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From Harvard-MIT Division of Health Science and Technology, Cambridge
Mass, and the Brigham and Women's Hospital, Harvard Medical School,
Boston, Mass.
Correspondence to Elazer R. Edelman, MIT 56–341, Cambridge, MA 02139.
The
angioplasty restenosis experience of the last 20
years has left us with two disturbing ideas: first, that
pharmacological control of this disease may well be beyond reach; and
second, that animal models of restenosis simply cannot predict
pharmacological success. Two recent double-blinded clinical trials with
probucol therapy for elective angioplasty, the MultiVitamins and
Probucol (MVP) trial1 and the Probucol
Angioplasty Restenosis Trial (PART),2
offer sustaining hope. Each study sought to examine the role of
oxidative stress on restenosis through the use of dietary
intake of antioxidants and assessment of effect with quantitative
angiography. Whereas the MVP trial examined the differential effects of
probucol and the combination of vitamins C and E with ß-carotene, the
PART trial compared probucol with placebo alone. The probucol arms of
these studies were based on the same fundamental cell culture and
preclinical animal experiments, used virtually identical designs, and
produced nearly identical reductions in restenosis
(Table
Taken together, this study,3 the parent MVP
trial,1 and the recently published PART
trial2 not only rejuvenate the search for the
elusive "magic bullet" for restenosis but pose intriguing
questions and offer critical insight into the mechanism of
restenosis, the validity of preclinical animal trials, and the
design of clinical studies. In particular, we must now consider:
Antioxidants and Vascular Disease
Oxidative stress is increasingly recognized as a potentially
important contributor to atherogenesis and restenosis after
vascular intervention and injury. Indeed, studies in this area have
renewed interest in the oxidative-modification hypothesis of
atherogenesis. The generation of reactive oxygen species and oxidation
of lipids have profound and wide-ranging effects that can dramatically
increase vascular toxicity and initiate a cascade of molecular and
cellular responses. Oxidized LDL affects the critical cells of
atherosclerosis, impairing endothelial
cell function, activating monocytes/macrophages, and increasing
toxicity to vascular smooth muscle cells. The oxidized lipoprotein
inhibits release of nitric oxide (NO) from endothelial
cells, stimulates macrophage release of monocyte
chemoattractant protein, and above all is far less sensitive to the
feedback control that can be exerted on reduced LDL.
It is not surprising then that modifications of oxidation have been
proposed for dealing with the atherosclerotic and mechanically
manipulated vessel. Diaz et al5 recently reviewed
the wealth of epidemiological data linking dietary and supplementary
intake of antioxidant vitamins with reduction in the clinical
manifestation of atherosclerosis. At the same time, a
range of studies have examined the impact of antioxidants on many of
the isolated cellular effects thought to be associated with
restenosis in cell culture and on intimal hyperplasia in animal
models of disease. Probucol and
Why does probucol decrease restenosis in clinical trials while
all other compounds appear to have failed? Perhaps it is because unlike
drugs with more focused activities, probucol has a broad range of
vascular effects. Pharmacological suppression of one specific axis of
vascular tissue control may lead to upregulation of others. Thus, only
compounds that can regulate the full gamut of the vascular response to
injury may prove efficacious against restenosis. Why then
probucol and not, for example, heparin, another drug with a multitude
of effects? The answer to this dilemma may reside in the
pharmacokinetics and physicochemical properties of probucol.
Pharmacokinetics Dictate Biological Response
The effects of the antioxidants appear to be dependent on the mode
of drug administration. Some of the most important early studies in
this field were those performed by Reaven et
al.9 10 They showed that the lipid-soluble
probucol and
Pharmacokinetic concerns need to be extended to issues of timing of
administration. In fact, in virtually every case in which a benefit has
been observed with antioxidant compounds, pretreatment has been used.
When no pretreatment period was used, probucol, like
lovastatin, failed to demonstrate benefit in
restenotic lesions.11 It is, however, not
as clear how long therapy must be initiated before intervention. The
PART2 and MVP trials1 3
began therapy 1 month before angioplasty, whereas other preliminary
positive trials12 13 provided probucol for only 1
week before intervention. Finally, the dose itself can regulate the
vascular response to angioplasty.
The Battle of the Antioxidants: Vitamins Reverse the Probucol
Benefit
It is disturbing that data from the study by Rodes et
al3 continue to show the trend reported in the
full MVP trial1 : loss of probucol benefit when
administered concomitantly with vitamins C and E and ß-carotene. As
discussed above, there are differences in both the physicochemical
properties and observed effects of the other vitamins and probucol or
Restenosis in Large and Small Vessels
By now, it is well accepted that reference-vessel size predicts
restenosis rates after balloon angioplasty. In the M-HEART
trial, restenosis was 30% greater in vessels <2.9 mm
than in vessels of greater size.16
Univariate analysis of the PART trial demonstrated
that the minimal lumen diameter before and after angioplasty in
patients with restenosis was significantly smaller than in
patients without restenosis.4 It is
therefore reasonable to examine whether benefit seen for a
pharmacological therapy of restenosis applies to the cohort of
patients with "small vessels" and equally reasonable to ask whether
the biology of restenosis depends on size. As these questions
are presented, a number of issues arise. First, it should be
noted that in both the MVP trial and PART, the mean reference diameter
for all groups was <2.8 mm, and at least 60% of the patients in
the MVP trial and 78% of those enrolled in PART had vessels that
qualified for consideration as "small coronary arteries."
Thus, by some classifications, the entire populations for both trials
can be seen as having "small arteries." If the parent trials
exhibited benefit, it is not all that surprising that similar benefit
will be observed when post hoc analysis is performed on such a
significant subset of the general trial population. Second, in light of
the above, we might have the story backward; it may well be that only
small vessels achieve benefit from probucol. In fact, subgroup
analysis of PART showed benefit only in the group of patients
with reference diameters <2.7 mm.4 One
wonders if the same is true for the MVP patients and, for that matter,
whether we ought to be directing pharmacotherapy for use in the smaller
vessels.
Finally, "small" is a relative term and one that must be considered
in light of the interventional setting and measurement technique used.
In stents, for example, dimensional issues encompass the question of
the ability of a vessel to accept and retain the patency of a
small-diameter endovascular implant, whereas in angioplasty we are
dealing with the diameter of what is likely a lumen narrowed by
atherosclerosis. In the angioplastied vessel, there may
well be a difference in the biological response to drugs between a
truly small artery and a larger artery in a vascular bed with a
significant obstructive burden. Size, as assessed angiographically,
cannot distinguish between these two alternatives. Parenthetically it
might be more precise to refer to small vessels as small lumen
arteries to include the possibility of significant obstructing
mass rather than just a small diameter. Intravascular ultrasound can
provide more definite discrimination of true arterial
dimension, assessing in more valid terms the absolute extent of the
blood vessel.17 18 Future trials can well make
use of this and other emerging technologies to address dimensional
concerns.
Correlation of Preclinical and Clinical Trials in
Restenosis
Another of the dismaying issues in restenosis is the
apparent lack of predictability of animal models of vascular disease to
identify agents for pharmacological control. Until now, this comment
has always been made in the attempted reconciliation of negative
clinical trials with positive animal studies. The experience with
probucol finally offers the opportunity to examine this issue from
vantage points that involve positive and negative preclinical studies
and clinical trials. Just as mixed results were observed in a limited
number of animal trials, so too were variable results noted in
human studies with probucol. Although this drug appears to be
successful against restenosis, it is not effective against
native atherosclerotic disease. It is interesting that in light of
these recently published beneficial effects on angioplasty
restenosis,1 2 3 the Probucol Quantitative
Regression Swedish Trial reported no regression in femoral
arteriosclerosis in patients treated with
probucol.19 The absence of effect was thought in
large part to be the result of the decrement in HDL by
probucol.20 It may be, however, that the mode of
administration is just as critical a factor. Atherosclerotic lesions
were far less prominent and less frequent when probucol was provided to
rabbits fed high-fat diets or to Watanabe heritable
hypercholesterolemic
rabbits.21 22 In nonhuman primates fed high-fat,
high-cholesterol diets, probucol administration was
initiated after 14 weeks on the diet, and regression was restricted to
the thoracic aorta. The abdominal aorta and iliac arteries were
unaffected, and in each segment intimal thickening was inversely
related to resistance to oxidative stress.23
Intimal hyperplasia after balloon injury was reduced in the
hypercholesterolemic rabbit24 and
in domestic swine25 when probucol was begun 2 to
14 days before injury.
Pretreatment is a distinct and realistic possibility when used in
concert with vascular interventions; the same is not true for attempts
at atherosclerosis regression.
Atherosclerosis is a lifelong illness, sensitive to the
cumulative effects of global and systemic exposures and risk factors.
In contrast, restenotic lesions begin precisely at the time of
the specific intervention and develop in a well-characterized,
time-dependent fashion, usually restricted to a few months after the
procedure. As a result, unlike general atherosclerosis,
there may well be a window of sensitivity for restenosis that
can allow for temporally limited therapy. The clinical trial results
are in fact presaged by animal experiments, and in retrospect many of
the seeming discrepancies between preclinical animal and clinical human
trials may be reflective of inappropriate extrapolation of protocols
from one to the other. The beneficial effects of drugs obtained in
animals and not observed in humans usually involved continuous
administration, truly local release, or pretreatment with the former
and intermittent administration begun after intervention in the
latter.26 Pharmacokinetics has become an
essential parameter to ensure drug effect. When drug
administration in humans is matched to positive animal trial protocols,
one might expect concomitant positive effects in the human, and when
not followed, divergent effects may well be observed.
Subgroup Analysis and Clinical Trials in
Restenosis
The report by Rodes et al3 retrospectively
analyzes a smaller subset of a small number of patients
enrolled in a clinical trial. The authors should be commended for the
care with which the trial was performed and the innovative nature of
their comparison of these different antioxidants. Nonetheless, as
discussed by the authors, the trial was not intended to demonstrate an
effect on small vessels. Moreover, the probucol-treated group consisted
of only 46 patients, and in the full PART trial, only 51 patients were
treated with the experimental agent (Table
Where Do We Go From Here?
What do we do now that we know that the 46 patients who received
probucol had less restenosis after angioplasty of
coronary arteries <2.7 mm in diameter than the 47
patients with the same-sized arteries who did not get the probucol? The
data are solid, and it should be recalled that these numbers of
patients are the same as in other widely touted and well-run trials,
for example, those discerning benefit from radiation therapy. Thus, it
seems incumbent on us to organize a well-run prospective trial with far
larger numbers of patients making use of other imaging modalities such
as intravascular ultrasound. Three additional issues are worthy of
note. First, if oxidative stress is critical and if macrophages
play a central role in this phase of the vascular response to injury,
then one would surmise that endovascular implant injury, with its
abundant monocyte/macrophage
recruitment,27 28 might be even more sensitive to
antioxidant therapy. Second, if it is true that a part of the benefit
of antioxidants arises from physicochemical properties of the
compounds, we may be able to reexamine past restenosis trials
and previously rejected candidate agents. Hydrophilic compounds
administered after injury should not work, and administration of
promising lipophilic agents begun before intervention could have
benefit. It would be of great interest to compare probucol with a
promising vasoactive, lipophilic agent that previously failed to show
benefit when administered only after intervention, when both drugs are
begun a month before injury. Finally, the issues of dosing and
administration will need to be fully delineated if probucol and like
drugs are to be considered for use in angioplasty restenosis. A
drug that must be initiated a month before intervention will likely see
limited use and offer marginal benefit for the highest-risk cadre of
patients undergoing angioplasty in the urgent and semielective
setting.
The study by Rodes et al3 in this issue of
Circulation leaves us with renewed hope, not only for the
introduction of a therapeutic modality for a disturbing disease, but
for possibly providing a framework by which to organize our thoughts
and characterize our experiences in this field. Issues related to trial
design and drug properties and use may now help us develop a more
reasoned understanding of the vascular response to injury. As of today,
pharmacological modulation of restenosis is probably a valid
goal for even the smallest vessel, as long as the right drug is used
and in accordance with an appreciation for both the drug's mode of
action and its pharmacokinetics. We might now say that the target
vessel may never be too small, and the drug dose is not often too
little, but the agents applied can occasionally simply be administered
too late to control restenosis.
Acknowledgments
I am supported by grants from the National Institutes of Health
(RO1 GM/HL 49039), the Burroughs-Welcome Foundation in Experimental
Therapeutics, and the Whitaker Foundation for Biomedical Engineering. I
am deeply indebted to Drs John Keaney and Campbell Rogers for their
careful review of this manuscript, novel insights, and critical
suggestions.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Schneider JE, Berk BC, Gravanis MB, Santoian EC,
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© 1998 American Heart Association, Inc.
Editorials
Vessel Size, Antioxidants, and Restenosis
Never Too Small, Not Too Little, but Often Too Late
Key Words: Editorials • angioplasty • antioxidants • restenosis
). As reported in this issue of
Circulation, Rodes et al3 have
extended analysis of the MVP trial post hoc to patients with
small-diameter vessels. As with a similar subgroup analysis of
the PART trial,4 the benefit of probucol was
retained in vessels <2.7 mm in diameter (Table), and as in the
parent MVP trial with all patients and arteries of all sizes, the
addition of vitamins C and E with ß-carotene negated the beneficial
effect.
View this table:
[in a new window]
Table 1. Summary of Data From Clinical Trials Examining Probucol in
Angioplasty Restenosis 
-tocopherol can regulate
oxidative stress both directly and indirectly. Aside from their ability
to lower levels of the LDL substrate, these compounds can also protect
LDL from oxidation and cells from the toxic effects of the oxidized
lipoprotein. Probucol can inhibit production and release of
growth factors like platelet-derived growth factor and
cytokines like interleukin-1 through a range of potential
effects. -Tocopherol restores NO release from cells
inhibited by oxidized LDL,6 eliminates
macrophage binding to interleukin-1ß–stimulated
endothelium by regulation of the surface expression of
E-selectin,7 increases the resistance of
endothelial cells and macrophages to oxidized
LDL, and decreases platelet activation by
arachidonic acid and phorbol ester through a decrease
in protein kinase C.8 All of these actions can
also by themselves inhibit smooth muscle mitogenesis and when viewed in
general context might provide powerful regulation of intimal
hyperplasia. -tocopherol are incorporated into LDL and
increase resistance of LDL to oxidative modification but require
several months of oral administration to achieve adequate plasma
levels, and presumably tissue levels, for sufficient antioxidant
protection in humans.9 10 ß-Carotene does not
provide the same resistance to oxidation despite accumulation within
the lipoprotein, and the water-soluble vitamin C is not incorporated
within the LDL particle. Heparin for that matter is an especially
soluble compound. Despite its multitudinous potential effects on the
vascular biology of injury, this compound may simply rapidly diffuse
into and then out of the target area without a sustainable tissue
concentration, well before it has had a chance to exert any impact on
vessel wall repair. -Tocopherol increased
the resistance of LDL to oxidation in cholesterol-fed
rabbits at all doses,14 but whereas
endothelium-derived NO-mediated vasorelaxation was
preserved at low doses, it was impaired when the dose was increased
10-fold. A final point regarding the pharmacology of probucol and like
compounds is that for every percentage decrement in LDL, there was a
3-fold greater decrease in HDL (Table
). The positive impact on
restenosis, therefore, is that much more intriguing and
significant. Yet this adverse effect on HDL, coupled with the need for
pretreatment, may mean the difference between possible clinical utility
on the one hand and inconvenient obsolescence on the other. Probucol
may have a limited role in restenosis if it can only be used 1
month before intervention and drives HDL down to a far greater extent
than its effects on LDL. -tocopherol. Differences in lipid solubility and LDL
particle entry may be responsible for the diverse effects. One might
then speculate that the loss of benefit when vitamins are present
with probucol could be derived from an interaction between the two
classes of antioxidants or their metabolites. It would be interesting
to determine whether these various antioxidants bind to one another and
whether the same reversal of effects is observed on cultured smooth
muscle cells. It should also be noted that probucol is metabolized in
vivo to a number of metabolites that are also biologically
active.15 The variability of effect seen in
different animal models with probucol may be derived in part from
differences in metabolism. Vitamins C and E and
ß-carotene might interfere with the conversion of probucol to active
metabolites. Alternatively, vitamins C and E and/or ß-carotene may
directly block the beneficial cellular biology elicited by
probucol. ). As with all retrospective
and post hoc analyses and as in studies with small numbers of
patients, one must determine how and in what context we are to
appreciate the reported findings. Some would have us reject both
analyses that are not performed under the rubric of a
predetermined hypothesis and trials with limited number of
participants. Others would argue that such harsh restrictions would
limit our ability to discern important potential trends that might
otherwise go unnoticed, such as those reported in the article by Rodes
et al.3 All would probably agree that further
evaluation is in order. -tocopherol
prevents endothelial dysfunction due to oxidized LDL by
inhibiting protein kinase C stimulation. J Clin Invest. 1996;98:386–394.[Medline]
[Order article via Infotrieve]-Tocopherol inhibits aggregation of human platelets
by a protein kinase C-dependent mechanism. Circulation. 1996;94:2434–2440.-tocopherol improves and high-dose
-tocopherol worsens endothelial
vasodilator function in cholesterol-fed rabbits.
J Clin Invest. 1994;93:844–851.
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