Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies
BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b1665 (Published 19 May 2009) Cite this as: BMJ 2009;338:b1665
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When Wald and Law originally proposed their polypill, it was as a
“low cost Polypill” which “could use generic components that are not
subject to patent protection”.1 Yet, the same authors have patents
(granted and pending) on the formulation of a combined pill to
simultaneously reduce four cardiovascular risk factors, including blood
pressure.2 Call me naïve, but is not this a paradox? As someone interested
in the epidemiology of cardiovascular diseases in low-middle income
countries, what implication will this patent have on those in these
settings?
I appreciate the ‘intellectual property’ market now, but frankly, I
had this idea 10 years ago as a junior doctor.I thought is was obvious!
How remiss of me to not pursue it! It’s not rocket science to put together
the components, and it is likely to work in terms of prevention of
cardiovascular events. However, will the provision of a polypill among
populations of lower socioeconomic status, in developing world settings,
to individuals at high risk of experiencing a cardiovascular result in
better adherence to indicated therapies compared with usual care? Probably
not if it is protected by a patent! And can you measure the use of
cardiovascular preventative therapy, and barriers or enablers to such use
(prescription and patient adherence / persistence), as the principle of
taking drugs to prevent poor health is still unknown in many settings. Try
prescribing a hypertensive in a rural clinic in Kolkata to a patient who
has to pay for his drugs who has come in with smoking-induced obstructive
lung disease and you have found them to have a blood pressure of 140/90.
As part of our duty of care as health professionals, the fact that
the majority of the causes of cardiovascular disease are known and
modifiable arguably confers a moral obligation on us to try to prevent the
appearance of such diseases. However, if an increasingly larger proportion
of the entire population needs to be targeted by medication to reduce
risk, then mass medication paradoxically may be the wrong approach. Does
it then follow that we should we treat and medicalise all? Drugs do not
eliminate the underlying societal-level causes of the disease. For
example, the greatly increased fat consumption in developed, and
increasingly, in developing countries3 should be dealt with by a change in
food policy, not using cholesterol-lowering medication to deal with its
consequences. Encouraging the whole-population uptake of healthy
behaviours through changes in food, alcohol and physical activity policies
is surely preferable to the widespread taking of tablets.
1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by
more than 80%. BMJ 2003;326(June 25, 2003):1419
2. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs
in the prevention of cardiovascular disease: meta-analysis of 147
randomised trials in the context of expectations from prospective
epidemiological studies. BMJ 2009;338(May 19, 2009):b1665
3. Drewnowski A, Popkin BM. The nutrition transition: new trends in
the global diet. Nutr Rev 1997;55(2):31-43.
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor,
The conclusions of Law and colleagues that “drugs are offered to
people of all levels of blood pressure” seems to completely contradict the
conclusions of a more recent Cochrane review on the treatment of blood
pressure targets for hypertension (1).
This systematic review, which disturbingly seems to look at exactly the
same data that Law and colleagues considered, comes to an entirely
different conclusion.
The author’s conclusion is that “Treating patients to lower than standard
BP targets, </=140-160/90-100 mmHg, does not reduce mortality or
morbidity. Because guidelines are recommending even lower targets for
diabetes mellitus and chronic renal disease, we are currently conducting
systematic reviews in those groups of patients”.
As generalists we find these conflicting conclusions very disturbing.
Who is right and who is wrong?
Dr Ray O’Connor MB FRCGP
Dr Ruth Moloney MB
Mid-West Specialist Training Programme in General Practice,
University of Limerick,
Plassey,
Limerick,
Ireland.
References:
1. Arguedas JA, Perez MI, Wright JM. Treatment blood pressure targets for
hypertension. Cochrane Database Syst Rev. 2009 Jul 8; (3): CD004349.
(Review) PMID: 19588353
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
In conclusions of their meta-analysis on efficacy of antihypertensive
therapy, Law, Morris and Wald conclude that blood pressure should be
lowered in everyone over certain age (1). We would like to emphasize the
presence of particular patients’ population that may highly benefit from
blood pressure lowering.
After elimination of human immunodeficiency virus from blood
replacement products that have been used in haemophilia, intracerebral
haemorrhage (ICH) has become the major cause of death in these patients.
ICH is 20–50 times more frequent in subjects with haemophilia as compared
with a non-haemophiliacs and it is characterized by higher mortality and
long term disability in the majority of affected subjects (2). Although
hypertension is a major contribution to all kind of stroke, relationship
between blood pressure lowering and risk reduction appears to be stronger
for haemorrhagic than ischaemic cerebrovascular incidents. In the PROGRESS
study on secondary prevention of stroke, lowering blood pressure with
perindopril and indapamide reduced the relative risk of subsequent
haemorrhagic stroke by 50% (3). So far high blood pressure has not been
established as a risk factor for ICH in haemophilia patients but in one
study arterial hypertension was reported in 12,5% haemophiliacs who
experienced ICH (4).
We think that it would be prudent to carefully evaluate blood
pressure in patients with haemophilia and introduce pharmacological
therapy at the high normal values for systolic (>130 mm Hg), and
diastolic (>85 mm Hg) blood pressure.
Tomasz Pasierski, specialist in cardiology, Warsaw Medical
University, Poland
Jerzy Windyga, specialist in haematology, Institute of Haematology
and Transfusion Medicine, Warsaw, Poland
Jacek Zaborski, specialist in neurology, Miedzyleski Hospital,
Warsaw, Poland
Authors declare no conflict of interest
1. LawMR, Morris JK and Wald NJ . Use of blood pressure lowering
drugs in the prevention of cardiovascular disease: meta-analysis of 147
randomised trials in the context of expectations from prospective
epidemiological studiesBMJ 2009;338:b1665doi:10.1136/bmj.b1665
2. Darby SC, KanSW, Rosemary J. Spooner RJ et al. Mortality rates,
life expectancy, and causes of death in people with hemophilia A or B in
the United Kingdom who were not infected with HIV. Blood. 2007;110:815-825
3. PROGRESS Collaborative Group Randomised trial of a perindopril-
based blood-pressure-lowering regimen among 6105 individuals with previous
stroke or transient ischaemic attac Lancet 2001; 358: 1033–41
4. Stieltjes, N., Calvez, T., Demiguel, V., et.al. Intracranial
haemorrhages in French haemophilia patients (1991–2001): clinical
presentation, management and prognosis factors for death. Haemophilia,
2005: 11, 452–458.
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor,
May I draw your attention to the relative rarity of papers which
discuss the pathophysiology of a disorder. As a result, publications
dealing with drug treatments fail to discuss how a treatment relates to
the cause of a health problem, even though the relevant information had
been published previously.
Two papers can be cited as good examples in which published
information with direct pathophysiological significance was not referred
to. The paper by Law et al, concerned blood pressure-lowering drugs; and
the paper by McCowan et al which dealt with the effects of smoking during
pregnancy.
It would seem very unlikely that a meta-analysis of papers which
failed to recognise the pathophysiology of the disorder being studied
would provide useful information. Since 1930, many authors have noted
that blood pressure is related directly to blood viscosity. In addition,
there are several reports which show that some of the drugs used to lower
blood pressure, reduce blood viscosity. As blood is a thixotropic system
in which blood viscosity is related inversely to the rate of blood flow,
any reduction in flow rate is accompanied by an increase in blood
viscosity. In his Hunterian Lecture in 1970, Dormandy discussed the
relation between blood viscosity and the rate of blood flow. Stimulated
by the demonstration by Floras of a circadian rhythmn in blood pressure,
in a letter to the BMJ
I drew attention to the potential hazards of lowering blood pressure in
the absence of information concerning blood viscosity, which was published
in 1991.
But the recognition of the role of blood viscosity in high blood
pressure implies that the management of hypertension could be based upon
changes in the personal behaviour of the patient which related to diet,
physical activity and not smoking. Note that all three factors contribute
to blood viscosity. Getting patients to assume responsibility for their
health problem, without the use of drugs would result in substantial
savings in health costs. In addition it would show that the concept of a
"polypill" was both inappropriate and unacceptable.
In the McCowan et al paper, there is no indication that the
investigators had addressed the question, "What are the effects of smoking
?" Even a cursory search of the literature would show that smoking
increases blood viscosity, and as we found that smoking reduced the
filterability of blood, it seems that smoking also reduces red cell
deformability. Of direct relevance to the finding that cessation of
smoking led to normal birth weights etc, is the 1987 report by Ernst and
Matrai that abstention from smoking normalised blood rheology. As modern
search engines provide a simple means of searching the literature, this
implies that there had been no investigation into what had been published
about the effects of smoking.
It must be a matter for concern that those referees who reviewed the
papers failed to recognise their deficiencies.
I conclude with the suggestion that until there is greater
recognition of the need to relate treatment to a recognised
pathophysiology, patients will continue to evade their responsibility for
the maintenance of good health. I apologise for my verbosity, but I hope
that you will accept that authors proposing new treatments should be
required to relate their treatment to the pathophysiological processes
involved.
Yours sincerely.
Les Simpson.
Competing interests:
None declared
Competing interests: No competing interests
I have waited to learn if any contributors responded to Professor
Law's statement on June 26, "There is no reason to believe that blood
pressures around 100mm Hg systolic are harmful since they are not unusual
in youth with no untoward effect."
For about 70 years it has been known that there is a direct
relationship between blood pressure and blood viscosity, with hypertension
being associated with high levels of blood viscosity. Therefore to
sustain blood flow, blood pressure must be sufficient to overcome the
resistance of viscous blood. Furthermore, because blood is a thixotropic
system, the slower blood flows, the more viscous it becomes.
Floras showed that a circadian rythmn exists which for about 2 hours
in the early morning is manifested as a drop in blood pressure. This
implies that patients taking anti-hypertensive drugs may not have a
sufficient reserve to maintain blood flow during that time and many
myocardial infarctions occur in the early hours of the morning.
Rather than assuming that a particular blood pressure is not harmful,
Professor Laws needs to recognise that blood pressure is related to the
physical properties of blood.
Competing interests:
None declared
Competing interests: No competing interests
I fear that promulagation of the polypill will have the inevitable
consequence of worsening our obesity epidemic. Currently many patients
are motivated to take up exercise, lose weight and eat healthily to reduce
their cardiovascular risk. The unintended effect of the polypill will
surely be to reduce this motivation.
Unfortunately by neglecting sensible lifestyle changes the
accompanying obesity leads to high levels of diabetes, many cancers and
joint problems to mention a few.
Stampfer and colleagues showed in 2000 that in the Nurses Health
Study 5 simple lifestyle measures, ie not smoking, BMI under 25, moderate
alcohol consumption, exercise of 30 minutes a day and a moderately healthy
diet reduced the risk over their 14 study period of cardiovascular events
to 0.17 of that of the group as a whole! It is inconceivable that the
polypill will be as efficacious.
Forget the pills and get out there and exercise and eat well! (Or
alternatively add orlistat to the polypill!)
Paul Corwin
Competing interests:
None declared
Competing interests: No competing interests
Law, Morris and Wald failed to answer my question, "If the initial
blood pressure had no predictive value for cardiovascular diseases what
disease was being treated?". The question is important for accepting that
hypertension is a disease rather than one of several abnormal findings in
a disease, entrenches false meme complexes including the notion that
reducing the risk of cardiac events and stroke equates with reducing the
risk of death from all causes.
They claim that, "Glaser’s division of society into “hypertensives”
and “normotensives” is an artificial dichotomy which ignores the fact that
reducing blood pressure from any level reduces risk [of cardiac events and
stroke]..Glaser also suggests that offering blood pressure lowering
treatment to all people above a specified age regardless of blood pressure
“medicalises” people. It does not because they do not become “patients”
with a medical diagnosis".
What is that supposes to mean? That a medical diagnosis is not a
prerequisite for treating a patient? Or is it an acknowledgement that
hypertension is not a disease and a way of justifying having treated the
blood pressure in the absence of compelling evidence of a reduction in
mortality from all causes.
Competing interests:
None declared
Competing interests: No competing interests
Malcolm Law states that "Glaser’s division of society into
“hypertensives” and “normotensives” is an artificial dichotomy
...".
http://www.bmj.com/cgi/eletters/338/may19_1/b1665#215796
But, a decision to treat or not treat someone creates a real
dichotomy.
I don't think that there is a fundamental difference between
artificial and real dichotomies. The fundamental difference is
in the decision-making: based on blood pressure or based on
risk.
Competing interests:
None declared
Competing interests: No competing interests
Law persists in defending his contention that benefits accrue across
his assembled RCTs of BP-lowering, down to a level of 110mmHg. Such an
optimistic Public Health perspective fits neatly with the epidemiology of
the wide-ranging correlation of pre-treatment BP to CVD risk, but lacks
any jobbing-GP reality check.
So far as I can tell Law's enthusiasm takes no account of
1 . the diminishing size of benefit at lower CVD risks, and
2. the HARMS of BP-lowering drugs, across the board, and the lower
the BP.
I apply the guidelines that exhort me as a GP to lower the BP below
140/85 in certain high-risk patients ( eg: CKD / high CVD-Risk / Older
Diabetics /recent MI ). This I believe worthwhile because HIGH-CVD-RISK
is accompanied by larger absolute benefits of treatment, which must
outweigh the harms of BP-lowering drugs to justify my prescription. Low-
cvd-risk patients will likely suffer more harm than good, as first mooted
in the J-shaped curve controversy of the 1970s.
If Law continues to believe that polypill-style approaches should
reach deeper into 'healthy' populations, without limit, he needs to
examine the current Aspirin controversy, which clearly show that low-risk
patients ( even Doctors aged 60 such as myself) suffer roughly as much
harm as benefit from that drug.
We need to row back, using Actual CVD Risk should be a key measure.
Law should recognise the need for a floor.
Yours, etc
sam lewis
REF:
Aspirin in the primary and secondary prevention of vascular disease:
collaborative meta-analysis of individual participant data from randomised
trials
The Lancet, Volume 373, Issue 9678, Pages 1849 - 1860, 30 May 2009
Competing interests:
Harms versus Benefits
Competing interests: No competing interests
Combination blood pressure lowering therapy: a corrected and updated meta-analysis
We recently found an error in a 2009 meta-analysis of blood pressure lowering trials (1), which remains one of the most cited papers in the area. The ADVANCE trial (2), in which 11,140 people with type 2 diabetes were randomised to a perindopril-indapamide fixed dose combination or placebo, should have been included among the trials of combination therapy rather than monotherapy. In addition, while the HYVET pilot trial was included, the main HYVET trial (3) was published after the cut-off time of December 2007 in the search strategy. The HYVET trial was the last major endpoint trial of blood pressure lowering compared to placebo, and was also essentially a trial of combination therapy. In this trial 3,845 patients aged over 80 years with systolic blood pressure over 160 mmHg at baseline were randomised to indapamide or placebo, with additional perindopril or placebo added among 79% of participants.
We therefore added the ADVANCE and HYVET trials to the meta-analysis estimates of combination therapy in the 2009 paper, to assess all completed endpoint trials of combination therapy vs placebo or no treatment. The key results are shown in the Figure. Overall, there were reductions of 16% in coronary heart disease (CHD; p=0.005), 28% in stroke (p<0.001) and 17% in total mortality (p<0.001). The reductions in mortality were separately significant for each patient group. There was no significant heterogeneity between the trials for the CHD and mortality outcomes. There was heterogeneity for stroke across the trials, which is likely due at least in part to the different blood pressure reductions between groups and the fact that this is a highly blood pressure dependent outcome.
This updated analysis confirms and extends the key conclusion of the original meta-analysis (1) on the benefits of combination therapy among a wide range of patient groups.
1. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338: b1665.
2. Patel A, Group AC. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. The Lancet 2007; 370(9590): 829-40.
3. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. New England Journal of Medicine 2008; 358(18): 1887-98.
Contact: Anthony Rodgers: arodgers@georgeinstitute.org
Competing interests: No competing interests