10.1164/rccm.200912-1891ED
Control of Hypertension in Nonsleepy Patients with Obstructive Sleep Apnea In this issue of the Journal (pp. 718–726), Barbe´ and colleagues describe the results of a multicenter study aimed at exploring the long-term effects of continuous positive air pressure (CPAP) ventilation on hypertension control in patients with obstructive sleep apnea (OSA) (1). The demonstration of a close link between OSA and hypertension has been provided by longitudinal investigations supporting the hypothesis of a causal link between OSA and the appearance or worsening of a high blood pressure condition (2, 3). Based on such data, the presence and severity of repeated airway obstruction during sleep may represent an independent risk factor for a persistent increase in blood pressure values often associated with a loss of the typical ‘‘dipping’’ pattern during ambulatory blood pressure monitoring (4, 5). The mechanisms responsible for hypertension in OSA are only partly understood. Alterations in autonomic responses, with increased sympathetic activity secondary to chemoreflex stimulation by repeated hypoxemia, have been reported to play an important role, together with disruption of ventilatory mechanics, activation of inflammatory processes, endothelial dysfunction, and alterations in arousal mechanisms (2, 6, 7). In particular, the occurrence of autonomic dysfunction in OSA has
been demonstrated through assessment of plasma and urinary catecholamines as well as microneurographic recordings from peroneal nerves. Alterations in autonomic cardiovascular modulation in OSA have also been shown through time and frequency domain computer analysis of continuous blood pressure and heart rate tracings, obtained either during wakefulness or sleep (8–10). Alterations in cardiac autonomic function, as quantified by heart rate variability and spontaneous baroreflex sensitivity analysis, seem to be particularly pronounced in patients with OSA affected by daytime somnolence (11), suggesting that daytime sleepiness may represent an additional factor increasing the likelihood of developing hypertension in patients with OSA. OSA-related hypertension is often difficult to control pharmacologically (12). Indeed, recent hypertension management guidelines (e.g., JNC VII and ESH-ESC 2007 recommendations) highlight OSA as an important identifiable cause of resistant hypertension (13, 14). Although anti-hypertensive treatment may not easily control hypertension in patients with OSA, treatment of nocturnal apnea episodes with CPAP ventilation has been suggested to reduce blood pressure. However, it is still unclear whether the benefits of CPAP treatment in terms of hypertension
Editorials
control are evident in all patients with OSA or whether they may be restricted to as yet poorly defined subgroups. An analysis of the results of available studies on the cardiovascular effects of CPAP in patients with OSA underlines a number of methodological problems that may have affected the results (Table 1). First, the sample size of these studies is variable, ranging from less than fifty up to several hundred patients. Second, CPAP-treatment duration is widely different among studies, ranging from 1 night to more than 1 year. Such discrepancy is particularly relevant due to the limited information so far available on the minimum time needed to observe a significant reduction in blood pressure with CPAP therapy and on whether the obtained blood pressure reduction persists over a long term. Third, although most studies have assessed the blood pressure effects of treatment selectively during wakefulness, only a few have extended such evaluation to the night sleep period. Important issues in the precise assessment of the lowering effects of CPAP on blood pressure are also related to the use of different methods for blood pressure measurement. Indeed, whereas most trials have focused on isolated and often inaccurate office blood pressure measurements, only a few studies so far have made use of more reliable and reproducible methods such as home and 24-h ambulatory monitoring, the latter carrying the unique advantage of allowing blood pressure measurements to be taken also at night, i.e. during a time period when blood pressure is of acknowledged prognostic relevance (13). Fourth, the interpretation of data on the blood pressure lowering effect of CPAP in hypertensive subjects is often difficult because of interference by concomitant antihypertensive therapy. Finally, limited information is available on the possible interaction between genetic background and blood pressure reduction following CPAP treatment (15–18). Despite all of these methodological difficulties, recent metaanalyses have demonstrated a general positive effect of CPAP treatment on blood pressure reduction in patients with OSA. In particular, a significant decrease in blood pressure has been observed in patients with so-called refractory hypertension (i.e., increased blood pressure persisting despite administration of more than three antihypertensive drugs), in patients with severe OSA at baseline, and in those with satisfactory daily compliance with CPAP (15–18). Evidence is also available that CPAP may contribute to reduce daytime somnolence and may facilitate normalization of autonomic cardiovascular control (19), endothelial function, and inflammatory markers (2, 19). However, it is still matter of debate whether CPAP is equally effective in reducing blood pressure in hypertensive OSA patients with or without daytime somnolence and with different degrees of hypertension. An interesting feature of the multicenter-controlled trial by Barbe´ and colleagues (1) is represented by its focus on the blood pressure effect of 1-year CPAP treatment in asymptomatic hypertensive patients with OSA, that is, in those without sleepiness during the daytime. The authors conclude that in nonsleepy OSA patients with hypertension, CPAP had no effect on blood pressure after 3 months of treatment, whereas a small but significant reduction in blood pressure (22.21 mm Hg systolic and 22.89 mm Hg diastolic pressure) was observed after 1 year of treatment. This data suggests that, in nonsleepy patients, the reduction in blood pressure achieved by CPAP is less than in sleepy patients and needs more time to become manifest. Although focus on patients with OSA without daytime somnolence and long-term follow-up are important positive features of the present study, some of its limitations should also be considered carefully. As this is a retrospective analysis of data previously collected in a larger group of subjects, the post-hoc selection of patients because of their elevated blood pressure at baseline might have interfered with a balanced
651 TABLE 1. FACTORS AFFECTING BLOOD PRESSURE (BP) REDUCTION BY CONTINUOUS POSITIVE AIRWAY PRESSURE (CPAP) TREATMENT IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA (OSA) d d d d d d d d d
Presence or absence of daytime sleepiness in association with OSA OSA severity Blood pressure levels before treatment Resistant hypertension Patients’ age and gender Duration of treatment (short vs long follow-up) CPAP proper titration Patients’ compliance with CPAP treatment Methods of BP measurement (conventional measurements vs home or ambulatory BP monitoring)
randomization between the active treatment and the control subgroups, as suggested by the fact that the CPAP group had a more severe OSA at baseline. Moreover, in this study, only blood pressure measurements obtained at the time of planned clinic visits by nurses not blinded to the subjects’ condition were considered. Clinic blood pressure measurements are known to be affected by problems such as a ‘‘white coat effect,’’ observer bias, digit preference, limited reproducibility, and intrinsic inaccuracy of the auscultatory technique, which may have reduced the reliability of the changes in blood pressure observed during follow-up in this study. Adoption of more objective and reproducible blood pressure measurement techniques, such as home or ambulatory monitoring, would have strengthened the conclusions of this study, in the latter case also by adding information on night-time blood pressure changes. Despite these limitations, the study by Barbe´ and colleagues (1) has the merit to draw the attention of both clinicians and investigators to the fact that asymptomatic patients with OSA and hypertension may benefit from regular and long-term CPAP treatment. Moreover, the results of this study suggest that apparent lack of effects on blood pressure after a few months of treatment should not lead to CPAP discontinuation, because reduction in blood pressure may become evident with a longer treatment period. Given the clinical relevance of this issue, future studies should be aimed at confirming, with a proper experimental design, whether CPAP indeed affects blood pressure differently in sleepy and non-sleepy patients with hypertension and OSA. These studies should focus on the more objective and reproducible information on blood pressure levels offered by currently available home or ambulatory blood pressure monitoring techniques. Conflict of Interest Statement: G.P. has received lecture fees ($1001–$5000) from Daichij Sankyo. C.L. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Gianfranco Parati, M.D. and Carolina Lombardi, M.D., Ph.D. S. Luca Hospital Milan, Italy and University of Milano-Gicocca Milan, Italy References 1. Barbe´ F, Duran-Cantolla J, Capote F, de la Pen˜a M, Chiner E, Masa JF, Gonzalez M, Marin JM, Garcia-Rio F, az-de-Atauri J, et al. 2009. Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010;181: 718–726.
652
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
2. Parati G, Lombardi C, Narkiewicz K. Sleep apnea: epidemiology, pathophysiology, and relation to cardiovascular risk. Am J Physiol Regul Integr Comp Physiol 2007;293:R1671–R1683. 3. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82–93. 4. Davies CW, Crosby JH, Mullins RL, Barbour C, Davies RJ, Stradling JR. Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects. Thorax 2000;55:736–740. 5. Baguet JP, Barone-Rochette G, Pepin JL. Hypertension and obstructive sleep apnoea syndrome: current perspectives. J Hum Hypertens 2009; 23:431–443. 6. Khayat R, Patt B, Hayes D Jr. Obstructive sleep apnea: the new cardiovascular disease. Part I: obstructive sleep apnea and the pathogenesis of vascular disease. Heart Fail Rev 2009;14:143–153. 7. Dopp JM, Reichmuth KJ, Morgan BJ. Obstructive sleep apnea and hypertension: mechanisms, evaluation, and management. Curr Hypertens Rep 2007;9:529–534. 8. Narkiewicz K, Wolf J, Lopez-Jimenez F, Somers VK. Obstructive sleep apnea and hypertension. Curr Cardiol Rep 2005;7:435–440. 9. Cortelli P, Parchi P, Sforza E, Contin M, Pierangeli G, Barletta G, Lugaresi E. Cardiovascular autonomic dysfunction in normotensive awake subjects with obstructive sleep apnoea syndrome. Clin Auton Res 1994;4:57–62. 10. Bonsignore MR, Parati G, Insalaco G, Castiglioni P, Marrone O, Romano S, Salvaggio A, Mancia G, Bonsignore G, Di RM. Baroreflex control of heart rate during sleep in severe obstructive sleep apnoea: effects of acute CPAP. Eur Respir J 2006;27:128–135. 11. Lombardi C, Parati G, Cortelli P, Provini F, Vetrugno R, Plazzi G, Vignatelli L, Di RM, Lugaresi E, Mancia G, et al. Daytime sleepiness and neural cardiac modulation in sleep-related breathing disorders. J Sleep Res 2008;17:263–270. 12. Logan AG, Perlikowski SM, Mente A, Tisler A, Tkacova R, Niroumand M, Leung RS, Bradley TD. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 2001;19:2271–2277.
VOL 181
2010
13. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, et al. Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–1187. 14. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr., et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–2572. 15. Alajmi M, Mulgrew AT, Fox J, Davidson W, Schulzer M, Mak E, Ryan CF, Fleetham J, Choi P, Ayas NT. Impact of continuous positive airway pressure therapy on blood pressure in patients with obstructive sleep apnea hypopnea: a meta-analysis of randomized controlled trials. Lung 2007;185:67–72. 16. Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007;50:417–423. 17. Giles TL, Lasserson TJ, Smith BH, White J, Wright J, Cates CJ. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006;3:CD001106. 18. Haentjens P, Van MA, Moscariello A, De WS, Poppe K, Dupont A, Velkeniers B. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials. Arch Intern Med 2007;167:757–764. 19. Bonsignore MR, Parati G, Insalaco G, Marrone O, Castiglioni P, Romano S, Di RM, Mancia G, Bonsignore G. Continuous positive airway pressure treatment improves baroreflex control of heart rate during sleep in severe obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2002;166:279–286.
DOI: 10.1164/rccm.201001-0031ED
A Trial Involving HIV-Tuberculosis in India The Minute Particulars In this issue of the Journal (pp. 743–751), Swaminathan and colleagues report on a significant clinical trial involving persons with HIV-tuberculosis (HIV-TB) in India (1). The trial was organized by the Tuberculosis Research Centre in Chennai (TRC), which has a long history of addressing important issues in TB care (2). This trial sought to evaluate the efficacy of the standard 6-month thrice-weekly regimen, which has been applied nationally in India’s National Tuberculosis Program, for the treatment of high-risk persons with HIV-associated TB (3). The clinical study compares a standard duration of 6 months to an extended 9-month treatment period. A number of investigations have sought to determine whether HIV-associated TB responds to therapy as well as TB in HIV-negative persons, and some recent evaluations suggest that it may not (4–6). The findings of the trial are notable for (1) high rates of failure during therapy; (2) high rates of acquired rifampin resistance; (3) substantial rates of recurrence after completion of therapy, with lower rates of recurrent TB in those treated for the longer period; (4) high mortality; and (5) a significant association of acquired rifampin resistance (ARR), with the presence of baseline isoniazid (INH) resistance. These are important observations; if confirmed in other settings, they could have substantial influence on TB control programs worldwide. The authors have carefully sought to respond to many of the questions that arise for the informed reader: d
They have compared the results of modified intention-totreat analyses to those of Protocol Correct analyses, and
d
d
d
d
d
they have analyzed outcomes in several manners (crude, Kaplan-Meier, proportional hazards regression). These approaches demonstrate consistency within their findings. They have reported on extensive genotyping of the large majority of failure and recurrence isolates, permitting in most cases the distinction of endogenous failure or relapse from exogenous reinfection. They have addressed concerns about supervision of trial therapy (all doses in intensive phase; one of every three doses in continuation phase) and about adherence (through pill counts and multiple spot urine checks). They have carefully assessed the impact of baseline characteristics, such as drug resistance, to limit any unrecognized confounding. They have satisfied many of the CONSORT criteria (7). They are helpfully transparent in acknowledging the potential for nosocomially transmitted reinfection to explain some of the TB recurrences, noting that several patients with rifamycin-resistant failure or recurrence underwent prolonged hospitalizations during which others might have been infected.
Nonetheless, there remain a few sources of uncertainty. One concerns the fact that genotyping results were not available for many of the failure or recurrence isolates and, in particular, were not available for any of the rifampin-resistant recurrence
