Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
doxazosin
- Harvey D Sanders (14 October 2005)
-
Should we be second guessing NICE/BHS?
- Matthew Robinson (14 October 2005)
-
But are ARBs any better?
- Onisillos Sekkides (14 October 2005)
-
“Where there is discord, may we bring harmony. Where there is error, may we bring truth.”
- Des Spence (14 October 2005)
-
Don't lose your head over ASCOT
- David G Phizackerley (14 October 2005)
-
If atenolol is a wise choice, depends on the point of view.
- Thomas Kuehlein (14 October 2005)
-
Critical Appraisal Exercices are more useful than opinions
- Teresa Molina (15 October 2005)
-
Is ASCOT-BPLA being hyped-up?
- Peter D Burrill (15 October 2005)
-
Betting on ASCOT changing practice? Odds are that it’s hype.
- Martin G Duerden (16 October 2005)
-
ASCOT study can't provide guidelines for treatment of hypertension in the general population
- Fernando Prattichizzo, Fabio Galetta (16 October 2005)
-
Two more arguments why ASCOT should not lead to reconsideration of thiazide diuretics as first step in a first line treatment
- Dirk Van Duppen (16 October 2005)
-
I do not seek. I find.
- BM Hegde (16 October 2005)
-
Ascot: All it's cracked up to be?
- James A Cave (17 October 2005)
-
What level of competing interests?
- Kevin P Barraclough (17 October 2005)
-
"LIFE" for thiazides,yet.
- John S Ashcroft (17 October 2005)
-
ASCOT soundbites........or 40 years of evidence on the treatment of hypertension?
- Neal Maskrey, Jonathan L. Underhill (17 October 2005)
-
The burden of hypertension in the UK: are GPs really to blame?
- Raj Thakkar (19 October 2005)
-
"Absence of proof is not proof of absence"
- Steve Williams (21 October 2005)
-
Advice for the guideline makers
- David G Taylor (21 October 2005)
-
ASCOT - what about other beta-blockers
- Bhavisha Pattani MRPharmS (21 October 2005)
-
ASCOT: We have seen it all before
- David F. Blackburn (26 October 2005)
-
An unfair comparison, an unhelpful interpretation.
- Brett D Montgomery (26 October 2005)
-
Old or new drugs for hypertension? Don't worry, it's the same!
- Giulio Rigon, Alessandro Battaggia MD, Buzzati Agostino MD, Alberto Vaona MD, Maddalena Sarti MD (7 November 2005)
-
The ASCOT-study – a more balanced view
- Knud Landmark, Ivar Aursnes, Åsmund Reikvam (8 November 2005)
|
|
|||
|
Harvey D Sanders, Retired V7R 1K4
Send response to journal:
|
I will assume that this is a typographical error. Doxazosin is an alpha -not beta - adrenergic blocking agent. Competing interests: None declared |
|||
|
|
|||
|
Matthew Robinson, Pharmacist Blackpool, FY3 8LZ
Send response to journal:
|
This is an interesting and thought provoking editorial that may only function to add to the hype surrounding the ASCOT Study. The editorial quotes impressive looking reductions in outcomes such as CV mortality and strokes, however on closer examination of the original paper one would find that these figures are relative risk reductions and the benefits of the absolute risk reduction is by the ASCOT Authors own admissions "fairly small". The Editorial also points out that while there are (expected) differences in the rates of new onset diabetes, economic modelling of the benefits of the "newer" drugs has yet to be completed (presumably by NICE). It is therefore dangerous to second guess exactly what will happen to Hypertension Guidelines produced by NICE and BHS as this article does in the final paragraph. ASCOT adds to our knowledge and experience of Hypertension, but it does not discount all that came before it. Trials like ALLHAT should not be abandoned following the results of a smaller trial that did not reach statistical significance in its primary outcome! Competing interests: None declared |
|||
|
|
|||
|
Onisillos Sekkides, Medical Editor London, NW1
Send response to journal:
|
None of the studies presented so far have demonstrated that ARBs are any better at treating hypertension than existing, cheaper, therapies. Could it be that getting hung up on the end-organ effects of antihypertensives is just an attempt to shift the focus away from the efficacy of these drugs? Competing interests: None declared |
|||
|
|
|||
|
Des Spence, GP Glasgow
Send response to journal:
|
Newer is always better. This editorial uses the word “newer” no less than 7 times as it seeks to usher a new era in the politics of Hypertension. Oddly enough these “newer” medications are some 20 years old so the choice of such provocative language is interesting. The only “newer” antihypertensive medications are the ACE II or angiotension receptor blockers - still odder they were not even studied in ASCOT. In ASCOT, even if we assume that the observed difference between the treatment arms is not merely related to a simple lowering of blood pressure of 2.1 mmHg– which is a big IF. The NNT per year to prevent death would be around 645 and for any vascular event 220. Diabetes is arbitrary point on a metabolic continuum and therefore any reduction in incidence is questionable especially with annual NNT of over 200. Don’t look - but royal ASCOT this year is being held at Redcar ASCOT is indeed a landmark. Time for transparency. If authors receive money from companies that have direct financial interests in the results - then let us know the amount. If medical charities offer advice on treatments but receive money from companies with a financial interest in this advice - then let us know the amount. Give me old friends any day as “newer” friends aren’t always as they appear. Competing interests: NoFreeLunch-UK |
|||
|
|
|||
|
David G Phizackerley, Prescribing Team Manager, Western Sussex PCT Chichester PO19 6FX
Send response to journal:
|
For patients with hypertension and for the clinicians helping to manage their blood pressure this must be the best of times and the worst of times. The best of times - currently we have a wealth of clinical trials on the management of blood pressure, giving us a mass of data, statistics and information to absorb. The worst of times - whenever a new trial is published, the headlines are presented as though the paper gives the missing clue to a previously unsolvable riddle. Often the media are alerted and unhelpful and simplistic messages are broadcast to the nation. ASCOT merely adds to our understanding of the importance of managing blood pressure effectively. It does not cancel out the key trials of the past. In the same way ALLHAT(1) gives an indication of the benefit of diuretics in treating hypertension. ASCOT does not trump ALLHAT and the authors' assertion that diuretics will become adjunctive treatment is not supported by the evidence. The difficulty we have with ASCOT is interpreting the absolute value of the results given that the trial itself was stopped before the primary end-point reached clinical significance. Had the trial been allowed to continue would it have shown a clinically significant difference in the primary end-point? We do not know. We should not overlook the importance of some of the secondary endpoints but equally we need to see them in context, and appreciate the absolute risk reductions (ARR) and numbers needed to treat (NNT) rather than the relative risk reductions (RRR) that the editorial misleadingly quotes: All cause mortality ARR = 0.87% RRR = 11% NNT = 115 Cardiovascular mortality ARR = 0.83% RRR = 30% NNT = 120 Coronary events ARR = 1.04% RRR = 13% NNT = 96 Stroke ARR = 1.00% RRR = 29% NNT = 100 The editorial also fails to mention that the NICE Clinical Guideline (2) on hypertension actually has two arms - one combining diuretic and beta-blocker and the other combining diuretic and ACEI. Certainly the place of beta-blockers is coming under scrutiny and clarification of their position in the algorithm would be helpful. In the meantime it will be a far, far better thing that we do if we concentrate on managing the blood pressure using a range of agents. The current NICE algorithm of starting with a thiazide and adding in an ACE inhibitor seems well supported by the evidence from previous trials. We shouldn't lose our heads over ASCOT. References 1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomised to ACE inhibitor or calcium channel blocker vs diuretic – The ALLHAT Trial. JAMA 2002; 288: 2981-2997. 2. NICE Clinical Guideline 18 Competing interests: None declared |
|||
|
|
|||
|
Thomas Kuehlein, general practitioner Unterzettlitzerstr. 31, D-96231 Bad Staffelstein, Germany
Send response to journal:
|
Last year Bo Carlberg and collegues asked in the Lancet whether atenolol is a wise choice as a suitable drug for hypertensive patients or as a reference drug in outcome trials in hypertension (1). In their systematic review they found, despite major differences in blood pressure lowering, no significant outcome differences between atenolol and placebo. They found a higher cardiovascular mortality with atenolol than with other active treatment. Stroke was also more frequent with atenolol treatment. Even the authors of the ASCOT-BPLA trial adress this study and say that the results observed are not necessarily applicable to all ß-blockers. So why do all commentarys I read until now, not make a distinction at this important point? Some days ago I read the report of the Health Committee of the House of Commons on the "Influence of the Pharmaceutical Industry" and an essay by Richard Smith (2)about the role of medical journals. As an example of methods for pharmaceutical companies to get the results they want from clinical trials he recommends to conduct a trial against a treatment known to be inferior. This is what shortly came into my mind, when I read the study design of the ASCOT-BPLA trial. There is something else to be addressed. The baseline characteristics show, that 63% of the patients where older than 60 years, 33% where current smokers, mean total cholesterol was 5.9 mmol/L, 11% had previous stroke or TIA and 27% had diabetes. There is no doubt, that the patients of the study where at a fairly high risk of cardiovascular events. So why did only 11% of them get a lipid-lowering therapy and only 19% low-dose aspirin at baseline? How was the distribution of these drugs during or at the end of the 5.5 years of the study? The use of both drugs is an important variable for cardiovascular endpoints and hypertension is well known, not to be an isolated entity. What was really the question the study wanted to answer? Was it to find the best way to treat our hypertensive patients or did it just want to prove the superiority of newer drugs? As we all know, the answer depends heavily on the question and the one who poses it. 1.Carlberg B, Samuelsson O,Lindholm LH, Atenolol in hypertension: is it a wise choice? Lancet 2004;364:1684-89 2.Smith R (2005), Medical journals are an extension of the marketing arm of pharmaceutical companies, PLoS Med 2(5):e138 Competing interests: None declared |
|||
|
|
|||
|
Teresa Molina, Pharmaceutical Adviser Seville (41007 Spain)
Send response to journal:
|
ASCOT Study has been published in an academic journal, in two scientific papers. For BMJ´s readers, it would have been more useful and necessary to have included in this issue the critical appraisal of both scientific papers than to have only the editorial. The Editorial does not tell us clearly that in the second published paper, an adjusted analysis does not find differences between groups. It is surprising that BMJ publishes, without the critical appraisal exercise, an opinion about the role of “newer” drugs, including a guess about what NICE and BHS are going to recommend about first line treatment. Competing interests: None declared |
|||
|
|
|||
|
Peter D Burrill, Assistant Director of Public Health (Prescribing & Clinical Effectiveness) Chesterfield PCT, S41 7PF
Send response to journal:
|
The authors of this editorial discuss whether the small absolute differences in secondary outcomes seen in the ASCOT-BPLA study were attributable to the blood pressure differences achieved. They use the accompanying paper to argue that this was in fact not so. However, the editorial that accompanies the ASCOT-BPLA study(1) severely criticises this post-hoc analysis and considers that the 2.7mmHg systolic gradient is sufficient to explain the cardiovascular benefit of amlodipine with or without perindopril. The authors go as far as saying 'Unfortunately, the companion article in today's Lancet, by Neil Poulter and colleagues, weakens the key message that in hypertensive patients it is the lowering of blood pressure that produces most of the benefit, and thereby opens the door for possible misinterpretation, or even misuse of post-hoc results by drug marketers'. This is indeed happening and probably keeping the ABPI busy dealing with complaints. I am puzzled why, given the evidence base, that a thiazide was not chosen as the first-line drug in the 'old arm' and when atenolol was chosen, why the dose was increased to 100mg daily. The BNF has, for as long as I can remember, advised not to go above 50mg daily as all you do is increase side-effects. How much has this 'high' dose of atenolol contributed to new -onset diabetes? It is not surprising therefore that the 'old arm' lowered BP less effectively. What happened to the third line drug, doxazosin? Was it used more frequently in the atenolol arm? Given its poor performance vs thiazide in ALLHAT, this might be very important information. For an alternative view of ASCOT-BPLA, and in my opinion a more reasonable one, I would direct readers to http://www.pharmj.com/pdf/spectrum/pj_20051001_ascot.pdf. 1. Staessen JA and Birkenhager WH. Lancet 2005; 366: 869-71 Competing interests: None declared |
|||
|
|
|||
|
Martin G Duerden, General Practitioner Meddygfa Gyffin, Conwy, LL32 8LT
Send response to journal:
|
The editorial on ASCOT appears to back hype rather than evidence- based medicine[1]. The 2004 update of the British Hypertension Society’s Guideline recommends first-line use of angiotensin-modifying drugs in non- black people under 55 years of age apparently based on a study with 56 patients which looked at blood pressure response[2]. The contemporaneous NICE guideline recommendations, based on a big review which looked at tens of thousands of subjects in studies examining the clinical outcomes of death, stroke and myocardial infarction, concluded that thiazides are the most cost-effective first-line therapy for most people[3], with either ACE inhibitors or beta-blockers added in, at the next step. Should ASCOT change the NICE conclusion? Last week in the BMJ an article by Freemantle exhorted caution about reading too much into a study which failed to reach significance for the primary outcome[4]. ASCOT failed to reach significance for the primary outcome. The authors of the ASCOT editorial back ‘newer’ drugs in initial management of blood pressure[1] but ASCOT compared amlodipine (a calcium channel blocker) based therapy versus atenolol (a beta-blocker) based therapy. Amlodipine is not a new drug and is out of patent. Perindopril, a ‘newer’ drug in the ACE inhibitor class, was used as add-in therapy to amlodipine in ASCOT and is still in patent and actively promoted: Could this be related to current hype? A previous BMJ article exploring the role of perindopril in the PROGRESS study stated, “…..let's set aside arguments about elusive special drug effects and focus on the issue of prime importance. To adapt the well known words of a recent US president: "It's the blood pressure, stupid"”[5]. The odds are that it is the blood pressure and thiazides still remain cheap and effective as the first treatment for most people. [1] McDougall C, Brady AJB, and Petrie JR. ASCOT: a tale of two treatment regimens. BMJ 2005;331:859-860. [2] Dickerson JC, Hingorani AD, Ashby MJ, Palmer CR, and Brown MJ. Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet 1999:353:2008-2013. [3] National Institute for Health and Clinical Evidence. Management of hypertension in primary care. Clinical Guideline 18, August 2004. From www.nice.org.uk (accessed 14/10/05). [4] Freemantle N. How well does the evidence on pioglitazone back up researchers' claims for a reduction in macrovascular events? BMJ 2005;331:836-838. [5] MacMahon S, Neal B, Rodgers A, and Chalmers J. The PROGRESS trial three years later: time for more action, less distraction. BMJ 2004;329:970-971. Competing interests: None declared |
|||
|
|
|||
|
Fernando Prattichizzo, Medical Manager 50053 Empoli General Hospital, Fabio Galetta
Send response to journal:
|
ASCOT study was performed in a large group of patients at high risk of myocardial infarction. The finding of a better outcome in subjects treated with amlodipine and perindopril can't be extended to a general population. Large and important trials, conducted in a general population, such as ALLHAT, indicated that diuretics are first-line therapy, in black as well as in non-black patients. Competing interests: None declared |
|||
|
|
|||
|
Dirk Van Duppen, GP B-2100 Antwerp
Send response to journal:
|
Besides the already mentioned arguments against the statement of the editorial, that because of ASCOT we should reconsider thiazide diuretics as the first choice for starting a first-line treatment of hypertension as there are: the extreme-high NNT; the ASCOT-trial is in his first step a comparison between amlodipine and atenolol, and not in the first place between amlodipine and a thiazide diurectic; the fact that atenolol as first choice drug for hypertension is now questioned; the difference in blood pressure outcome between the two arms explains probably a great part of difference in clinical outcomes etc… I would like to add two more arguments. 1. The patients of the ASCOT trial are at a far high global risk of cardiovascular events. They are not representative for the patients where we must decide in the first line to start a antihypertensive drug on. If you would apply the RRR of the ASCOT trial to the baseline absolute risk of our patients, the NNT per year would probably be double or more of the figures of 645 to prevent death or 220 to prevent any vascular event. 2. This year also the results of the ALLHAT trial, where 31.512 patients were stratified by glycemic status (DM, n=13.101), impaired fasting glucose (IFG, n=1399) and normoglycemia (NG, n=17.012), have been published.(1) Neither lisinopril nor amlodipine is superior to the thiazide diuretic chlorthalidone for lowering cardiovascular risk in high- risk adults with DM, IFG or normalglycemia. Heart failure was more common in DM and NG patienst assigned amlodipine or lisinopirl as compared with chlorthalidone. And this trial was a real head to head trial between amlodipine and a thiazide diuretic. (1) Whelton P, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration and normoglycemia. Arch inter med 2005;165;1401-9. Competing interests: I'm author of "De cholesteroloorlog. Waarom geneesmiddelen zo duur zijn" (The war on cholesterol. Why drugs are so expensive. Written in Dutch.) A critical study on the influence of the pharmaceutical industry. |
|||
|
|
|||
|
BM Hegde, Retired Vice Chancellor Mangalore-575004, India
Send response to journal:
|
Dear Editor, This study makes good reading. When any study shows recent, very expensive drugs in bad light a new study gets mounted immediately and it is bound to show the previous results to be wrong! This is not the first time. When the JNC V showed thiazides to be the first line drugs in hypertension management, the next JNC report came very soon after to show that ACE inhibitors and other recent more expensive drugs are better than thiazides! ALLHAT study did show the truth, anyway. All these small studies, with study periods being short, do not give the true story. In the case of anti-hypertensive drugs, as in anti- diabetics, it is the long term results that matter. With larger numbers studied over longer periods of time, most of the studies, like the one reported here, are shown to be wrong. Statistical science of medicine is not perfect anyway. Researchers, these days, do not seek; they find, in the words of Pablo Picasso. It is our duty to help patients in distress and those who have symptoms of diseases. Any drug, including antibiotics, will have to be given to relieve symptoms and many of them in short courses do not harm the system at all. Even then care must be taken to see that the minimum drugs are used with the right indications. When it comes to long term use almost all drugs are dangerous. There are many reasons for this. One of the most important reasons is that time evolution in any dynamic system, like the human body, does not follow the linear rules. To give concrete example let us consider anti-hypertensive drugs. Most of them effectively lower the box blood pressure. If given in a healthy young man on a life long basis in the fond hope that it would keep the pressure down and do good to the patient, the results could be harmful. (Heart 1999; 82: 477-81) If the patient with hypertension has symptoms or has evidence of organ damage we have to take this risk in giving drugs on long term basis. In an otherwise healthy individual with just elevated blood pressure long term use of any drug has not been shown to be safe. It could even be harmful. (Lancet 1998; 352: 571) Long term audit did show that “well” controlled hypertensives have had two to three times higher mortality after the first five years, compared to their normotensive cousins in society. (BMJ 1998; 317: 167-71) To make matters worse, all the six international guidelines for treating high blood pressure cover just about 39% of the hypertensive population in their inclusion criteria. The rest will have to depend on their doctor’s wisdom! Similar is the story of anti-diabetic drugs. While anti-diabetic drugs do very well in managing symptomatic diabetics, they might have, possibly, even harmed some healthy asymptomatic hyperglycaemics. (Diabet. Med 1999; 16: 23-30) Reanalysis of the famous UKPDS study showed, if anything, more harm done than good to patients on oral anti-diabetic drugs in the long run. (BMJ 2000; 320: 1720-23) Yours ever, bmhegde Competing interests: None declared |
|||
|
|
|||
|
James A Cave, GP partner The Downland Practice, Chieveley, Newbury RG20 8UY
Send response to journal:
|
I wonder if I am alone in thinking the ASCOT study1 fails to answer the question it was set to answer, and moreover raises a number more. Clair McDougall and her co-authors Adrian Brady and John Petie in this week’s editorial2 seem sure that it has clearly demonstrated that the new combination of ACEI and calcium antagonist is beneficial compared with a beta-blocker and thiazide. Having now read the original papers I would now like to challenge them and at the same time ask a number of questions. I would also like to point out what the study does provide in the way of questions that might help a GP such as myself. Contrary to the editorial GPs have been responsible for their hypertensive patients for a great deal longer than 2 years.
My first question is, did the inclusion criteria bias the study against Beta-blockers? Patients with peripheral vascular disease and microalbuminuria were included whilst patients with biochemical abnormalities were not. This looks like it might favour ACEI over beta-blockers? Secondly the study showed not significant difference between the two groups with regard the primary end-points and, something that seems to be glossed over, nor was there any significant difference for secondary end-points once blood pressure differences between the two groups were allowed for3,4. The authors of the editorial state, “This analysis found it was unlikely that all the benefits seen in the patients allocated to the amlodipine-perindopril regimen were attributable solely to more effective systolic blood pressure lowering”. Does that mean they agree there is not a statistical significance or not? Thus has the ASCOT study shown that the lower the reduction in blood pressure the better (at least with regard to cardiovascular morbidity and mortality)? I think so. What ASCOT does do clearly is demonstrate the large difference in diabetes in the two groups; roughly 5.9% prevalence in the amlodipine group vs. 8.3% in the atenolol group. I would love somebody to tell me how much the difference between the two figures is “prevention” and how much is “cause”. As a GP I was also interested to see that 78% of patients required two or more agents by the end of the study, with 8% on 4 or more. Indeed only 15% of patients were on a single agent by the end of the five years. I was not surprised to see that only 53% of the patients in the study reached their target blood pressure and within the non-insulin diabetics this figure was just 32%. And lastly, as I have asked before in this journal, does a single more recent paper out weigh a meta-analysis: does this single study outweigh such meta-analyses as that by Pahor, M et al5 that clearly concluded that calcium antagonists could not be recommended as first line agents? Each new research paper provides another piece of the jigsaw (and this study adds further to the atenolol decline6) but this jigsaw will always be incomplete until we can improve concordance with our patients7 and, by matching the therapy with the individual (including the discussion of risk), ensure that greater than half reach target and a great deal less than one in five suffer adverse effects of their treatment. 1. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers GD, Caulfield M, et al. Prevention of cardiovascular events with an antihyepretensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian cardiac outcomes trial-blood pressure lowering arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906. 2. McDougall C, Brady A and Petrie J. Editorial: Ascot: a tale of two treatment regimens. BMJ 2005;331:859-60 3. Poulter NR, Wedel H, Dahlof B, Sever PS, Beevers GD, Caulfield M, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian cardiac outcomes trial-blood pressure lowering arm (ASCOT-BPLA). Lancet 2005;366:907-13 4. Poulter . Personal communication. 5. Pahor M et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies; a meta-analysis of randomised controlled trials. Lancet 2000; 356: 1949-1954 6. Carlberg B et al. Atenolol in hypertension: it is a wise choice? Lancet 2004; 364:1684-89. 7. Benson J, and Britten N. Patients' views about taking antihypertensive drugs: questionnaire study BMJ 2003; 326:1314 - 1315 Competing interests: I am a dispensing doctor and shareholder of Downland Services, a pharmacy. If I change to prescribing newer more expensive drugs I may lose out from our PCTs prescribing incentive scheme if I overspend the practice budget. Conversely use of more expensive drugs may attract more income from dispensing for myself and the pharmacy |
|||
|
|
|||
|
Kevin P Barraclough, GP Painswick, Glos GL6 6RD
Send response to journal:
|
For the first time I find myself slightly uneasy about what degree of competing interests we are supposed to consider among the authors of this editorial. It surely makes a difference whether the authors have received a few hundred pounds for sacrificing an evening to give a talk sponsored by a drug company, or, alternatively, whether the amount over a one or two year period is a hundred thousand pounds. The former would not effect my opinion as to the independence of their views. The latter amount would. It is certainly helpful to know that the authors have competing interests, but to be truly useful to readers I think it is necessary to quantify the size of those competing interests. It is not unreasonable to expect transparency in those putting themselves forward as opinion formers for the profession. Competing interests: I have experienced the luxury associated with drug company sponsorship |
|||
|
|
|||
|
John S Ashcroft, General Practitioner DE72 3EA
Send response to journal:
|
Thiazides have proven themselves time and again to be one of the safest of anti-hypertensives, and one of the best tolerated; certainly better than drugs like amlodipine and perindopril(1). Should we really be thinking of relegating thiazides from first line treatment to adjunctive therapy on the basis of the ASCOT study? One glaring omission in the authors of this editorial was of the only other study to claim a drug regime better than with "older drugs"; the LIFE study (2). Both studies where remarkably similar in that they took a particularly high risk group of patients, and they were essentially both studies of "two regimes"; the LIFE study was even more so than ASCOT. Both also used a high dose atenolol with add in thiazide as the comparator regime. The combination was used on 54.9% of days in ASCOT but on 72.4% of days in the LIFE study. The study regime in ASCOT was, as we now well know, was amlodipine with perindopril added in, with the combination used 49.5% of the time. In LIFE it was losartan with hydrochlorothiazide added in, used 73.9% of the time. Both studies showed statistically better results, of a similar magnitude, with the "newer regime", than against the atenolol based regime. The LIFE study gives considerable support to the view that thiazides still have a central role in the management of hypertension, even in combination regimes with newer drugs; so much so that following the trial a combination therapy of losartan and hydrochlorthiazide was brought out with FDA approval. The obvious explaination should be that atenolol based treatment is less effective than treatments where atenolol is not used; but then Carlberg et al (3) have already told us that. 1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomised to ACE inhibitor or calcium channel blocker vs diuretic – The ALLHAT Trial. JAMA 2002; 288: 2981-2997. 2.Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359(9311):995-1003. 3.Carlberg B, Samuelsson O,Lindholm LH, Atenolol in hypertension: is it a wise choice? Lancet 2004;364:1684-89 Competing interests: None declared |
|||
|
|
|||
|
Neal Maskrey, Medical Director National Prescribing Centre, Liverpool, L69 3GF, Jonathan L. Underhill
Send response to journal:
|
ASCOT-BPLA is a large randomised trial in an important clinical area and deserves both careful analysis and setting in the context of the rest of the evidence about the treatment of hypertension. We believe the BMJ's editorial describing the results and implications of ASCOT-BPLA paints an extreme interpretation. What questions was ASCOT-BPLA set up to answer? The main objective of ASCOT ¡V BPLA was to compare the effects of two antihypertensive regimens on the prevention of CHD in a relatively high- risk primary care population with hypertension. The primary endpoint was a composite of non-fatal MI + fatal CHD; secondary endpoints included all- cause mortality, cardiovascular (CV) mortality, stroke, heart failure, and total cardiovascular events + procedures. Two further, post-hoc combined endpoints were added during analysis of the results. These were CV mortality + MI + stroke and non-fatal MI + fatal CHD + coronary revascularisation procedures. The authors give reasons for these additions, but any post-hoc analyses need to be viewed with caution, especially in studies such as this where differences in the primary endpoint did not reach statistical significance. 19,257 patients aged 40-79 years with hypertension and at least three other cardiovascular risk factors were included and followed up for a median of 5.5 years. Risk factors included left ventricular hypertrophy, type 2 diabetes, peripheral arterial disease, previous stroke/TIA, male sex, >55 years, microalbuminuria or proteinuria, smoking, TC:HDL ratio >6, family history of premature CHD. Therefore these were people with hypertension at high risk of an event given their other multiple risk factors. However, It is not possible to identify a baseline risk fort his population since there was no placebo group. Those with previous myocardial infarction (MI), angina, a cerebrovascular event within the past three months, triglycerides >4.5mmol/l, heart failure, uncontrolled arrhythmias were excluded. Patients were mainly white and male, mean age was 63 years, BMI almost 29kg/m2, TC 5.9mmol/l and BP 164/95mmHg. 80% of patients were taking previous antihypertensive drugs, but only 11% lipid-lowering drugs and 19% aspirin - not very high proportions considering the relatively high risk of the patient population. A regimen based on a beta-blocker (atenolol) + diuretic (bendroflumethiazide plus potassium) as required was compared with one based on a calcium channel blocker (CCB, amlodipine) + ACE inhibitor (perindopril) as required. Patients were stepped through monotherapy of either atenolol or amlodipine at increasing doses, then the addition of either the thiazide diuretic or perindopril, respectively, at increasing doses, then the addition of doxazosin in order to reach target blood pressures. Initial dose titration of atenolol was from 50mg to 100mg. Initial dose titration of amlodipine was from 5mg to 10mg. With this regimen, the relatively flatter dose response curve of atenolol (the BNF says 50mg as the dose for hypertension with 100mg being "rarely necessary") would have been expected to reduce BP less, and this difference would be expected to be greater in the first part of the trial. The next titration being to 1.25mg bendroflumethiazide rather than 2.5mg may also have contributed to the less impressive early BP lowering in the atenolol-based group. At the end of the trial, 78% of patients were taking at least two antihypertensive drugs. Only 9% were taking atenolol monotherapy and 15% amlodipine monotherapy. The average number of antihypertensives used was 2.3 in the atenolol/diuretic group and 2.2 in the amlodipine/perindopril group. Given the results from the doxazosin arm of ALLHAT , it is interesting that how many patients were taking doxazosin is not stated in the paper. What happened to blood pressure in ASCOT? BP reduced substantially in both treatment groups from a mean of 164/95mmHg to a mean of 137/78mmHg. This suggests a systematic approach to managing hypertension with regular follow-up and a stepped approach to drug treatment (regardless of which drugs are used) can produce results. However, the intensity of treatment should be guided by patients, balancing their acceptance of treatment (concordance, polypharmacy, side effects) with the desired reduction in BP. Even in this trial environment, only 32% of patients with diabetes and 60% of those without diabetes had reached the BP targets set by the end of the trial. BP was reduced more in the amlodipine/perindopril group compared with the atenolol/thiazide group with an average difference throughout the trial of 2.7/1.9mmHg. This difference was statistically significant (P<0.0001). These differences were largest at three months (5.9/2.4mmHg). This difference is crucial to interpreting ASCOT. It could be that there is some factor in "newer" drugs that means they have advantages compared to older drugs -- as the authors claim in an accompanying paper based on complicated modelling techniques. However, it is well established that on a population basis very small blood pressure differences can exert large effects on CV events. Blood pressure is likely to be a key driver of differences seen in the CV morbidity and mortality endpoints, but these may also be confounded by other factors that differed between the groups such as patients mean BMI and HDL- cholesterol levels. What about the morbidity and mortality endpoints? There was no difference between the groups in the primary endpoint, non-fatal MI + fatal CHD. This occurred in 4.5% of the amlodipine/perindopril group and 4.9% of the atenolol/thiazide group (HR 0.90; 95%CI 0.79-1.02). There were statistically significant differences between the antihypertensive groups in some secondary endpoints favouring the amlodipine-based regimen (and the post-hoc endpoints that need to be viewed with caution). However, all of these differences were fairly small when viewed in absolute terms rather than in relative terms - a c1% absolute difference in all-cause mortality, CV mortality, fatal and non- fatal stroke, and in fatal and non-fatal heart failure. Total CV events + procedures occurred in 14.1% of the amlodipine/perindopril group and 16.7% of the atenolol/thiazide group (HR 0.84; 95%CI 0.78-0.90). This is an absolute difference of 2.6% or a number needed to treat (NNT) of 38 over 5.5 years. CV death + MI + stroke occurred in 8.3% and 9.7% (HR 0.84; 95%CI 0.76 to.0.92). This is an absolute difference of 1.4% or a NNT of 71 over 5.5 years. There must be a real possibility that these important differences just reflect the differences obtained in blood pressure, which may be, at least in part, a consequence of the regimens and especially the doses selected. When the results of ASCOT are set in the context of the rest of the literature of hypertension, it is grossly over-simplistic to think of drug selection in terms of "new drugs good, old drugs bad". And in terms of absolute benefits, the numbers in ASCOT are important but likely to be far less impressive in a population with hypertension but no or fewer additional risk factors. Why was the trial stopped early and what does this mean? ASCOT was stopped early when interim analysis showed significant disadvantages for patients on the atenolol-based regime. These were all- cause mortality 8.5% with atenolol/thiazide and 7.7% with amlodipine/perindopril (P=0.0247), NNT=115 over 5.5 years and CV mortality of 3.6% with atenolol/thiazide and 2.7% with amlodipine/perindopril (P=0.0010), NNT=121 over 5.5 years Stopping an RCT early creates problems. The power of the study is calculated on the primary end point -- in this case the composite of non- fatal MI + fatal CHD. In the case of ASCOT the above findings were secondary end points. As with all major trials, endpoint mortality and morbidity events were reported to a Data Safety Monitoring Board (DSMB), who decide, before the trial has started, statistical boundaries that, if exceeded, would require the trial to be stopped early. In October 2004, the DSMB recommended the trial be stopped as the atenolol/thiazide arm had significantly higher mortality than the amlodipine arm. When trials are stopped early, there is a possibility that follow up will not be long enough for sufficient endpoints to be reached, leaving the trial underpowered for these endpoints. When ASCOT was set up it was estimated that at least 18,000 patients would need to be followed up for an average of five years. This was based on an anticipated 1150 patients experiencing a primary event in the study overall, a hazard ratio (HR) for this primary event of 0.84 and a power of 80%. When the trial was stopped, fewer primary endpoints than this had been reached, 903 in total but the trial had continued for 5.5 years with 19,257 patients. The authors of ASCOT argue that this has happened here for the primary endpoint. This may be the case, but it does not mean that if the trial had continued and was powered for the primary endpoint that this would have reached statistical significance. The answer here is - we just don't know - and we shouldn't be accepting that there was no difference in the primary event rate just because the trial was stopped early. There may still have been no difference between the two antihypertensive groups if the study had continued for its planned duration. On the other hand, it is unfair to call the trial a negative study. Perhaps it should be described as a trial that did not produce a positive result for the primary endpoint. What about the diabetes issue? There was a significant increase in likelihood of developing diabetes in patients on the beta-blocker regimen compared with the amlodipine regimen (HR 0.70, 95%CI 0.63 to 0.78). The Kaplan-Meier curve suggests an absolute difference in the proportion of patients who develop diabetes of about 2% at 5 years (approx. 6% vs 8%). The clinical significance of such a finding is unclear. An analysis of the long-term SHEP data found that patients who were taking a diuretic -based regimen were more likely to develop diabetes (defined according to raised blood glucose levels) but actually had a decrease in patient- oriented outcomes (living longer or living better) than those on placebo. In keeping with ALLHAT and several other trials, ASCOT-BPLA confirms that a treatment strategy based on a beta-blocker and diuretic can increase the risk of new-onset diabetes and have other unfavourable metabolic side effects. This is recognised in the NICE guideline for hypertension, which suggests the use of an ACE inhibitor, and not a beta- blocker in combination with a diuretic is the preferred option in those at high risk of developing diabetes. What about the side effects and serious adverse events? 25% of patients stopped therapy because of an adverse event, with no significant difference between allocated treatment groups. Patterns of adverse events were mostly predictable - joint swelling 14% on amlodipine vs 3% on atenolol; peripheral oedema 23% on amlodipine vs 6% on atenolol; cough 19% on amlodipine vs 8% on atenolol; peripheral coldness 1% on amlodipine vs 6% on atenolol. Erectile dysfunction was 6% on amlodipine vs 7% on atenolol. Safety and side effects are important determinants of prescribing strategy in individual patients. That 25% of patients stopped therapy because of an adverse event points us towards an individual-based policy for drug selection in hypertension rather than a "new drugs good, old drugs bad" philosophy. So what does the publication of ASCOT-BPLA mean for practice? The findings of ASCOT should be carefully considered in the context of the rest of the evidence on hypertension treatment, which is substantial in volume and has been accumulated over more than 40 years. Just because ASCOT is the latest RCT does not mean therapy should now be based on it. ALLHAT remains the largest hypertension RCT, and arguably has a more relevant design than ASCOT. NICE recommends a thiazide as first choice for hypertension. ASCOT provides no direct evidence that the NICE guideline is inappropriate. Furthermore, the use of an atenolol-based regimen using a dose not routinely recommended for the management of uncomplicated hypertension seriously questions the validity of any results. The alternative BHS guidelines would advocate a calcium channel blocker or a diuretic as first choice in people over 55 years or who are black (these two group comprising the vast majority of people with hypertension in the UK). Setting aside that fact that the BHS ABCD approach has not been shown to have morbidity or mortality benefits in large RCTs, if we were to consider the evidence for ASCOT, ALLHAT, and the Pahor and BPLT meta-analyses of calcium channel blockers together - could we really say we should select amlodipine over a thiazide routinely, all other things being equal? Nevertheless, the study provides considerable new information on the effect of drug treatment on outcomes that matter to patients with hypertension. It strengthens the case of those who urge caution in the widespread use of beta blockers (or at least atenolol) in hypertension. But whether the NICE or BHS guidelines are followed most people without compelling co-morbidities should not be receiving atenolol as their first drug for hypertension. Hence the major thrust of ASCOT is irrelevant in the context of both UK guidelines. It is appropriate that the results of ASCOT are considered together with all the other evidence by NICE in due course. Only if and when revised guidance is issued, should a revised algorithm for use of antihypertensive drugs to that recommended by NICE be followed. So what does the publication of ASCOT-BPLA mean for individual patients? When managing patients we believe it is important to consider the treatment paradox - for individuals, unless the blood pressure is significantly raised, a few mmHg more or less make very little difference to that person¡¦s overall CV risk . However, these small differences in individual risk when multiplied by thousands produce significant reductions in CV endpoints when these are counted at the population level. One way of resolving this paradox is to manage patients on an individual basis, using a choice of regimen which the patient can tolerate, remember to take regularly and which produces a satisfactory set of blood pressure readings. It remains important to take the blood pressure precisely using immaculate technique and a recently calibrated and maintained sphygmomanometer. And most importantly - it has very recently been shown than on a population basis it is possible to reduce CV events by drug therapy, but the same paper shows conclusively that greater benefits in a population come from smoking cessation and dietary changes. Yours, Neal Maskrey
Jonathan Underhill
1. ALLHAT Officers and coordinators for the ALLHAT Collaborative Research Group. Diuretic versus alpha-blocker as first-step antihypertensive therapy. Final results from the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Hypertension 2003; 42: 239-246. 2. Staessen JA, Birkenhager WH. Evidence that new antihypertensives are superior to older drugs. Lancet 2005;366:869-870. 3. Kostis JB et al. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol 2005; 95: 29-35 4. Pahor M, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials. Lancet 2000; 356: 1949-1954. 5. Blood Pressure Lowering Treatment (BPLT) Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure- lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000; 356: 1955-1964. 6. Hansson L, et al. Effects of intensive blood-pressure lowering and low- dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1755-1762. 7. Unal B, Critchley JA, Capewell S. Modelling the decline in coronary heart disease deaths in England and Wales, 1981 ¡V 2000: comparing contributions from primary prevention and secondary prevention. BMJ 2005; 331: 614 - 7. Competing interests: None declared |
|||
|
|
|||
|
Raj Thakkar, GPSI in cardiology Wooburn Green, Buckinghamshire, HP10 0EE
Send response to journal:
|
McDougall, Brady and Petrie's overview of the ASCOT trial was succint, well written but clearly misinformed. The article infered GPs were largely to blame for the excess hypertension related deaths in the UK, a comment which only served to widen the hospital/GP gap and perhaps raise a few eyebrows amongst community doctors. So let's set the matter straight. I agree, management of the hypertension burden does largely fall on the GP. In order for the blood pressure to be controlled, the patient has to visit their doctor on a number of occasions, change their lifestyle, take medication on a regular basis and adhere to follow up. Personal choice not to take medication, side effects and continuing adverse lifestyle behaviours are common reasons why GPs can not manage to treat all patients with hypertension and reduce cardiovascular risk. Also in reference to the article, not all PCTs offer prescribing incentives. Admittedly, the quality outcome framework (QOF) provides an incentive to be agressive in hypertension management and the evidence as to whether this will impact on cardiovascular disease is awaited. I agree, there may be GPs who are unsure of the drug management of hypertension but there are also many who do. Nevertheless, patient choice and side effect profile may well influence drug making decisions. I wonder if there is any recent evidence to support the authors' comment as to whether GPs may be unsure of what drug to use first? The message here is simple, before making statements regarding the working practises and effectiveness of our colleagues, perhaps we should make an effort to be properly informed and consider issues on the other side of the fence. Dr Raj Thakkar, Principal Competing interests: None declared |
|||
|
|
|||
|
Steve Williams, Prinicipal clincal pharmacist South Manchester
Send response to journal:
|
I agree with messers Sekkides and Spence. Where in the ASCOT trial is the proof that angiotensin II blockers are not worse (ie better) than the "older" agents at treating hypertension? So is it just me that feels the conclusion to this editorial, about using angiotensin II blockers as possible first line treatment, may smack of "big pharma" influence? Competing interests: None declared |
|||
|
|
|||
|
David G Taylor, GP principal Birminham B31
Send response to journal:
|
I hope the BHS and NICE take good notice of the rapid responses here. I hear many saying thiazide first and then probably an ACE, but above all strive to find something which suits the patient and brings down the blood pressure. These seem practical resposes by the practical people who are looking after normal people with blood pressure. They are mostly GPs (but also thanks to Neal Maskrey for a useful critical summary). Could we have a less "grasshopper" responses to a new trial? I seem to remember Richard Lilford asking for a more Bayesian approach some years ago. Could we also (please Mr Editor!) ask for NNTs in all papers? Lots of us have done it on this paper; it is the only way to make sense of the relative risks they all quote. Competing interests: None declared |
|||
|
|
|||
|
Bhavisha Pattani MRPharmS, Lead Pharmacist Cardiorespiratory Glenfield Hospital, Leicester, LE5 0AG
Send response to journal:
|
I see that the authors note that not all antihypertensive agents are equal, but what about the class effect. Are all beta-blockers the same? What about the newer beta-blockers? Should there use be discouraged as first line? Many prescribers are using bisoprolol as a first line agent. What should we advise? Thanks Competing interests: None declared |
|||
|
|
|||
|
David F. Blackburn, Assistant Professor College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada, S7N
Send response to journal:
|
I read with interest the editorial of ASCOT BPLA in the October 15 issue of BMJ. Unfortunately, I must disagree with the authors’ interpretations about old versus new drugs in hypertension. Before we classify all old drugs as bad, let’s remember a recent study, ALLHAT[1], which compared the ‘old’ drug, chlorthalidone, to two newer drugs, lisinopril and amlodipine. After almost five years of follow up, chlorthalidone provided blood pressure control and cardiovascular protection that was as good as or better than newer agents. The findings of ASCOT do not trump ALLHAT and thiazide diuretics should remain a mainstay of therapy. Similarly, we have seen a comparison of atenolol with a new therapy before. In the LIFE study[2], atenolol was compared with losartan as initial therapy in patients with hypertension and LVH. Compared to atenolol, the absolute risk reductions in favour of the ‘new’ therapy were very similar to those observed in ASCOT. For example, the absolute risk reduction (ARR) in total mortality was 1.1% in LIFE versus only 0.8% in ASCOT; for death due to a cardiovascular cause, the ARR was 0.7% versus 0.9%; for stroke, the ARR was 1.7% versus 1.0% respectively. Despite equal or greater absolute differences in these endpoints, only the stroke endpoint reached statistical significance in LIFE, whereas in ASCOT, all 3 endpoints reached statistical significance on their own. The statistical differences in ASCOT were undoubtedly due to its power from a sample size at least twice that of LIFE. In the absense of compelling indications, guidelines from both Canada[3] and the UK[4] discourage using beta-blockers as initial therapy in elderly patients such as those found in LIFE, mean age 67, and ASCOT, mean age 63. Therefore, it is not clear to me how ASCOT should change guidelines so drastically, considering we have seen this all before. 1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. December 18, 2002 2002;288(23):2981-2997. 2. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. The Lancet. 2002;359(9311):995-1003. 3. Evidenced Based Recommendations Task Force of the Canadian Hypertension Education Program. 2005 Canadian Hypertension Education Program Recommendations: The bottom line version. Available at: http://www.hypertension.ca/recommendations_2005/execsummary2005.pdf. Accessed March 31st, 2005. 4. Williams B, Poulter NR, Brown MJ, et al. British Hypertension Society guidelines for hypertension management 3004 (BHS-IV): summary. BMJ. 2004;328:634-640. Competing interests: None declared |
|||
|
|
|||
|
Brett D Montgomery, General Practice Registrar Hospital General Practice, PO Box 480, Fremantle WA 6959, Australia
Send response to journal:
|
McDougall et al,1 in their commentary on the recent ASCOT-BPLA study,2 unfairly conclude that thiazides should be relegated to an adjunctive rather than first-line role in the treatment of hypertension.
As they say, ASCOT compared amlodipine +/- perindopril against atenolol +/- bendroflumethiazide, finding better outcomes for the former combination. This comparison may have been reasonable at the time that the study was planned, but in recent years, a meta-analysis of studies on atenolol in hypertension has clearly shown that it performs poorly in the prevention of cardiovascular endpoints.3 Caution is therefore needed in interpreting these results. Imagine, if you will, a comparative study of wines that compared a blend of two fine New World pinots with a blend of an excellent red Burgundy and a larger quantity of vin ordinaire. Clearly, the French wines would suffer in comparison, but to suggest that this proved the general superiority of New World wine would be to unfairly malign the Burgundy. In the context of current hypertension literature, the study design of ASCOT is similarly unfair on the thiazides. When studied on their own, thiazides prove their worth: the large and well-designed ALLHAT trial showed that a thiazide was the equal of amlodipine or an ACE inhibitor.4 ASCOT does add to the existing evidence that atenolol is a poor first-line choice for uncomplicated hypertension, but thiazides should remain the agent of first choice for many.
References 1. McDougall C, Brady AJB, Petrie JR. ASCOT: a tale of two treatment regimens. BMJ 2005;331:859-860. 2. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers GD, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian cardiac outcomes trial-blood pressure lowering arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906. 3. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet 2004; 364:1684-9. 4. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized 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: None declared |
|||
|
|
|||
|
Giulio Rigon, MD 37122, Alessandro Battaggia MD, Buzzati Agostino MD, Alberto Vaona MD, Maddalena Sarti MD
Send response to journal:
|
EQM, Evidence Quality Methods in Primary Care SIMG - Società Italiana di Medicina Generale A CRITICAL APPRAISAL “In God we trust, everyone else has to have data”: the necessity of an evidence based medicine, based on strong and rigorous data, is a common patrimony of modern western medicine. Nonetheless this necessity seems to be a wish, a trend rather than a reached goal. “ASCOT” is probably a confirmation of this impression. ASCOT is a well-conducted trial with an high methodological quality: a superiority trial, built to test the hypothesis an antihypertensive therapy based on amlodipine+perindopril is more effective than atenolol+bendroflomethazide to reduce incidence of coronary death and non fatal myocardial infarction (primary outcome). A correct randomization gave two perfectly comparable groups at the starting point with respectively 9639 and 9618 patients. Sample size was correctly tailored to primary outcome assuming an HR of 0,84, a study power of 80% (=0,20) at a two-sided significance level of 5% (=0,05). All statistical analysis techniques were correct (“intention to treat” analysis, log-rank procedure and Cox’s proportional hazards model). Even if the study was “double open”, outcomes detection was blind, saving methodological quality. Follow-up was well conducted, with a low drop-out rate (1,51%). Transferibility to real practice is fair in a western population, despite of 77% of male. The trial was halted after a mean follow-up of 5,5 years because of secondary outcomes’ (particularly all-cause mortality) excess in control group (atenolol + bendroflumethiazide). At the end of the study incidence of primary outcome (coronary mortality + non fatal myocardial infarction) was not significantly different between the two groups (HR=0,90 with CI 95% 0,79-1,02). There was a significant difference between groups, against “atenolol” group, in many secondary outcomes (all-cause mortality, cardiovascular mortality, stroke, total cardiovascular events and procedures, non fatal MI excluding silent IM + fatal CHD). Also the analysis of secondary combine outcome “total cardiovascular events and procedures” in 18 subgroups shows a significant higher incidence of events in atenolol group. Authors conclude that a therapy based on amlodipine+perindopril is more effective than a therapy based on atenolol+bendroflumethazide, because it reduces the incidence of total cardiovascular events, total mortality, and diabetes developing risk (tertiary outcome); therefore they recommend not to prescribe as first line blocker-diuretic, if it is possible to prescribe amlodipine+perindopril. It is exactly here that our “EBM-wishes” crash into reality: authors built their conclusions on data regarding secondary outcomes and emphasize subgroups analysis of a secondary and composite outcome, even if it is (or “should be” by this time) a common patrimony to consider methodologically correct only conclusions based on primary outcomes analysis. This is the reason because FDA requires randomized and well-conducted trials in which statistical power is tailored to a primary (and not secondary) outcome to authorize marketing of new drugs. Methodology teaches us that sample size is tailored to the primary outcome (1): once chosen primary outcome, the whole statistical power of the trial is spent in the analysis concerning it. Secondary outcome analyses and subgroups analyses should be consider “value added” to support conclusions of primary outcome analysis or at least to produce working hypothesis. Multiple comparisons inside the same sample presents two risks: a) a higher probability to detect differences between groups where there
are no difference ("false positive", Type I Error).
So, to analyse many secondary outcome (even statistically significant) expose to the danger that results detected represent a pure effect of chance: this danger increase with the number of comparisons applied to one sample. In the original sample ASCOT-BPLA authors made 16 comparisons in secondary outcome analysis and 18 comparisons in 9 categories of subgroups. Secondary outcomes (composite and not-indipendent) analyses in 62,5% (10/16) of the cases has inadequate sample size to demonstrate the differences they detected. The authors’ choice to base their conclusions on secondary outcome and not on primary outcome - that is hidden and minimized - is what Moyè calls “'to lock the crazy aunt in the attic” (2). Authors in 18 subgroups emphasized results of a secondary large outcome, “total cardiovascular events and procedures”: it is a skilful trick to shift results towards an increase of effects’ dimensions (3). Moreover they do not report results of primary outcome analysis in the same 18 subgroups, even though they declare they made it: did it end in the attic as the aunt? Probably a correct reading of the trial should only answer to this question: “Was the primary hypothesis of the trial satisfied or not (superiority of treatment based on amlodipine+perindopril vs atenolol+bendroflumethazide in terms of reduction of incidence of coronary deaths and non fatal myocardial infarction)?” On the basis of results reported the answer is “Not”, because values of CI95% of HR for primary outcome were 0,72-1,02. You know...Data, by means of torturing, at the end admit also they did not commit. REFERENCES 1)-Freemantle N. “Interpreting the results of secondary end-points and subgroup analyses in clinical trial: should we lock the crazy aunt in the attic?” BMJ 2001 322:989-991 2)- Moyè LA “End-point interpretation in clinical trial: the case for discipline” Control Clin.Trials 1999 20:40-9 3)- Sackett DL “ Why randomized controlled trials fail but needn’t: failure to employ phisiological statistics, or the only formula a clinician-trialist is ever likely to need ( or understand )” JAMA 2001 165(9): 1226-1237 Competing interests: None declared |
|||
|
|
|||
|
Knud Landmark, professor emeritus Departement of Pharmacotherapeutics, PB 1065 Blindern, N-0316 Oslo, Norway, Ivar Aursnes, Åsmund Reikvam
Send response to journal:
|
EDITOR - On the basis of the ASCOT-study findings, an editorial comment in BMJ recommends “more frequent prescriptions of ACE inhibitors or angiotensin receptor blockers plus calcium channel blockers as first line treatments and in combinations”.1 We do not agree that one should jump to this conclusion. Was atenolol a wise choice as a β-blocker reference drug? Certainly not, as some clinical trials have found that atenolol compared to placebo did not lower the stroke frequency, and was without effect on cardiovascular mortality.2 Moreover, in spite of similar blood-pressure reductions, cardiovascular mortality tended to be higher in atenolol-based treatments than in treatments with other antihypertensive drugs, and with a raised risk of stroke. 2,3 Other β-blockers have fared better than atenolol in clinical trials.3 As atenolol seems to have low efficacy with regard to prevention of cardiovascular events, it should not be used as a reference drug in future hypertension studies. In addition, when two antihypertensive drug regimens are compared, it is mandatory that they are equipotent with respect to the blood pressure lowering effect. That was not the case in the ASCOT-study. In conclusion, the results of the ASCOT-study do not lend support to an uncritical endorsement of the newer antihypertensive drugs. Rather, given some apparent limitations of the comparator drug regimen, the amlodipine-based treatment did not stand out in a particularly remarkable way. Knud Landmark Ivar Aursnes Åsmund Reikvam Department of Pharmacotherapeutics, University of Oslo, PB 1065
Blindern, 0316 Oslo, Norway
Competing interests: KL has received a fee for speeking from LEO Pharma A/S. 1 McDougall C, Brady AJB, Petrie JR. ASCOT: a tale of two treatments regimens. Better blood pressure, fewer deaths, and less diabetes with newer antihypertensive agents. BMJ 2005; 331: 859-60. 2 Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet 2004; 364: 1684-9. 3 Lindholm LH, Carlberg B, Samuelsson O. Should β blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005; 366: 1545-53. Competing interests: KL has received a fee for speeking from LEO Pharma A/S |
|||