Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Regarding ALLHAT, heart failure, and race
- George A Heckman (30 May 2003)
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In poor countries the things are even worse
- Cristian Baicus, Romania (2 June 2003)
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Clinical trials: evidence based conclusions.
- Ettore Ambrosioni (12 July 2003)
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Information from drug companies and opinion leaders. Conflict of interests can be many-sided...
- Enrico Agabiti Rosei (12 July 2003)
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Is the main message that matters
- Alessandro Liberati, Dr Nicola Magrini MD, Centro Valutazione Efficacia Assistenza Sanitaria (CEVEAS) Azienda USL Modena, Italia (30 July 2003)
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George A Heckman, Clinical Scholar McMaster University, Box 2000 Station A, Hamilton, ON, CAN L8N 3Z5
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Dear editors: I agree with the authors that reports from so-called opinion leaders are overused by the pharmaceutical industry, whereas more relevant and quality evidence is rarely, if ever, discussed. However, I take issue with the seeming dismissal of some of the criticism levelled at ALLHAT as being biased and thus less than credible. First, I disagree that the absence of washout was not significant. Davis et al (BMJ 2002;325:1156) reported a very high prevalence(22.1%) of left ventricular (LV) systolic dysfunction in a community cohort of high cardiovascular risk patients, half of whom were asymptomatic. Men were more likely to have systolic dysfunction. By design, ALLHAT participants were at high-risk for cardiovascular events, and the prevalence of systolic dysfunction in ALLHAT was undoubtably important. Abrupt withdrawal of stable diuretic therapy certainly had the potential to unmask asymptomatic LV systolic dysfunction in some of these patients. The early difference in heart failure incidence between the lisinopril and chlorthalidone groups is entirely consistent with this possibility. Furthermore, the heart failure curves started merging towards the end of the trial, suggesting that perhaps longer follow-up would have shown at least equivalence, if not superiority, of lisinopril in heart failure prevention. Second, the authors suggest that the heart failure end-point was "totally validated". In ALLHAT, the heart failure diagnosis was left up to the local investigator. A single sample of 39 heart failure hospitalizations was reviewed by an ALLHAT subcommittee, who only agreed with 85% of heart failure diagnoses. In contrast, blinded endpoint committees found no difference in heart failure incidence in STOP- Hypertension 2 (Hansson et al, Lancet 1999;354:1751) or in ANBP2 (Wing et al, NEJM 2003; 348:583). In the latter study, men in particular appeared to benefit more from ACE inhibitors than diuretics, perhaps a reflection of the findings by Davis et al. Third, the authors suggest that in ALLHAT "results did not change according to race". In the ALLHAT report (JAMA 2002; 288:2981), there do appear to be race-based differences between the lisinopril and chlorthalidone group with respect to the risks of stroke, and possibly combined coronary heart disease, combined cardiovascular disease, and indeed heart failure. Unfortunately, the statistical significance of these apparent interactions is not provided. While the tone of the entire ALLHAT debate has been somewhat strident, the arguments for and against the study results should not be dismissed lightly, for we may neglect to pursue potentially important racial and gender differences. Respectfully, George A. Heckman MD FRCPC Heart and Stroke Fellow Geriatrics and Internal Medicine McMaster University Competing interests: As a geriatric medicine resident, I received funding from Astra Zeneca to attend the 1999 AHA meeting in Atlanta. |
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Cristian Baicus, Spitalul Colentina Bucharest Internal medicine / clinical epidemiology, Romania
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Dear Sirs, Romania is a poor country, and here the facts are even worse. Poor people are recommended to buy expansive drugs, whose benefit is not formidable in comparison with older and much cheaper ones. The wealthy pharmaceutical industry is not interested in promoting
the local clinical research – a lot of their money is going here in:
And probably some other destinations if we take into account the presence of a few drugs whose efficacy was never proved, on the list of reimbursed drugs. (And where do the funds of pharmaceutical industry never go? In original local research! In evidence-based medicine education!) Up to date medical information is sparse here; the majority of doctors take it from the pharmaceutical industry brochures or abstracts. A minority who enjoys the Internet can read BMJ, which is free for anybody, and the specialty journals of BMJ Group and NEJM, which are free for undeveloped countries. You cannot find recent journals at University libraries – the last subscriptions were made a decade ago. ALLHAT study is a good example for Romania, too. The titles of articles in non-professional journals and symposiums sponsored by the producer of amlodipine were: “ALLHAT demonstrated that amlodipine was efficient in lowering blood pressure”. This was true – but it wasn’t the point. Diuretics, which are 100 times cheaper, lowered blood pressure as well and with lesser side effects. A cardiology “third party” was driven the whole country in the car of the producer of rofecoxib, in order to demonstrate that this drug didn’t do any harm to the coronary patients. And this "play" culminated with a presentation at 2003 Congress of Internal Medicine, where another “third party” claimed that celecoxib, the other blockbuster among the COX2 inhibitors, might be even protective for the heart. Sincerely, I am not amazed these things happen here; I am amazed by the fact that the same happens in the super-civilized world! For example, the European Respiratory Society still recommends the chronic inhalatory corticosteroid treatment in COPD, although 3 RCT were negative, and only one, of uncertain validity, showed a reduction of exacerbations from 1,2 per year to 0,9 per year. Competing interests: None declared |
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Ettore Ambrosioni, President Italian Society of Hypertension Division of Internal Medicine University Hospital S.Orsola Via Massarenti,9 -40138 Bologna Italy
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I refer to the editorial “Information from drug companies and opinion leaders. -Double standards in information for medical journal and practitioners should go “by Alessandro Liberati and Nicola Magrini BMJ 2003;326:1156-7. As an example of this double standard which “represents a predefined strategy aimed at challenging unwelcome results” they quoted my article on ALLHAT trial printed in an Italian newspaper (1). In their editorial on BMJ the authors not only did not furnish any proof of their offensive affirmations but they operated a full distortion of my writing by omitting substantial parts and misquoting other ones. They did not even mentioned the content of the first part of my article: in this part I wrote “that ALLHAT, the largest study ever performed on treatment of hypertension, has properly found large space on the press. A minor part of these articles was reserved to the important informations obtained by the study and great emphasis was given to a partial interpretation of the results suggested by the authors” And this was of particular relevance because the results on primary end point were conditioned by those on secondary end points on which the conclusions were based. In this completely ignored first part of my article I reported the results of ALLHAT on primary end points as they have been printed on the ALLHAT main report: chlortalidone, amlodipine and lisinopril gave the same protection on coronary mortality and non fatal myocardial infarction. I do not see any possibility of a different interpretation of these results and any chance for those who wrote the editorial to evaluate my position as “double standard or a prespecified strategy aimed….” if not by ignoring the first part of my article. Following this part I continued: “the frequency of some secondary end points, stroke and combined cardiovascular diseases, was higher in the lisinopril group than in chlortalidone group”; between the two groups there was a significant difference in systolic blood pressure levels. Then I considered the possible causes of these differences in blood pressure and their consequences. The authors of the editorial beside ignoring this substantial part of my article misquoted my sentences in many ways. Let us compare what the authors of editorial attributed to me and what I wrote. In the editorial: Liberati and Magrini wrote that I saw as a major flaw in ALLHAT “the ineffectiveness of monotherapy”. What I wrote: In “more than 60% of the patients it was necessary to add a second drug to control blood pressure and some one of these drugs may increase the effect of diuretic and not that of ACE inhibitor”, which is substantially different. In the editorial: “the fact that 90% of the population was already treated with an antihypertensive drugs (doesn’t this happen in almost all hypertension trials?) What I wrote: “it is difficult to evaluate the real incidence of some cardiovascular events (i.e. heart failure)” “in absence of a period of washout when 90% of the patients were on treatment “ (mainly with diuretics). In the editorial: “heart failure was not a prespecified end point (it was, and totally validated too)”. What I wrote: “nevertheless the high number of patients, hospitals and physicians participating into the study, only 10% of diagnosis have been randomily evaluated”. On the main report of ALLHAT (2) page 2983 is stated: more detailed information was collected on a random (10%) subset of CHD and stroke events to validate the procedure of using physician diagnosis”. In the editorial: “and the follow up was too short to show differences that could became important with long term treatments (ALLHAT has one of the longest follow up among hypertension trials)”. What I wrote: “the diuretic used in ALLHAT study caused negative metabolic effects: the increase of incidence of diabetes and of cholesterol levels represents a serious problem. This problem can not be solved by saying, as the authors of ALLHAT did, that in the 2-4 years of follow up these metabolic differences did not cause any increase in cardiovascular events or in all cause mortality”. I never questioned the duration of the ALLHAT trial but I only discussed the fact that metabolic changes started in the course of the trial may causes detectable cardiovascular events before the conclusion of the trial. In the editorial: “in conclusions where the article says that ALLHAT’s results should not be applied to Italian or European clinical practice, given the countries’ low percentage of black patients (who benefit most from a thiazide diuretic treatment). Interestingly in ALLHAT main report a sub group analysis indicated that results did not change according to race”. For the first time they did not misquote me but challenged my interpretation of data. But if one examines the subgroup analysis reported in fig.6 page 2993 of the ALLHAT’s main report it can observe that the higher incidence (about + 40%) of stroke in the group receiving ACEi is in black patients. No difference between diuretic and chlortalidone could be detected in non black patients. Since the population(s), like intervention (s) and primary end point represent the basis on which one has to measure the results of a trial, I am still convinced that what I concluded does correspond to the results. It is even a paradox that expressing different opinions or drawing different conclusions on a clinical trial (an essential part of any scientific evaluation) could represent a definite demonstration of a partecipation to “a predefined strategy aimed at challenging unwelcome results”. And it is absolutely unacceptable that in order to charge other opinion leaders with these accusations the authors of the editorial have misquoted many sentences of my article and have given misleading interpretations of its content. 1)Ambrosioni E. Valutare l'effectiveness pesando tutti gli effetti.Troppa distanza dalla pratica clinica. SOLE 24 ORE SANITA'2003 4 March;21 2)ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high risk hypertensive patients randomised to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002;288:2981-97 Competing interests: EA received personal compensation for articles or lectures from following industries during the past 5 years: ABBOTT, ASTRA-ZENECA, AVENTIS PHARMA, BAYER, BOEHRINGER, BRISTOL MYERS SQUIBB, CHIESI FARMACEUTICI, GLAXOSMITHKLINE, GUIDOTTI, LUSOFARMACO, MENARINI, MERCK SHARP & DOHME, NOVARTIS, PFIZER ITALIA, PHARMACIA, RECORDATI, SANOFI-SYNTHELABO, SERVIER ITALIA, SOLVAY, SIGMA-TAU |
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Enrico Agabiti Rosei, Professor of Medicine University of Brescia
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In a recent Editorial on BMJ (1), Liberati and Magrini referred to a “predefined strategy aimed at challenging unwelcome results” from the ALLHAT study. Such a strategy would be a kind of conspiracy between “pharmaceutical companies and some opinion leaders”, aimed at denigrating ALLHAT on national journals read by practitioners or policy makers, while international journals “substantially praised the strengths” of that study.
The Editorial includes some wrong statements that must be brought to the readers’ attention because they may give them an idea of the methodology used by the authors in dealing with this matter. First, Drs. Liberati and Magrini accused me, among others, of adopting a “double standard” of information. In fact, I have expressed my view on ALLHAT in one article only (how can this be “double standard”?), i.e. the Editorial on Ipertensione e Prevenzione Cardiovascolare(2) of which I have now provided the English version at http://www.unibs.it/~castell/IPCenglish.pdf, so that the readers of BMJ may actually read what I have written and not what Liberati e Magrini wanted them to read. Second, Liberati and Magrini write that in the Journal of Hypertension ALLHAT received only favourable reports. This is false because highly critical commentaries on ALLHAT were published both in this and in other European and American Journals, including BMJ(3). For those interested, I have provided a link (http://www.unibs.it/~castell/IPCenglish.pdf) with a list of them. I hope Liberati and Magrini will consult it and avoid in the future the sin they accuse other people of, i.e. selective suppression of information. Third, Liberati and Magrini were wrong in stating that in ALLHAT 55% of the patients were controlled by monotherapy; in fact, it has been clarified that 63% of the patients required two or more drugs(4). In addition, they were also clearly wrong in stating that heart failure was “a totally validated end-point”; in fact, there was no independent Event Committee and a “soft” end-point such as heart failure was checked post-hoc in only a small sample of hospitalized cases. I fully agree that doctors must not be influenced in any biased or unfair way by drug companies and that patients should be given the best possible treatment for their disease, based on scientific evidence. I’m also convinced, however, that bias may also come from health providers and that this type of conflict of interest, namely that of Drs. Liberati and Magrini, cannot be sublimated just by defining it as a “struggle for truly independent information”. References 1. Liberati A, Magrini N. Information from drug companies and opinion leaders. BMJ 2003;326: 1156-1157. (31 May.) 2. Agabiti Rosei E. Quali nuovi insegnamenti dallo studio ALLHAT per il trattamento dell’ipertensione arteriosa. Ipertensione e Prevenzione Cardiovascolare 2002; 9:133-135. or [English translation: http://www.unibs.it/~castell/IPCenglish.pdf] 3. Williams B. Drug treatment of hypertension. BMJ 2003;326: 61-62. (11 January) 4. Cushman W.C. et al – Success and Predictors of Blood Pressure Control in Diverse North American Settings: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hyp 2002; 4: 393-404 Competing interests: EAR has received research grants, fees for consulting and reimbursements for attending symposiums from many different pharmaceutical companies as well from public institutions. He believes that this fact does not influence his view of scientific data |
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Alessandro Liberati, Associate Professor Universita´di Modena e Reggio Emilia. Modena, Italy, Dr Nicola Magrini MD, Centro Valutazione Efficacia Assistenza Sanitaria (CEVEAS) Azienda USL Modena, Italia
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Sir The responses to our editorial call for some clarifications. Overall, we believe that our alert or the risk of double standard in information between peer reviewed, non peer reviewed journals, conferences and opinion leaders remain unchallenged. We tried to support our alert with two examples: the document of the European Federation of Pharmaceutical Companies (EFPIA) and the debate that followed the publication of the ALLHAT study on hypertension management. Nobody has so far challenged our remarks about the EFPIA’s document poor quality and misleading contents and we are concerned that Dr Baicus (BMJ Rapid Responses June 2, 2003) suggested that the situation may be even worse than the one we alluded to. We are glad that Prof.’s Heckman’s (BMJ Rapid Responses May 30, 2003), Ambrosioni’s (BMJ Rapid Responses July 12, 2003) and Agabiti Rosei’s (BMJ Rapid Responses July 12, 2003) provide us with the opportunity to clarify further some points that for space reasons could not be adequately discussed in our editorial. Before going into the details, however, we want to draw readers’attention to the fact that Prof Ambrosioni confirmed what he said in the concluding message of the article we quoted (1) “it is unacceptable the transfer of ALLHAT results to Europeans, and in particular to Italian clinical practice where the percentage of black people (those who benefit of diuretic treatment) where the percentage of black people is low and very far from the 36% of the population in the study”. All those caring for hypertensive patients can judge this statement by themselves and compare it with articles and commentaries that followed the publication of ALLHAT (2) including those published in the Journal of Hypertension and referred to in Prof Agabiti Rosei’s response as well as in our Editorial Specific points were raised against ALLHAT in the two articles (1, 3) and in the Rapid Response by Heckman GA (BMJ Rapid response May 30, 2003) we referred to in our editorial: the absence of a washout period in ALLHAT, the lack of a proper validation of heart failure events, the better control of hypertension achieved with thiazides is responsible of the higher incidence of some end-points in the early stopped doxazosin arm and more recently with amlodipine and lisinopril 1 The fear of a harmful effect or the potential negative effect of switching (randomising) a patient with left ventricular disfunction already on thiazide treatment to one of the other treatments (amlodipine, lisinopril or doxazosin) is a far-fetched argument: are we really saying that a hypertensive patient should not be abruptly switched from a diuretic to another drug? Are prescribers to be informed that a patient cannot be switched so easily? We admit to be puzzled by such a statement. 2 Lack of adequate validation of heart failure and the fact it was not a pre-specified end-point. The endpoint was specified in the original protocol and the validation, as reported in the discussion in JAMA, was extensive. In their reply to critiques in fact Wright and co-workers (2) stated: “Furthermore, although heart failure events were not designed to be centrally reviewed in the original protocol, when large differences were noted between treatments groups, a staged review of the hospitalised and fatal cases, approximately 1773 of 2188 cases or 81% of heart failure cases, was initiated. … The clinical presentation, diagnostic criteria, and high-case fatality (2-year mortality rate of 20%) after the diagnosis of the heart failure observed in ALLHAT was certainly more than “ankle edema” (2). The better control of hypertension with thiazides is true in comparison with lisinopril and doxazosin whereas it is not so for amlodipine though the difference in heart failure is increased with all three. The fact that everything is due to lowering blood pressure per se seems to be contradicted by these results. Surprisingly, no comment is made by Ambrosioni and Agabiti Rosei to the fact that amlodipine - a calcium- channel blockers - is still the top-selling antihypertensive drug in Italy (4). Finally, we envy Prof Agabiti Rosei’s assertive confidence that his judgment has never been influenced by relationship with drug companies. Many articles included in the BMJ special issue and illustrating the problems emerging when “dancing with porcupines” would -in our opinion - suggest a humbler and more prudent attitude. Alessandro Liberati MD,
Nicola Magrini, MD,
REFERENCES Ambrosioni E Valutare l’effectiveness pesando tutti gli effetti. Troppa distanza dalla pratica clinica: Il Sole 24 Ore Sanità 2003, Marzo 4 pag 21 Wright JT, Davis BR, Cutler JA Long term cardiovascular consequences of diuretics vs. calcium channel blockers vs angiotensin-converting enzymes inhibitors (Reply to) JAMA 2003;289:2069-2070 Agabiti Rosei E Quali nuovi insegnamenti dallo studio ALLHAT per il trattamento della ipertensione arteriosa Ipertensione e Prevenzione Cardiovascolare 2002; 9:133-135 (available in English at http://www.unibs.it/castell/IPCenglish.pdf) Ministero della Salute. Osservatorio Nazionale dei Medicinali (OSMED) “L’uso dei farmaci in Italia. Rapporto Nazionale 2002” Roma, Il Pensiero Scientifico 2003 Competing interests: None declared |
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