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Rapid Responses: Rapid Responses published:
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Misleading statement re statin benefit in primary prevention.
- Eddie Vos (14 February 2004)
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Re: Misleading statement re statin benefit in primary prevention.
- L S Lewis (15 February 2004)
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Re: Re: Misleading statement re statin benefit in primary prevention.
- Eddie Vos (16 February 2004)
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'Padma Therapy' : Say 'Cheerio' To Statins
- Joseph . C . Obi (17 February 2004)
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Stain Use
- Robert W Johns, ST16 3SA (18 February 2004)
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Italy: last position both in use of statins therapy and in the sensitivity of own coronary risk assessment chart
- Giavarina Davide (20 February 2004)
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Italy: increasing statin consumption and low compliance
- Iosief Abraha, Carlo Romagnoli, Mariangela Rossi, Alessandro Montedori (25 February 2004)
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The use of DDDs may lead to invalid comparisons
- Aukje K. Mantel-Teeuwisse, Olaf H. Klungel, Wim G. Goettsch, and Anthonius de Boer (11 March 2004)
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Statin usage in Australia and New Zealand, and problems with use of DDDs
- Scott Metcalfe, Peter Moodie (17 March 2004)
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Eddie Vos, maintains health-heart.org Sutton (Qc) Canada J0E 2K0
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The introduction by Walley et al states that statins “..reduce coronary events [sic] by about 30% in both primary and secondary prevention.” This statement is inaccurate to the point of being misleading. For example, it does not apply to anyone in the largest ever North American study [ALLHAT] and it contradicts the findings of the University of British Columbia Therapeutics
Initiative that concludes that pooled "events" in primary prevention were not reduced in women (1).
The statement by the authors leads to the common misconception that an "event" prevented equates with potentially a life saved or a life extended. From a recent letter in BMJ entitled Might money spent on statins be better spent?: "I have yet to find a paper showing a significant reduction in mortality in women for groups treated with statins. It therefore seems that any benefit, if found, will be minimal." (2) In other words, the suggested "event" reduction in most trials does not equate with an all-cause mortality benefit in males [EXCEL, PROSPER, ALLHAT, ASCOT] while a mortality benefit from statins in women is simply absent [not significantly increased in 4S, no significant change in HPS (2)]. Incidentally, the HPS per gender year-by-year mortality data are still under wraps (2). Maybe the variation in statin use across Europe lies in the better reading of the study data: cholesterol lowering by any means has not shown to increase life expectancy in females, and there is a serious question if statins extend life in any but the highest MI risk males. 1. http://www.ti.ubc.ca/pages/letter48.htm#comment [accessed 2004-2-13] 2. A. Jenkins, BMJ 2003;327:933 (18 October) http://bmj.bmjjournals.com/cgi/content/full/327/7420/933-b
Competing interests: None declared |
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L S Lewis, General Practitioner Surgery, Newport, Pembrokeshire
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I do agree with you that subset analysis shows that women rarely reach any significant level of benefit. Indeed the seminal 4S study showed a higher crude mortality for women treated WITH Simvastatin. But Walley is also 'correct'. Studies of Statin intervention are compatible with the hypothesis that a Statin benefit of 30% risk reduction across a wide range of individuals in disregard of initial cholesterol level, or other risk factor status, occurs. Could it be that you are both right ? Women have a low coronary risk. There are few women in the trials. Therefore subset analyses are statistically unlikely to show significant benefits in women ( or any other low-risk low-volume subset, eg: young diabetics, etc. ) It is the coronary risk in any subset which dictates the absolute number of coronaries, and hence the COST-benefit and NNT. Following Guidelines based on coronary risk would reduce the exposure of women to statin, but unfortunately UK GMS Quality incentivisation is leaving 'coronary risk' dead in the water.. Competing interests: Cost versus benefit |
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Eddie Vos, maintains health-heart.org Sutton Qc Canada
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I thank Dr. Lewis for his important response. Women
were "subgroups" in many trials but they are the main group in our society
and in CVD. The about 400 women in 4S and 2540 in HPS on statin for about
five years should have shown a mortality benefit considering their [very]
high risk status: it did not.
Then we have PR Jackson et al (1) concluding in primary prevention: "..the relationship between mortality benefit and risk suggests that statin use could be associated with an increase in mortality of 1% in 10 years." Dr. Lewis points out that statin effects are not linked to baseline cholesterol levels and logically they should not be prescribed on this basis unlike the guidelines indicate. I note that statins in most medical ads are suggested to treat "dyslipidemia" [with its ever changing definitions], not heart disease. A trial of 1 person will establish that the effect of alcohol is related to baseline status and to percentage of change; trials totaling tens of thousands of female patient-years have: 1) not shown such dose / response via cholesterol, 2) have shown a lack of mortality benefit in women and 3) have revealed a mortality risk increase in primary prevention in all (1). If statin/cholesterol-treatment is ineffective in most and expensive in all, let me suggest to consider the following: If life-long homocysteine (Hcy) levels above those near age 10, about 6 umol/L, predispose to atherosclerosis, the consistently lower levels in women would explain inter-gender CVD differences [U.K. median 9.4 vs. 10.6 in men] (2). Maybe when women reach the age when CVD affects them, they are also near the age-territory of the massive mortality failure of PROSPER -and in which significantly more "new" cancers were detected in the statin group that had 52 fewer current smokers [p=0.02]. The cholesterol-lowering emperor of statin drugs appears to have little clothes, and the lack of mortality benefit and of CVD prevention in women have conclusively exposed the nakedness of this approach. On the other hand, reduction of Hcy with a multivitamin supplement is among the safest and rapid interventions and it may well surpass the cost effectiveness of fish oils in prevention (3). Skeptics may say the trials are not finished; true, but there are no conceivable benefits of higher than minimal amounts of homocysteine [about 6 umol/L vs. U.K. median =10, mean/average value = 11] and randomized trials may well be unethical if not impossible in life-long cardio-health management. Statins cannot be the underlying cause of any disease but low nutrient intake is the cause of many -and Hcy is the best medical marker for low nutrient status. If statins proved "cholesterol management" as a dead horse approach, it's time to change horses. Eddie Vos (1) Jackson PR et al. Statins for primary prevention: at what coronary risk is safety assured? Br J Clin Pharmacol. 2001 Oct;52(4):439-46 PMID 11678788 (2) NDNS, adults aged 19 to 64, Vol 4 2004 tables 4.21 and 4.24. (3) Tom Marshall Prevention of coronary heart disease BMJ 2004;328:405-406 (14 February) Competing interests: None declared |
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Joseph . C . Obi, Chief Consultant WellnessClinics.co.uk
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Look East... In addition to healthy lifestyle choices, the people of Ancient Tibet have consistently used a '5000 Year Old Preparation' called 'Padma'; to effectively reduce the long term complications of a vast array of cardiovascular ,cerebrovascular and peripheral vascular diseases. Apart from it's generous anti-oxidant, anti-inflammatory and anti- thrombotic potential, 'Padma' is also exceedingly useful at lowering both 'LDL Cholesterol' and 'Total Cholesterol'; while miraculously elevating 'HDL Cholesterol'. 'Padma' costs well under 5% of the 'going price' of the average 'Statin'...and also has well under 5% of the 'side effects' attributed to 'Statins'. Thankfully, 'Padma Tablets' are now freely available in both the UK and the USA...in rightful step with almost 30 other progressive Nations. Competing interests: Dr Joseph Chikelue Obi MBBS MD MPH DSc FRIPH FACAM is also the Chairman of the General Wellness Assembly (GWA); an International Professional Body for Independent Wellness Consultants.He has recently just accepted an unpaid role as an 'NHS Champion' for the rights of Older People ;and also humbly invented the 'Omnipill'. |
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Robert W Johns, Consultant Anaesthetics Stafford General Hospital, ST16 3SA
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I read with interest "This Week in the BMJ" which points out that "Stains are widely used in Europe" Is this a new way of administering red wine for cardiovascular disease prevention? Personally I prefer the gastrointestinal route! Rob Johns. Competing interests: None declared |
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Giavarina Davide, Clinical Chemistry and Haematology Laboratory San Bortolo Hospital, 36100 Vicenza, (Italy)
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Walley and co-workers reported that Italy has the lowest
use of statins of Europe, with
only 14.74 daily doses/1000 of population covered/day, against 23.86 in
England, 26.47 in Germany, 30.85 in France, 59.28 in Norway [1]. They suppose
that this low use may reflect low coronary morbidity of o poor adherence of
Italian patients to statins, worse than elsewhere in Europe. Really, the
reference to this sentence proved only that the adherence to statins is worse
in Bologna (Italy) than in Funen (Denmark), and ten years ago, from 1994 to
1996 [2].
On
the contrary, national guidance and policies, could be the major causes of the
Italian situation too. In the same number of the BMJ
Raithatha and Smith reported that may people who could benefit from
statins are not currently receiving them, largely for economic reason [3]. In
Italy the reimbursement of the statins therapy is regulated by the Unique
Commission of Drugs (CUF). The rule number 13 of the CUF recommends the
statins treatment only for people with high global risk and recommends also to
use the Italian Risk Chart to estimate the global risk. In
a previous experience we demonstrate that the first edition of the Italian
Risk Chart[4] had a very low
sensitivity, since more than 80% of patients at risk for coronary disease, so
classified by the Framingham equation[5], were misdiagnosed. To
this aim, we employed the Italian chart to estimate how many subjects would
have been treated with statins in a population including 536 healthy blood
donors and 213 patients with non-insulin dependent diabetes mellitus. Results
were compared with those calculated by using the Framingham equation as
reference method and with alternative risk assessment screening methods,
including the New Zealand chart [6], the new Sheffield tables [7], the chart
of the Joint Task Force of European Societies on Coronary Prevention [8], and
criteria of the Joint British Societies [9]. Only
1,7% of a donors population and only 9,5% of a diabetic population should have
been admitted the a statins therapy, according to the chart (table). But only
a private prescription could be proposed to the other 80% of patient with high
risk. In
the last weeks the Italian High Institute of Health, who realized the first
risk Chart, modified the risk classes, improving the sensibility.
Notwithstanding this change, it remain one of the lowest sensitive, compared
with other European or international ones. Table:
Comparison of the Framingham equation with alternative screening methods and
estimated risk assessment.
5.
Anderson KM, Odell PM, Wilson WF, Kannel WB. Cardiovascular disease risk
profile. Am Hearth J 1990;121:293-8. 6.
Wallis EJ, Ramsay LE, Ul Haq I, Ghahramani P, Jackson PR, Rowland-Yeo K, Yeo
WW. Coronary and cardiovascular risk estimation for primary prevention:
validation of a new Sheffield table in the 1995 Scottish health survey
population. BMJ. 2000;320:671-6. 7.
Jackson R. Updated New Zealand cardiovascular disease risk-benefit prediction
guide. BMJ. 2000 Mar 11;320(7236):709-10. 8.
Wood D, De Backer G, Faergeman O, Graham I, Mancia G, Pyorala K. Prevention of
coronary heart disease in clinical practice: recommendations of the Second
Joint Task Force of European and other Societies on Coronary Prevention.
Atherosclerosis. 1998;140:199-270 9.
British Cardiac Society, British Hyperlipidaemia Association, British
Hypertension Society, and British Diabetic Association. Joint British
recommendations on prevention of coronary heart disease in clinical practice:
summary. BMJ 2000; 320: 705-708. Competing interests: None declared |
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Iosief Abraha, consultant Osservatorio Epidemiologico, Assessorato alla Sanità, Fontivegge, 06100, Perugia, Carlo Romagnoli, Mariangela Rossi, Alessandro Montedori
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Editor - The paper by Walley T1, gives an interesting picture of statin consumption in However, beyond its lowest prescription with respect to other European countries, Although the increase of drug prescriptions may open different interpretations, we want to draw doctors’ attention to compliance to lipid lowering drugs. In a recent retrospective study in 4.5 years of follow-up (1997-2002), we observed a very low adherence to statin therapy in our population. This is definitely translated into a wastage of a huge amount of money; and, moreover, tens of thousands of subjects has been exposed to statins and quitted treatment prematurely before gaining any benefit. Those who showed a better compliance were patients that experienced major cardiovascular events and they were the minority among the entire cohort.2 Other points of interest of lipid lowering drug use in Italy are their sporadic use; a higher usage in women (55%) than in men; a number of older subjects (even > 85) receiving their first statin prescription; and a higher use in primary prevention2,3. Probably as the authors said there may be a ‘growing awareness of the effectiveness of these drugs’ but certainly physicians and health authorities must be aware of patients’ compliance to avoid misuse of the limited health resources. Table. Statin use in
*DDD: defined daily doses References
Competing interests: None declared |
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Aukje K. Mantel-Teeuwisse, PhD student Utrecht Institute for Pharmaceutical Sciences, Sorbonnelaan 16, 3584 CA Utrecht, the Netherlands, Olaf H. Klungel, Wim G. Goettsch, and Anthonius de Boer
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Dear Editor – In their paper, Walley et al compare variation and increase in use of statins between a large number of European countries.1 The use of defined daily doses (DDDs) as the main measure, however, may lead to invalid comparisons. As we showed in a previous study, the use of DDDs has several disadvantages.2 This measure cannot be used to assess statin use on a patient level, unless the underlying assumption that the mean prescribed daily dose equals 1 DDD is met in daily medical practice. We question this assumption for several reasons. In 1994, the DDD for simvastatin changed from 20 mg to 15 mg.3 In the Netherlands, however, this daily dose was hardly ever prescribed (less than 1% of all prescriptions).4 The measure is also susceptible to prescribing regimens. In our study, a larger average number of DDDs were prescribed to men than to women.2 A similar pattern can probably be observed for different age categories. Differences between countries in the age and gender distribution of the treated population may therefore influence the presented results. Finally, differences between use of statins may also be the result of differences in prescribed daily doses instead of real differences in the number of patients using these agents. Data from the PHARMO database show that in patients starting statin therapy in the period 1998-2001, the mean prescribed daily dose differs considerably between individual statins (see Table). Although the paper by Walley et al provides some interesting information on trends in statin use across European countries, their results would have been more useful if they would have presented their data on a patient level. Aukje K. Mantel-Teeuwisse, Olaf H. Klungel,
Anthonius de Boer Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, the Netherlands Wim G. Goettsch PHARMO Institute, Utrecht, the Netherlands Table
References 1. Walley T, Folino-Gallo P, Schwabe U, van Ganse E. Variations and increase in use of statins across Europe: data from administrative databases. BMJ 2004;328:385-6. 2. Mantel-Teeuwisse
AK, Klungel OH, Verschuren WM, Porsius A, de Boer A. Comparison of different
methods to estimate prevalence of drug use by using pharmacy records. J Clin Epidemiol 2001;54:1181-6. 3. Illingworth DR, Erkelens DW, Keller U, Thompson GR, Tikkanen MJ. Defined daily doses in relation to hypolipidaemic efficacy of lovastatin, pravastatin, and simvastatin. Lancet 1994;343:1554-5. 4. Leufkens HG, Herings RM, Urquhart J. Efficacy of low-density-lipoprotein lowering with statins. Lancet 1994;344:683-4. Competing interests: None declared |
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Scott Metcalfe, public health physician Pharmaceutical Management Agency (PHARMAC), Peter Moodie
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There is a possible bias with the use of defined daily doses (DDDs) when looking at statin usage, as used in Walley and colleagues’ analysis of statin usage rates in Europe [1]. This is because the DDD for simvastatin is 15 mg/day, c.f. 10mg for atorvastatin (http://www.whocc.no/atcddd/). Arguably, a more realistic DDD for simvastatin should be 20mg/day – this is certainly our understanding of relative potencies, and is in line with average daily doses for simvastatin in Australia and New Zealand since the year 2000. The use of 15mg DDD for simvastatin will tend to overestimate patient-based usage for statins across populations, by a factor of 20/15 = 1.33 of the simvastatin proportion of total statin DDD. This means those countries with relatively higher simvastatin use will have overstated statin use (e.g. Norway, Sweden), compared with countries like Ireland with very little simvastatin use compared to other statins. We have adjusted for this anomaly, and think this means that France’s usage rate in 2000 surpassed that of Norway, while Ireland’s rate surpassed that of Germany (i.e. swapping rankings). We have also made a crude estimate of usage rates in 2002, using Walley et al’s "annual average increase 1998 to 2002 (%)", which we assume gives exponential increases. If we were to assume the annual average increase 1998-2002 equally applied to the two years between 2000 and 2002, then usage varies across countries even more. This is shown in the following table and graph, where we have also included actual data for New Zealand and Australia [2]. New Zealand had DDD rates similar to England in 2000, whereas Australia had uptake higher than anywhere in Europe.
However, since the lifting of prescribing restrictions for statins for New Zealand in mid 2000, by November 2003 New Zealand’s DDD rates for statins were equal with Australia, which we estimated to be at 74 DDDs/1000/day for both countries that month. Of course, the use of DDDs depends upon the average daily dose of statins used. In countries with higher average daily doses, this means their DDDs (and “uptake”) will seem higher than other countries with the same rates of usage per head of population. In terms of measuring uptake, patient-based measures (e.g. patient-year equivalents from dispensing data) may be more appropriate. Scott Metcalfe Public Health Physician Peter Moodie Medical Director Pharmaceutical Management Agency (PHARMAC) Wellington NEW ZEALAND References: [1] Walley T, Folino-Gallo P, Schwabe U, van Ganse E; EuroMedStat group. Variations and increase in use of statins across Europe: data from administrative databases. BMJ. 2004;328:385-6. [2] PHARMAC analysis of PBS data at http://www.hic.gov.au/statistics/dyn_pbs/forms/pbs_tab1.shtml, and PHARMAC New Zealand PharmHouse data, denominated by Australian and New Zealand census data (with intercensal interpolations and extrapolations) Competing interests: None declared |
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