- Email: [email protected]
Multimorbidity: another key issue for cardiovascular medicine
Correspondence
evident. By definition a heterosexual epidemic requires multiple partnering in some form. That leaves only two broad categories—serial monogamy and the range of overlapping or concurrent partnerships I describe in my Comment. Concurrent partnerships allow for infection to pass to and from connecting sexual networks. By contrast, within a monogamous relationship, infection is essentially trapped, often for some years. It is simply not plausible that serial monogamy by itself could generate the explosive generalised epidemics of eastern and southern Africa, especially in view of HIV’s fortunately relatively low heterosexual infectivity. Indeed, modelling studies indicate that serial monogamy fails to generate propagation at generalised epidemic levels.1 Thus, ironically, one of the correspondence authors (BW) recently coauthored a paper that resorted to unrealistically high concurrency to emulate South Africa’s epidemic— eight partners per year, with four concurrently at any time!2 However, assessing concurrency does present challenges. One chief difficulty is under-reporting of multiple partners, particularly among women. Another is the somewhat distal relation with infection: the link between current infection and previous behaviour can be many years. And it is mainly one’s partner’s concurrency that increases one’s risk, not one’s own concurrency. These and other reasons obscure assessment of a possible link in the studies cited by Lurie and colleagues. Conversely, Lurie and colleagues overlook more precise epidemiological evidence to support a key role for concurrency. For example, an analysis of new infections in couples in Uganda’s national HIV/AIDS serobehavioural survey3 found that most new infections were introduced from outside the partnership into a previously negative couple. Either one partner became infected, or both in rapid succession. Another intensive study from Zimbabwe4 found a two-fold higher www.thelancet.com Vol 374 October 24, 2009
risk of HIV prevalence among young women whose “Recent partner has other partners.” And a cohort study from Uganda5 found “The single most important behavioral characteristic associated with incident HIV infection was the number of times in the past 6 months, a participant had sex with person(s) they suspected were having sex with others.” That this evidence emerges notwithstanding the analytical difficulties described above, implies a very strong association. Multiple partnering includes many behaviours. Programmatically we need to help people understand the risks from any of them and underlying sexual networks. I declare that I have no conflicts of interest.
James D Shelton [email protected] US Agency for International Development, Washington, DC 20523, USA 1
2
3
4
5
Hollingsworth DT, Anderson RM, Fraser C. HIV transmission by stage of infection. J Infect Dis 2008; 198: 687–93. Granich R, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy fro elimination of HIV transmission: a mathematical model. Lancet 2009; 373: 48–57. Mermin J, Musinguzi J, Opio A, et al. Risk factors for recent HIV infection in Uganda. JAMA 2008; 300: 540–48. Gregson S, Nyamukapa CA, Garnett GP, et al. Sexual mixing patterns and sex-differentials in teenage exposure to HIV infection in Zimbabwe. Lancet 2002; 359: 1896–903. Guwatudde D, Wabwire-Mangen F, Eller LA, et al. Relatively low HIV infection in rural Uganda, but with a high potential for a rise: a cohort study in Kayunga district, Uganda. PLoS ONE 2009; 4: e4145.
Have we reached a plateau in adjuvant breast cancer therapy? We congratulate Paul Ellis and colleagues (May 16, p 1681)1 for doing the TACT trial of sequential docetaxel as adjuvant chemotherapy for early breast cancer. Patient accrual was rapid, the population large, the control group appropriate, and quality of life was assessed. The question was also very relevant: many oncologists
considered the role of adjuvant taxanes as something already settled. The study has a definite “positive” result: we are now justified in sparing our patients the toxicity and inconvenience of docetaxel treatment which caused a “significantly greater impairment” in quality of life. Given the lack of efficacy of taxanes in the adjuvant setting, despite their acknowledged activity in metastatic disease, have we reached a sort of plateau in the adjuvant treatment of breast cancer? After the progress provided by cyclophosphamide, methotrexate, and fluorouracil, there has been a smaller improvement with the introduction of anthracyclines, and taxanes are apparently unable to further increase results. It seems likely that, after the removal of the primary tumour and of regional lymph nodes, some cells do remain that are resistant to most anticancer agents. This resistance might be due to the biochemical properties of these cells or to a sort of “dormant state” that might confer resistance to antiproliferative agents We declare that we have no conflicts of interest.
*Giovanni Codacci-Pisanelli, Gian Paolo Spinelli, Fedro A Peccatori [email protected] University of Rome “La Sapienza”, 00161 Rome, Italy (GCP, GPS); and European institute of Oncology, Milan. Italy (FAP) 1
Ellis P, Barrett-Lee P, Johnson L, et al. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet 2009; 373: 1681–92.
Multimorbidity: another key issue for cardiovascular medicine Colette Jackson and colleagues (Aug 15, p 543)1 show that an increased urinary albumin to creatinine ratio is a powerful and independent predictor of prognosis in heart failure. This increased recognition of the potential interplay between heart 1421
Science Photo Library
Correspondence
See Articles page 1441
disease and chronic kidney disease is welcome since multimorbidity—the simultaneous coexistence in single patients of more than one disease—is the rule rather than the exception in primary care.2 However, the failure of your associated Editorial3 to highlight this interplay is another example of a “barrier” that exists in the fight against heart disease. This is the barrier of reductionism, whereby most research and the evidence-based clinical guidelines that follow are diseasespecific. The practice of excluding patients with significant multimorbidity from clinical trials contributes to a lack of evidence with regard to appropriate interventions in this group. The identification of trial participants through secondary-care settings and the lack of reporting of multimorbidity in patients enrolled4 further limits the applicability of some research findings to the primary-care population. We must begin to see our patients without the blinkers of reductionism and our research must come to reflect this approach. A step in the right direction is the concept of cardiovascular multimorbidity (coexisting cardiovascular disease, diabetes, and chronic kidney disease), which has already been shown to be an independent predictor of prognosis in patients with established cardiovascular disease.5 Cardiovascular multimorbidity, therefore, is not simply an accumulation of conditions but rather an important collision of risk factors promoting the specific outcomes of death and cardiovascular events. I declare that I have no conflicts of interest.
Liam G Glynn [email protected] Department of General Practice, National University of Ireland, Galway, Ireland 1
1422
Jackson CE, Solomon SD, Gerstein HC, et al. Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet 2009; 374: 543–50.
2
3 4
5
Fortin M, Bravo G, Hudon C, Vanasse A, Lapointe L. Prevalence of multimorbidity among adults seen in family practice. Ann Fam Med 2005; 3: 223–28. The Lancet. Heart disease: breaking down barriers. Lancet 2009; 374: 501. Fortin M, Dionne J, Pinho G, Gignac J, Almirall J, Lapointe L. Randomized controlled trials: do they have external validity for patients with multiple comorbidities? Ann Fam Med 2006; 4: 104–08. Glynn LG, Reddan D, Newell J, Buckley B, Dinneen S, Murphy AW. Multimorbidity and risk among patients with established cardiovascular disease: a cohort study. Br J General Practice 2008; 58: 488–94.
exposed repeatedly—using whichever forms of written text and speech seem to have been successful in the past in persuading some people to take them seriously. Did you really wish to imply that the interests of readers and editors (and probably publishers) should trump those of patients? I declare that I have no conflicts of interest.
Iain Chalmers [email protected] James Lind Library, Oxford OX2 7LG, UK 1
Intentional self-plagiarism The title of your Aug 29 Editorial1 implies that self-plagiarism must be either “unintentional, harmless, or fraud”. I have suggested previously in The Lancet that forms of scientific misconduct should be ranked by their potential for doing harm to patients: biased reporting of research, for example, has more serious consequences for patients than undeserved authorship and plagiarism.2 This sentence is an example of intentional self-plagiarism. I have reused words used in a previous publication because they help me to challenge the Editorial’s implication. The Editorial characterises selfplagiarism in review or opinion papers as “an attempt to deceive editors and readers”, and that, at best, it “constitutes intellectual laziness”. Most of my recent publications are “opinion” papers, so I resent this ex cathedra judgment, unsupported by any references to empirical evidence. I reuse my previously used words intentionally in my repeated attempts to persuade readers and editors to take serious problems seriously. Problems such as publication bias and failure to set reports of research, systematically, in the context of other relevant evidence are serious because they have been shown empirically to threaten the interests of patients.3 Because such important problems continue to be widely ignored4 they must be
2 3
4
The Lancet. Self-plagiarism: unintentional, harmless or fraud? Lancet 2009; 374: 664. Chalmers I. Preventing scientific misconduct. Lancet 2006; 368: 450. Chalmers I. The lethal consequences of failing to make use of all relevant evidence about the effects of medical treatments: the need for systematic reviews. In: Rothwell P, ed. Treating individuals: from randomised trials to personalised medicine. Amsterdam: Elsevier, 2007: 37–58. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet 2009; 374: 86–89.
Department of Error Pagel C, Lewycka S, Colbourn T, et al. Estimation of potential effects of improved communitybased drug provision, to augment health-facility strengthening, on maternal mortality due to post-partum haemorrhage and sepsis in subSaharan Africa: an equity-effectiveness model. Lancet 2009; 374: 1441–48—In this Article (Oct 24), the degree for Tarek Meguid should have been MD, and the degree for Grace Chiudzu should have been FCOG(SA). Smolen JS, Kay J, Doyle M K, et al, for the GO-AFTER study investigators. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet 2009; 374: 210–21— In this Article (July 18), the affiliation for R Landewé (p 210) should have been: “Maastricht University Medical Center and CAPHRI School, Maastricht University, Maastricht, Netherlands”. The number of patients on 100 mg golimumab with a DAS28 (EULAR) response at week 14 in table 3 (p 214) should have been “90 (59%)”. The GO-AFTER study investigator from Tamarac, FL, USA was Steven Kimmel (p 220). In the webappendix, the heading for section B (p 5) should have been “Proportions of patients who achieve an ACR20 response at week 14 by previous TNF-α inhibitor for patients who had previously received 1 TNF-α inhibitor and discontinued that agent because of lack of effectiveness”.
www.thelancet.com Vol 374 October 24, 2009
evident. By definition a heterosexual epidemic requires multiple partnering in some form. That leaves only two broad categories—serial monogamy and the range of overlapping or concurrent partnerships I describe in my Comment. Concurrent partnerships allow for infection to pass to and from connecting sexual networks. By contrast, within a monogamous relationship, infection is essentially trapped, often for some years. It is simply not plausible that serial monogamy by itself could generate the explosive generalised epidemics of eastern and southern Africa, especially in view of HIV’s fortunately relatively low heterosexual infectivity. Indeed, modelling studies indicate that serial monogamy fails to generate propagation at generalised epidemic levels.1 Thus, ironically, one of the correspondence authors (BW) recently coauthored a paper that resorted to unrealistically high concurrency to emulate South Africa’s epidemic— eight partners per year, with four concurrently at any time!2 However, assessing concurrency does present challenges. One chief difficulty is under-reporting of multiple partners, particularly among women. Another is the somewhat distal relation with infection: the link between current infection and previous behaviour can be many years. And it is mainly one’s partner’s concurrency that increases one’s risk, not one’s own concurrency. These and other reasons obscure assessment of a possible link in the studies cited by Lurie and colleagues. Conversely, Lurie and colleagues overlook more precise epidemiological evidence to support a key role for concurrency. For example, an analysis of new infections in couples in Uganda’s national HIV/AIDS serobehavioural survey3 found that most new infections were introduced from outside the partnership into a previously negative couple. Either one partner became infected, or both in rapid succession. Another intensive study from Zimbabwe4 found a two-fold higher www.thelancet.com Vol 374 October 24, 2009
risk of HIV prevalence among young women whose “Recent partner has other partners.” And a cohort study from Uganda5 found “The single most important behavioral characteristic associated with incident HIV infection was the number of times in the past 6 months, a participant had sex with person(s) they suspected were having sex with others.” That this evidence emerges notwithstanding the analytical difficulties described above, implies a very strong association. Multiple partnering includes many behaviours. Programmatically we need to help people understand the risks from any of them and underlying sexual networks. I declare that I have no conflicts of interest.
James D Shelton [email protected] US Agency for International Development, Washington, DC 20523, USA 1
2
3
4
5
Hollingsworth DT, Anderson RM, Fraser C. HIV transmission by stage of infection. J Infect Dis 2008; 198: 687–93. Granich R, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy fro elimination of HIV transmission: a mathematical model. Lancet 2009; 373: 48–57. Mermin J, Musinguzi J, Opio A, et al. Risk factors for recent HIV infection in Uganda. JAMA 2008; 300: 540–48. Gregson S, Nyamukapa CA, Garnett GP, et al. Sexual mixing patterns and sex-differentials in teenage exposure to HIV infection in Zimbabwe. Lancet 2002; 359: 1896–903. Guwatudde D, Wabwire-Mangen F, Eller LA, et al. Relatively low HIV infection in rural Uganda, but with a high potential for a rise: a cohort study in Kayunga district, Uganda. PLoS ONE 2009; 4: e4145.
Have we reached a plateau in adjuvant breast cancer therapy? We congratulate Paul Ellis and colleagues (May 16, p 1681)1 for doing the TACT trial of sequential docetaxel as adjuvant chemotherapy for early breast cancer. Patient accrual was rapid, the population large, the control group appropriate, and quality of life was assessed. The question was also very relevant: many oncologists
considered the role of adjuvant taxanes as something already settled. The study has a definite “positive” result: we are now justified in sparing our patients the toxicity and inconvenience of docetaxel treatment which caused a “significantly greater impairment” in quality of life. Given the lack of efficacy of taxanes in the adjuvant setting, despite their acknowledged activity in metastatic disease, have we reached a sort of plateau in the adjuvant treatment of breast cancer? After the progress provided by cyclophosphamide, methotrexate, and fluorouracil, there has been a smaller improvement with the introduction of anthracyclines, and taxanes are apparently unable to further increase results. It seems likely that, after the removal of the primary tumour and of regional lymph nodes, some cells do remain that are resistant to most anticancer agents. This resistance might be due to the biochemical properties of these cells or to a sort of “dormant state” that might confer resistance to antiproliferative agents We declare that we have no conflicts of interest.
*Giovanni Codacci-Pisanelli, Gian Paolo Spinelli, Fedro A Peccatori [email protected] University of Rome “La Sapienza”, 00161 Rome, Italy (GCP, GPS); and European institute of Oncology, Milan. Italy (FAP) 1
Ellis P, Barrett-Lee P, Johnson L, et al. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet 2009; 373: 1681–92.
Multimorbidity: another key issue for cardiovascular medicine Colette Jackson and colleagues (Aug 15, p 543)1 show that an increased urinary albumin to creatinine ratio is a powerful and independent predictor of prognosis in heart failure. This increased recognition of the potential interplay between heart 1421
Science Photo Library
Correspondence
See Articles page 1441
disease and chronic kidney disease is welcome since multimorbidity—the simultaneous coexistence in single patients of more than one disease—is the rule rather than the exception in primary care.2 However, the failure of your associated Editorial3 to highlight this interplay is another example of a “barrier” that exists in the fight against heart disease. This is the barrier of reductionism, whereby most research and the evidence-based clinical guidelines that follow are diseasespecific. The practice of excluding patients with significant multimorbidity from clinical trials contributes to a lack of evidence with regard to appropriate interventions in this group. The identification of trial participants through secondary-care settings and the lack of reporting of multimorbidity in patients enrolled4 further limits the applicability of some research findings to the primary-care population. We must begin to see our patients without the blinkers of reductionism and our research must come to reflect this approach. A step in the right direction is the concept of cardiovascular multimorbidity (coexisting cardiovascular disease, diabetes, and chronic kidney disease), which has already been shown to be an independent predictor of prognosis in patients with established cardiovascular disease.5 Cardiovascular multimorbidity, therefore, is not simply an accumulation of conditions but rather an important collision of risk factors promoting the specific outcomes of death and cardiovascular events. I declare that I have no conflicts of interest.
Liam G Glynn [email protected] Department of General Practice, National University of Ireland, Galway, Ireland 1
1422
Jackson CE, Solomon SD, Gerstein HC, et al. Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet 2009; 374: 543–50.
2
3 4
5
Fortin M, Bravo G, Hudon C, Vanasse A, Lapointe L. Prevalence of multimorbidity among adults seen in family practice. Ann Fam Med 2005; 3: 223–28. The Lancet. Heart disease: breaking down barriers. Lancet 2009; 374: 501. Fortin M, Dionne J, Pinho G, Gignac J, Almirall J, Lapointe L. Randomized controlled trials: do they have external validity for patients with multiple comorbidities? Ann Fam Med 2006; 4: 104–08. Glynn LG, Reddan D, Newell J, Buckley B, Dinneen S, Murphy AW. Multimorbidity and risk among patients with established cardiovascular disease: a cohort study. Br J General Practice 2008; 58: 488–94.
exposed repeatedly—using whichever forms of written text and speech seem to have been successful in the past in persuading some people to take them seriously. Did you really wish to imply that the interests of readers and editors (and probably publishers) should trump those of patients? I declare that I have no conflicts of interest.
Iain Chalmers [email protected] James Lind Library, Oxford OX2 7LG, UK 1
Intentional self-plagiarism The title of your Aug 29 Editorial1 implies that self-plagiarism must be either “unintentional, harmless, or fraud”. I have suggested previously in The Lancet that forms of scientific misconduct should be ranked by their potential for doing harm to patients: biased reporting of research, for example, has more serious consequences for patients than undeserved authorship and plagiarism.2 This sentence is an example of intentional self-plagiarism. I have reused words used in a previous publication because they help me to challenge the Editorial’s implication. The Editorial characterises selfplagiarism in review or opinion papers as “an attempt to deceive editors and readers”, and that, at best, it “constitutes intellectual laziness”. Most of my recent publications are “opinion” papers, so I resent this ex cathedra judgment, unsupported by any references to empirical evidence. I reuse my previously used words intentionally in my repeated attempts to persuade readers and editors to take serious problems seriously. Problems such as publication bias and failure to set reports of research, systematically, in the context of other relevant evidence are serious because they have been shown empirically to threaten the interests of patients.3 Because such important problems continue to be widely ignored4 they must be
2 3
4
The Lancet. Self-plagiarism: unintentional, harmless or fraud? Lancet 2009; 374: 664. Chalmers I. Preventing scientific misconduct. Lancet 2006; 368: 450. Chalmers I. The lethal consequences of failing to make use of all relevant evidence about the effects of medical treatments: the need for systematic reviews. In: Rothwell P, ed. Treating individuals: from randomised trials to personalised medicine. Amsterdam: Elsevier, 2007: 37–58. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet 2009; 374: 86–89.
Department of Error Pagel C, Lewycka S, Colbourn T, et al. Estimation of potential effects of improved communitybased drug provision, to augment health-facility strengthening, on maternal mortality due to post-partum haemorrhage and sepsis in subSaharan Africa: an equity-effectiveness model. Lancet 2009; 374: 1441–48—In this Article (Oct 24), the degree for Tarek Meguid should have been MD, and the degree for Grace Chiudzu should have been FCOG(SA). Smolen JS, Kay J, Doyle M K, et al, for the GO-AFTER study investigators. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet 2009; 374: 210–21— In this Article (July 18), the affiliation for R Landewé (p 210) should have been: “Maastricht University Medical Center and CAPHRI School, Maastricht University, Maastricht, Netherlands”. The number of patients on 100 mg golimumab with a DAS28 (EULAR) response at week 14 in table 3 (p 214) should have been “90 (59%)”. The GO-AFTER study investigator from Tamarac, FL, USA was Steven Kimmel (p 220). In the webappendix, the heading for section B (p 5) should have been “Proportions of patients who achieve an ACR20 response at week 14 by previous TNF-α inhibitor for patients who had previously received 1 TNF-α inhibitor and discontinued that agent because of lack of effectiveness”.
www.thelancet.com Vol 374 October 24, 2009