Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Coronary heart disease prevention
- Undurti N Das, Walpole, MA 02081, USA (29 November 2003)
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Coronary Heart Disease Prevention: Issues with Incremental Cost Effectiveness
- William C D'Avanzo (30 November 2003)
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Is a cure is too expensive?
- G Alastair Cooke (30 November 2003)
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Statins are even less effective
- Philipp A. Conradi (1 December 2003)
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Drugs and the Cause of Atheroma
- Eddie Vos (2 December 2003)
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From the individual patient's perspective
- Jeffrey Mann (2 December 2003)
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simavastain costs falling
- John N Fells (2 December 2003)
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Long-term efficacy of clopidogrel therapy
- Jeffrey Mann (3 December 2003)
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Further commentary on the long-term efficacy of clopidogrel in preventing adverse cardiac events
- Jeffrey Mann (4 December 2003)
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Statin side efffects
- Michael O'Donnell (4 December 2003)
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We should be looking at overall mortality
- Malcolm E Kendrick (4 December 2003)
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Simvastatin will be the "New Aspirin", even on Price
- john s ashcroft (5 December 2003)
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More thoughts on cost-effectiveness
- Adam Jacobs (5 December 2003)
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Tables of Marshall's article
- Andrea Messori, Benedetta Santarlasci (7 December 2003)
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More attention on the quality of the economic analyses is needed
- Borislava N Mihaylova, Andrew H. Briggs, and Alastair M. Gray (11 December 2003)
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Author's response
- Tom Marshall (12 December 2003)
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Independence of treatment effects
- Adam Jacobs (13 December 2003)
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Setting Risk Thresholds For Coronary Event Prevention
- Tom Love, Tom Fahey (15 December 2003)
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Undurti N Das, Research Director UND Life Sciences, 1083 Main Street, Walpole, MA 02081, USA
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I read with interest the article by Tom Marshall and the accompanying editorial Rebecca Warburton on the cost effectiveness of statins in the prevention and treatment of coronary heart disease (CAD). It is true that statins have an important role in CAD but obviously their importance has been over emphasized. There are certainly other more less expensive and dependable methods to reduce the risk of CAD. Some of them include: regular exercise, control of saturated and trans fatty acids intake, and consumption of sufficient and appropriate amounts of long-chain polyunsaturated fatty acids (LCPUFAs) such as docosahexaenoic acid (DHA) and eiocsapentaenoic acid (EPA). Several studies showed that fish oil supplementation or EPA/DHA prevents CAD, protects against cardiac arrhythmias, lowers serum cholesterol, arrests the progression of atherosclerosis, and reduces the risk of second myocardial infarction. There is reasonable evidence to suggest that EPA/DHA may function as endogenous statins (1). EPA/DHA inhibit HMG-CoA reductase activity, enhance parasympathetic activity (by enhancing brain acetylcholine levels), show to some extent actions similar to beta-blockers, suppress COX-2 activity and thus show anti-inflammatory actions (2). By virtue of these actions EPA/DHA may be considered as endogenous HMG-CoA reductase inhibitors, beta-blockers, and anti-inflammatory molecules. Based on this, I sggest that supplementation of EPA/DHA to prevent and treat CAD may be more cost-effective than using statins. References: 1. Das UN. Essential fatty acids as possible mediators of the actions of statins. Prostaglandins Leukot Essen Fatty Acids 2001; 65: 37-40. 2. Das UN. A Perinatal Strategy for Preventing Adult Disease: Thye Role of Long-chain Polyunsaturated Fatty Acids. Kluwer Academic Publishers, Boston, 2002. Competing interests: I am employed in a biotech company that supports research in the area of essential fatty acids. But does not have any products directly related to the text of the article. |
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William C D'Avanzo, none (retired) 21B Kenneth Stuart Pl., Mohegan Lake, NY 10547
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A major problem I have with the study is that it apparently did not include the cost to the health system of treatment after a MI occurs. One might even go further and estimate the cost to society of prematurely losing productive members. For example, assume in a group of 100 1 MI was prevented with treatment A and 2 with treatment B. If A costs $1/year and B $10 than A would be 5 times as cost effective as B per event prevented. However, if the cost of treatment after an event occurs is high, B could be the most cost effective. In fact, if they opperate independently A and B together may well be the best treatment. The author might have discussed what dose of statins were used. In the US, anyway, the cost is fairly constant with dose but the effectiveness on a given patient could change and, thus, so would the cost effectiveness. The author assumed a (pre-treatment) patient with a 10% risk of a coronary event over 5 years - which seems pretty low for a patient seeing a cardiologist - and then applied a relative risk based on other studies. Thus, based on meta analysis of other studies, out of 100 people who would have had a coronary event, 69 would while taking a statin. The similar figure for Aspirin is 72. (And the combined figure is 50 - from .72*.69 - which to me is a significant reduction.) I have some problems with the above. First, the 10% risk of a coronary event group biases the results toward the lower cost treatment. (If you picked a group with a very low chance of a coronary event over 5 years, e.g. 25 year old women, then obviously the cheaper treatment would be quite cost effective.) Second I'm not sure how one was able to assume some kind of population consistency between the aspirin and statin group and, more particularly, whether these groups are consistent with the 10% coronary risk group the author assumes. However, I do agree that it would be appropriate to be a little more aggressive with those at lower risk. It is the implications that some might draw that this might done at the expense of those at higher risk or the sense of an either/or between statins and asprin that others might see in this study that concerns me. William C. D'Avanzo Competing interests: None declared |
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G Alastair Cooke, Consultant Cardiologist King's Mill Hospital, Mansfield, MG17 4JL
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As Warburton(1) points out in her editorial we are now approaching a stage were we may be able to reduce the event rate in patients at risk of coronary heart disease to towards zero. The present cocktail of drugs is likely to decrease events by up to 88%(2). We have been fortunate that most of the drugs in this cocktail are very cheap (Aspirin, thiazides, Beta blockers). The article by Marshall(3) shows that aspirin (NHS price £0.18 per 28 days) is much more cost effective than clopidogrel (NHS price £35.31 per 28 days) and statins (NHS price £29.68 per 28 days). I doubt that anybody would have been surprised by this finding. If we continue to pursue new therapies which will further reduce the risks of IHD, it is inevitable that they will be much less cost effective than aspirin. As the event rate goes down with each successful intervention then the number needed to treat for each new drug will increase. If we follow the logic expressed in this article then we should give up trying, as nothing will ever be as cost effective as aspirin. The effective cure of the biggest killer in the western world would have been a triumph for mankind, medicine and big pharma. It seems that like going to the moon it isn’t going to be very cost effective. 1. Warburton R.N. What do we gain from the sixth coronary heart disease drug? BMJ 2003;327:1237-1238, 2. Wald N.J., Law M.R., A strategy to reduce cardiovascular disease by more than 80% BMJ, Jun 2003; 326: 1419 - 0. 3. Marshall T., Coronary heart disease prevention: insights from modelling incremental cost effectiveness BMJ 2003;327:1264, Competing interests: None declared |
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Philipp A. Conradi, part time GP Bloomsbury Health Centre, 63 Rupert Street, Nechells, Birmingham, B 7 5 DT
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Marshall (1) is to be applauded for questioning current policies in cardiovascular disease prevention. He looks at the cost effectiveness of aspirin, anti hypertensive treatment, simvastatin 40 mg and clopidogrel by assessing pooled data from different clinical trials. Treatment effects are balanced with costs. The expenditure for Simvastatin 40 mg is calculated as prescribing costs plus the costs for 6 monthly consultations with the physician and the annual measurements of blood lipids and liver function tests. A close look at the Heart Protection Study ( Marshalls main reference for statins) quickly calls this equation into question. Simvastatin 40mg was even less well tolerated and less effective than portrayed by the authors. We previously published our serious concerns with the Heart Protection Study (BMJ 27.09.2003) and want to add some additional points which underline Marshall’s correct conclusions. 1) Tolerability: Against all claims simvastatin was not well tolerated. A substantial number of patients did not enter the trial after a six week run-in with simvastatin prior to randomisation (63,603 entered the original screening, 32,145 went forward to the run-in phase and 11, 609 dropped out at this pre-trial stage, leaving the 20,536 who were randomised.) These were the “best behaved” patients; real life would not be so easy! 2) Independent treatment effects: Marshall assumes that statins work independently of other cardio protective treatment. This is one of the core findings of the Heart Protection Study. However, most of the patients in HPS did not take appropriate non-statin medication for example only 47% of all patients with peripheral vascular disease were on aspirin. This may not reduce the relative risk, but as Rebecca Warburton points out in the accompanying editorial, this omission reduces the absolute gain of statins. 3) Reduced treatment effects for women: Jenkins alerted the scientific community to the fact that simvastatin did not improve mortality amongst women. Indeed, the composite end point of all first vascular events in Heart Protection Study is much less impressive for women than men. Two of the signatories of this response ( AJ, PC) sent several letters to the research team in Oxford to clarify this matter. Unfortunately we did not receive any proper response so far . In summary Marshall questions the cost effectiveness of different cardiovascular treatments including statins. After looking closely at the Heart Protection Study he might be even more correct. Future health care strategies should indeed take notice of Marshalls paper and the correctly interpreted results of the Heart Protection Study. co-written David Taylor, GP principal South Birmingham, Arnold Jenkins, GP principal Burnley and Philipp Conradi GP Central Birmingham References: as in the text and in the main paper Competing interests: None declared |
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Eddie Vos, maintains www.health-heart.org Sutton Qc Canada J0E 2K0
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It is evidently important (1) to analyze the cost effectiveness
of drugs in cardio-vascular prevention but the fact that a 430 day supply
of the suggested 75 mg/d of brand name Aspirin [32 g] can be obtained in
the U.S.A. at a "dollar store" for exactly that amount does not alleviate
its side effects that no amount of medical supervision will prevent.
The cost analysis per cardio "event" prevented or postponed ranges from £3500 to over £60,000 and clearly lack of the examined drugs is not the underlying cause of atheroma in artery walls. The analysis also does not discuss all-cause mortality, an area where specifically statins have failed to perform [ALLHAT, PROSPER, ASCOT, EXCEL, 4S in women, while HPS has not published year-by-year mortality figures]. A drug cost analysis must be compared with that of nutritional approaches that deal with atheroma causes and effects. For example, a switch to 10% omega-3 canola oil, away from zero omega-3 sunflower, corn or safflower oil would add nothing to the family or nation's health budget. Canola oil was the only study-supplied food in arguably the most successful heart study ever (2). Such switch, or the use of flax oil, would bring the Western intake closer to the 1% of energy proposed for plant-based omega-3 by ISSFAL while the regular use of fish oil would decrease common deficiencies in the other omega-3's (3). Omega-3's have short-term antiarrhythmic and long-term antiinflammatory effects (2). The addition of folic acid to flour and pasta reduced homocysteine in the U.S. population at a vitamin cost of under 5 pence/year. In addition, the use of a high-dose multiple B-vitamin would reduce homocysteine closer to target levels of 6-8µmol/L in most people, and this without any safety concern (4). Let me suggest that obstructive artery atheroma is not described in free living birds and mammals and may well be unique to Homo sapiens. Our use of heat, refining, blanching, freezing, storing and canning reduces vitamins B2, B6, B9 (folic acid) by a factor of near 3. This raises homocysteine as does a deficiency in B12. Increasing the turnover (metabolism) of homocysteine can only be achieved with increasing (restoring) B-vitamin intake. This reduces at no risk and little cost a risk factor in a host of vascular diseases, and others such as Alzheimer's disease. True, placebo controlled trials have not been finalized, but neither have the drug trials. The study of heart and other illnesses as "long-latency multiple nutrient deficiency disease" is probably the principal challenge facing nutritional science today (5). As things stand, our best marker for less than optimal nutrient intake and the most likely causal factor in cardiovascular disease is homocysteine. The health benefits of first optimizing the micro- or "minor" nutrients appear obvious; the cost issue of drugs may then well take on more manageable proportions. Eddie Vos (Sutton (Qc), Canada) (1) Marshal T. Coronary heart disease prevention: insights from modelling incremental cost effectiveness. BMJ 2003;327:1264-0 (2) Leaf A. Dietary Prevention of Coronary Heart Disease. The Lyon Diet Heart Study. Circ.1999;99:733-5 (3) International Society for the Study of Fatty Acids and Lipids. ISSFAL Adequate Intakes 1999. (4) U.K. Expert Group on Vitamins and Minerals. 2003 www.food.gov.uk/multimedia/pdfs/vitmin2003.pdf (5) Heaney RP. Long-latency deficiency disease: insights from calcium and vitamin D. AJCN 2003 Nov (78): 912-9. Competing interests: None declared |
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103
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The author concludes his article as follows:- "Incremental cost effectiveness analysis of treatments produces robust, practical cost effectiveness rankings. Authors of guidelines should take account of this when making treatment recommendations. If the aim of treatment is to maximise prevention of coronary disease, these results have clear implications for current treatment recommendations. They cast doubt on the wisdom of present policy, which emphasises achievement of target blood pressures and the use of statins for people at 15% five year risk of a coronary event.23 A more efficient prevention strategy would be to offer aspirin and initial antihypertensive treatment to all people at over 7.5% five year coronary risk before offering statins to patients at 30% five year risk. According to national survey data, 87% of men and 56% of women aged over 65 are at over 7.5% five year risk." Should a person who has a 7.5% five year coronary risk take aspirin therapy? If the patient has a five year risk of not having an adverse cardiac event of 92.5% and chronic aspirin therapy changes that risk to approximately 94.6%, then why should the patient subject himself to the considerable inconvenience of taking daily aspirin therapy (and the significant ongoing risk of a GIT bleed or a hemorrhagic stroke) if his projected individual five-year benefit is so small? Jeff Mann. Competing interests: None declared |
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John N Fells, GP Kimbolton Cambridgeshire PE28 0JF
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Since simvastatin's patent expired in May 2003 the price has fallen rapidly. Drug wholesalers are currently selling a month's supply of the 10mg and 20mg tablets for less than £2. The NHS drug tariff price will also fall in time. This means that the cost could soon be a tenth of that quoted in the article, making simvastatin more cost effective than low dose aspirin! Competing interests: None declared |
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103.
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The author states that:-"Compared with aspirin, the relative risk of a coronary event while taking clopidogrel is 0.88 (0.76 to 1.01).11 Empirical studies suggest that an indirect estimate of the effects of clopidogrel compared with placebo should be accurate provided that the population groups in studies are similar.12 Compared with placebo, the relative risk of a coronary event with clopidogrel is therefore 0.63 (0.45 to 0.82) (0.63 = 0.72x0.88)." On what basis do we know that clopidogrel therapy has long-term benefit if taken chronically? The evidence apparently comes from the CURE trial, which applied to ACS patients who received clopidogrel therapy as secondary preventive therapy. Did clopidogrel have benefit after 3 months? Consider figure 3 from the CURE trialists own paper [1]. To freely view figure 3 online, download this article "The long-term benefit of clopidogrel therapy in the prevention of adverse cardiac events" from the soapbox section of my website at:- http://www.homestead.com/emguidemaps/JeffMannEMguidemaps.html How can one rationally argue that chronic clopidogrel is effective for the secondary prevention of adverse cardiac events in ACS patients after studying that graph from reference number 1? If clopidogrel is not effective as secondary preventive therapy for ACS patients, on what basis does one argue that it will be effective as primary preventive therapy in patients without known CAD? Jeff Mann. References: 1. Yusuf S. Early and Late Effects of Clopidogrel in Patients With Acute Coronary Syndromes. Circulation. 2003;107: 966-972. Competing interests: None declared |
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103.
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In a recent rapid response letter [1], I challenged the author's contention that clopidogrel is significantly efficacious in the long-term primary preventive treatment of CAD by referring to the CURE trial's results. After re-reading the author's article, I noticed that the author stated the following:- "Compared with aspirin, the relative risk of a coronary event while taking clopidogrel is 0.88 (0.76 to 1.01). {11}. I looked up reference {11}, which was the Cochrane review by Hankey G J et al. I could only find one comment in the Cochrane review that would allow the authors to deduce that the relative risk of a coronary event while taking clopidogrel is 0.88 compared to aspirin. First, consider the Cochrane reviewers overall impression of the value of thienopyridines. "This review summarises the available data from the four published randomised trials of a thienopyridine versus aspirin in patients at high risk of vascular events. Although data were incomplete for some of the outcome events, they were available for all outcomes of interest from the largest trial, contributing 85% of the patients randomised (CAPRIE) and for almost all of these outcomes for the second largest trial, contributing 14% of the patients randomised (TASS). Although there have only been four trials, these included a large number of patients (over 20,000), and serious vascular outcome events (over 2500). Most of the data reflect the results of the CAPRIE and TASS studies. Pooling the data from trials of clopidogrel and ticlopidine into one group (the thienopyridines) increases the sample size and therefore the accuracy of the estimates. Similarly, combining the vascular outcome events into a composite outcome of stroke, MI or vascular death also increases the statistical power and it is this analysis which provides the most reliable (i.e. statistically robust) estimate of the effect of thienopyridines in high risk patients. This analysis reveals that the thienopyridines are statistically significantly more effective than aspirin in preventing serious vascular events among high vascular risk patients, but the magnitude of the additional benefit appears to be modest and somewhat uncertain. The proportional odds (and risk) reduction is about 9%, but may be as low as 2% or as high as 16% (the 95% confidence limits). If the average absolute annual risk of a serious vascular event with aspirin therapy is about 6% per year (CAPRIE), our best estimate would be that substituting aspirin with a thienopyridine may reduce this rate to about 5.5% (91% of 6%), but could reduce it to anywhere between 5.9% (98% of 6%) and 5.0% (84% of 6%). This corresponds to an absolute risk reduction (ARR) of about 0.5%, ranging between 0.1% and 1.0%, and means that treating 1000 patients with thienopyridines may prevent between 1 and 10 extra events each year compared with aspirin. The number of high vascular risk patients who would need to be treated with a thienopyridine to prevent one event per year, compared with aspirin, may therefore vary from 100 to 1000." Note that the above comments refer to clopidogrel and ticlopidine, and it also refers to all CV events including stroke. With respect to cardiac events alone, the Cochrane reviewers state the following with respect to high vascular risk patients. "Myocardial infarction: The thienopyridines were associated with a non-significant reduction in MI (380/11159 [3.4%] vs 431/11157 [3.9%]; OR 0.88, 95% CI: 0.76 to 1.01)." I presume that this is where the authors got the OR figure of 0.88. However, that figure applies to all those studies, which includes ticlodipine. If one examines the CAPRIE study alone, then one notes the following results for patients with a previous MI [2] -- The RRR of clopidogrel therapy to prevent a subsequent MI (fatal or not fatal) in recent MI patients in the CAPRIE trial was 5.37%, the ARR was 0.16% and the yearly NNT figure is 625. In other words, if there is no substantial evidence that clopidogrel is effective in preventing future MIs in high risk coronary patients (who had a previous MI), the why should we expect it to have benefit when used as primary preventive therapy in low risk coronary patients (7.5-15% five year risk of an adverse cardiac event)? Jeff Mann. References: 1. Mann J. Rapid response letter to the bmj. Long-term efficacy of clopidogrel therapy. December 3rd 2003. Available at http://bmj.bmjjournals.com/cgi/eletters/327/7426/1264#42061. 2. Mann J. The cost-effectiveness of clopidogrel therapy in the secondary prevention of heart attacks and ischemic stroke: Weighing the evidence from the CAPRIE trial. Available at http://www.homestead.com/emguidemaps/files/de- clopidogrel.html Also available in the soapbox section of my website -- listed as the title "Cost-effectiveness of clopidogrel in the prevention of heart attacks and ischemic stroke" -- at http://www.homestead.com/emguidemaps/JeffMannEMguidemaps.html Competing interests: None declared |
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Michael O'Donnell, FRCGP. Retired GP and journeyman writer Loxhill GU8 4BD
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Drs Conradi, Taylor, and Jenkins confirm what I have heard from others. The incidence of side effects from statins that many GPs see in their practices is higher than that recorded in published trials. I have heard the same observation from the head of the academic department that keeps an eye on my lipids. Today many protocols, and most evidence-based utterance, draw on data from large trials, often financed by the makers of the drugs under study. So why do we allow these trials a “run in period”? To an innocent like me these “run ins” seem to be used – as Dr Conradi and colleagues suggest happened in the Heart Protection Study – to eliminate subjects who suffer side effects, and even sometimes to select the subjects most likely respond. As someone who seems to meet a remarkably high number of people who have suffered side effects from statins, I would be grateful for a convincing answer to my question. I have been given a few unconvincing “good” reasons but as a sceptical GP – and later as a writer – I have learned to discriminate between the two reasons used to justify most forms of human activity: the good reason and the real reason. Competing interests: Having suffered distinctly unpleasant side effects from statins I am less inclined than the editor of the BMJ to indulge in extravagant fantasies about magic “polypills”. |
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Malcolm E Kendrick, Medical Director Adelphi Lifelong Learning Adelphi Lifelong Learning, Adelphi Mill Bollington SK10 5JB
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Reduction of CV events and mortality is, of course, a great benefit. However, what any patient would ask about a drug is 'Will it save my life.' Not 'Will it make me less likely to die of a CV event, whilst at the same time increasing my chance of dying of something else.' I can't quite see the point of doing cost-effectiveness analysis without taking into consideration the effect of treatment on overall mortality. Which, in this case, was not done. Competing interests: None declared |
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john s ashcroft, general practitioner Old Station Surgery,Ilkeston,Derbyshire. DE72 3EA
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Tom Marshall (1) is almost certainly correct with the conclusions of his paper, and I would go further: the expenditure on "statins" for patients at high risk, by the NHS, has in all probability resulted in more people dying, because of lost opportunity costs, than they have saved. However the timing of his paper is most unfortunate. With Simvastatin now "off patent", low cost generic supplies are now flooding into the market. The Department of Health has just cut the price it pays to £16/pack.(5) But will the price fall from by the 70% that Marshall feels would be necessary to match the cost effectiveness of initial hypertensive therapy with bendroflumethazide and atenolol? The evidence is that it will. The United States Department of Defense currently contract with Merck(2) at 44 cents/ 20mg tablet (approximately £7.16/ pack). I have recently been quoted £3.70/pack by a leading UK supplier, and generics appear to be available around £2.00/pack in other countries (3). The net ingredient cost is probably around £1.00/pack for 20mg tablets (based on US$4780/kg)(4). The wholesale price should continue to fall with time. How much the NHS wishes to pay, however, is quite a different matter. For the time being I am prepared to take the department of health at their word that they "will keep reimbursement prices under review" (5), and to support moving the prescribing of simvastatin on the NHS to those with a 10year cardiovascular risk of greater than 20% {15% 10year CHD risk), based on Framingham. 1. T.Marshall 2003;327:1264 2. www.pec.ha.osd 3. www.phmovement.org/pubs/issuepapers/bala1.html 4. www.indian-chemical.com/importprices/bulkdrugs/ 5. www.doh.gov.uk/generics/fourgenericmedicinesconsultation2003.htm Competing interests: None declared |
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Adam Jacobs, Director Dianthus Medical Limited, London SW19 3TZ
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First, I would like to congratulate Marshall on an interesting paper. I need no further convincing that incremental, rather than average, cost- effectiveness is the best way to consider the benefits of the more expensive drugs. I have two comments on the paper. The first concerns the impact of prescription charges, which are paid in the UK by patients under 60 years old, but not by patients over 60. A prescription charge of £6.30 is more than the cost of a prescription for a month’s supply of off-patent diuretics or beta-blockers. Given that the analysis was conducted from the health service perspective, this means that prescriptions of cheap drugs to patients under 60 should actually generate income rather than incur costs. Presumably this would make it spectacularly cost-effective to prescribe diuretics to all patients under 60, regardless of their cardiovascular risk, although this really raises the question of whether the health service perspective was the most appropriate one to take. My second comment is that the analyses appear to be based on rather a strong assumption, namely that the relative risk reductions resulting from treatment are independent of baseline risk. What is the evidence for this? Trials that have failed to detect differences in relative risk reductions between high-risk and low-risk groups may simply have lacked the statistical precision to do so, as detecting statistical interactions of this kind requires greater statistical power than that required for detecting main effects of treatment. The trials of antihypertensive treatment cited in the paper mainly included patients with hypertension. Do normotensive patients really derive the same relative benefit from antihypertensive treatment as hypertensive patients do? If the relative benefits of treatment are less for patients at lower risk, then the relative cost-effectiveness of different treatment strategies could change, favouring strategies targeting high-risk patients. Competing interests: None declared |
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Andrea Messori, coordinator Laboratorio SIFO di Farmacoeconomia, Careggi University Hospital, 50134 Firenze, Italy, Benedetta Santarlasci
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The cost-effectiveness study published by Marshall
(BMJ 2003;327:1264) is very difficult to
understand in its technical details not only for the average reader but also
for people with some expertise in pharmacoeconomics. In our view, the part of this
study that presents the data of the average cost-effectiveness (Table 1 of the
article) is useless because the practical implications of this study, along
with the assessment of the pharmacoeconomic profile of the various drugs, rely
exclusively on the findings of the incremental cost-effectiveness analysis
(i.e. the data presented in Table 2). On the other hand, Table 2 has a drawback in that
it is not adequately explained by the author. For this reason, we propose herein
a more detailed printout of this table (see below) in which much more
information is presented and the labelling of each row is made much more
explicit.
Competing interests: None declared |
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Borislava N Mihaylova, NHS Training Fellow Health Economics Research Centre University of Oxford Oxford OX3 7LF, UK, Andrew H. Briggs, and Alastair M. Gray
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Marshall(1) analysed a number of interventions to prevent coronary heart disease and presented analyses of their incremental cost- effectiveness in terms of incremental drug treatment cost per incremental first major coronary event prevented. We welcome the author’s reiteration of the principles of incremental cost-effectiveness analysis and agree that such an approach should form the basis of guideline development in this area. However, the analysis as presented has a number of major limitations, and does not even comply with the BMJ’s guidelines for economic submissions(2): • The impact of the interventions on subsequent major coronary events and on other major vascular events within the timeframe of the analysis is ignored. For example, the Heart Protection Study reports on the benefit of statin intervention on first and subsequent major vascular events (3). • The savings to the health service due to the avoidance of coronary (and other vascular events) are not included in the analysis. • The evidence for the effectiveness of interventions is largely based on intention-to-treat analysis of naturalistic RCTs (or their meta-analysis), while the costs of the drug interventions are estimated according to a treatment protocol; in consequence, incremental effectiveness and incremental cost are not calculated on the same basis. For example, the economic analysis of the LIPID study showed that patients in the placebo arm incurred significantly more non-study cholesterol-lowering drug costs (4). • The author has ignored the impact of uncertainty in the resource use and cost data on the estimated cost-effectiveness. Furthermore, the cost- effectiveness of statin treatment is very sensitive to the cost of statin, which is rapidly changing in Britain at present due to the recent expiration of the patent for simvastatin. In Sweden, where simvastatin has recently come off patent, the price has decreased by 85%. Although it might be argued that these limitations affect all interventions such that any rank ordering of interventions would be unaffected, this would be to miss the aim of the cost-effectiveness analysis entirely. The point is that, as the accompanying editorial suggested, treatment thresholds are points on a continuum. In order to provide reliable bases for issuing guidance, what is required are credible analyses that capture all important concerns to decision makers. Unfortunately, the present ‘back of the envelope’ model does not provide a credible basis for choosing the most appropriate treatment thresholds. (1) Marshall T. Coronary heart disease prevention: insights from modelling incremental cost effectiveness. BMJ 2003; 327(7426):1264-0. (2) Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. Br Med J 1996; 313:275-283. (3) Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. The Lancet 2003; 361(9374):2005-2016. (4) Glasziou PP, Eckermann SD, Mulray SE, Simes RJ, Martin AJ, Kirby AC et al. Cholesterol-lowering therapy with pravastatin in patients with average cholesterol levels and established ischaemic heart diesease: is it cost-effective? MJA 2002; 177:420-426. Competing interests: We are currently involved in the economic analysis of the Heart Protection Study. |
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Tom Marshall, Harkness Fellow in Health Policy Brigham & Women's Hospital, Boston MA 02120
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Correspondence following publication of my article raises a number of interesting issues. Nevertheless no correspondent disputes either the approach (incremental cost-effectiveness analysis) or the fundamental findings: that aspirin and antihypertensive treatment with bendrofluazide and atenolol are markedly more cost-effective than statins and clopidogrel. Conradi and O’Donnell indicate that the side-effect profile of statins may be less benign than is generally believed to be the case. If so, this strengthens the paper’s conclusions. Mann indicates that I may have been generous in accepting that clopidogrel is effective in primary prevention. Again this strengthens the paper’s conclusions. I agree with Mann’s suggestion that individuals need information on the risk reduction with treatment in order to decide if it is worthwhile. Cooke suggests that development of further drugs to prevent coronary heart disease may not be cost-effective. It is certainly clear that it is very efficient to prevent coronary disease is using existing, low-cost treatments. If, as Jacobs suggests, treatment effects are not be independent, second and third treatments may be even less cost-effective than the analysis suggests. Under present criteria, 80% of those eligible for one preventive treatment are eligible for at least two and 53% are eligible for all three. Das and Vos suggest with oily fish may be more cost-effective than statins. I agree. Cost per event prevented with sardines three times a week is similar to that of initial antihypertensive treatment. However fish oil capsules are much more costly than oily fish and there are wide confidence intervals around the estimated effectiveness. For this reason fish oil as an intervention was excluded from the published paper. Kendrick argues that cost-effectiveness analysis should consider only overall mortality. This may be problematic when clinical trials are not powered to detect mortality changes. D’Avanzo and Mihaylova et al suggest that the analysis should include cost savings from heart disease prevented. This will not affect the cost- effectiveness rankings but may indicate that the most efficient treatments are cost-saving. Mihaylova et al also suggest further refinements to the model, but acknowledge that these are unlikely to affect the rankings or overall message. In my view the purpose of economic evaluation is to improve decision-making. Complex economic evaluation is costly and may not be understood by clinicians or guideline authors. My analysis is not intended to assist a decision on allocation of resources between preventive cardiology and other interventions, only to improve the efficiency of current preventive cardiology services. It is sufficient for this purpose. It is an open question as to whether a more complex and costly evaluation might be justified by even greater service improvements. Mihaylova et al, Ashcroft and Fells all refer to an immanent fall in the price of simvastatin. At a pack (28) of £4.45, simvastatin is the third most cost-effective intervention. Under these circumstances a rational policy would offer aspirin at 5% coronary risk, bendrofluazide and atenolol at 7.5%, and simvastatin at 15%. A third antihypertensive would never be offered, obviating the need to “treat to target”. (Table 1) The onus is now on pharmaceutical manufacturers to provide simvastatin at this cost. A final point not raised by any correspondent concerns the cost of antihypertensive treatment. With some antihypertensives costing over £200 a year, the cost-effectiveness of antihypertensive treatment is very sensitive to the treatment regime chosen. Antihypertensive treatment in the current primary care system is much less cost effective than it could be because drug costs currently average £150 to £200 per patient year of treatment. This is hardly surprising given the huge range of services that primary care teams are expected to provide. Perhaps it is time to look at new models for provision of prevention services making greater use of treatment protocols and supplementary prescribers. Table 1: Cost effectiveness of preventive treatments in patients at different risk levels if simvastatin’s price falls by 85% CHD risk level-----------------5%-------7.5%-------10%------15%------ 20%-------25%------30% Aspirin-----------------------£7,900----£4,900----£3,500----£2,200--- -£1,600----£1,300----£1,100 Bendrofluazide & Atenolol-----£24,000---£16,000--£12,000---- £8,000---£6,000-----£4,800----£4,000 Simvastatin (£4.45 for 28)----£34,900---£23,300--£17,500---£11,600--- £8,700----£7,000-----£5,800 Enalapril---------------------£98,200---£65,500--£49,100----£32,700-- £24,600---£19,600---£16,400 Clopidogrel----------------£1,054,400--£702,900--£527,200-£351,500- £263,600--£210,900--£175,700 Competing interests: None declared |
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Adam Jacobs, Director Dianthus Medical Limited, London SW19 3TZ
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I thank Tom Marshall for clarifying some of the points raised above. However, his response to my comment about independence of treatment effects did not refer to exactly what I had in mind, so apologies if I did not explain myself very clearly the first time around. It is indeed true that, if the effects of multiple treatments in a single patient are not independent, the more expensive treatments will be even less cost effective, but that was not the point I was trying to make. My point was this. Can we be sure that the effects of treatment are independent of the patient's baseline risk? In other words, if a treatment given to patients with a baseline risk of 15% reduces that risk to, say, 7.5% (50% relative risk reduction), does it necessarily follow that the same treatment given to patients with a baseline risk of 5% will reduce the risk to 2.5% (also a 50% relative risk reduction)? Marshall's analysis is based on this assumption, but if it were not true, then intensive treatment of patients at high baseline risk might become a more cost-effective strategy than less intensive treatment of patients at low baseline risk. Perhaps a sensitivity analysis could shed some light on this? Competing interests: None declared |
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Tom Love, Research Fellow, Health Informatics Centre University of Dundee DD2 4BY, Tom Fahey
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EDITOR - Tom Marshall advocates a stepped approach to therapy for preventing coronary events, introducing more expensive therapies at progressively higher levels of risk (1). This approach contrasts with those who argue that these treatments should all be used very widely, or even universally (2, 3). Extending Marshall’s incremental cost effectiveness analysis to a
greater range of risk values shows some interesting effects. The
relationship between the 5 year coronary event risk (x) and the
incremental cost per event avoided (y) is given by: The graph shows that the incremental cost is extremely high for small values of risk. The relationship illustrates two points. Firstly, those who argue for the universal use of multiple therapies to prevent coronary events must be willing to countenance enormous costs for each event avoided in low risk individuals. Secondly, the cost for the more expensive agents decreases only slowly. The full curve shows that the implications are more extreme than Marshall himself suggests. If avoiding an event is valued by society at some pre-specified cost, then this can be used to find the degree of absolute coronary risk at which it is acceptable to use a given drug. For example, Marshall suggests using statins at 30% or greater five year risk of a coronary event, with an incremental cost of £40,800. If £40,800 is the value placed upon avoiding a coronary event (indicated by the horizontal line on the graph), then this implies that it is reasonable to use aspirin at a level of less than one percent risk, bendrofluazide at a level of 2.9% and enalapril at 8.3%. If £40,800 is an acceptable cost to avoid a coronary event, then it could arguably be reasonable to use aspirin universally, while clopidogrel would never be used. As more agents become available for preventing coronary events, there will be continuing controversy about their cost-effectiveness. It is time the debate regarding cardiovascular risk moves forward from simple assumptions using relative benefits to cost effectiveness studies, such as Marshall’s, that include absolute risk, patient utilities and the cost of treatment (4). References (1) Marshall T. Coronary heart disease prevention: insights from modeling incremental cost effectiveness BMJ 2003;327:1264-8 (2) Law MR, Wald NJ. Risk factor thresholds: their existence under scrutiny. BMJ 2002;324:1570-6 (3) Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80% BMJ 2003 326:1419-23 (4) Montgomery AA, Fahey T, Ben-Shlomo Y, Harding J. The influence of absolute cardiovascular risk, patient utilities, and costs on the decision to treat hyptertension: a Markov decision analysis J Hypertension 2003 21:1753-9 Figure
Competing interests: None declared |
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where (a)
is the incremental cost per event reported for 10% five year risk in Table
2 of Marshall’s analysis (in the case of aspirin this formula is a
simplification which slightly underestimates the true cost, as it
disregards adverse events). The curves for the five drugs are shown in
the figure.
