(Hypertension. 2000;36:e1.)
© 2000 American Heart Association, Inc.
Letters to the Editor |
Pravastatin, Blood Pressure, and Stroke
Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, UK, Department of Cardiology, Wales Heart Research Institute, University Hospital, Cardiff, UK
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To the Editor:
We read with interest the recent paper in Hypertension by Glorioso et al1 demonstrating that the HMG-CoA reductase inhibitor pravastatin significantly lowers blood pressure in patients with coexisting essential hypertension and primary hypercholesterolemia. This is an important finding that may, in part, explain the significant reduction in stroke observed in both the CARE2 and LIPID3 studies, as previously suggested.4
Although epidemiological observations do not suggest any relationship
between serum cholesterol and stroke,5 several
studies have reported a positive correlation between blood pressure and
cholesterol.6 Moreover, indirect evidence from
several trials investigating cholesterol-lowering regimens
suggests that lowering cholesterol may reduce blood
pressure by between 2 and 5 mm Hg.6 Although such an
effect is small, it is similar to the reduction in
diastolic blood pressure of 5 mm Hg observed by
Glorioso et al and, if sustained for 5 years, would be expected
to reduce the incidence of stroke by 
34%.7 Therefore,
we believe that the 31% and 19% reduction in stroke reported in the
CARE and LIPID studies, respectively, may be, in part, attributable to
a blood pressure–lowering effect of pravastatin although,
unfortunately, changes in blood pressure were not recorded in
either trial.
One inconsistency in this argument is that some studies have failed to show any effect of pravastatin on blood pressure, as discussed by Glorioso et al, who suggest that, as with traditional antihypertensive agents, statins may only reduce blood pressure in hypertensive individuals and not normotensive subjects. They go on to speculate that any effect of pravastatin on blood pressure would be difficult to detect in large studies because of the high proportion of normotensive subjects, which would "dilute" any effect of pravastatin amongst the hypertensive individuals. However, in both CARE2 and LIPID,3 normotensive subjects appear to have a greater reduction in the incidence of stroke compared with those who were hypertensive at entry, suggesting that the beneficial effects of statins on stroke may not be confined to the hypertensive population. Perhaps, a more likely explanation for the failure of some studies to detect any change in blood pressure is simply that they were not specifically designed to look at blood pressure and, therefore, may have missed small, but clinically significant changes.
In addition to any effect on peripheral blood
pressure, statins may also reduce the incidence of stroke by altering
arterial compliance.
Hypercholesterolemia, hypertension, and
atherosclerosis per se are associated with
endothelial dysfunction and arterial
stiffening at an early stage.8 Stiffening of the aorta and
large arteries results in decreased buffering of the large pressure
changes produced by intermittent ventricular ejection.
Arterial stiffening increases the speed at which the forward
ventricular ejection wave generated in the aortic root at
the start of systole propagates throughout the vascular tree. Increases
in PWV lead to early reflectance of the forward going pressure wave at
the periphery, such that the reflected wave arrives back at the heart
while the aortic valve is still open, causing an augmented rise in late
systolic pressure. This has a number of adverse
hemodynamic consequences, including raising central
arterial pressure and promoting left
ventricular hypertrophy.
Pravastatin decreases aortic stiffness,9 and
one might therefore expect this to lead to a reduction in central
arterial pressure, although this has yet to be tested
directly. Furthermore, brachial and central arterial
pressure may differ by 
20 mmHg,10 and changes in
arterial stiffness tend to have less influence on brachial
pressure compared with central pressure. Therefore, simply measuring
peripheral pressure will tend to underestimate any effect
of pravastatin therapy on central pressure and may account
for the lack of correlation between cholesterol and
brachial artery pressure in the study by Glorioso et al. It is,
however, interesting to note that they did observe a small (3
mm Hg) reduction in peripheral pulse pressure, a good
surrogate marker of arterial stiffness, in those subjects
assigned pravastatin, supporting the finding that
pravastatin reduces arterial stiffness in
hypercholesterolemic individuals. The mechanism behind
this is unclear but may be related to the beneficial effect of statins
on endothelial function.4
To investigate further the effect of statins on arterial stiffness and central arterial pressure, noninvasive assessment of both these parameters has been included in a substudy of the SEARCH Study, designed to compare high versus low-dose simvastatin, with or without folate, in high-risk patients. However, we believe that the question of blood pressure lowering and statins deserves further investigation and future long-term interventional trials with statins, particularly those in the elderly, should be designed to fully investigate such effects.
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References |
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TopIntroductionReferencesIntroduction |
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1. Glorioso N, Troffa C, Filigheddu F, Dettori F, Soro A, Parpaglia PP, Collatina S, Pahor M. Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension.. 2000;34:1281–1286.
2.
Sacks FM, Pfeffer MA, Moye LA, for the
Cholesterol and Recurrent Events Trial Investigators. The
effects of pravastatin on coronary events after
myocardial infarction in patients with average cholesterol
levels. N Engl J Med. 1996;335:1001–1009.
3.
The Long-Term Intervention with
Pravastatin in Ischaemic Disease (LIPID) Study Group.
Prevention of cardiovascular events and death with
pravastatin in patients with coronary heart disease
and a broad range of initial cholesterol levels.
N Engl J Med. 1998;339:1349–1357.
4. Wilkinson IB, Cockcroft JR. Cholesterol, endothelial function and arterial stiffness. Curr Opin Lipidol. 1998;9:237–242.[Medline] [Order article via Infotrieve]
5.
Gordon T, Kannel WB, Castelli WP, Dawber TR.
Lipoproteins, cardiovascular disease, and death: the
Framingham study. Arch Intern Med. 1981;141:1128–1131.
6. Goode GK, Miller JP, Heagerty AM. Hyperlipidaemia, hypertension, and coronary heart disease. Lancet. 1995;354:362–364.
7. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke and coronary heart disease, I: prolonged differences in blood pressure: prospective observational studies corrected for regression dilution bias. Lancet. 1990;335:765–774.[Medline] [Order article via Infotrieve]
8.
Cockcroft JR, Wilkinson IB, Webb DJ. The Trevor Howell
Lecture: age, arterial stiffness and the
endothelium. Age Ageing. 1997;26:53–60.
9. Muramatsu J, Kobayashi A, Hasegawa N, Yokouchi S. Hemodynamic changes associated with reduction in total cholesterol treatment withthe HMG-CoA reductase inhibitor pravastatin. Atherosclerosis. 1997;130:179–182.[Medline] [Order article via Infotrieve]
10.
Pauca AL, Wallenhaupt ST, Kon ND, Tucker WY. Does
radial artery pressure accurately reflect aortic pressure?
Chest. 1992;102:1193–1198.
Response
University of Sassari Medical School, Clinica Medica, Sassari, Italy \.
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I agree with what Dr Cockroft says in his Letter to the Editor with regard to our paper entitled "Effect of HMG-CoA Reductase Inhibitors on Blood pressure in Essential Hypertensive Patients with Primary Hypercholesterolemia" published in the December 1999 issue of Hypertension. In addition to being definitely preliminary, our data were obtained in a very select sample of never-treated essential hypertensives under carefully controlled clinical and experimental conditions.
To enroll the patients who participated in the trial, we had to screen twice as many patients who presented with characteristics that fulfilled the inclusion criteria: only 49 of them were actually included in the 8-week run-in phase before randomization, and 30 out of those 49 were actually enrolled. Moreover, patient enrollment occurred from late September to early November to avoid interferences from high air temperatures on blood pressure regulation during the summer because the randomized, placebo-controlled, crossover phase lasted 32 weeks. Thus, we had to enroll the patients over 3 consecutive years to complete the study cohort, the size of which was calculated a priori.
I believe that slight differences in blood pressure are almost impossible to detect if very stringent selection criteria are not used in patient selection and trial planning. I am aware that no differences in blood pressure were observed when statins were added to conventional antihypertensive treatment in hypertensive patients with primary hypercholesterolemia who had participated in several large intervention trials; these trials studied the effects of statins on cardiovascular mortality and morbility. I think this is not the ideal setting to observe such differences, if any.
To the best of my knowledge, other placebo-controlled trials using different statins with the same objective (ie, additive effect on blood pressure by these drugs when added to antihypertensive treatment) are presently under way and at least one well-known pharmaceutical company is planning to associate a calcium-entry blocker and a statin in the same pill. Our study is presently being duplicated by using cerivastatin in a large cohort of patients with hypertension and primary hypercholesterolemia in a collaborative study designed on the basis of our study.
I completely agree with Dr Cockroft that our findings, although confirmatory of plausible pathophysiological mechanisms actually relevant in patient’s handling but still unknown, deserve further confirmation that comes from properly designed, large scale clinical trials before being accepted as evidence by the medical community. Our goal was simply to validate in vivo, following an ethically acceptable design, a theory on the effect of cholesterol lowering, which comes from convincing experimental data, and to offer our preliminary conclusions to the scientific community.
Now we know that our findings are in keeping with the data on the effects of statins on cardiovascular and cerebrovascular primary and secondary prevention. We also know that at least part of the beneficial effects of statins on cardiovascular and cerebrovascular prevention are not entirely explained by their cholesterol-lowering effects (ie, the magnitude of cholesterol reduction), which was confirmed by our study in which a correlation between the reduction of cholesterol (either total or LDL) and the reduction of blood pressure was not found.
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