(Circulation. 1998;97:1874-1875.)
© 1998 American Heart Association, Inc.
Functional Evaluation of Lipid-Lowering Therapy by Pravastatin
Frank-Chris Schoebel, MD;
Thomas Walter Jax, MD;
Bodo-Eckehard Strauer, MD, FACC;
; Matthias Leschke, MD
Heinrich Heine Universität Düsseldorf,
Medizinische Klinik und Poliklinik B,
Klinik für Kardiologie, Pneumologie und Angiologie,
Düsseldorf, Germany
To the Editor:
With great interest we read the article of Dr Aengevaeren and coworkers
on further functional aspects of lipid-lowering therapy in patients
with coronary artery disease as derived from the REGRESS
Study.1 In comparison to placebo, 2 years of
treatment with 40 mg of pravastatin resulting in a decrease
of LDL-cholesterol by 23% not only preserved
coronary flow reserve (videodensitometric hyperemic
mean transit time of contrast media after intracoronary
injection of papaverine) but also proved to be superior in respect to
its influence on clinical symptoms. Anginal functional class according
to the criteria of the Canadian Cardiovascular
Society2 demonstrated a change of 2.1±0.5 to
1.8±0.8 in the verum versus 1.4±1.0 to 1.7±1.0 in the placebo group,
resulting in a mean difference of 0.7 between groups
(P=.03). Even though the absolute difference in patients
treated was not reported to be significant this is the first
placebo-controlled trial in patients with stable coronary
artery disease, which describes not solely antiischemic
properties of LDL-cholesterol reduction as other clinical
studies have done previously3 4 5 but also
supplies evidence for relative antianginal properties when compared to
the natural course of the disease over a period of 2 years. As
morphologic regression of coronary
arteriosclerosis was minimal functional,
LDL-cholesterol dependent determinants of coronary
blood flow like a decreased coronary vasomotor tone in the
epicardial conductance6 7 and microvascular
resistance vessels5 are likely to account for the
therapeutic effect.
Another substudy of the REGRESS-Study by Dr Boven and coworkers
reported antiischemic effectiveness of the same therapeutic
regimen in patients who underwent 48-hour ambulatory ST-Holter
monitoring before and after 2 years of
treatment.4 Unfortunately, even though both
studies are presumably derived from the same study protocol, Dr Boven
and coworkers did not report the effect of treatment on the functional
clinical impairment due to angina pectoris. A variability of the
ischemic threshold at the level of the epicardial conductance
vessels documented by an increased time to ischemic end points
during standardized exercise tests after the intake of fast-release
nitrates can be found in at least 30% of the patients with stable
coronary artery disease.8 It would be
interesting to know, whether Dr Boven and coworkers observed a
particular benefit of treatment in patients with a variable
threshold for the onset of ST-segment depression and anginal symptoms
for example defined by a variability in heart rate of >20 bpm at the
onset of pathologic changes during the 48 hours ST-Holter
recordings.9 In case this was true, it
would probably prove that lowering of LDL-cholesterol has
an absolute and significant antianginal effect when compared with
placebo in this subset of patients with a variable threshold of
ischemic changes.
Regardless of its beneficial effect in the secondary prevention of
coronary artery disease antianginal properties of
LDL-cholesterol reduction would have important implications
in particular for the treatment of patients with end-stage
coronary artery disease and chronic refractory angina pectoris
as they are currently subject to studies on various new
anti-ischemic interventions such as low-dose intermittent
urokinase therapy, spinal cord stimulation, and transmyocardial laser
revascularization (see also Reference 10). These
patients without a feasible option for successful coronary
revascularization are characterized by anginal
functional class III or IV resulting in a high rate of anginal episodes
(23.4±11.4 episodes/wk) despite maximally tolerated antianginal
combination therapy (nitrates, ß-blockers, calcium
antagonists).10 If antianginal
effectiveness of LDL-cholesterol reduction can be shown
based on the considerations mentioned above and if they occurred within
a short period as implied by the antiischemic effectiveness
after only 3 months of treatment in the study by Dr Gould and
coworkers,5 this would call for intensified
lipid-lowering treatment with documented LDL-cholesterol
levels ranging 
100 mg/dL as a necessary precondition before
alternative treatment modalities are used.
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References
1.
Aengevaeren WRM, Uijen GJH, Jukema JW, Bruschke AVG, van
der Werf T. Functional evaluation of lipid-lowering therapy by
pravastatin in the Regression Growth Evaluation Statin
Study (Regress). Circulation. 1997;96:429–435.[Abstract/Free Full Text]
2.
Campeau L. Grading of angina pectoris.
Circulation. 1976;54:522–523.[Medline]
[Order article via Infotrieve]
3.
Andrews TC, Raby K, Barry J, Naimi CL, Allred E, Ganz P,
Selwyn AP. Effect of cholesterol-lowering on myocardial
ischemia in patients with coronary artery disease.
Circulation. 1997;95:324–328.[Abstract/Free Full Text]
4.
van Boven ADJ, Jukema JW, Zwinderman AH, Crijns HJGM, Lie KL,
Bruschke AVG, on behalf of the Regress Study Group. Reduction of
transient myocardial ischemia in addition to the conventional
treatment in patients with angina pectoris. Circulation. 1997;94:1503–1505.[Abstract/Free Full Text]
5.
Gould KL, Martucci JP, Goldberg DI, Hess MJ, Edens RP, Latifi
R, Dudrick SJ. Short-term cholesterol lowering decreases
size and severity of perfusion abnormalities by positron emission
tomography after dipyridamole in patients with
coronary artery disease: a potential noninvasive marker of
healing coronary endothelium.
Circulation. 1994;89:1530–1538.[Abstract/Free Full Text]
6.
Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Inou T,
Takeshita A. Reduction in serum cholesterol with
pravastatin improves endothelium dependent
coronary vasomotion in patients with
hypercholesterolemia. Circulation. 1994;89:2519–2524.[Abstract/Free Full Text]
7.
Treasure CB, Klein JL, Weintraub WS, Talley J, Stillablower
ME, Kosinski AS, Zhang J, Bocuzzi SJ, Cedarholm JC, Alexander W.
Beneficial effect of cholesterol-lowering therapy on the
coronary endothelium in patients with
coronary artery disease. N Engl J Med. 1995;332:481–487.[Abstract/Free Full Text]
8.
Kaski JC, Plaza LR, Meran DO, Araujo L, Chierchia S, Maseri
A. Improved coronary supply: prevailing mechanisms of action of
nitrates in chronic stable angina. Am Heart J. 1985;110:238–245.[Medline]
[Order article via Infotrieve]
9.
Maseri A. Medical therapy of chronic stable angina pectoris.
Circulation. 1990;82:2258–2262.[Free Full Text]
10.
Schoebel FC, Frazier OH, Jessurun GAJ, DeJongste MJL,
Kadipasaoglu KA, Jax TW, Heintzen MP, Cooley DA, Strauer BE, Leschke M.
Refractory angina pectoris in end-stage coronary artery
disease: evolving therapeutic concepts. Am Heart J.. 1997;134:587–602.[Medline]
[Order article via Infotrieve]
Response
Wim R. M. Aengevaeren Ad J. van Boven A. H. Zwinderman J. Wouter Jukema Albert V. G. Bruschke Tjeerd van der Werf
on behalf of the REGRESS Study Group,
University Hospital Nijmegen,
Nijmegen, The Netherlands
The antianginal properties of lipid-lowering therapy by
HMG-CoA inhibitors are a potential challenging feature. The
basic mechanism of the antianginal effect is not yet completely
understood. Although improved endothelial function of
epicardial conductance and/or resistance vessels probably is the major
contributor to this antianginal effect, antiplatelet activity and
decreased blood viscosity might also be properties of additional
benefit.1 2 3
"Whether patients with variable threshold angina pectoris might
have an increased benefit over patients with stable angina" is an
interesting question, for which we have analyzed the data
again. In the ambulatory ECG substudy of REGRESS a reduction of 1.23
episode was found in the pravastatin group versus a
reduction of 0.53 episode in the placebo group
(P=.047).4 Patients with
ischemia on ambulatory ECG decreased from 28% to 19% in the
pravastatin group versus an increase from 20% to 23% in
the placebo group (P=.021). Total duration of
ischemic burden was also significantly reduced by
pravastatin as compared with placebo. When we now divide
the periods of ischemia in groups with a variability in heart
rate of more or less than 20 bpm during ischemia, we found that
in the group with a change 
20 bpm, patients receiving
pravastatin showed an increase from 1.11 to 1.83 episode
per patient (P=.001) and patients receiving placebo an
increase from 1.27 to 1.96 (P=.14), respectively. In
patients with ischemic episodes and a difference of <20 bpm,
patients receiving pravastatin showed a reduction from 4.15
to 3.18 ischemic episode per patient (P=.27),
whereas patients receiving placebo showed an increase from 3.06 to 3.64
episode per patient (P=.077). These findings suggest that
pravastatin therapy is more effective in ischemic
episodes with a low rise in heart rate. These findings support the
hypothesis that lipid lowering by HMG-CoA inhibitors has an
anti-ischemic effect through an improvement of
endothelial function of the coronary (micro)
circulation. Most of the episodes of transient ischemia in this
study were asymptomatic. The change in angina pectoris
classification for this group of patients was not available.
We agree with Dr Schoebel and colleagues that lipid lowering by HMG-CoA
inhibitors should be an early step in the treatment of
patients with angina pectoris, independent from the
cholesterol level to prevent further progression of
coronary artery disease. The positive effect on anginal
complaints might be advantageous, but at this moment the degree of
functional improvement from HMG-CoA inhibitors is largely
unknown. Therefore, to state that HMG-CoA inhibitors are a
necessary precondition in patients with chronic refractory angina
pectoris because of the antianginal properties is questionable. The
degree of improvement in myocardial perfusion in absolute terms in the
pravastatin group of REGRESS was very limited, It was the
placebo group that deteriorated over 2 years of
therapy.5 These results are in agreement with the
LAARS study; in this study patients with extensive coronary
artery disease were randomized between
LDL-apheresis+simvastatin 40 mg once daily versus
simvastatin 40 once daily only. After 2 years of treatment,
myocardial perfusion and exercise-induced ischemia improved
significantly in the group of patients with
LDL-apheresis+simvastatin, whereas patients on
simvastatin had no change in myocardial perfusion or
exercise-induced ischemia.6 7 In this
context it is doubtful if HMG-inhibitors in patients with
end-stage coronary artery disease and chronic refractory angina
pectoris will have a dramatic effect on anginal complaints.
Whether lipid lowering with LDL-cholesterol levels 100
mg/dL (2.6 mmol/L) are necessary for functional improvement
neither is evident. There are indications that the positive effect of
lipid-lowering therapy is not attributed to the degree of lipid
lowering but rather to the use of HMG-CoA inhibitors. In
the 4S and CARE trial there was no close relation between the degree of
lipid lowering and the decrease in major cardiac
events.8 9 Furthermore, drugs of a total
different class may improve endothelial function
without lipid lowering.10
References
1.
Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Inou
T, Takeshita A. Reduction of serum cholesterol with
pravastatin improves endothelium-dependent
coronary vasomotion in patients with
hypercholesterolemia. Circulation. 1994;89:2519–2524.
2.
Lacoste L, Lam JY, Letchacovski G, Solymoss CB, Waters D.
Hyperlipidemia and coronary disease: correction
of the increased thrombogenic potential with cholesterol
reduction. Circulation. 1995;92:3172–3177.[Abstract/Free Full Text]
3.
Tsuda Y, Satoh K, Takahashi T, Kitadai M, Ichihara S, Ayada
Y, Hosomi N, Kawanishi K, Sada Y, Yamamoto M, et al. Effect of
medication with pravastatin sodium on hemorheological
parameters in patients with
hyperlipoproteinemia. Int Angiol. 1993;12:360–364.[Medline]
[Order article via Infotrieve]
4.
van Boven AJ, Jukema JW, Zwinderman AH, Crijns HJGM, Lie KL,
Bruschke AVG, on behalf of the Regress Study Group. Reduction of
transient myocardial ischemia with pravastatin
addition to the conventional treatment in patients with angina
pectoris. Circulation. 1996;94:1503–1505.
5.
Aengevaeren WRM, Uijen GJH, Jukema JW, Bruschke AVG, van der
Werf T. Functional evaluation of lipid-lowering therapy by
pravastatin in the Regression Growth Evaluation Statin
Study (REGRESS). Circulation. 1997;96:429–435.
6.
Kroon AA, Aengevaeren WRM, van der Werf T, Uijen GJH, Reiber
JHC, Bruschke AVG, Stalenhoef AFH. The LDL-Apheresis
Atherosclerosis Regression Study (LAARS): effect of
aggressive versus conventional lipid lowering treatment on
coronary atherosclerosis.
Circulation. 1996;93:1826–1835.[Abstract/Free Full Text]
7.
Aengevaeren WRM, Kroon AA, Stalenhoef AFH, Uijen GJH, van der
Werf T. Low density lipoprotein-apheresis improves regional myocardial
perfusion in patients with hypercholesterolemia
and extensive coronary artery disease: the LDL-Apheresis
Atherosclerosis Regression Study (LAARS). J
Am Coll Cardiol. 1996;28:1696–1704.[Abstract]
8.
The Scandinavian Simvastatin Survival Study
Group. Randomised trial of cholesterol lowering in 4444
patients with coronary heart disease: the Scandinavian
Simvastatin Survival Study (4S). Lancet. 1994;344:383–389.
9.
Sacks FM, Pheffer MA, Moye LA, Rouleau JL, Rutherford JD,
Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davies BR, Braunwald
E, for the Recurrent Events Trial Investigators. The effect of
pravastatin on coronary events after myocardial
infarction in patients with average cholesterol levels.
N Engl J Med. 1996;335:1001–1009.[Abstract/Free Full Text]
10.
Mancini GBJ, Henry GC, Macaya C, O'Neill BJ, Pucillo AL,
Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE,
Uprichard AC, Pepine CJ, Pitt B. Angiotensin-converting
enzyme inhibition with quinapril improves endothelial
vasomotor dysfunction in patients with coronary artery disease:
the TREND Study. Circulation. 1996;94:258–263.[Abstract/Free Full Text]
