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Quality of drug advertisements in medical journals
THE LANCET
(32%). Overall, 12·6% of all printed material is dedicated to editorial comments. Finally, close inspection of the editorial comments shows that the list of references of the editorial comment are often longer than that of the article being editorialised. If the articles are so obscure, so abstract, or incomplete, or whatever, why not have the authors amend their submission before it is accepted for publication? If the commentator knows so much about the subject, why does not he write his own article and submit it to some other journal and subject himself to the process of peer and editorial review, rather than bypassing it completely? Antonio Boba 20 Echo Valley Road, Red Hook, NY 12571, USA
ED L: This letter should have followed the one from Agnes Vitry and Peter Mansfield (Nov 15, p 1477), and we apologise to Servier International for this accidental omission.
Quality of drug advertisements in medical journals SIR—With respect to our position in the ABPI Appeal Board ruling.1 The board accepted that Servier had evidence that perindopril had an effect on cardiovascular structure and that in hypertensive patients the changes that were seen tended to be a reversal of those associated with the natural progression of the disease and which were also believed to play a part in its complications. The board stated that there was little evidence that these arterial effects were accompanied by clinical benefit, and did not accept that the evidence was sufficient to enable Servier to use the word proven. Servier has many experimental and clinical data showing that perindopril can correct structural cardiovascular changes. In studies of gluteal biopsy specimens from hypertensive patients, perindopril treatment for 1 year returned to normal the increased media-to-lumen ratio of small resistance arteries and the increased lumen diameter.2 This effect was obtained independently of blood pressure reduction, since the comparative group treated with atenolol did not show any correction of its media-to-lumen ratio, or of its lumen diameter. As seen in small resistance arteries, left-ventricular hypertrophy becomes normal after perindopril in hypertensive patients. In the large arteries, compliance improved with perindopril, through to intrinsic modification of the arterial wall. In another comparative study, perindopril
1636
substantially increased carotid distensibility (an index of arterial elasticity) as opposed to the absence of improvement in the diuretic group, although blood pressure became normal in both groups.3 This clinical evidence, in our view, shows that perindopril has the ability to correct cardiovascular structural changes in hypertensive patients. That is why we disagree with the appeal board finding, but we complied with the ABPI ruling and the term proven has been withdrawn from our advertisement. With regard to the second point raised by the Medical Lobby of Appropriate Marketing (MaLAM), we dispute the statement that we claim “Coversyl provides a safer start in CHF” (congestive heart failure) on the basis of only one small study (MacFadyen et al). In fact there are three studies. Haïat and co-workers4 compared perindopril and captopril in 788 patients observed for 36 h after the first dose of perindopril (2 mg once a day for 2 days) and captopril (6·25 mg thrice daily for 2 days). Seven patients who were on perindopril had orthostatic hypotension, compared with 19 in the captopril group. Squire and colleagues5 showed differing blood pressure responses to the first oral dose of perindopril 2 mg and enalapril 2·5 mg in CHF. They stated that the firstdose response with perindopril was barely indistinguishable from the response to placebo. These three studies are accepted by regulatory authorities. In the UK, the wording of the Conversyl Summary of Product Characteristics is “In comparative studies versus placebo and other ACE [angiotensin-converting enzyme] inhibitors the first administration of Coversyl to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure as compared to placebo”. The European guidelines for data sheet’s for ACE inhibitors recommends that initiation of an ACE inhibitor should be undertaken under close medical supervision in hospital in highrisk patients in whom hypotension is likely to occur, including those with severe heart failure and those already on multiple or high-dose diuretics. This clearly includes the patient described by Bagger and alluded to by MaLAM, who had severe heart failure confirmed by an echocardiogram after a myocardial infarction. A group of experts immediately reacted to The Lancet’s consideration of this anecdotal case report which created confusion and unnecessary concern; they concluded that “perindopril is likely to keep the first-dose effect to a minimum”. L Alliot Division for Medical Affairs, Servier International, 92415 Courbevoie, France
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5
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Vitry A, Mansfield P. Quality of drug advertisements in medical journals. Lancet 1997; 350: 1477–78. Thybo NK, Stephens N, Cooper A, Aslkjacr C, Heagerty AM, Mulvany MJ. Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension. Hypertension 1995; 25: 474–81. Kool MJ, Lusterhans P, Breed JG, et al. The influence of perindopril and the diuretic combination amiloride+ hydrochlorothiazine on the vessel wall properties of large arteries in hypertensive patients. J Hypertens 1995; 13: 839–48. Haïat R, Hanania G, Gallois H. Changes in blood pressure with perindopril and captopril at initiation of treatment of left ventricular systolic dysfunction. Arch Mal Coeur Vaiss. 1996; 89: 127. Squire IB, MacFadyen RJ, Reid JL, Devlin A, Lees KR. Differing early blood pressure and renin-angiotensin system responses to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure. J Cardiovasc Pharmacol. 1996; 27: 657–66. Lees KR, Reid JL. Adverse event with firstdose perindopril in congestive heart failure. Lancet 1997; 350: 520.
DEPARTMENT OF ERROR Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension—In this article by Jan Staessen and colleagues (Sept 13, p 757–64), the information about withdrawal from the study in the left hand column, p 759, should have read: 1708 patients were not included because of blood pressure values (n=570 [33·4%]) or age (n=9 [0·5%]) outside the recruitment range, withdrawal of consent (n=275 [16·1%]), the presence or occurrence of cardiovascular illnesses prohibiting randomisation (n=126 [7·4%]), symptoms on treatment with masked placebo (n=33 [1·9%]), the need to prescribe drugs with blood-pressurelowering action (n=28 [1·6%]), or for other undocumented reasons (n=667 [39·1%]). In the right-hand column of the same page, the sentence “Among the patients in open follow-up at 2 years, 65 (36·5%) of 174 randomly assigned active treatment . . .” should have said “of 178”. In table 2, the row titles “All study drugs” and “All open follow-up” should be excluded and those numbers moved up one line to run beside the bold headings “Double-blind follow-up” and “Open follow-up”. In figure 2, in the final boxes, the numbers 1517 and 1738 should both be related to double-blind follow-up. Why “underpowered” trials are not necessarily unethical—In this viewpoint by S J L Edwards and colleagues (Sept 13, pp 804–07), the seventh sentence of the “Ethical argument” (p 806) was duplicated text and should not have appeared. Also, the concept of equipoise was misrepresented at some points in the text. Equipoise is not a property of the study or the treatments in a trial, but of individual patients. Different patients, even with identical beliefs about the likely affects of alternative treatments, will not generally have identical views about the relative benefit of the treatments. The utilities, or values, placed on a-priori outcomes vary from patient to patient. Equipoise is a patient’s belief state of agnosticism or indifference between treatments (it is best explained by Decision Analysis, which takes prior probabilities and patient utilities in account to calculate expected utilities of alternative treatments. Equipoise arises when expected utilities are equal).
Vol 350 • November 29, 1997
(32%). Overall, 12·6% of all printed material is dedicated to editorial comments. Finally, close inspection of the editorial comments shows that the list of references of the editorial comment are often longer than that of the article being editorialised. If the articles are so obscure, so abstract, or incomplete, or whatever, why not have the authors amend their submission before it is accepted for publication? If the commentator knows so much about the subject, why does not he write his own article and submit it to some other journal and subject himself to the process of peer and editorial review, rather than bypassing it completely? Antonio Boba 20 Echo Valley Road, Red Hook, NY 12571, USA
ED L: This letter should have followed the one from Agnes Vitry and Peter Mansfield (Nov 15, p 1477), and we apologise to Servier International for this accidental omission.
Quality of drug advertisements in medical journals SIR—With respect to our position in the ABPI Appeal Board ruling.1 The board accepted that Servier had evidence that perindopril had an effect on cardiovascular structure and that in hypertensive patients the changes that were seen tended to be a reversal of those associated with the natural progression of the disease and which were also believed to play a part in its complications. The board stated that there was little evidence that these arterial effects were accompanied by clinical benefit, and did not accept that the evidence was sufficient to enable Servier to use the word proven. Servier has many experimental and clinical data showing that perindopril can correct structural cardiovascular changes. In studies of gluteal biopsy specimens from hypertensive patients, perindopril treatment for 1 year returned to normal the increased media-to-lumen ratio of small resistance arteries and the increased lumen diameter.2 This effect was obtained independently of blood pressure reduction, since the comparative group treated with atenolol did not show any correction of its media-to-lumen ratio, or of its lumen diameter. As seen in small resistance arteries, left-ventricular hypertrophy becomes normal after perindopril in hypertensive patients. In the large arteries, compliance improved with perindopril, through to intrinsic modification of the arterial wall. In another comparative study, perindopril
1636
substantially increased carotid distensibility (an index of arterial elasticity) as opposed to the absence of improvement in the diuretic group, although blood pressure became normal in both groups.3 This clinical evidence, in our view, shows that perindopril has the ability to correct cardiovascular structural changes in hypertensive patients. That is why we disagree with the appeal board finding, but we complied with the ABPI ruling and the term proven has been withdrawn from our advertisement. With regard to the second point raised by the Medical Lobby of Appropriate Marketing (MaLAM), we dispute the statement that we claim “Coversyl provides a safer start in CHF” (congestive heart failure) on the basis of only one small study (MacFadyen et al). In fact there are three studies. Haïat and co-workers4 compared perindopril and captopril in 788 patients observed for 36 h after the first dose of perindopril (2 mg once a day for 2 days) and captopril (6·25 mg thrice daily for 2 days). Seven patients who were on perindopril had orthostatic hypotension, compared with 19 in the captopril group. Squire and colleagues5 showed differing blood pressure responses to the first oral dose of perindopril 2 mg and enalapril 2·5 mg in CHF. They stated that the firstdose response with perindopril was barely indistinguishable from the response to placebo. These three studies are accepted by regulatory authorities. In the UK, the wording of the Conversyl Summary of Product Characteristics is “In comparative studies versus placebo and other ACE [angiotensin-converting enzyme] inhibitors the first administration of Coversyl to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure as compared to placebo”. The European guidelines for data sheet’s for ACE inhibitors recommends that initiation of an ACE inhibitor should be undertaken under close medical supervision in hospital in highrisk patients in whom hypotension is likely to occur, including those with severe heart failure and those already on multiple or high-dose diuretics. This clearly includes the patient described by Bagger and alluded to by MaLAM, who had severe heart failure confirmed by an echocardiogram after a myocardial infarction. A group of experts immediately reacted to The Lancet’s consideration of this anecdotal case report which created confusion and unnecessary concern; they concluded that “perindopril is likely to keep the first-dose effect to a minimum”. L Alliot Division for Medical Affairs, Servier International, 92415 Courbevoie, France
1
2
3
4
5
6
Vitry A, Mansfield P. Quality of drug advertisements in medical journals. Lancet 1997; 350: 1477–78. Thybo NK, Stephens N, Cooper A, Aslkjacr C, Heagerty AM, Mulvany MJ. Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension. Hypertension 1995; 25: 474–81. Kool MJ, Lusterhans P, Breed JG, et al. The influence of perindopril and the diuretic combination amiloride+ hydrochlorothiazine on the vessel wall properties of large arteries in hypertensive patients. J Hypertens 1995; 13: 839–48. Haïat R, Hanania G, Gallois H. Changes in blood pressure with perindopril and captopril at initiation of treatment of left ventricular systolic dysfunction. Arch Mal Coeur Vaiss. 1996; 89: 127. Squire IB, MacFadyen RJ, Reid JL, Devlin A, Lees KR. Differing early blood pressure and renin-angiotensin system responses to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure. J Cardiovasc Pharmacol. 1996; 27: 657–66. Lees KR, Reid JL. Adverse event with firstdose perindopril in congestive heart failure. Lancet 1997; 350: 520.
DEPARTMENT OF ERROR Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension—In this article by Jan Staessen and colleagues (Sept 13, p 757–64), the information about withdrawal from the study in the left hand column, p 759, should have read: 1708 patients were not included because of blood pressure values (n=570 [33·4%]) or age (n=9 [0·5%]) outside the recruitment range, withdrawal of consent (n=275 [16·1%]), the presence or occurrence of cardiovascular illnesses prohibiting randomisation (n=126 [7·4%]), symptoms on treatment with masked placebo (n=33 [1·9%]), the need to prescribe drugs with blood-pressurelowering action (n=28 [1·6%]), or for other undocumented reasons (n=667 [39·1%]). In the right-hand column of the same page, the sentence “Among the patients in open follow-up at 2 years, 65 (36·5%) of 174 randomly assigned active treatment . . .” should have said “of 178”. In table 2, the row titles “All study drugs” and “All open follow-up” should be excluded and those numbers moved up one line to run beside the bold headings “Double-blind follow-up” and “Open follow-up”. In figure 2, in the final boxes, the numbers 1517 and 1738 should both be related to double-blind follow-up. Why “underpowered” trials are not necessarily unethical—In this viewpoint by S J L Edwards and colleagues (Sept 13, pp 804–07), the seventh sentence of the “Ethical argument” (p 806) was duplicated text and should not have appeared. Also, the concept of equipoise was misrepresented at some points in the text. Equipoise is not a property of the study or the treatments in a trial, but of individual patients. Different patients, even with identical beliefs about the likely affects of alternative treatments, will not generally have identical views about the relative benefit of the treatments. The utilities, or values, placed on a-priori outcomes vary from patient to patient. Equipoise is a patient’s belief state of agnosticism or indifference between treatments (it is best explained by Decision Analysis, which takes prior probabilities and patient utilities in account to calculate expected utilities of alternative treatments. Equipoise arises when expected utilities are equal).
Vol 350 • November 29, 1997