- Email: [email protected]
COPD: more than respiratory
Correspondence
came from the effect of the diuretic component, probably via the additional small decrement in blood pressure. Since ACE inhibitors were allowed in the control group, unlike in the PROGRESS study,2 the design does not let us decide whether the combination is any better than indapamide alone. I declare that I have no conflict of interest.
Edmund Dunstan [email protected] Selly Oak Hospital, Raddlebarn Road, Selly Oak, Birmingham B29 6JD, UK 1
2
Patel A; ADVANCE Collaborative Group. Effect of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370: 829–40. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033–41.
Authors’ reply
See Comment page 12
26
The main issue raised by both Flávio Fuchs and Michel Procopiou concerns the access of patients in ADVANCE to treatment with angiotensinconverting-enzyme (ACE) inhibitors. Patients already receiving an ACE inhibitor were eligible for inclusion if the responsible physician believed it reasonable to substitute such therapy with open-label perindopril (up to 4 mg daily). This dose has been shown to provide effective ACE inhibition and blood pressure reduction,1 and furthermore it ensured that patients randomised to active study treatment did not receive more than the maximum recommended dose of perindopril (8 mg daily). Among patients randomised to placebo, 60% were taking an ACE inhibitor by the end of follow-up and 13% were taking an angiotensinreceptor blocker. The suggestion by Fuchs and Procopiou that patients in ADVANCE somehow received suboptimum treatment in this regard is inconsistent with the fact that most of those assigned placebo received an inhibitor of the renin–angiotensin system at a recommended main-
tenance dose. Certainly, the background treatment provided in ADVANCE is entirely consistent with all major guidelines for the treatment of diabetes or hypertension. Contrary to Fuchs and Procopiou’s suggestions, for major clinical outcomes there is no evidence either of differences between ACE inhibitors or of differences between doses of ACE inhibitor at levels above those required to provide inhibition of ACE and a reduction in blood pressure. Nevertheless, the study design took account of the possibility that, for some patients, an ACE inhibitor other than perindopril or a dose of perindopril greater than 4 mg daily might be regarded as indicated by the responsible physician. If this indication was apparent before randomisation, the patient was ineligible for inclusion. If it became apparent after randomisation, active study treatment was withdrawn and open-label treatment provided. Similar provisions were made for the management of patients with a definite indication for treatment with a thiazide diuretic. Furthermore, all other blood-pressure-lowering agents, including angiotensin-receptor blockers, could be provided at the discretion of the patient’s doctor without any modification to the study treatment. These aspects of the study design avoid the ethical issues that arise when access to indicated treatments are limited by the terms of the study protocol. The patients enrolled in ADVANCE were very well treated, with high rates of use of statins, antiplatelet drugs, and hypoglycaemic agents, as well as blood-pressure-lowering drugs. This background produced cardiovascular risk factor levels (eg, mean HbA1c 6·9%, LDL cholesterol 2·6 mmol/L) that were more favourable than those commonly seen in community surveys among people with diabetes2,3 and event rates lower than those seen in previous trials.4 Although such intensive treatment inevitably makes it more difficult to detect benefits of additional interventions, ADVANCE showed that the routine inclusion of perindopril and
indapamide in the treatment regimens of patients with diabetes produced worthwhile benefits for important outcomes, including death. As Edmund Dunstan correctly states, ADVANCE was not designed to determine the separate effects of perindopril and indapamide. The results of ADVANCE, which can only be reliably attributed to the fixed combination as a whole, indicate that the study regimen lowered blood pressure, was well tolerated, and reduced the risks of major vascular events and death, with no clear difference between effects in those receiving background ACE inhibitor therapy and in those not receiving such treatment. ADVANCE was funded by grants from Servier and the National Health and Medical Research Council of Australia. SM and JC have received honoraria for speaking engagements and travel grants from Servier.
*Anushka Patel, Stephen MacMahon, Bruce Neal, Laurent Billot, John Chalmers, on behalf of the ADVANCE Collaborative Group [email protected] The George Institute for International Health, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW 2050, Australia 1
2
3
4
Hurst M, Jarvis B. Perindopril: an updated review of its use in hypertension. Drugs 2001; 61: 867–96. Chuang L-M, Tsai ST, Huang BY, Tai TY. The status of diabetes control in Asia—a crosssectional survey of 24 317 patients with diabetes mellitus in 1998. Diabetic Med 19; 12: 978–85. Saaddine JB, Cadwell B, Gregg EW, et al. Improvements in diabetes processes of care and intermediate outcomes: United States, 1988–2002. Ann Intern Med 2006; 144: 465–74. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–58.
COPD: more than respiratory Leonardo Fabbri and Klaus Rabe (Sept 1, p 797)1 have to be commended on their attempt at reshaping the common view of chronic obstructive pulmonary disease (COPD) as being a purely respiratory disease. Their Viewpoint provides useful suggestions to www.thelancet.com Vol 371 January 5, 2008
Correspondence
researchers and practising clinicians, but to state positive diagnostic criteria without exclusion criteria could be misleading. For instance, a 45-year-old woman with a 12 pack-year history of smoking and high C-reactive protein secondary to asymptomatic thyroiditis might receive a diagnosis of chronic systemic inflammatory syndrome according to Fabbri and Rabe’s proposed set of criteria. Furthermore, the diagnosis of heart failure is quite problematic in older people as well as in obese patients and those with respiratory disease.2–4 Thus, coexisting heart failure and COPD, mainly in older and obese patients, creates a true diagnostic conundrum affecting the accuracy of the final diagnosis. Further complicating the issue is the finding that metabolic syndrome associates more with restrictive than with obstructive lung dysfunction in older people.5 Accordingly, although we share and reinforce Fabbri and Rabe’s recommendation for a comprehensive and not purely respiratory view and care of patients with COPD, we think that available knowledge prevents us from developing a reliable diagnostic index of chronic systemic inflammatory syndrome. Thus, the core value of Fabbri and Rabe’s Viewpoint lies in the promotion of a new clinical and research approach to COPD. Such an approach should translate into a systematic and multidisciplinary effort to categorise, on solid scientific bases and in a practical perspective, the chronic syndrome that characterises most patients with COPD. We declare that we have no conflict of interest.
Raffaele Antonelli-Incalzi, *Claudio Pedone [email protected] Università Campus Biomedico, 00128 Rome, Italy 1
2
Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory disease? Lancet 2007; 370: 797–99. Di Bari M, Chiara Cavallini M, Kitzman DW, et al. Limited utility of the subcostal view for the echocardiographic evaluation of left ventricular mass in epidemiological studies of older persons. Int J Cardiol 2004; 97: 521–27.
www.thelancet.com Vol 371 January 5, 2008
3
4
5
Taylor JA, Christenson RH, Rao K, Jorge M, Gottlieb SS. B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide are depressed in obesity despite higher left ventricular end diastolic pressures. Am Heart J 2006; 152: 1071–76. Lien CT, Gillespie ND, Struthers AD, McMurdo ME. Heart failure in frail elderly patients: diagnostic difficulties, comorbidities, polypharmacy and treatment dilemmas. Eur J Heart Fail 2002; 4: 91–98. Fimognari FL, Pasqualetti P, Moro L, et al. The association between metabolic syndrome and restrictive ventilatory dysfunction in older persons. J Gerontol A Biol Sci Med Sci 2007; 62: 760–65.
The Sept 1 issue of The Lancet was important for raising awareness of chronic obstructive pulmonary disease (COPD). None of the articles, however, refers to the fact that around 90% of COPD patients are managed solely by general practitioners.1,2 The transfer of new scientific insights to primary care is crucial. For example, as Leonardo Fabbri and Klaus Rabe point out,3 pulmonary and systemic COPD manifestations affect prognosis. In a survey of 75 of about 150 general practitioners attending a continuing medical education conference in Lucerne, Switzerland, in June, 2006, we found that participants knew that assessment of patients with COPD should not be restricted to the lungs (table). For example, 71% routinely enquired about physical activity, the latter being associated with severe exacerbations and death.4 However, they did not seem to be aware that variables other than lung function are of key importance for good prognostication. 28% of general practitioners said they had heard of the BODE index5 but none of them was able to list any of its four components (body-mass index [B], degree of airflow obstruction [O] and functional dyspnoea [D], and exercise capacity [E]). Following examples from cardiovascular medicine (eg, the PROCAM score), COPD research should provide a composite prognostic score (predicting, for example, the risk of severe exacerbations). Such a score must be based on methodologically sound derivation and validation studies and
feasibility considerations in primary care. A systematic risk assessment of patients in primary care is likely to bring about more individually tailored COPD management. We declare that we have no conflict of interest.
*M A Puhan, M Zoller, G ter Riet [email protected] Horten Centre for Patient Oriented Research, University of Zurich, Postfach Nord, CH-8091 Zurich, Switzerland (MAP); Einheit für Hausarztmedizin, University of Zurich, Zurich, Switzerland (MZ); and Academic Medical Center, Department of General Practice, University of Amsterdam, Amsterdam, Netherlands (GtR) 1
2
3
Rothman AA, Wagner EH. Chronic illness management: what is the role of primary care? Ann Intern Med 2003; 138: 256–61. Tirimanna PR, van Schayck CP, den Otter JJ, et al. Prevalence of asthma and COPD in general practice in 1992: has it changed since 1977? Br J Gen Pract 1996; 46: 277–81. Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet 2007; 370: 797–99.
Number of GPs (n=75) Routine assessments Smoking status
75 (100%)
Physical activity
53 (70·7%)
History of exacerbations
50 (66·7%)
Social environment
43 (57·3%)
Body-mass index
41 (54·7%)
Vaccination status
29 (38·7%)
Dyspnoea score
29 (38·7%)
Depressive symptoms
14 (18·7%)
Ergometry
5 (6·7%)
Blood gases
2 (2·7%)
Fat free mass
1 (1·3%)
6-min walk test
1 (1·3%)
Assessment of prognosis Based on spirometry
35 (46·7%)
Other parameters (history of exacerbations, dyspnoea)
21 (28·0%)
None
19 (25·3%)
Awareness of BODE index None
54 (72·0%)
Heard of
21 (28·0%)
Know any of the 4 parameters
0
Basis of treatment selection Clinical experience
56 (74·7%)
Guidelines
46 (61·3%)
Continuing medical education
44 (58·7%)
Patient’s prognosis
18 (24·0%)
Table: Self-reported routine assessments for COPD by Swiss general practitioners
27
came from the effect of the diuretic component, probably via the additional small decrement in blood pressure. Since ACE inhibitors were allowed in the control group, unlike in the PROGRESS study,2 the design does not let us decide whether the combination is any better than indapamide alone. I declare that I have no conflict of interest.
Edmund Dunstan [email protected] Selly Oak Hospital, Raddlebarn Road, Selly Oak, Birmingham B29 6JD, UK 1
2
Patel A; ADVANCE Collaborative Group. Effect of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370: 829–40. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033–41.
Authors’ reply
See Comment page 12
26
The main issue raised by both Flávio Fuchs and Michel Procopiou concerns the access of patients in ADVANCE to treatment with angiotensinconverting-enzyme (ACE) inhibitors. Patients already receiving an ACE inhibitor were eligible for inclusion if the responsible physician believed it reasonable to substitute such therapy with open-label perindopril (up to 4 mg daily). This dose has been shown to provide effective ACE inhibition and blood pressure reduction,1 and furthermore it ensured that patients randomised to active study treatment did not receive more than the maximum recommended dose of perindopril (8 mg daily). Among patients randomised to placebo, 60% were taking an ACE inhibitor by the end of follow-up and 13% were taking an angiotensinreceptor blocker. The suggestion by Fuchs and Procopiou that patients in ADVANCE somehow received suboptimum treatment in this regard is inconsistent with the fact that most of those assigned placebo received an inhibitor of the renin–angiotensin system at a recommended main-
tenance dose. Certainly, the background treatment provided in ADVANCE is entirely consistent with all major guidelines for the treatment of diabetes or hypertension. Contrary to Fuchs and Procopiou’s suggestions, for major clinical outcomes there is no evidence either of differences between ACE inhibitors or of differences between doses of ACE inhibitor at levels above those required to provide inhibition of ACE and a reduction in blood pressure. Nevertheless, the study design took account of the possibility that, for some patients, an ACE inhibitor other than perindopril or a dose of perindopril greater than 4 mg daily might be regarded as indicated by the responsible physician. If this indication was apparent before randomisation, the patient was ineligible for inclusion. If it became apparent after randomisation, active study treatment was withdrawn and open-label treatment provided. Similar provisions were made for the management of patients with a definite indication for treatment with a thiazide diuretic. Furthermore, all other blood-pressure-lowering agents, including angiotensin-receptor blockers, could be provided at the discretion of the patient’s doctor without any modification to the study treatment. These aspects of the study design avoid the ethical issues that arise when access to indicated treatments are limited by the terms of the study protocol. The patients enrolled in ADVANCE were very well treated, with high rates of use of statins, antiplatelet drugs, and hypoglycaemic agents, as well as blood-pressure-lowering drugs. This background produced cardiovascular risk factor levels (eg, mean HbA1c 6·9%, LDL cholesterol 2·6 mmol/L) that were more favourable than those commonly seen in community surveys among people with diabetes2,3 and event rates lower than those seen in previous trials.4 Although such intensive treatment inevitably makes it more difficult to detect benefits of additional interventions, ADVANCE showed that the routine inclusion of perindopril and
indapamide in the treatment regimens of patients with diabetes produced worthwhile benefits for important outcomes, including death. As Edmund Dunstan correctly states, ADVANCE was not designed to determine the separate effects of perindopril and indapamide. The results of ADVANCE, which can only be reliably attributed to the fixed combination as a whole, indicate that the study regimen lowered blood pressure, was well tolerated, and reduced the risks of major vascular events and death, with no clear difference between effects in those receiving background ACE inhibitor therapy and in those not receiving such treatment. ADVANCE was funded by grants from Servier and the National Health and Medical Research Council of Australia. SM and JC have received honoraria for speaking engagements and travel grants from Servier.
*Anushka Patel, Stephen MacMahon, Bruce Neal, Laurent Billot, John Chalmers, on behalf of the ADVANCE Collaborative Group [email protected] The George Institute for International Health, University of Sydney, PO Box M201, Missenden Road, Sydney, NSW 2050, Australia 1
2
3
4
Hurst M, Jarvis B. Perindopril: an updated review of its use in hypertension. Drugs 2001; 61: 867–96. Chuang L-M, Tsai ST, Huang BY, Tai TY. The status of diabetes control in Asia—a crosssectional survey of 24 317 patients with diabetes mellitus in 1998. Diabetic Med 19; 12: 978–85. Saaddine JB, Cadwell B, Gregg EW, et al. Improvements in diabetes processes of care and intermediate outcomes: United States, 1988–2002. Ann Intern Med 2006; 144: 465–74. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–58.
COPD: more than respiratory Leonardo Fabbri and Klaus Rabe (Sept 1, p 797)1 have to be commended on their attempt at reshaping the common view of chronic obstructive pulmonary disease (COPD) as being a purely respiratory disease. Their Viewpoint provides useful suggestions to www.thelancet.com Vol 371 January 5, 2008
Correspondence
researchers and practising clinicians, but to state positive diagnostic criteria without exclusion criteria could be misleading. For instance, a 45-year-old woman with a 12 pack-year history of smoking and high C-reactive protein secondary to asymptomatic thyroiditis might receive a diagnosis of chronic systemic inflammatory syndrome according to Fabbri and Rabe’s proposed set of criteria. Furthermore, the diagnosis of heart failure is quite problematic in older people as well as in obese patients and those with respiratory disease.2–4 Thus, coexisting heart failure and COPD, mainly in older and obese patients, creates a true diagnostic conundrum affecting the accuracy of the final diagnosis. Further complicating the issue is the finding that metabolic syndrome associates more with restrictive than with obstructive lung dysfunction in older people.5 Accordingly, although we share and reinforce Fabbri and Rabe’s recommendation for a comprehensive and not purely respiratory view and care of patients with COPD, we think that available knowledge prevents us from developing a reliable diagnostic index of chronic systemic inflammatory syndrome. Thus, the core value of Fabbri and Rabe’s Viewpoint lies in the promotion of a new clinical and research approach to COPD. Such an approach should translate into a systematic and multidisciplinary effort to categorise, on solid scientific bases and in a practical perspective, the chronic syndrome that characterises most patients with COPD. We declare that we have no conflict of interest.
Raffaele Antonelli-Incalzi, *Claudio Pedone [email protected] Università Campus Biomedico, 00128 Rome, Italy 1
2
Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory disease? Lancet 2007; 370: 797–99. Di Bari M, Chiara Cavallini M, Kitzman DW, et al. Limited utility of the subcostal view for the echocardiographic evaluation of left ventricular mass in epidemiological studies of older persons. Int J Cardiol 2004; 97: 521–27.
www.thelancet.com Vol 371 January 5, 2008
3
4
5
Taylor JA, Christenson RH, Rao K, Jorge M, Gottlieb SS. B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide are depressed in obesity despite higher left ventricular end diastolic pressures. Am Heart J 2006; 152: 1071–76. Lien CT, Gillespie ND, Struthers AD, McMurdo ME. Heart failure in frail elderly patients: diagnostic difficulties, comorbidities, polypharmacy and treatment dilemmas. Eur J Heart Fail 2002; 4: 91–98. Fimognari FL, Pasqualetti P, Moro L, et al. The association between metabolic syndrome and restrictive ventilatory dysfunction in older persons. J Gerontol A Biol Sci Med Sci 2007; 62: 760–65.
The Sept 1 issue of The Lancet was important for raising awareness of chronic obstructive pulmonary disease (COPD). None of the articles, however, refers to the fact that around 90% of COPD patients are managed solely by general practitioners.1,2 The transfer of new scientific insights to primary care is crucial. For example, as Leonardo Fabbri and Klaus Rabe point out,3 pulmonary and systemic COPD manifestations affect prognosis. In a survey of 75 of about 150 general practitioners attending a continuing medical education conference in Lucerne, Switzerland, in June, 2006, we found that participants knew that assessment of patients with COPD should not be restricted to the lungs (table). For example, 71% routinely enquired about physical activity, the latter being associated with severe exacerbations and death.4 However, they did not seem to be aware that variables other than lung function are of key importance for good prognostication. 28% of general practitioners said they had heard of the BODE index5 but none of them was able to list any of its four components (body-mass index [B], degree of airflow obstruction [O] and functional dyspnoea [D], and exercise capacity [E]). Following examples from cardiovascular medicine (eg, the PROCAM score), COPD research should provide a composite prognostic score (predicting, for example, the risk of severe exacerbations). Such a score must be based on methodologically sound derivation and validation studies and
feasibility considerations in primary care. A systematic risk assessment of patients in primary care is likely to bring about more individually tailored COPD management. We declare that we have no conflict of interest.
*M A Puhan, M Zoller, G ter Riet [email protected] Horten Centre for Patient Oriented Research, University of Zurich, Postfach Nord, CH-8091 Zurich, Switzerland (MAP); Einheit für Hausarztmedizin, University of Zurich, Zurich, Switzerland (MZ); and Academic Medical Center, Department of General Practice, University of Amsterdam, Amsterdam, Netherlands (GtR) 1
2
3
Rothman AA, Wagner EH. Chronic illness management: what is the role of primary care? Ann Intern Med 2003; 138: 256–61. Tirimanna PR, van Schayck CP, den Otter JJ, et al. Prevalence of asthma and COPD in general practice in 1992: has it changed since 1977? Br J Gen Pract 1996; 46: 277–81. Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet 2007; 370: 797–99.
Number of GPs (n=75) Routine assessments Smoking status
75 (100%)
Physical activity
53 (70·7%)
History of exacerbations
50 (66·7%)
Social environment
43 (57·3%)
Body-mass index
41 (54·7%)
Vaccination status
29 (38·7%)
Dyspnoea score
29 (38·7%)
Depressive symptoms
14 (18·7%)
Ergometry
5 (6·7%)
Blood gases
2 (2·7%)
Fat free mass
1 (1·3%)
6-min walk test
1 (1·3%)
Assessment of prognosis Based on spirometry
35 (46·7%)
Other parameters (history of exacerbations, dyspnoea)
21 (28·0%)
None
19 (25·3%)
Awareness of BODE index None
54 (72·0%)
Heard of
21 (28·0%)
Know any of the 4 parameters
0
Basis of treatment selection Clinical experience
56 (74·7%)
Guidelines
46 (61·3%)
Continuing medical education
44 (58·7%)
Patient’s prognosis
18 (24·0%)
Table: Self-reported routine assessments for COPD by Swiss general practitioners
27