- Email: [email protected]
Telmisartan in high-risk patients intolerant of ACE inhibitors
Correspondence
Our modest interpretation of this trial is that most patients were not on proven treatments—eg, just over half were on statins. The reporting of trials is an important issue: one that has been shown to lead to interpretation bias when different stakeholders assign their individual values to the conclusions.4 We declare that we have no conflict of interest.
*Matthew Thompson, Carl Heneghan, Rafael Perera [email protected] Oxford Centre for Monitoring and Diagnosis (MT, RP) and Centre for Evidence Based Medicine (CH), Department of Primary Health Care, University of Oxford, Oxford OX3 7LF, UK 1
2
3
4
The Telmisartan Randomised AssesssmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008; 372: 1174–83. Montori VM, Busse JW, Permanyer-Miralda G, Ferreira I, Guyatt GH. How should clinicians interpret results reflecting the effect of an intervention on composite endpoints: should I dump this lump? ACP J Club 2005; 143: A8. Dickersin K, Min YI. Publication bias: the problem that won’t go away. Ann N Y Acad Sci 1993; 703: 135–46. McCormack J, Greenhalgh T. Seeing what you want to see in randomised controlled trials: versions and perversions of UKPDS data. BMJ 2000; 320: 1720–23.
On the basis of a comparison with related trials, the TRANSCEND investigators1 state that their results “should help to dispel concerns that [angiotensin-receptor blockers] might not reduce MI”. We disagree. In the TRANSCEND study,1 patients assigned telmisartan had an identical 5-year mortality (12·3%) to those assigned placebo in the HOPE study2 (12·2%) despite a major difference in the reported rate of “MI [myocardial infarction] events” (3·9% vs 12·3%). Death from all causes has the advantage of being consistently defined and occurring only once per patient. “MI events” is a less clearly defined outcome. In the ONTARGET trial,3 for example, patients could have more than one MI event. This method of counting contrasts with 458
the one reported for the HOPE trial,2 which considered a single MI event per patient, including those that might have occurred after stroke— the other non-fatal component of a composite primary endpoint. In further contrast, the PROFESS trial4 counted MI as a single event per patient, but excluded those that might have occurred after stroke or heart failure. The TRANSCEND data for MI are reported without clarification as to which of these three methods of event counting was used. Interpretation and comparison are therefore impossible. Given the importance of this issue, we request that MI event rates are given for TRANSCEND (as well as for ONTARGET and PROFESS) according to the method for counting events used in the index HOPE study. AH has received research grants from AstraZeneca, Servier UK, and Sanofi-Aventis UK; has received honoraria from AstraZeneca and Servier UK; and has been paid consultant fees by Servier UK. MHS has received honoraria from Sanofi-Aventis, Pfizer, and Abbott; has served as an expert witness for Sanofi-Aventis; and has served as a consultant/advisory board member for Sanofi-Aventis, Novartis, and Pfizer.
Alistair Hall, *Martin H Strauss [email protected] Clinical Cardiology, C-NET Research Group, LIGHT (Leeds Institute for Genetics Health and Therapeutics), Faculty of Medicine, University of Leeds, Leeds, UK (AH); and Division of Cardiovascular Surgery, Saint Michael’s Hospital, Toronto, Ontario M5B 1W8, Canada (MHS) 1
2
3
4
The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008; 372: 1174–83. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145–53. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–59. Yusuf S, Diener HC, Sacco RL, et al, for the PROFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008; 359: 1225–37.
In the TRANSCEND study,1 the angiotensin-receptor blocker telmisartan was no better than placebo in preventing the primary outcome of cardiovascular death, myocardial infarction, stroke, or hospital admission for heart failure (p=0·216). In particular, the lack of effect of telmisartan on admission for heart failure is unexpected, in light of the HOPE trial results2 and the noninferiority of ONTARGET.3 A closer inspection of co-medication use in TRANSCEND shows that nonstudy diuretics were more commonly used in the placebo group than the telmisartan group: 33·7% of the patients on telmisartan versus 40·0% on placebo (p<0·0001). In ALLHAT,4 diuretics had more effect on heartfailure-relatedendpointsthandidangiotensin-converting-enzyme inhibitors, possibly by masking symptoms of volume overload in the placebo group. This possibility should be commented on by the TRANSCEND investigators. In conclusion, the positive effects of telmisartan might have been counterbalanced by the favourable effects of diuretics, acting as “kill-joys” in TRANSCEND. We declare that we have no conflict of interest.
*Andreas Link, Jan Christian Reil, Simina Selejan [email protected] Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany 1
2
3
4
The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008; 372: 1174–83. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145–53. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–59. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-lowering Treatment to prevent Heart Attack Trial. JAMA 2002; 288: 2981–97.
www.thelancet.com Vol 373 February 7, 2009
Our modest interpretation of this trial is that most patients were not on proven treatments—eg, just over half were on statins. The reporting of trials is an important issue: one that has been shown to lead to interpretation bias when different stakeholders assign their individual values to the conclusions.4 We declare that we have no conflict of interest.
*Matthew Thompson, Carl Heneghan, Rafael Perera [email protected] Oxford Centre for Monitoring and Diagnosis (MT, RP) and Centre for Evidence Based Medicine (CH), Department of Primary Health Care, University of Oxford, Oxford OX3 7LF, UK 1
2
3
4
The Telmisartan Randomised AssesssmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008; 372: 1174–83. Montori VM, Busse JW, Permanyer-Miralda G, Ferreira I, Guyatt GH. How should clinicians interpret results reflecting the effect of an intervention on composite endpoints: should I dump this lump? ACP J Club 2005; 143: A8. Dickersin K, Min YI. Publication bias: the problem that won’t go away. Ann N Y Acad Sci 1993; 703: 135–46. McCormack J, Greenhalgh T. Seeing what you want to see in randomised controlled trials: versions and perversions of UKPDS data. BMJ 2000; 320: 1720–23.
On the basis of a comparison with related trials, the TRANSCEND investigators1 state that their results “should help to dispel concerns that [angiotensin-receptor blockers] might not reduce MI”. We disagree. In the TRANSCEND study,1 patients assigned telmisartan had an identical 5-year mortality (12·3%) to those assigned placebo in the HOPE study2 (12·2%) despite a major difference in the reported rate of “MI [myocardial infarction] events” (3·9% vs 12·3%). Death from all causes has the advantage of being consistently defined and occurring only once per patient. “MI events” is a less clearly defined outcome. In the ONTARGET trial,3 for example, patients could have more than one MI event. This method of counting contrasts with 458
the one reported for the HOPE trial,2 which considered a single MI event per patient, including those that might have occurred after stroke— the other non-fatal component of a composite primary endpoint. In further contrast, the PROFESS trial4 counted MI as a single event per patient, but excluded those that might have occurred after stroke or heart failure. The TRANSCEND data for MI are reported without clarification as to which of these three methods of event counting was used. Interpretation and comparison are therefore impossible. Given the importance of this issue, we request that MI event rates are given for TRANSCEND (as well as for ONTARGET and PROFESS) according to the method for counting events used in the index HOPE study. AH has received research grants from AstraZeneca, Servier UK, and Sanofi-Aventis UK; has received honoraria from AstraZeneca and Servier UK; and has been paid consultant fees by Servier UK. MHS has received honoraria from Sanofi-Aventis, Pfizer, and Abbott; has served as an expert witness for Sanofi-Aventis; and has served as a consultant/advisory board member for Sanofi-Aventis, Novartis, and Pfizer.
Alistair Hall, *Martin H Strauss [email protected] Clinical Cardiology, C-NET Research Group, LIGHT (Leeds Institute for Genetics Health and Therapeutics), Faculty of Medicine, University of Leeds, Leeds, UK (AH); and Division of Cardiovascular Surgery, Saint Michael’s Hospital, Toronto, Ontario M5B 1W8, Canada (MHS) 1
2
3
4
The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008; 372: 1174–83. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145–53. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–59. Yusuf S, Diener HC, Sacco RL, et al, for the PROFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008; 359: 1225–37.
In the TRANSCEND study,1 the angiotensin-receptor blocker telmisartan was no better than placebo in preventing the primary outcome of cardiovascular death, myocardial infarction, stroke, or hospital admission for heart failure (p=0·216). In particular, the lack of effect of telmisartan on admission for heart failure is unexpected, in light of the HOPE trial results2 and the noninferiority of ONTARGET.3 A closer inspection of co-medication use in TRANSCEND shows that nonstudy diuretics were more commonly used in the placebo group than the telmisartan group: 33·7% of the patients on telmisartan versus 40·0% on placebo (p<0·0001). In ALLHAT,4 diuretics had more effect on heartfailure-relatedendpointsthandidangiotensin-converting-enzyme inhibitors, possibly by masking symptoms of volume overload in the placebo group. This possibility should be commented on by the TRANSCEND investigators. In conclusion, the positive effects of telmisartan might have been counterbalanced by the favourable effects of diuretics, acting as “kill-joys” in TRANSCEND. We declare that we have no conflict of interest.
*Andreas Link, Jan Christian Reil, Simina Selejan [email protected] Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany 1
2
3
4
The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008; 372: 1174–83. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145–53. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547–59. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-lowering Treatment to prevent Heart Attack Trial. JAMA 2002; 288: 2981–97.
www.thelancet.com Vol 373 February 7, 2009