- Email: [email protected]
Are β2-adrenoceptor polymorphisms important in asthma—an unravelling story
Comment
colleagues for measuring brain atrophy has good accuracy and reproducibility,12 little work has been done to compare the many promising methods that are currently available. We now need to define the sample sizes and techniques best able to measure atrophy. The report by Filippi and colleagues is encouraging and commends investigators to include brain atrophy as an outcome measure in future trials of potential diseasemodifying treatments in multiple sclerosis. It should also stimulate further work to address the issues that I have raised.
2
3 4 5
6
7
David H Miller
8
NMR Research Unit, Department of Neuroinflammation, Institute of Neurology, University College London, London WC1N 3BG, UK [email protected]
9
I have received grant support from Biogen Idec, Elan, Schering, and GlaxoSmithKline for performance of MRI analyses in clinical trials. I have received honoraria for advisory or consultancy work, lectures, and related travel and accommodation expenses from Aventis, Biogen Idec, Bristol Myers Squibb, GlaxoSmithKline, Schering, Serono, UCB Pharma, and Wyeth. 1
Paty DW, Li DK, for the UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Interferon-1b is effective in relapsing-remitting multiple sclerosis II. MRI analysis result of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 662–67.
10
11
12
Jacobs LD, Cookfair Dl, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39: 285–94 Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis. Lancet 2001; 357: 1576–82. Miller DH. Biomarkers and surrogate outcomes in neurodegenerative disease: lessons from multiple sclerosis. NeuroRx 2004; 1: 284–94. Evangelou N, Esiri MM, Smith S, Palace J, Mathews PM. Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 2000; 47: 391–95. Peterson JW, Bo L, Mork S, Chang A, Trapp BD. Transected neuritis, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001; 50: 389–400. Miller DH, Barkhof F, Frank JA, Parker GJM, Thompson AJ. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 2002; 125: 1676–95. Dalton CM, Chard DT, Davies GR, et al. Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain 2004; 127: 1101–07. Molyneux PD, Kappos L, Polman C, et al. The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. Brain 2000; 123: 2256–63. Jones CK, Riddehough A, Li DKB, Zhao GJ, Paty DW. MRI cerebral atrophy in relapsing remitting MS: results of the PRISMS trial. Neurology 2001; 56 (suppl 3): A379. Rudick RA, Fischer E, Lee J-C, Simon J, Jacobs L. Use of brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 1999; 53: 1698–704. Smith SM, Zhang Y, Jenkinson M, et al. Accurate, robust and automated longitudinal and cross-sectional brain change analysis. NeuroImage 2002; 17: 479–89.
Are 2-adrenoceptor polymorphisms important in asthma— an unravelling story See Articles page 1505
1464
Large clinical studies have addressed the question of whether regular use of short-acting 2 agonists helps or harms patients with asthma. The two largest studies showed little net change in asthma control when 2 agonists were used regularly rather than as required.1,2 However, several reasonably large studies did show deterioration in one or more aspects of control,3–5 in keeping with some smaller studies.6 Could differences between patients, due to 2-adrenoceptor polymorphisms, explain these inconsistencies? Four single-nucleotide polymorphisms in the coding region of the 2-adrenoceptor gene cause aminoacid changes in the receptor, and two are common, namely those causing substitution of glycine for arginine at codon 16 and glutamic acid for glutamine at codon 27. Both polymorphisms affect 2-adrenoceptor down-regulation in response to isoprenaline in vitro, with cells transfected with the Gly 16 polymorphism showing increased downregulation and those with the Glu 27 polymorphism being relatively resistant.7 Initial clinical studies provided some support for the findings in vitro, with the Gly 16 polymorphism being associated with greater airway responsiveness and bronchodilator desensitisation while the Glu 27 polymorphism was protective.8–10 However, when three of the larger studies that had compared the
use of short-acting 2 agonists taken regularly versus as required1,3,5 were reanalysed according to genotype, the Gly 16 polymorphism was associated with a more favourable response to regular 2-agonist treatment.11–13 The stage was set for a careful prospective investigation. Elliott Israel and colleagues report such a study in The Lancet today: the -agonist response by genotype (BARGE) study. These investigators identified patients with asthma who were taking short-acting agonists only, and then matched 78 patients in pairs by forced expiratory volume in 1 s, with one being homozygous for Arg 16 (Arg/Arg 16) and one for Gly 16 (Gly/Gly 16). After a 6-week run-in, all the patients received 16 weeks’ treatment with salbutamol (albuterol) 200 g four times a day or placebo in random order with an 8-week washout after each treatment. Patients used ipratropium bromide as first-line relief medication throughout the study but could use salbutamol if necessary. The primary endpoint was the withingenotype difference in morning peak flow between salbutamol and placebo. Israel and colleagues found that patients with the Gly/Gly 16 genotype improved with salbutamol but not with placebo while those with the Arg/Arg 16 genotype improved with placebo but not salbutamol. The treatment attributable difference in peak flow was 14 L/min for the www.thelancet.com Vol 364 October 23, 2004
Comment
Science Photo Library
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Gly/Gly 16 group and –10 L/min for the Arg/Arg 16 group, a difference between genotypes of 24 L/min. Furthermore, peak flow increased by 23 L/min in the Arg/Arg 16 group during the initial run-in when ipratropium replaced shortacting 2 agonists as primary relief medication. Parallel changes were seen in several other endpoints. Israel and colleagues conclude that patients with the Arg/Arg 16 genotype can deteriorate with use of short-acting 2 agonists. This conclusion is almost certainly true although close inspection of the data raises several unexpected and important issues. First, the improvement in morning peak flow with salbutamol in the Gly/Gly 16 group continued during the 8-week washout, implying that the effects of regular salbutamol continue for several weeks after ending treatment. Second, although the Arg/Arg 16 group improved progressively during the 16 weeks with placebo, there was no deterioration with regular salbutamol to explain this. Third, there was a large increase in peak flow (23 L/min) in the Arg/Arg 16 group during the initial run-in, which Israel and colleagues attribute to patients stopping their 2-agonist relief medication. However, patients were averaging only one puff of 2 agonist a day before the run-in. This finding was not a primary endpoint of the study but, if true, has profound implications for asthma management because it means that Arg/Arg 16 patients, some 14% of the white population,14 might deteriorate with only occasional use of short-acting 2 agonists. An alternative explanation for www.thelancet.com Vol 364 October 23, 2004
these findings would be a positive interaction between the Arg/Arg 16 2-adrenoceptor genotype and ipratropium responsiveness. So should all patients with asthma undergo 2-adrenoceptor genotyping? That would be premature at present in our view, but the questions raised by Israel and colleagues’ study need urgent attention. Because some of the findings were unexpected and the clinical implications are large, the findings require confirmation. We also need to know whether the findings can be extrapolated to long-acting 2 agonists and to patients who also take an inhaled corticosteroid. At a mechanistic level we need to understand why the effect of salbutamol in the Gly/Gly 16 group continued for several weeks after ending treatment; whether the effects are due to the polymorphisms studied or to others in linkage disequilibrium with those at locus 16; and why the findings differ from those expected from down-regulation studies in vitro. It is important to understand the mechanism underlying the improvement in the run-in period seen in the Arg/Arg 16 group and to explore whether, in view of the complex cross-talk between contractile and relaxant pathways in the airways,15 2-adrenoceptor genotype can affect the response to antimuscarinic drugs. In view of the almost universal use of short-acting 2 agonists by patients with asthma, finding answers to these questions must be a high priority.
*A E Tattersfield, Ian P Hall Respiratory Division, Nottingham City Hospital NHS Trust, Nottingham, NG5 1PB, UK (AET); and Division of Therapeutics and Molecular Medicine, Queens Medical Centre, University Hospital NHS Trust, Nottingham, UK (IPH) anne.tattersfi[email protected] AET has received grant support from AstraZeneca, speakers fees from AstraZeneca and Schering Plough, and consultancy fees from Schering Plough. IPH receives grant support from Novartis Pharma. 1
2
3 4
5
6
7
8
Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. N Engl J Med 1996; 335: 841–47. Dennis SM, Sharp SJ, Vickers MR, et al. Regular inhaled salbutamol and asthma control: the TRUST randomised trial. Lancet 2000; 355: 1675–79. Sears MR, Taylor DR, Print CG, et al. Regular inhaled -agonist treatment in bronchial asthma. Lancet 1990; 336: 1391–96. Taylor DR, Sears MR, Herbison GP, et al. Regular inhaled -agonist in asthma: effects on exacerbations and lung function. Thorax 1993; 48: 134–38 Taylor DR, Town GI, Herbison GP, et al. Asthma control during long term treatment with regular inhaled salbutamol and salmeterol. Thorax 1998; 53: 744–52. Vathenen AS, Knox AJ, Higgins BG, Britton JR, Tattersfield AE. Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988; 1: 554–58. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of 2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995; 13: 25–33. D’Amato M, Vitiani LR, Petrelli G, et al. Association of persistent bronchial hyperresponsiveness with β2 adrenoceptor (ADRB2) haplotypes. Am J Respir Crit Care Med 1998; 158: 1968–73.
1465
Comment
9
10
11
12
Hall IP, Wheatley A, Wilding P, Liggett SB. Association of Glu 272 adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet 1995; 345: 1213–14. Tan S, Hall IP, Dewar J, Dow E, Lipworth B. Association between 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 1997; 350: 995–99. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term 2-agonist use: influence of 2-adrenoceptor polymorphism. Thorax 2000; 55: 762–67. Hancox RJ, Sears MR, Taylor DR. Polymorphism of the 2-adrenoceptor and
13
14
15
the response to long-term 2-agonist therapy in asthma. Eur Respir J 1998; 11: 589–93. Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the 2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000; 162: 75–80. Dewar JC, Wheatley AP, Venn A, Morrison JFJ, Britton J, Hall IP. 2 adrenoceptor polymorphisms are in linkage disequilibrium, but are not associated with asthma in an adult population. Clin Exp Allergy 1998; 28: 442–48. Hall IP. The -agonist controversy revisited. Lancet 2004; 363: 183.
Drug-eluting stents: some bare facts See Research Letters page 1519
1466
In this issue of The Lancet, Eugène McFadden and colleagues report four cases of coronary thrombosis that occurred many months after implantation of drug-eluting stents. Each case developed shortly after antiplatelet therapy was interrupted: in three patients when aspirin was discontinued, and in one patient when both aspirin and clopidogrel were stopped. Strikingly, in the two patients who had both a bare-metal and a drug-eluting stent, only the drugeluting stent showed evidence of thrombosis. Although stent thrombosis has previously been reported with drugeluting stents,1,2 the patients reported by McFadden and colleagues deserve serious attention because of their extraordinarily late presentations. Two cases occurred 11 months after implantation of the drug-eluting stent, and two occurred after more than a year. Balloon angioplasty is associated with restenosis rates of 30–40% and bare-metal stents with rates of 20–30%.3,4 Bare metal stents have now been coated with polymers from which drugs such as sirolimus and paclitaxel are eluted. Because restenosis rates are less than 10% with drug-eluting stents,5–7 there has been an explosive growth in their use over a very short period. Coronary thrombosis has long been recognised as a rare but catastrophic complication after stent implantation. This event typically presents in the first few days after the procedure, almost always causes an acute myocardial infarction, and not uncommonly results in death. Thrombosis is associated with the use of undersized stents and with inadequate stent expansion. Consequently, optimally sized stents and deployment with high balloonpressures have become the norm. These techniques, coupled with dual antiplatelet therapy with aspirin plus a thienopyridine, reduce stent thrombosis rates to under 2%. Because bare-metal stents become endothelialised within a few weeks of implantation, dual antiplatelet therapy is only required for 2–4 weeks. Rapid endothelialisation of such stents makes late thrombosis (>30 days after stent implantation) exceedingly rare. Until the advent of drug-eluting stents, late stentthrombosis had been almost entirely limited to patients receiving coronary brachytherapy. Brachytherapy uses intracoronary radiation as a treatment for restenosis. Many cases
of late thrombosis after brachytherapy have been reported. Animal studies show that late thrombosis is related to the delayed endothelialisation caused by brachytherapy.8 Clinical trials indicate that prolonged treatment with dual antiplatelet therapy largely prevents this complication.9,10 Because drug-eluting stents also cause delayed endothelialisation, trial protocols with these stents have mandated more prolonged antiplatelet therapy than earlier trials with bare-metal stents. Prolonged and continuous antiplatelet therapy might explain why late thrombosis has not been prominent in the trials with drug-eluting stents. A pooled analysis we did in over 5000 patients in trials with drugeluting stents showed similar rates of stent thrombosis in patients receiving bare-metal or drug-eluting stents.11 However, because stent thrombosis is such a rare event, our meta-analysis had less than 50% power to exclude a two-fold higher risk of stent thrombosis with drug-eluting stents. What can we do to avoid late thrombosis after implantation with a drug-eluting stent? First, we should strongly reflect on the potential clinical consequences before we insert such a stent. Will the patient need a subsequent surgical procedure necessitating the interruption of antiplatelet therapy? If so, a drug-eluting stent might not be the best choice. Will the patient be compliant with prolonged antiplatelet therapy? If not, a bare-metal stent might be preferable. Second, we need more information about how to manage patients with a drug-eluting stent. We need largescale registries and post-marketing surveillance studies. We also need to identify high-risk characteristics that may predispose to late thrombosis. Most importantly, we need to determine the optimum duration for antiplatelet therapy. Third, we need to develop strategies to deal with the unanticipated interruption of antiplatelet therapy after implantation of a drug-eluting stent. In some cases, it might be advisable to do a surgical procedure without stopping antiplatelet therapy despite the increased bleeding risks. In patients for whom this is not possible, it might be better to stop antiplatelet therapy for less than the 5 days we currently wait. In cases of elective surgery, it might be best to delay the procedure until a year or more after implantation of the drug-eluting stent. www.thelancet.com Vol 364 October 23, 2004
colleagues for measuring brain atrophy has good accuracy and reproducibility,12 little work has been done to compare the many promising methods that are currently available. We now need to define the sample sizes and techniques best able to measure atrophy. The report by Filippi and colleagues is encouraging and commends investigators to include brain atrophy as an outcome measure in future trials of potential diseasemodifying treatments in multiple sclerosis. It should also stimulate further work to address the issues that I have raised.
2
3 4 5
6
7
David H Miller
8
NMR Research Unit, Department of Neuroinflammation, Institute of Neurology, University College London, London WC1N 3BG, UK [email protected]
9
I have received grant support from Biogen Idec, Elan, Schering, and GlaxoSmithKline for performance of MRI analyses in clinical trials. I have received honoraria for advisory or consultancy work, lectures, and related travel and accommodation expenses from Aventis, Biogen Idec, Bristol Myers Squibb, GlaxoSmithKline, Schering, Serono, UCB Pharma, and Wyeth. 1
Paty DW, Li DK, for the UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Interferon-1b is effective in relapsing-remitting multiple sclerosis II. MRI analysis result of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 662–67.
10
11
12
Jacobs LD, Cookfair Dl, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39: 285–94 Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis. Lancet 2001; 357: 1576–82. Miller DH. Biomarkers and surrogate outcomes in neurodegenerative disease: lessons from multiple sclerosis. NeuroRx 2004; 1: 284–94. Evangelou N, Esiri MM, Smith S, Palace J, Mathews PM. Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 2000; 47: 391–95. Peterson JW, Bo L, Mork S, Chang A, Trapp BD. Transected neuritis, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001; 50: 389–400. Miller DH, Barkhof F, Frank JA, Parker GJM, Thompson AJ. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 2002; 125: 1676–95. Dalton CM, Chard DT, Davies GR, et al. Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain 2004; 127: 1101–07. Molyneux PD, Kappos L, Polman C, et al. The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. Brain 2000; 123: 2256–63. Jones CK, Riddehough A, Li DKB, Zhao GJ, Paty DW. MRI cerebral atrophy in relapsing remitting MS: results of the PRISMS trial. Neurology 2001; 56 (suppl 3): A379. Rudick RA, Fischer E, Lee J-C, Simon J, Jacobs L. Use of brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 1999; 53: 1698–704. Smith SM, Zhang Y, Jenkinson M, et al. Accurate, robust and automated longitudinal and cross-sectional brain change analysis. NeuroImage 2002; 17: 479–89.
Are 2-adrenoceptor polymorphisms important in asthma— an unravelling story See Articles page 1505
1464
Large clinical studies have addressed the question of whether regular use of short-acting 2 agonists helps or harms patients with asthma. The two largest studies showed little net change in asthma control when 2 agonists were used regularly rather than as required.1,2 However, several reasonably large studies did show deterioration in one or more aspects of control,3–5 in keeping with some smaller studies.6 Could differences between patients, due to 2-adrenoceptor polymorphisms, explain these inconsistencies? Four single-nucleotide polymorphisms in the coding region of the 2-adrenoceptor gene cause aminoacid changes in the receptor, and two are common, namely those causing substitution of glycine for arginine at codon 16 and glutamic acid for glutamine at codon 27. Both polymorphisms affect 2-adrenoceptor down-regulation in response to isoprenaline in vitro, with cells transfected with the Gly 16 polymorphism showing increased downregulation and those with the Glu 27 polymorphism being relatively resistant.7 Initial clinical studies provided some support for the findings in vitro, with the Gly 16 polymorphism being associated with greater airway responsiveness and bronchodilator desensitisation while the Glu 27 polymorphism was protective.8–10 However, when three of the larger studies that had compared the
use of short-acting 2 agonists taken regularly versus as required1,3,5 were reanalysed according to genotype, the Gly 16 polymorphism was associated with a more favourable response to regular 2-agonist treatment.11–13 The stage was set for a careful prospective investigation. Elliott Israel and colleagues report such a study in The Lancet today: the -agonist response by genotype (BARGE) study. These investigators identified patients with asthma who were taking short-acting agonists only, and then matched 78 patients in pairs by forced expiratory volume in 1 s, with one being homozygous for Arg 16 (Arg/Arg 16) and one for Gly 16 (Gly/Gly 16). After a 6-week run-in, all the patients received 16 weeks’ treatment with salbutamol (albuterol) 200 g four times a day or placebo in random order with an 8-week washout after each treatment. Patients used ipratropium bromide as first-line relief medication throughout the study but could use salbutamol if necessary. The primary endpoint was the withingenotype difference in morning peak flow between salbutamol and placebo. Israel and colleagues found that patients with the Gly/Gly 16 genotype improved with salbutamol but not with placebo while those with the Arg/Arg 16 genotype improved with placebo but not salbutamol. The treatment attributable difference in peak flow was 14 L/min for the www.thelancet.com Vol 364 October 23, 2004
Comment
Science Photo Library
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Gly/Gly 16 group and –10 L/min for the Arg/Arg 16 group, a difference between genotypes of 24 L/min. Furthermore, peak flow increased by 23 L/min in the Arg/Arg 16 group during the initial run-in when ipratropium replaced shortacting 2 agonists as primary relief medication. Parallel changes were seen in several other endpoints. Israel and colleagues conclude that patients with the Arg/Arg 16 genotype can deteriorate with use of short-acting 2 agonists. This conclusion is almost certainly true although close inspection of the data raises several unexpected and important issues. First, the improvement in morning peak flow with salbutamol in the Gly/Gly 16 group continued during the 8-week washout, implying that the effects of regular salbutamol continue for several weeks after ending treatment. Second, although the Arg/Arg 16 group improved progressively during the 16 weeks with placebo, there was no deterioration with regular salbutamol to explain this. Third, there was a large increase in peak flow (23 L/min) in the Arg/Arg 16 group during the initial run-in, which Israel and colleagues attribute to patients stopping their 2-agonist relief medication. However, patients were averaging only one puff of 2 agonist a day before the run-in. This finding was not a primary endpoint of the study but, if true, has profound implications for asthma management because it means that Arg/Arg 16 patients, some 14% of the white population,14 might deteriorate with only occasional use of short-acting 2 agonists. An alternative explanation for www.thelancet.com Vol 364 October 23, 2004
these findings would be a positive interaction between the Arg/Arg 16 2-adrenoceptor genotype and ipratropium responsiveness. So should all patients with asthma undergo 2-adrenoceptor genotyping? That would be premature at present in our view, but the questions raised by Israel and colleagues’ study need urgent attention. Because some of the findings were unexpected and the clinical implications are large, the findings require confirmation. We also need to know whether the findings can be extrapolated to long-acting 2 agonists and to patients who also take an inhaled corticosteroid. At a mechanistic level we need to understand why the effect of salbutamol in the Gly/Gly 16 group continued for several weeks after ending treatment; whether the effects are due to the polymorphisms studied or to others in linkage disequilibrium with those at locus 16; and why the findings differ from those expected from down-regulation studies in vitro. It is important to understand the mechanism underlying the improvement in the run-in period seen in the Arg/Arg 16 group and to explore whether, in view of the complex cross-talk between contractile and relaxant pathways in the airways,15 2-adrenoceptor genotype can affect the response to antimuscarinic drugs. In view of the almost universal use of short-acting 2 agonists by patients with asthma, finding answers to these questions must be a high priority.
*A E Tattersfield, Ian P Hall Respiratory Division, Nottingham City Hospital NHS Trust, Nottingham, NG5 1PB, UK (AET); and Division of Therapeutics and Molecular Medicine, Queens Medical Centre, University Hospital NHS Trust, Nottingham, UK (IPH) anne.tattersfi[email protected] AET has received grant support from AstraZeneca, speakers fees from AstraZeneca and Schering Plough, and consultancy fees from Schering Plough. IPH receives grant support from Novartis Pharma. 1
2
3 4
5
6
7
8
Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. N Engl J Med 1996; 335: 841–47. Dennis SM, Sharp SJ, Vickers MR, et al. Regular inhaled salbutamol and asthma control: the TRUST randomised trial. Lancet 2000; 355: 1675–79. Sears MR, Taylor DR, Print CG, et al. Regular inhaled -agonist treatment in bronchial asthma. Lancet 1990; 336: 1391–96. Taylor DR, Sears MR, Herbison GP, et al. Regular inhaled -agonist in asthma: effects on exacerbations and lung function. Thorax 1993; 48: 134–38 Taylor DR, Town GI, Herbison GP, et al. Asthma control during long term treatment with regular inhaled salbutamol and salmeterol. Thorax 1998; 53: 744–52. Vathenen AS, Knox AJ, Higgins BG, Britton JR, Tattersfield AE. Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988; 1: 554–58. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of 2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol 1995; 13: 25–33. D’Amato M, Vitiani LR, Petrelli G, et al. Association of persistent bronchial hyperresponsiveness with β2 adrenoceptor (ADRB2) haplotypes. Am J Respir Crit Care Med 1998; 158: 1968–73.
1465
Comment
9
10
11
12
Hall IP, Wheatley A, Wilding P, Liggett SB. Association of Glu 272 adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet 1995; 345: 1213–14. Tan S, Hall IP, Dewar J, Dow E, Lipworth B. Association between 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet 1997; 350: 995–99. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term 2-agonist use: influence of 2-adrenoceptor polymorphism. Thorax 2000; 55: 762–67. Hancox RJ, Sears MR, Taylor DR. Polymorphism of the 2-adrenoceptor and
13
14
15
the response to long-term 2-agonist therapy in asthma. Eur Respir J 1998; 11: 589–93. Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the 2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000; 162: 75–80. Dewar JC, Wheatley AP, Venn A, Morrison JFJ, Britton J, Hall IP. 2 adrenoceptor polymorphisms are in linkage disequilibrium, but are not associated with asthma in an adult population. Clin Exp Allergy 1998; 28: 442–48. Hall IP. The -agonist controversy revisited. Lancet 2004; 363: 183.
Drug-eluting stents: some bare facts See Research Letters page 1519
1466
In this issue of The Lancet, Eugène McFadden and colleagues report four cases of coronary thrombosis that occurred many months after implantation of drug-eluting stents. Each case developed shortly after antiplatelet therapy was interrupted: in three patients when aspirin was discontinued, and in one patient when both aspirin and clopidogrel were stopped. Strikingly, in the two patients who had both a bare-metal and a drug-eluting stent, only the drugeluting stent showed evidence of thrombosis. Although stent thrombosis has previously been reported with drugeluting stents,1,2 the patients reported by McFadden and colleagues deserve serious attention because of their extraordinarily late presentations. Two cases occurred 11 months after implantation of the drug-eluting stent, and two occurred after more than a year. Balloon angioplasty is associated with restenosis rates of 30–40% and bare-metal stents with rates of 20–30%.3,4 Bare metal stents have now been coated with polymers from which drugs such as sirolimus and paclitaxel are eluted. Because restenosis rates are less than 10% with drug-eluting stents,5–7 there has been an explosive growth in their use over a very short period. Coronary thrombosis has long been recognised as a rare but catastrophic complication after stent implantation. This event typically presents in the first few days after the procedure, almost always causes an acute myocardial infarction, and not uncommonly results in death. Thrombosis is associated with the use of undersized stents and with inadequate stent expansion. Consequently, optimally sized stents and deployment with high balloonpressures have become the norm. These techniques, coupled with dual antiplatelet therapy with aspirin plus a thienopyridine, reduce stent thrombosis rates to under 2%. Because bare-metal stents become endothelialised within a few weeks of implantation, dual antiplatelet therapy is only required for 2–4 weeks. Rapid endothelialisation of such stents makes late thrombosis (>30 days after stent implantation) exceedingly rare. Until the advent of drug-eluting stents, late stentthrombosis had been almost entirely limited to patients receiving coronary brachytherapy. Brachytherapy uses intracoronary radiation as a treatment for restenosis. Many cases
of late thrombosis after brachytherapy have been reported. Animal studies show that late thrombosis is related to the delayed endothelialisation caused by brachytherapy.8 Clinical trials indicate that prolonged treatment with dual antiplatelet therapy largely prevents this complication.9,10 Because drug-eluting stents also cause delayed endothelialisation, trial protocols with these stents have mandated more prolonged antiplatelet therapy than earlier trials with bare-metal stents. Prolonged and continuous antiplatelet therapy might explain why late thrombosis has not been prominent in the trials with drug-eluting stents. A pooled analysis we did in over 5000 patients in trials with drugeluting stents showed similar rates of stent thrombosis in patients receiving bare-metal or drug-eluting stents.11 However, because stent thrombosis is such a rare event, our meta-analysis had less than 50% power to exclude a two-fold higher risk of stent thrombosis with drug-eluting stents. What can we do to avoid late thrombosis after implantation with a drug-eluting stent? First, we should strongly reflect on the potential clinical consequences before we insert such a stent. Will the patient need a subsequent surgical procedure necessitating the interruption of antiplatelet therapy? If so, a drug-eluting stent might not be the best choice. Will the patient be compliant with prolonged antiplatelet therapy? If not, a bare-metal stent might be preferable. Second, we need more information about how to manage patients with a drug-eluting stent. We need largescale registries and post-marketing surveillance studies. We also need to identify high-risk characteristics that may predispose to late thrombosis. Most importantly, we need to determine the optimum duration for antiplatelet therapy. Third, we need to develop strategies to deal with the unanticipated interruption of antiplatelet therapy after implantation of a drug-eluting stent. In some cases, it might be advisable to do a surgical procedure without stopping antiplatelet therapy despite the increased bleeding risks. In patients for whom this is not possible, it might be better to stop antiplatelet therapy for less than the 5 days we currently wait. In cases of elective surgery, it might be best to delay the procedure until a year or more after implantation of the drug-eluting stent. www.thelancet.com Vol 364 October 23, 2004