- Email: [email protected]
Arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux
CORRESPONDENCE
Albumin and hypovolaemia
number of cases to attain a certain degree of competence. I submit that in the US a similar phenomenon is occurring in surgery and other specialties. For example, most residency programmes are mandated to give their residents a certain number of days off per month. This results in the aforementioned difficulties. Furthermore, some primary-care programmes limit the number of patients that a resident can admit while he or she is on call, and there are night float systems, for which a selected resident takes all of the calls in the middle of the night so the other residents on call can sleep uninterrupted. The deeper issue that I have noted as a resident is the decline in the old fashion apprenticeship model of training, which I too feel is invaluable and produces the most qualified and experienced physicians. It seems that, in the world of managed care, physicians now have to see two or three times as many patients as before and have less time to teach. In the current litigious society of the USA, attending physicians are less inclined to allow residents (and medical students) to take a more active role in patients’ management and in doing procedures. Ultimately, these two issues may lead some residents to feel that they are inadequately trained at the end of their residencies (especially in procedure-intensive fields) and lead them to pursue a fellowship for additional training. I am well aware of the good intentions of trying to limit the number of hours that residents spend working; there will be no-one to limit their hours when they have completed their training. Being a physician requires mastery of a large amount of information and the ability to deal with the demanding lifestyle. Yet it seems that medical education is being diluted. Whether the roots of these changes in the USA are an effort to decrease the risk of litigation, a result of the pressures of managed care, or from the endless complaints that come from residents that feel that they are all overworked, is unclear. The way in which residents and medical students are clinically educated is strikingly different from that seen as little as 10 years ago. Like Spitz and colleagues, I think that we are producing a generation of ill-equipped physicians, through no fault of their own.
Sir—In his response to the Viewpoint on quality of evidence on albumin and hypovolaemia, Ian Roberts (Jan 5, p 72)1 comments on activities of the plasma products industry to which we respond. Since the publication of the Cochrane report on the issue of albumin,2 there have been many questions about the strength and validity of the findings.3 The Plasma Products Therapeutics Association (PPTA) has an obligation to provide the medical community with science-based evidence about the appropriate use of albumin. Therefore, the PPTA has started several activities to provide this evidence. We cannot agree with Roberts’s statement that none of these activities help to resolve our uncertainty about albumin. We believe exactly the opposite. In May, 2001, an article was published in which the safety of albumin based on spontaneous serious (fatal and non-fatal) events was reported. These data covered around 100 million doses of albumin administrations from January, 1990, to December, 1997.4 This method is widely accepted to show safety. The study provided evidence that non-fatal and fatal serious adverse events in albumin recipients are very rare. Currently this report is being updated to include all albumin used until the end of 2000. Wilkes and colleagues5 concluded, in a meta-analysis, that postoperative blood loss is significantly lower in cardiopulmonary bypass patients exposed to albumin than in those exposed to hydroxyethyl starch. A thorough meta-analysis by Wilkes and Navickis3 could not support the findings of the Cochrane article, but showed no increase in mortality in patients receiving human albumin. In addition, the PPTA has and will continue to support research activities that help us to better understand the role and value of albumin in clinical practice. Results of these preclinical and clinical trials are and will be presented and published. That is in our view what needs to happen, in parallel with further metaanalysis that uses consistent criteria for selecting the articles similar to the process used by Wilkes and colleagues.3
William M Strub
Charles Waller
Department of Internal Medicine, Christ Hospital, 2139 Auburn Avenue, Cincinnati, OH 45219, USA 1
Spitz L, Kiely EM, Peirro A, Darke DP, McAndrew F. Decline in surgical training. Lancet 2002; 359: 83.
2278
Plasma Protein Therapeutics Association, Boulevard Brand Whitlock 114/5, 1200 Brussels, Belgium 1
Roberts I. Albumin and hypovolaemia: times to move on and generate new evidence. Lancet 2002; 359: 72–73.
2
3
4
5
Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ 1998; 317: 235–40. Wilkes MM, Navickis RJ. Patient survival after human albumin administration: a meta-analysis of randomised, controlled trials. Ann Intern Med 2001; 135: 149–64. Von Hoegen I, Waller C. Safety of human albumin based upon spontaneously reported serious adverse events. Crit Care Med 2001; 29: 994–96. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in cardiopulmonary surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg 2001; 72: 527–33.
Arterial-wall thickness and impairment in ABCA1driven cholesterol efflux Sir––In their report on cholesterol efflux and arterial-wall thickness, Marjel J van Dam and colleagues (Jan 5, p 37)1 predict the ages of reaching an intima-media thickness at the upper limit of normal (0·80 mm) in individuals with ATP-binding cassette A1 transporter (ABCA1) mutations and unaffected controls. However, I think there are some flaws in the study design and question their results. First, the prediction does not take into account the individual characteristics by which the association is affected. As described in the results, smoking and HDL cholesterol concentrations were significantly correlated with intima-media thickness. Therefore, based on van Dam and colleagues’ findings, the predicted age of reaching the upper of normal intima-media thickness should be different for smokers and non-smokers, and for individuals with different HDL cholesterol concentrations. Second, the age distributions in the two study groups differ. 15 (50·0%) patients with ABCA1 mutations and about the same number of controls are aged 30–60 years; however, a significantly lower proportion of controls (13·6%, n=15) was selected in this age range. Therefore, without specifying the matching criteria (such as within an age range or the frequency matching) in the study design, and relying only on the statistical non-significance in the mean ages, the differing age distributions violated the matching prerequisite of this study. The change of intima-media thickness with age should be assessed in a longitudinal study to assess changes over a period of time. Van Dam and colleagues used only one data point from each individual. Therefore, without evidence to describe and
THE LANCET • Vol 359 • June 29, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
support the relation within each individual, the estimated trend is meaningless and misleading. Yen-Hong Kuo Department of Research, Jersey Shore Medical Center, Meridian Health System, 1945 State Route 33, Neptune, NJ 07753, USA (e-mail: [email protected]) 1
van Dam MJ, de Groot E, Clee SM, et al. Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study. Lancet 2002; 359: 37–41.
Author’s reply Sir—Yen-Hong Kuo’s remarks are highly relevant. It is true that our main result on the upper limit of normal intima-media thickness is a global one, not discriminating between smoking and non-smoking individuals, and those with other risk factors. Since smoking and risk factors such as HDL cholesterol are associated with intima-media thickness, the upper limit will be reached later in life for non-smoking individuals and earlier for smokers. But since our controls are more or less randomly selected, our result is applicable for a random person from our population. We do not attempt to specify strata in our study since there are many risk factors, and our dataset is simply not large enough for that purpose. We used only global matching for selecting controls to compare with individuals with ABCA1 mutations to ensure the mean age was similar. Otherwise the age-distributions were not entirely similar, but our estimated regression line is still valid because age was the independent variable. Moreover, we did not select the unaffected controls on the basis of their intimamedia-thickness values. Kuo touches on the hidden premise in our analysis that the changes within individuals are supposed to be similar to the changes of the means; this assumption is basic to any crosssectional study. We have no longitudinal intimamedia-thickness measurements as yet (we are sampling these), and we cannot, therefore, confirm this assumption. The rate of intima-media-thickness change due to ageing will probably vary between individuals because of the effect of risk factors, but we believe that the average intima-media-thickness change pattern will be similar to our results, as illustrated in figure 3 in the report. John Kastelein, Eric de Groot, Koos Zwinderman Department of Vascular Medicine, Academic Medical Centre, Room G1-146, 1105 AZ, Amsterdam, Netherlands
Treatment of severe autoimmune thrombocytopenic purpura Sir—In their report, Bertrand Godeau and colleagues (Jan 5, p 23)1 elegantly show that intravenous immunoglobulin is more effective for the acute treatment of severe autoimmune thrombocytopenic purpura than methylprednisolone. However their use of a platelet count less than 50109/L as a surrogate marker for bleeding risk is slightly misleading. Bleeding risk is strongly correlated with age, the highest risk being patients older than 60 years,2 of whom their study only included small numbers. In fact a platelet count of more than 30109/L, rather than more than 50109/L is associated with an extremely low risk of haemorrhage.3 No mention is made of the difference in cost between these two treatments (around US$1228 vs $105 for a 70 kg patient), or the small but significant risks associated with intravenous immunoglobulin (anaphylaxis, haemolytic anaemia, aseptic meningitis). Thus, to recommend intravenous immunoglobulin and prednisone as first-line treatment for patients of all ages with severe thrombocytopenia (platelet count <20109/L) will lead to substantial treatment-related expense and expose some patients to potential risks when their risk of fatal haemorrhage is very low. The treatment does work, but is it needed for everyone? Duncan Carradice Department of Haematology, Christchurch Hospital, Christchurch, New Zealand (e-mail: [email protected]) 1
2
3
Godeau B, Chevtet S, Varet B, et al. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet 2002; 359: 23–29. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med 2000; 160: 1630–38. Cortelazzo S, Finazzi G, Buelli M, Molteni A, Viero P, Barbui T. High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura. Blood 1991; 77: 31–33.
Sir—We wonder why the primary outcome of Bertrand Godeau and colleagues’ trial1 was the number of days with platelet count more than 50109/L. It seems clear from the data that a platelet count at this concentration was of no real clinical use, especially in patients with no evidence
THE LANCET • Vol 359 • June 29, 2002 • www.thelancet.com
of bleeding. Indeed the risk of fatal haemorrhage is extremely low even with a platelet count lower than 30109/L.2 The so-called wet autoimmue thromobcytopenic purpura group, which is at an increased risk of haemorrhage, was excluded. Physicians need definitive answers in patients with severe autoimmue thromobcytopenic purpura, especially in those who have bleeding episodes. Unfortunately, Godeau and colleagues do not answer that question for intravenous immunoglobulin or high-dose methylprednisolone. These two treatments seem equally effective in patients with severe autoimmue thromobcytopenic purpura and no sign of haemorrhage. Rama Balaraman Ellis Fischel Cancer Hospitals and Clinics, University of Missouri, 115 Business Loop 70 West, Columbia, MO 65203, USA 1
2
Godeau B, Chevret S, Varet B, et al. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet 2002; 359: 23–29. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history of ITP in patients with persistently low platelet counts. Arch Intern Med 2000; 160: 1630–38.
Authors’ reply Sir—We agree with the remarks of Duncan Carradice and Rama Balaraman that the use of a platelet count lower than 50109/L as a surrogate marker for bleeding risk could be misleading. However, we show that the median number of days with platelet counts higher than 20109/L (and two-fold the baseline value) between day 1 and day 21 after treatment was started is significantly higher in patients assigned intravenous immunoglobulin at randomisation than in those assigned high-dose methylprednisolone. The proportion of patients who have platelet counts greater than 20109/L between day 2 and day 5 is also significantly higher in the intravenous immunoglobulin group. The number of days with platelet count greater than 20109/L also differs significantly in patients receiving intravenous immunoglobulin plus prednisolone and those receiving high-dose methylprednisolone plus prednisolone. Thus, we clearly show that intravenous immunoglobulin acts more rapidly, more frequently, and for a longer time than high-dose methylprednisolone.
2279
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Albumin and hypovolaemia
number of cases to attain a certain degree of competence. I submit that in the US a similar phenomenon is occurring in surgery and other specialties. For example, most residency programmes are mandated to give their residents a certain number of days off per month. This results in the aforementioned difficulties. Furthermore, some primary-care programmes limit the number of patients that a resident can admit while he or she is on call, and there are night float systems, for which a selected resident takes all of the calls in the middle of the night so the other residents on call can sleep uninterrupted. The deeper issue that I have noted as a resident is the decline in the old fashion apprenticeship model of training, which I too feel is invaluable and produces the most qualified and experienced physicians. It seems that, in the world of managed care, physicians now have to see two or three times as many patients as before and have less time to teach. In the current litigious society of the USA, attending physicians are less inclined to allow residents (and medical students) to take a more active role in patients’ management and in doing procedures. Ultimately, these two issues may lead some residents to feel that they are inadequately trained at the end of their residencies (especially in procedure-intensive fields) and lead them to pursue a fellowship for additional training. I am well aware of the good intentions of trying to limit the number of hours that residents spend working; there will be no-one to limit their hours when they have completed their training. Being a physician requires mastery of a large amount of information and the ability to deal with the demanding lifestyle. Yet it seems that medical education is being diluted. Whether the roots of these changes in the USA are an effort to decrease the risk of litigation, a result of the pressures of managed care, or from the endless complaints that come from residents that feel that they are all overworked, is unclear. The way in which residents and medical students are clinically educated is strikingly different from that seen as little as 10 years ago. Like Spitz and colleagues, I think that we are producing a generation of ill-equipped physicians, through no fault of their own.
Sir—In his response to the Viewpoint on quality of evidence on albumin and hypovolaemia, Ian Roberts (Jan 5, p 72)1 comments on activities of the plasma products industry to which we respond. Since the publication of the Cochrane report on the issue of albumin,2 there have been many questions about the strength and validity of the findings.3 The Plasma Products Therapeutics Association (PPTA) has an obligation to provide the medical community with science-based evidence about the appropriate use of albumin. Therefore, the PPTA has started several activities to provide this evidence. We cannot agree with Roberts’s statement that none of these activities help to resolve our uncertainty about albumin. We believe exactly the opposite. In May, 2001, an article was published in which the safety of albumin based on spontaneous serious (fatal and non-fatal) events was reported. These data covered around 100 million doses of albumin administrations from January, 1990, to December, 1997.4 This method is widely accepted to show safety. The study provided evidence that non-fatal and fatal serious adverse events in albumin recipients are very rare. Currently this report is being updated to include all albumin used until the end of 2000. Wilkes and colleagues5 concluded, in a meta-analysis, that postoperative blood loss is significantly lower in cardiopulmonary bypass patients exposed to albumin than in those exposed to hydroxyethyl starch. A thorough meta-analysis by Wilkes and Navickis3 could not support the findings of the Cochrane article, but showed no increase in mortality in patients receiving human albumin. In addition, the PPTA has and will continue to support research activities that help us to better understand the role and value of albumin in clinical practice. Results of these preclinical and clinical trials are and will be presented and published. That is in our view what needs to happen, in parallel with further metaanalysis that uses consistent criteria for selecting the articles similar to the process used by Wilkes and colleagues.3
William M Strub
Charles Waller
Department of Internal Medicine, Christ Hospital, 2139 Auburn Avenue, Cincinnati, OH 45219, USA 1
Spitz L, Kiely EM, Peirro A, Darke DP, McAndrew F. Decline in surgical training. Lancet 2002; 359: 83.
2278
Plasma Protein Therapeutics Association, Boulevard Brand Whitlock 114/5, 1200 Brussels, Belgium 1
Roberts I. Albumin and hypovolaemia: times to move on and generate new evidence. Lancet 2002; 359: 72–73.
2
3
4
5
Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ 1998; 317: 235–40. Wilkes MM, Navickis RJ. Patient survival after human albumin administration: a meta-analysis of randomised, controlled trials. Ann Intern Med 2001; 135: 149–64. Von Hoegen I, Waller C. Safety of human albumin based upon spontaneously reported serious adverse events. Crit Care Med 2001; 29: 994–96. Wilkes MM, Navickis RJ, Sibbald WJ. Albumin versus hydroxyethyl starch in cardiopulmonary surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg 2001; 72: 527–33.
Arterial-wall thickness and impairment in ABCA1driven cholesterol efflux Sir––In their report on cholesterol efflux and arterial-wall thickness, Marjel J van Dam and colleagues (Jan 5, p 37)1 predict the ages of reaching an intima-media thickness at the upper limit of normal (0·80 mm) in individuals with ATP-binding cassette A1 transporter (ABCA1) mutations and unaffected controls. However, I think there are some flaws in the study design and question their results. First, the prediction does not take into account the individual characteristics by which the association is affected. As described in the results, smoking and HDL cholesterol concentrations were significantly correlated with intima-media thickness. Therefore, based on van Dam and colleagues’ findings, the predicted age of reaching the upper of normal intima-media thickness should be different for smokers and non-smokers, and for individuals with different HDL cholesterol concentrations. Second, the age distributions in the two study groups differ. 15 (50·0%) patients with ABCA1 mutations and about the same number of controls are aged 30–60 years; however, a significantly lower proportion of controls (13·6%, n=15) was selected in this age range. Therefore, without specifying the matching criteria (such as within an age range or the frequency matching) in the study design, and relying only on the statistical non-significance in the mean ages, the differing age distributions violated the matching prerequisite of this study. The change of intima-media thickness with age should be assessed in a longitudinal study to assess changes over a period of time. Van Dam and colleagues used only one data point from each individual. Therefore, without evidence to describe and
THE LANCET • Vol 359 • June 29, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
support the relation within each individual, the estimated trend is meaningless and misleading. Yen-Hong Kuo Department of Research, Jersey Shore Medical Center, Meridian Health System, 1945 State Route 33, Neptune, NJ 07753, USA (e-mail: [email protected]) 1
van Dam MJ, de Groot E, Clee SM, et al. Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study. Lancet 2002; 359: 37–41.
Author’s reply Sir—Yen-Hong Kuo’s remarks are highly relevant. It is true that our main result on the upper limit of normal intima-media thickness is a global one, not discriminating between smoking and non-smoking individuals, and those with other risk factors. Since smoking and risk factors such as HDL cholesterol are associated with intima-media thickness, the upper limit will be reached later in life for non-smoking individuals and earlier for smokers. But since our controls are more or less randomly selected, our result is applicable for a random person from our population. We do not attempt to specify strata in our study since there are many risk factors, and our dataset is simply not large enough for that purpose. We used only global matching for selecting controls to compare with individuals with ABCA1 mutations to ensure the mean age was similar. Otherwise the age-distributions were not entirely similar, but our estimated regression line is still valid because age was the independent variable. Moreover, we did not select the unaffected controls on the basis of their intimamedia-thickness values. Kuo touches on the hidden premise in our analysis that the changes within individuals are supposed to be similar to the changes of the means; this assumption is basic to any crosssectional study. We have no longitudinal intimamedia-thickness measurements as yet (we are sampling these), and we cannot, therefore, confirm this assumption. The rate of intima-media-thickness change due to ageing will probably vary between individuals because of the effect of risk factors, but we believe that the average intima-media-thickness change pattern will be similar to our results, as illustrated in figure 3 in the report. John Kastelein, Eric de Groot, Koos Zwinderman Department of Vascular Medicine, Academic Medical Centre, Room G1-146, 1105 AZ, Amsterdam, Netherlands
Treatment of severe autoimmune thrombocytopenic purpura Sir—In their report, Bertrand Godeau and colleagues (Jan 5, p 23)1 elegantly show that intravenous immunoglobulin is more effective for the acute treatment of severe autoimmune thrombocytopenic purpura than methylprednisolone. However their use of a platelet count less than 50109/L as a surrogate marker for bleeding risk is slightly misleading. Bleeding risk is strongly correlated with age, the highest risk being patients older than 60 years,2 of whom their study only included small numbers. In fact a platelet count of more than 30109/L, rather than more than 50109/L is associated with an extremely low risk of haemorrhage.3 No mention is made of the difference in cost between these two treatments (around US$1228 vs $105 for a 70 kg patient), or the small but significant risks associated with intravenous immunoglobulin (anaphylaxis, haemolytic anaemia, aseptic meningitis). Thus, to recommend intravenous immunoglobulin and prednisone as first-line treatment for patients of all ages with severe thrombocytopenia (platelet count <20109/L) will lead to substantial treatment-related expense and expose some patients to potential risks when their risk of fatal haemorrhage is very low. The treatment does work, but is it needed for everyone? Duncan Carradice Department of Haematology, Christchurch Hospital, Christchurch, New Zealand (e-mail: [email protected]) 1
2
3
Godeau B, Chevtet S, Varet B, et al. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet 2002; 359: 23–29. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med 2000; 160: 1630–38. Cortelazzo S, Finazzi G, Buelli M, Molteni A, Viero P, Barbui T. High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura. Blood 1991; 77: 31–33.
Sir—We wonder why the primary outcome of Bertrand Godeau and colleagues’ trial1 was the number of days with platelet count more than 50109/L. It seems clear from the data that a platelet count at this concentration was of no real clinical use, especially in patients with no evidence
THE LANCET • Vol 359 • June 29, 2002 • www.thelancet.com
of bleeding. Indeed the risk of fatal haemorrhage is extremely low even with a platelet count lower than 30109/L.2 The so-called wet autoimmue thromobcytopenic purpura group, which is at an increased risk of haemorrhage, was excluded. Physicians need definitive answers in patients with severe autoimmue thromobcytopenic purpura, especially in those who have bleeding episodes. Unfortunately, Godeau and colleagues do not answer that question for intravenous immunoglobulin or high-dose methylprednisolone. These two treatments seem equally effective in patients with severe autoimmue thromobcytopenic purpura and no sign of haemorrhage. Rama Balaraman Ellis Fischel Cancer Hospitals and Clinics, University of Missouri, 115 Business Loop 70 West, Columbia, MO 65203, USA 1
2
Godeau B, Chevret S, Varet B, et al. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet 2002; 359: 23–29. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history of ITP in patients with persistently low platelet counts. Arch Intern Med 2000; 160: 1630–38.
Authors’ reply Sir—We agree with the remarks of Duncan Carradice and Rama Balaraman that the use of a platelet count lower than 50109/L as a surrogate marker for bleeding risk could be misleading. However, we show that the median number of days with platelet counts higher than 20109/L (and two-fold the baseline value) between day 1 and day 21 after treatment was started is significantly higher in patients assigned intravenous immunoglobulin at randomisation than in those assigned high-dose methylprednisolone. The proportion of patients who have platelet counts greater than 20109/L between day 2 and day 5 is also significantly higher in the intravenous immunoglobulin group. The number of days with platelet count greater than 20109/L also differs significantly in patients receiving intravenous immunoglobulin plus prednisolone and those receiving high-dose methylprednisolone plus prednisolone. Thus, we clearly show that intravenous immunoglobulin acts more rapidly, more frequently, and for a longer time than high-dose methylprednisolone.
2279
For personal use. Only reproduce with permission from The Lancet Publishing Group.