A cure for cardiovascular disease?
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7404.1407 (Published 26 June 2003) Cite this as: BMJ 2003;326:1407All rapid responses
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The Polypill has been proposed by Wald and Law [1] as a medication for
universal use by people aged over 55 years. In the editorial comments about the
Polypill, Rodgers [2] addresses the issue of the price that could be recognised
to this medication and discusses the cost-effectiveness implications of this
pharmacological intervention. Both the original paper [1] and the
above-mentioned editorial [2] implicitly or explicitly rely on the assumption
that the benefits of all the components of the Polypill, including the statin, are conclusively
demonstrated in terms of both effectiveness and cost-effectiveness.
A large number of
studies indicate that statins are effective and cost-effective for secondary
prevention of cardiovascular events [3]. However, their role in primary
prevention is more controversial. In the present analysis, we focused our
attention on the pharmacoeconomic studies published from 1995 to June 2003 that
evaluated statins for primary prevention. Extraction of these studies from the
PubMed MEDLINE data bank [syntax of the query: "(cost[titl] OR
economic[titl]) AND (simvastatin OR pravastatin OR atorvastatin OR fluvastatin
OR cerivastatin OR lovastatin OR statin*)"; time limits: from January 1995
to June 2003; query launched on 11 July 2003] yielded a preliminary database of
articles that were candidate for our analysis. Direct inspection by AM, BS, ST,
and MV of the abstracts and, when necessary, of the full text of the papers of
this preliminary database allowed us to identify a total of 18 original
pharmacoeconomic studies evaluating statins for primary prevention; 8 were not
sponsored by any pharmaceutical company (table 1), whereas the other 10 were sponsored
(table 2). The design of the analysis was similar across these 18 original
studies (i.e. either comparison or statins vs. no therapy or head-to-head
evaluations between statins). On the other hand, the pharmacoeconomic results
showed that different studies favoured different statins.
In the independent
reports, the inter-study variations in the cost per life year gained were
extremely wide (table 1); this indicates a profound uncertainty in the
pharmacoeconomic convenience of using statins for primary prevention.
The sponsored studies (table 2) raised another and more important
question, i.e. whether the sponsor had any influence on the pharmacoeconomic
results. For this purpose, we reviewed all of the studies listed in Table 2 and
we assessed the relationship, if any, between the study sponsor and the type of
pharmacoeconomic result. In more detail, we analysed each study to determine
whether or not the pharmacoeconomic results were in favour of the statin
produced by the study sponsor. The last
column of table 2 shows the results of our analysis. In all of these studies
(10 cases out of 10; 100%), the pharmacoeconomic results were in favour of the
statin produced by the study sponsor (p=0.00098 by signs’ test).
Thus, our overview of
these data provides a very negative picture on the scientific value of the
pharmacoeconomic research in the area of primary prevention with statins. One
negative finding is that most of these studies (N=10) were directly sponsored
by the pharmaceutical industry while the independent ones were fewer (N=8). In
addition, the research question of most of these studies did not address the
point of contrasting statins vs no statins for primary prevention (the most
relevant one from scientific and practical viewpoints), but considered various
head-to-head comparisons aimed at determining which statin is more
cost-effective than the others. In these head-to-head comparisons between
different statins, while the underlying question was the same across the
studies (“which statin has the best cost-effectiveness profile for primary
prevention?”), the results were surprisingly different. This casts doubts on
the robustness of the pharmacoeconomic methodology of these studies (inasmuch
as their results were conflicting from one another in the absence of specific
explanations). Last but not least, all of the sponsored pharmacoeconomic
studies found a better profile for the statin produced by the study sponsor
thus showing a clear bias towards favouring a pre-specified statin; this finding,
supported by a high statistical significance, is clearly the main result of our
literature analysis.
To explain our
findings, one hypothesis is that the high level of uncertainty in the
pharmacoeconomics of statins for primary prevention (table 1) has contributed
to creating a context where the sponsored studies could be guided towards the
"desired" result. Anyhow, one problem with pharmacoeconomic studies
in general is that the methods for constructing the statistical variability
around the primary result are still far from being standardised; so, interpreting these data can be extremely
difficult under certain circumstamces.
In conclusion, after
reading the paper by Wald and Law [1] and the editorial by Rodgers[2], we
wonder whether these authors have over-estimated the clinical and economic
evidence about primary prevention with statins. Our view is that more rigorous
data are still needed in this field (particularly as regards the
cost-effectiveness indexes) before one can propose an indiscriminate use of
these agents in people aged more than 55 years.
REFERENCES
1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more
than 80%. BMJ. 2003;326(7404):1419.
2. RodgersA. A
cure for cardiovascular disease?BMJ 2003; 326: 1407-1408.
3. Johannesson M, Jonsson B, Kjekshus J, Olsson AG, Pedersen TR, Wedel H.
Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with
coronary heart disease. Scandinavian Simvastatin
Survival Study Group.N Engl J Med. 1997;336(5):332-6.
Table 1. Cost-effectiveness of statins for primary prevention: list of
the studies not sponsored by pharmaceutical companies.
First author, year of publication, and
|
Type of economic analysis |
Comparative design |
Source of effectiveness |
Results of the |
Lim et al. (2001) (Australia) |
CEA (with simulation model) |
Pravastatin vs. no therapy |
Epidemiological data |
$110,000 (men) and $87,000 (women) |
Perreault et al. (2000) |
CEA |
Simvastatin |
Meta-analysis of RCTs |
Reduction in LDL-C less costly with simvastatin, pravastatin and (men & women) [NR] |
Pharoah and Hollingworth (1996) (UK) |
CEA (with simulation model) |
A statin vs. no therapy |
1 RCT (WOSCOPS trial) |
£136,000 per life year gained. (men) [5%] |
Pickin et al. (1999) (UK)
|
CEA (with simulation model) |
A statin vs. no therapy |
1 RCT (WOSCOPS trial) |
From £8,200 to £12,500 per life year gained. (men) [6%] |
Prosser et al. (2000) (USA) |
CEA (with simulation model) |
A statin vs. low-fat diet |
Published data |
From $54,000 to $420,000 (men) and from $62,000 to $1,400,000 (women) per quality-adjusted life year |
Rindone
|
CMA |
Fluvastatin vs. simvastatin (design |
Observational study §§ |
Mean saving of $120 per patient per year using this switch. (men & women) [NR] |
Spaans et al. (2003) (Canada) |
CEA (with simulation model) |
A statin vs. no therapy |
1 RCT plus a local cohort (with 1% of pre-existing coronary disease) |
From $Can 7,700 to $Can 11,800 per life year gained (men). [3%] |
Spearman et al. (1997) (USA)
|
CEA (including also indirect |
Fluvastatin or lovastatin or pravastatin or simvastatin vs. no therapy |
Observational study §§ |
Cost per 1% reduction of LDL-C lower for fluvastatin ($8.60) than for the other statins (from $19.93 to (men & women) [0%] |
§ Unless otherwise indicated, all of these analyses have considered
exclusively direct costs. The complete reference list is presented in the
footonote.
§§ = This study included both patients receiving primary prevention and
patients receiving secondary prevention.
† The figures enclosed by
brackets show the annual discount rate employed in the analysis.
ABBREVIATIONS: CEA = cost-effectiveness analysis ; CMA =
cost-minimization analysis; LDL-C = low-density lipoprotein cholesterol; Can$ =
Canadian dollar; RCT = randomised controlled trial; NR = not reported; £ =
sterling pounds; [6%],[5%],[3%] = value
obtained with a discount rate of 6% or 5% or 3% for both costs and benefits,
respectively; [0%]= undiscounted value; [NR]= The study does not indicate whether
or not report if costs and benefits were discounted.
FOOTNOTE:
-
Lim SS, Vos T, Peeters A, Liew D, McNeil
JJ.Cost-effectiveness of prescribing statins according to pharmaceutical
benefits scheme criteria. Med J Aust. 2001;175(9):459-64.
-
Perreault S, Levinton C, Le Lorier J. Efficacy
and cost of HMG-CoA reductase inhibitors in the treatment of patients with
primary hyperlipidemia. Can J Clin Pharmacol. 2000;7(3):144-54.
-
Pharoah PD, Hollingworth W. Cost effectiveness
of lowering cholesterol concentration with statins in patients with and without
pre-existing coronary heart disease: life table method applied to health
uthority population. BMJ. 1996;312(7044):1443-8.
-
Pickin DM, McCabe CJ, Ramsay LE, Payne N, Haq
IU, Yeo WW, Jackson PR. Cost effectiveness of HMG-CoA reductase inhibitor
(statin) treatment related to the risk of coronary heart disease and cost of
drug treatment. Heart. 1999;82(3):325-32.
-
Prosser LA, Stinnett AA, Goldman PA, Williams
LW, Hunink MG, Goldman L. Cost-effectiveness of cholesterol-lowering therapies
according to selected patient characteristics. Ann
Intern Med. 2000;132(10):769-79.
-
Rindone JP, Arriola G. Conversion from
fluvastatin to simvastatin therapy at a dose ratio of 8 to 1: effect on serum
lipid levels and cost. Clin Ther. 1998;20(2):340-6.
-
Spaans JN, Coyle D, Fodor G, Nair R,
Vaillancourt R, Grover SA, Coupal L. Application of the 1998 Canadian
cholesterol guidelines to a military population: Health benefits and cost
effectiveness of improved cholesterol management. Can J Cardiol.
2003;19(7):790-6.
-
Spearman ME, Summers K, Moore V, Jacqmin R,
Smith G, Groshen S. Cost-effectiveness of initial therapy with
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors to treat hypercholesterolemia in a primary care setting
of a managed-care organization. Clin Ther. 1997;19(3):582-602.
Table 2. Cost-effectiveness of statins for primary prevention: list of
the studies sponsored by pharmaceutical companies.§
First author, year of publication, and reference country (in |
Type of economic analysis |
Comparative design |
Source of effectiveness data |
Results of the pharmacoeconomic analysis† |
Sponsor |
Pharmacoeconomic results favouring the statin manufactured by the |
Badia et al. (1999) (Europe) |
CMA |
Simvastin vs. |
1 RCT |
Cost per patient (men & women) [NR] |
Merck |
Y |
Caro et al. (1997) (UK) |
CEA (with simulation model) |
Pravastatin vs. no therapy |
1 RCT (WOSCOPS |
£20,375 per life (men) [6%] |
Bristol Myers |
Y* |
Caro et al. (2000) (Belgium) |
CEA (with simulation model) |
Pravastatin vs. no |
1 RCT (WOSCOPS |
Euros 12,500 [0% |
Bristol Myers |
Y |
Huse et al. (1998) (USA) |
CEA (with simulation model) |
Atorvastatin Pravastatin or lovastatin vs. no therapy |
Physician Desk |
Cost per life year Values found for atorvastatin: -men: $16,795 to -women: less [3%] |
Pfizer |
Y |
Koren et al. (1998) (USA) |
CMA |
Atorvastatin vs. |
1 RCT §§ |
Cost per patient [NR] |
Parke Davis-Pfizer |
Y |
Lacour et al. (1998) (Canada) |
CMA |
Pravastatin 80mg vs. simvastatin 80mg vs. lovastatin 80mg vs. bexafibrate 80mg vs. lovastatin 80mg vs. simvastatin 40mg vs. simvastatin 30mg vs. simvastatin 20mg vs. phenofibrate 200mg fluvastatin 60mg |
124 studies (randomised or non-randomised) |
Among the agents (men & women) [NR] |
Fournier-Pharma |
Y |
McPherson et al.(2001) |
CMA |
Cerivastatin vs. branded |
1RCT |
Cost savings in |
Bayer |
Y |
Morris and Godber |
CEA |
Atorvastatin or Lovastatin or pravastatin no therapy |
116 studies |
Cost per 1% reduction of LDL-C lower for Cost per life year (men & women) [6% ] |
Novartis |
Y |
Russell et al. (2001) (Canada) |
CEA (with simulation model) |
Atorvastatin vs. no therapy |
Epidemiological |
Atorvastatin cost |
Parke Davis-Pfizer |
Y |
Smith and McBurney |
CMA |
Atorvastatin vs. fluvastatin |
1 RCT §§ |
Reduction in LDL-C |
Pfizer |
Y |
§ Unless otherwise indicated, all of these analyses have considered exclusively
direct costs. The complete reference list is presented in the footonote.
§§ = This study included both patients receiving primary prevention and
patients receiving secondary prevention.
† The figures enclosed by
brackets show the annual discount rate employed in the analysis.
* The pharmacoeconomic result of this study has been considered
favourable to the statin according to current international standards for
interpreting the cost per life year gained.
ABBREVIATIONS: Same as in Table
1.
FOOTNOTE:
-
Badia X, Russo P, Attanasio E. A comparative
economic analysis of simvastatin versus atorvastatin: results of the Surrogate
Marker Cost-Efficacy (SMaC) study. Clin Ther. 1999;21(10):1788-96.
-
Caro J, Klittich W, McGuire A, Ford I, Norrie
J, Pettitt D, McMurray J, Shepherd J. The West of Scotland coronary prevention
study: economic benefit analysis of primary prevention with pravastatin. BMJ.
1997;315(7122):1577-82.
-
Caro JJ, Huybrechts KF, De Backer G, De Bacquer
D, Closon MC.Are the WOSCOPS clinical and economic findings generalizable to
other populations? A case study for Belgium. The WOSCOPS Economic Analysis
Group. West of Scotland Coronary Prevention Study. Acta Cardiol.
2000;55(4):239-46.
-
Huse DM, Russell MW, Miller JD, Kraemer DF,
D'Agostino RB, Ellison RC, Hartz SC. Cost-effectiveness of statins. Am J
Cardiol. 1998;82(11):1357-63.
-
Koren MJ, Smith DG, Hunninghake DB, Davidson
MH, McKenney JM, Weiss SR, Schrott HG, Henley RW Jr, Tresh P, McLain RW,
Bakker-Arkema RG, Black DM. The cost of reaching National Cholesterol Education
Program (NCEP) goals in hypercholesterolaemic patients. A comparison of
atorvastatin, simvastatin, lovastatin and fluvastatin. Pharmacoeconomics.
1998;14(1):59-70.
-
Lacour A, Derderian F, LeLorier J. Comparison
of efficacy and cost among lipid-lowering agents in patients with primary
hypercholesterolemia. Can J Cardiol. 1998;14(3):355-61.
-
McPherson R, Hanna K, Agro A, Braeken A.
Canadian Cerivastatin Study Group Cerivastatin versus branded pravastatin in
the treatment of primary hypercholesterolemia in primary care practice in
Canada: a one-year, open-label, randomized, comparative study of efficacy,
safety, and cost-effectiveness. Clin Ther. 2001;23(9):1492-507.
-
Morris S, Godber E. Choice of
cost-effectiveness measure in the economic evaluation of cholesterol-modifying
pharmacotherapy. An illustrative example focusing on the primary prevention of
coronary heart disease in Canada. Pharmacoeconomics.
1999;16(2):193-205.
-
Russell MW, Huse DM, Miller JD, Kraemer DF, Hartz
SC. Cost effectiveness of HMG-CoA reductase inhibition in
Canada. Can J Clin Pharmacol. 2001;8(1):9-16.
-
Smith DG, McBurney CR. An economic analysis of the Atorvastatin
Comparative Cholesterol Efficacy and Safety Study (ACCESS). Pharmacoeconomics.
2003;21 Suppl 1:13-23.
Competing interests:
None declared
Competing interests:
For a long time I have made my students keenly aware that SAAB is not
the name of an imported Swedish automobile but rather the abbreviation
of the name of drugs which should be addded to the drinking
water..S...Statins... A...Ace inhibitors...A...Aspirin...B...Beta
blockers..It is now confirmed that SAAB in the drinking water should be
the new preventive medicine strategy!
Competing interests:
None declared
Competing interests: No competing interests
Dear Dr. Beeth,
Your suggestion that vitamin B12 should be included in Polypill [tm]
is a good one. Polypill's 0.8 mg folic acid (vitamin B9) is below the
several milligrams needed to mask possibly irreversible B12 deficiency
problems but B12 works with folic acid in homocysteine [Hcy] remethylation
to methionine. I would suggest to also include vitamin B6 that acts to
cover a second Hcy lowering pathway, to cysteine. Moreover, these
additions could be without increased cost and it's illogical to chose one
Hcy lowering pathway over another.
One problem with Polypill is that it has never been tested in a
population with ample omega-3 intake and with Hcy levels below 10
micromol/L, a level attainable in most with a high "potency" multiple B
vitamin supplement.
Let's assume for a moment that mortality and cardiovascular events
can be reduced by 70% with the omega-3 oil alpha-linolenic acid [found,
for example, in flax, canola and walnut oils]. This percentage is in line
with the Wald/Law estimate for Polypill and is not unrealistic according
to Medline PMID 12668490, 12433513 and 9989956.
My guess is that none of the studies in the Wald/Law meta analysis
were adjusted for these apparently enormously efficacious omega-3 oils or
for the family of Hcy lowering nutrients. It would seem to me that
unleashing the Wald/Law methodology on the omega-3 and Hcy lowering
pathways would yield results -not only in the cardio department- that may
well obviate the need for pharma-based polypills with side-effects that
these nutrient approaches clearly don't have. I note that high Hcy status
has now been positively associated with over 100 diseases or conditions
while the statins in Polypill are linked to the same number of harmfull
side-effects.
Competing interests:
None declared
Competing interests: No competing interests
A cure for 80% of cardiovascular diseases for people over 55. So,
people will die from a more painful cancer. Is that it? The greater the
hype, the more I suspect it. No way can there be long term, 20-30 year
studies on this magic drug.
I've been subject to congenital heart disease my entire adult life.
My mom died from it when I was 15, and her mom had a lethal stroke when
she was 15. My blood pressure was 198/88 when I was 22.
I maintain my health with long distance bicycling, 30 miles, or 50
kilometers most days, and decent vegetarian eating.
Competing interests:
None declared
Competing interests: No competing interests
Over the past years, a consensus has emerged that treatment decisions
should be based, wherever possible, on empirical evidence. And in few
areas of medicine have the demands placed on that evidence been as
stringent as in the field of prevention of cardiovascular disease in
general and coronary heart disease in particular.
The paper by Wald and Law, however, seems to cast doubt on this
rigorous approach, suggesting that a cocktail of six medications in a
single pill (“polypill”) would lower the incidence of ischaemic heart
disease events by 88% and of stroke by 80%, and that it might therefore be
given with impunity to “everyone aged 55 and older and [to] everyone with
existing cardiovascular disease”.
In spite of the claim by the authors that widespread use of this
cocktail might have a “greater impact on the prevention of disease in the
Western world than any other single intervention”, we feel obliged to
introduce a note of caution into the argument before this approach is made
the basis of treatment recommendations.
It is generally accepted that treatment effects can only be
determined within the context of a randomised controlled clinical trial.
The results of the trial must take non-compliance and a range of dose-
responses into account. It is not permissible to extrapolate from a post-
hoc analysis of a trial what result might be expected with 100% compliance
and taking account only of those individuals who showed maximum benefit in
terms of risk-factor reduction. Thus the theoretical figure of an expected
61% reduction in ischaemic heart disease events from cholesterol-lowering
using statins is about twice the actual risk reduction seen in any statin
trial to date. The same reasoning can be applied to blood-pressure
lowering – here trials have shown a lowering of ischaemic heart disease
risk of about 20%, not the 46% suggested by Wald and Law. Trial evidence
for the benefits of anti-thrombotic therapy in primary pervention is not
as strong as that for cholesterol or blood pressure lowering, while trial
evidence of a benefit from folate use does not exist. Moreover,
combination therapies must be subjected to the same scrutiny as therapies
containing single ingredients before claims can be made for their
effectiveness, and, of course, no such trial evidence for the polypill
exists.
It would be nice if we lived in a polypill world. One for heart
disease, one for mood (perhaps the “happy pill” suggested by the Dr.
Richard Smith in the editorial accompanying the paper), and maybe even one
for finding the right partner. However this is not the case, and we are
forced to deal with each problem in turn, often compromising and accepting
a less than perfect result. There are no quick fixes, in life or in
medicine, and the polypill is not one for heart disease.
Competing interests:
None declared
Competing interests: No competing interests
Was it any coincidence that the papers about the Polypill were
published the same week as the paper "Effect of interpretive bias on
research evidence" by Professor Kaptchuk?(1)
1 BMJ 2003;326:1453-1455 (28 June)
Effect of interpretive bias on research evidence
Ted J Kaptchuk
Competing interests:
None declared
Competing interests: No competing interests
In a couple of recent meetings on diets rich in fruits and vegetables
I half-seriously argued that whatever the uncertainties surrounding their
beneficial effects on ischaemic heart disease and stroke they may soon be
made irrelevant by eating a "banasta" a day, namely a genetically
engineered banana containing a dose of statin.
Wald and Law present an otherwise realistic preventive
scenario[1].Taking the estimated beneficial effect of the composite pill
at face value Richard Smith raises [2] , among other issues, the question
of medicalization of health interventions. Strictly speaking an
intervention, in the present case a pill, can be legitimately regarded as
inducing less rather than more medicalization if actually shown capable of
eliminating the need for screening for cardiovascular risk factors and of
reducing the need for therapeutic and rehabilitation services, intensive
in technology and personnel.
But equally important is the question of whether the intervention
enhances or reduces people's autonomy in the etymological meaning of self-
given rule of behaviour. Can a lifetime (after age 55) use of a pill
result in weakening of personal, and then collective, efforts to abandon
tobacco smoking, avoid overweight, exercise regularly ( which all affect
the risk of diseases like cancers at different sites) ? How far this may
in turn help in perpetuating, in a vicious circle, the influence of agents
like the tobacco industry ? How much will it reinforce the tendency to
depend on pills rather than on feasible but will-based behavioural changes
? Empirical evidence in different populations (eg by gender, country,
social class) is needed on these issues.
One of the less often quoted sections in the classic book [3] on
preventive strategies by Geoffrey Rose stresses (chapter 8, p.113 and
ff.) prevention as largely relying on responsible free choices rather than
on the passive adoption of ready made solutions or, in the health
education area, on conviction forced through propaganda. Primary and
primordial prevention on "healthy" people contribute not only to disease
avoidance but also, through the specific means it becomes implemented on a
vast scale, to the habit formation of citizens, hence to their general
attitude towards solving societal problems of direct personal
relevance.This aspect should not be underrated whenever a new preventive
approach is proposed.
[1] Wald NJ and Law MR. A strategy to reduce cardiovascular disease
by more than 80%. BMJ 2003; 326 : 1419-23.
[2] Smith R. The most important BMJ for 50 years ? BMJ 2003; 326 :
1405.
[3] Rose G. The strategy of preventive medicine.Oxford University
Press, Oxford, 1992.
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
Rodgers correctly writes in praise of the extensive analysis done by
Wald and Law in support of their concept that a combination of aspirin,
statin, angiotensin-converting enzyme inhibitor, beta-blocker, diuretic
and folic acid can significantly reduce cardiovascular disease (1,2,3,4).
Given that all these drugs are available in their generic forms, the
potential availability of an effective and inexpensive treatment to combat
the scourge of cardiovascular disease would be most welcomed.
It is thus disappointing to note that patents have been filed by the
authors for the proposed polypill. This can only have the effect of
increasing medical costs with the result that some who would benefit will
not be able to afford the treatment. Commercial consideration seems to
have penetrated the highest halls of British medical academia. How many
less would have been saved had Fleming filed a patent for penicillin?
Dr H T Ong FRCP (Edin, Glasg)
Consultant Cardiologist,
H T Ong Heart Clinic,
251C Burma Road,
Penang, Malaysia.
References :
1. Anthony Rodgers. A Cure for Cardiovascular Disease? Combination
Treatment has Enormous Potential, Especially in Developing Countries. BMJ
2003; 326:1407-8.
2. Wald NJ, Law MR. A Strategy to Reduce Cardiovascular Disease by more
than 80%. BMJ 2003; 326:1419-23.
3. Law MR, Wald, NJ, Rudnicka, AR. Quantifying Effect of Statins on Low
Density Lipoprotein Cholesterol, Ishaemic Heart Disease, and Stroke:
Systematic Review and Meta-analysis. BMJ 2003; 326:1423-27.
4. Law MR, Wald NJ, Morris JK, Jordan RE. Value of Low Dose Combination
Treatment with Blood Pressure Lowering Drugs: Analysis of 354 Randomised
Trials. BMJ 2003; 326:1427-31.
Competing interests:
None declared
Competing interests: No competing interests
Dear Dr Chaudhri,
A General Practioner like you, I see the un-acceptable side effects in the
thiazide and the beta-blocker (+ the asperin also, of-course depending on
the dose that was planned). I wrote the following response to Dr Wald and
Dr Law before reading these other reactions. Maybe you could swallow a
pill like this one day…
Dear Dr Wald and Dr Law,
The concept of the “Polypill” is a good one, but I believe an un-
necessary amount of the 8 to 15 % of the possible side effects will be
coming from the beta-blocker and the thiazide component.
On close examination, a very large amount of people detect a if all
so slight feeling of lack of spark, which influences their lives
negatively. They often don’t even realize how “spark-less” they had become
until they stop taking the beta-blocker, perhaps in favor of a slow-
release formulation of verapamil.
Verapamil, like the beta-blocker, has a negative chronotropic and
inotropic effect on the heart. Surprisingly though, it increases the
effort capacity test more than an ACE inhibitor can achieve on patients
who where not in a prior state of heart decompensation, something which
diltiazem, a calciumblocker with comparative negative chronotropic but
less inotropic, effect never managed to prove.
Another verapamil specific particularity is that it has increased
blood pressure lowering activity depending on the salt intake of the
patient: no more salt restrictions(, means also continued good hydration
and nutrition of the elderly).
It has a stabilizing effect on the smooth muscle of the airways,
causing less bronchial hyper-reactivity, while the beta-blocker could
actually destabilize an asthmatic patient, and there are VERY many of
these in the population group that the pill would be directed to.
Verapamil, like the beta-blockers are proven to be effective in the
prevention of arythmia, also in post-myocardial infarct studies. Slow-
release verapamil has a surprisingly beneficial profile, but it is often
looked over by the medical community because it became a generic during
the days when a lot of pharmaceutical attention was given to newer
molecules. It is rare to find a comparison between slow-release verapamil
and these other products, because there was little chance the newer
molecules could turn up better.
The problems one would encounter with verapamil would be a
potentially dangerous bradycardia if combined with a (especially i.v.
administered) beta-blocker. It quite often gives some constipation due to
the effect on the smooth muscle. This is practically always correctible by
increased fluid intake, and more fiber in the food. It causes much less
headaches and ankle edema than the dihydropyridines, in fact it is used to
prevent migraine. Many cardiologists fear the possibility of exacerbation
a state of heart decompensation with verapamil. This is because they are
used to verapamil under it’s injectable or immediate release oral form. In
my experience with the slow release form, it is much safer than a beta-
blocker, and it has none of the unpleasant side effects of beta-blockers.
It should of-course not be given if the patient is in a state of heart-
decompensation.
The combination of an ACE-inhibitor with slow-release verapamil is
one of my favorites, because of optimal effect on blood pressure (Without
hardly ever causing hypo-tension, or ortho-statism which we often see with
the combination thiazide + ACE inhibitor), on the kidneys, on the intima
of the blood-vessels (I prefer having a slight risk of dry cough, due to
decreased brady-kinine degradation that also increases nitric oxide and
prostacycline which is not increased to the same amount with the (more
expensive) sartans), and on sexual function, including stamina. These last
two decrease hopelessly with thiazides and beta-blockers. What-ever
negative inotropic effect that the slow release verapamil may have given
seems to clinically disappear thanks to the addition of the ACE-inhibitor.
The thiazides cause not only loss of precious water, but also of
minerals including Potassium, Magnesium and Calcium. This is not only a
frequent cause of cramps among the elderly, but also sudden death through
arythmia. This, combined with the hip fractures due to ortho-statism and
calcium depletion contributes to make also the thiazide component a
questionable asset to the “Polypill” (see also effect on uric-acid, lipid
profile, reflex activation of the angiotensine levels.. the diuretics
should only be given under strict indications, and preferably then loop-
diuretics).
So, if we throw out two components and substitute it with one, should
we add something else instead? How about selenium (and/or vitamin E). The
selenium has proven anti-cancer activity, and also helps maintain a
healthy thyroid function which is of great importance when considering
cardio-vascular risk. And vitamin E is the least questioned useful vitamin
supplement for a long and happy life.
That’s what we are here for, isn’t it!
With kind regards from Belgium, keep up the good work!
cc to Dr A. Rodgers (N.Z.)
Dr Eric Beeth
Family Practice
Av. de l’Armée 127,
B-1050 Brussels, Belgium
(Assistant teacher of GP medicine at the Vrije Universiteit Brussel)
drbeethbrux@msn.com
Competing interests:
None declared
Competing interests: No competing interests
Re: QUESTIONABLE COST-EFFECTIVENESS OF STATINS FOR PRIMARY PREVENTION OF CARDIOVASCULAR EVENTS
Our rapid response contained the following typographical errors which
we would like to correct:
(1) Second paragraph of the text, line 8:
“comparison or” should read “comparison of”; (2) Abbreviations of Table 1,
last sentence: the words “report if” should be deleted; (3) Table 2, row
3, paper by Caro et al. (2000): the information on the study sponsor –last
column- should be “Y*” (and not “Y”). We apologise for these errors.
Competing interests:
None declared
Competing interests: No competing interests