(Circulation. 1997;96:429-435.)
© 1997 American Heart Association, Inc.
Articles |
Functional Evaluation of Lipid-Lowering Therapy by Pravastatin in the Regression Growth Evaluation Statin Study (REGRESS)
From the Department of Cardiology, University Hospital Nijmegen, and Interuniversitary Cardiology Institute the Netherlands (J.W.J., A.V.G.B.), Utrecht, the Netherlands.
Correspondence to W.R.M. Aengevaeren, Department of Cardiology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, Netherlands. E-mail w.aengevaeren{at}cardio.azn.nl
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Abstract |
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Background Lipid-lowering therapy during 2 years in the Regression Growth Evaluation Statin Study (REGRESS) was associated with less progression of coronary atherosclerosis in the pravastatin group compared with the placebo group. The effect of lipid-lowering therapy on the functional state of the coronary circulation is less well known. The purpose of this study was to evaluate this effect.
Methods and Results In a substudy of REGRESS, 69 patients were randomized to pravastatin or placebo. Thirty-seven of these patients were allocated to the medical management stratum. Quantitative coronary angiography, regional myocardial perfusion, exercise testing, and classification of angina pectoris were assessed at baseline and after 2 years of therapy. Regional myocardial perfusion was assessed by digital subtraction angiography after intracoronary papaverine with videodensitometric calculation of the hyperemic mean transit time (HMTT) of contrast. In the medical management stratum, regional myocardial perfusion was assessed in 31 regions in the pravastatin group and 25 regions in the placebo group. The change in HMTT in the pravastatin group was -0.18 seconds (-5%) and in the placebo group +0.52 seconds (+18%), a difference of 0.70 seconds (P=.004). The mean difference in change in classification of angina pectoris (scale, 1 to 4) between pravastatin and placebo was 0.7 (P=.03) in favor of the pravastatin-treated patients. The change in HMTT was correlated with the change in exercise time (r=-.65, P=.002).
Conclusions In patients with symptomatic coronary artery disease, treatment with the HMG-coenzyme A reductase inhibitor pravastatin during 2 years resulted in a preserved regional myocardial perfusion, whereas patients on placebo deteriorated. The classification of angina pectoris improved only in patients receiving pravastatin. In lipid-lowering therapy, the evaluation of myocardial perfusion by assessment of the HMTT reveals a combined measure of functional and structural changes in the coronary circulation.
Key Words: perfusion • exercise • coronary disease • angiography • lipids
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Introduction |
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In the multifactorial pathogenesis of coronary atherosclerosis, an elevated cholesterol level is a causal factor.1 Numerous studies have shown that in patients with coronary artery disease, HMG-coenzyme A reductase inhibitors have a beneficial effect on the incidence of cardiovascular events and development of coronary atherosclerosis.2 3 4 5 6 7 In several angiographic trials, the reduction of clinical events was more pronounced than would be expected by the modest influence of lipid lowering on progression of atherosclerosis, which suggests the possibility of a plaque stabilizing effect.7 8 In normal coronary arteries, the endothelium produces endothelium-derived relaxing factor, which protects the vessel wall by inhibiting platelet adhesion and aggregation, smooth muscle cell proliferation, and smooth muscle cell contraction. Atherosclerosis and hypercholesterolemia have a detrimental effect on endothelial function in both the epicardial coronary arteries and the resistance vessels.9 10 11 Exercise induces a metabolic vasodilatation in the resistance vessels and a flow-mediated dilatation of the epicardial vessels, which is endothelium dependent.12 Endothelial dysfunction leads to paradoxical vasoconstriction with impairment of myocardial perfusion and contributes to the pathogenesis of myocardial ischemia. Cholesterol lowering may restore the endothelial function.13 14 15 Translated to the clinical situation, lipid-lowering therapy should have a beneficial effect on maximal myocardial perfusion and the occurrence of myocardial ischemia. The impact of lipid-lowering drugs on functional parameters such as myocardial perfusion, exercise-induced ischemia, and anginal complaints in patients with coronary atherosclerosis is not well known. In this study, we evaluated the functional effect of pravastatin therapy and compared the results with the anatomic evaluation by QCA in symptomatic patients with normal to moderately elevated cholesterol.
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Methods |
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REGRESS is a double-blind, placebo-controlled, multicenter study designed to assess the effect of 2 years of treatment with the HMG-coenzyme A reductase inhibitor pravastatin on progression and regression of angiographically documented coronary atherosclerosis in male patients with a cholesterol level between 4 and 8 mmol/L (155 and 310 mg/dL). Patients participating in this study were recruited from the waiting list of patients scheduled to undergo coronary angiography. Patients who were included at the University Hospital Nijmegen underwent, in addition to the REGRESS protocol, assessment of regional myocardial perfusion for functional evaluation of the effect of pravastatin. The study was approved by the ethics committee of the University Hospital Nijmegen, and written informed consent was obtained from all patients. In short, included were 18- to 70-year-old male patients with proven coronary artery disease (at least one coronary diameter stenosis
50%). The
study design, definition of clinical events, and methods assessment of
lipid levels and QCA have been reported previously.7 After
cardiac catheterization, patients were stratified in
three strata—medical management, PTCA, or CABG—and subsequently
randomized to pravastatin 40 mg once daily or placebo.
Because bypass grafts and PTCA may have a major impact on flow,
distribution of flow, and exercise results, patients who underwent
these procedures were excluded from functional evaluation of the effect
of pravastatin. QCA was evaluated by assessment of MOD and
MSD on the basis of per-patient and per-segment measurements.
Assessment of Myocardial Perfusion
Myocardial perfusion was assessed by digital subtraction
angiography with videodensitometric calculation of the HMTT of contrast
passage through the capillary bed. This method has been developed in
our laboratory in accordance with the principles of the indicator
dilution theory and has been validated in model studies, animal
experiments, and humans.16 17 18 The short-term
reproducibility of the method has been evaluated with a relative
difference of 5±5% for repeated measurements with a correlation
coefficient of .97.18 To exclude autoregulatory changes in
the coronary circulation and to ensure a constant and maximal
vascular volume, the assessment of myocardial perfusion was performed
during maximal hyperemia induced by papaverine. The derived
time parameter, HMTT, is inversely related to myocardial
perfusion. We used this method to compare the maximal regional
myocardial perfusion in the areas of the left anterior descending
artery, right circumflex artery, and right coronary artery at
baseline and at follow-up. The methods of image acquisition,
analysis of the time-density curves, and correction of the HMTT
to a mean aortic blood pressure of 100 mm Hg and the final
calculations of the regional HMTTs have been described
previously.19 Calculation of the HMTTs was performed with
blinding to treatment allocation. Effect analysis of the
lipid-lowering treatment was based primarily on the regional change in
myocardial perfusion. The patient-based evaluation was performed by
averaging the regional HMTT values to one value per patient as a global
estimate of myocardial perfusion.
Exercise Testing
Exercise testing was performed at baseline and at follow up
after 2 years. Antianginal medication was not discontinued. An
electronically braked bicycle ergometer (Marquette Case 15, Marquette
Electronics Inc) was used, along with continuous ECG monitoring. The
exercise was started at a load of 50 W, followed by a 10-W increase
every minute until maximal exercise was achieved, chest discomfort
occurred, or usual criteria for stopping a test were applied. Blood
pressure was recorded every 2 minutes, directly after maximal
exercise, and at rest in the second and fifth minute. Automated
calculation was performed of ST-segment depression 80 ms beyond the
J-point. Variables used for analysis included maximal
workload, time until the onset of 0.1-mV (1-mm) horizontal or
downsloping ST-segment depression, maximal ST-segment depression, and
maximal rate-pressure product. The patients who underwent
nonscheduled interventions in the medical management stratum were
excluded from the effect analysis. Patients with an abnormal
ECG at the baseline exercise test were also excluded from
analysis.
Classification of Angina Pectoris
After randomization at the first visit and at follow-up after 2
years, angina pectoris was classified in all patients according to the
Canadian Cardiovascular Society.20 The
data were analyzed in two ways: first, for the whole group,
regardless of nonscheduled interventions; second, in the medical
management stratum. However, the moment of classification of the angina
pectoris was taken before any nonscheduled intervention.
Statistical Analysis
Comparison of prespecified continuous variables was
performed within the groups by two-sided paired t tests;
between-group analysis was performed by unpaired t
tests and one-way ANOVA. For categorical comparisons, a
2 test or the Kruskal-Wallis test was performed
when appropriate. Correlations were tested with Pearson's correlation
coefficient. Regression analysis was used to compare the change
in HMTT with change in exercise parameters and change in
QCA data. Calculations were performed on a personal computer with the
statistical package SPSS for Windows (releases 6.1 and 7.0). A
two-sided value of P<.05 was considered significant.
Results were expressed as mean±SD unless otherwise indicated.
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Results |
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Sixty-nine patients were included; subsequently, 35 patients were randomized to the pravastatin group and 34 patients to the placebo group. The groups were well matched for demographic variables (Table 1
). The final distribution of the
study group in the three treatment strata resulted in 37 patients in
the medical management stratum (pravastatin, n=19; placebo,
n=18), 16 patients in the PTCA stratum, and 16 patients in the CABG
stratum. Fifty-seven patients completed the study according to the
protocol: 32 patients in the medical management stratum, 11 in the PTCA
stratum, and 14 in the CABG stratum. Dropouts were due to refusal of
the second cardiac catheterization in 7 patients, death
in 3 patients (two sudden deaths—one in the medical management stratum
and one in the PTCA stratum—and one death in the CABG stratum in a
patient who died shortly after CABG because of heart failure), and
noncardiac causes in 2 patients. In the medical management stratum, 6
nonscheduled interventions were carried out: 1 PTCA in the
pravastatin group and 4 PTCAs and 1 CABG in the placebo
group. Table 2 gives the mean lipid levels at baseline
and during the study. Table 3 shows the QCA data of the
medical management stratum. During the study, there was no important
change in antianginal medication.
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Myocardial Perfusion
In the medical management stratum group, comparative baseline and
follow-up digital subtraction angiographies were available in 25
patients. Table 4 gives the results of the region-based
HMTT assessment in the perfusion areas of the left anterior descending
coronary artery, right circumflex artery, and right
coronary artery. The baseline value of regional HMTT in the
pravastatin group was 3.36±1.03 versus 2.92±0.75 seconds
in the placebo group (P=.08). In the per-patient evaluation,
the HMTT in the pravastatin group (n=15) changed from
3.33±0.81 to 3.23±0.60 seconds, a difference of -0.10 seconds
(-3%; P=.75). In the placebo group (n=10), the per-patient
HMTT changed from 2.91±0.33 to 3.39±0.59 seconds, a difference of
+0.48 seconds (+16%; P=.01). The difference in change
between the pravastatin and placebo groups was 0.58 seconds
(P=.045). The baseline values of the pravastatin
and placebo groups on a per-patient base were not significantly
different (P=.14).
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In the PTCA stratum group, 11 patients had follow-up cardiac
catheterization. PTCA was performed in 12 vessels in
these 11 patients. In 1 vessel, repeated PTCA was performed. Baseline
and follow-up regional HMTT values were available in 9 regions of the
PTCA vessels and 15 regions of the nonintervention vessels. Table 5 shows the results of regional HMTT in the PTCA
stratum.
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Exercise Testing
In the medical management stratum, 24 of 35 patients had a
follow-up exercise test without intercurrent PTCA or CABG. If patients
had a nonscheduled PTCA or CABG in the medical management stratum, most
often this occurred after a period of progressive or unstable angina
pectoris, and in this setting, no exercise tests were performed. Table 6 gives the effect analysis of the exercise
testing in the medical management stratum. Baseline exercise tests were
positive (1-mm horizontal or downsloping ST-segment depression) in only
11 of 30 tests (37%): 6 in the pravastatin group and 5 in
the placebo group. At follow-up, exercise tests were positive in 4
patients in the pravastatin group and 3 patients in the
placebo group.
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In the PTCA and CABG strata, baseline exercise tests were judged as positive in 18 of 29 tests (62%). At follow-up, 12 of 24 available tests converted to negative. None of the negative tests changed to positive. In these strata, no change in exercise response existed between pravastatin and placebo.
Classification of Angina Pectoris
In the medical management stratum, the angina pectoris
classifications (at a scale of 1 to 4) for the pravastatin
and placebo groups at baseline were 2.1±0.5 and 1.8±0.8; at
follow-up, they were 1.4±1.0 and 1.7±1.0, respectively. In 3 patients
in the placebo group and 1 patient in the pravastatin
group, follow-up was not available. The mean difference in change of
angina pectoris classification between pravastatin and
placebo was 0.7 (P=.03; Fig 1).
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In the combined PTCA and CABG stratum (n=32), the baseline classification of angina pectoris was 3.1±0.6, whereas in the medical management stratum (n=37), the baseline classification was 1.9±0.7 (a difference of 1.2, P<.001). At follow-up, the classification of angina pectoris was 1.6±0.8 for the medical management stratum and 1.3±0.5 for the combination of PTCA and CABG strata (a difference of 0.3, P=.12). In the CABG and PTCA strata, angina pectoris reduced from baseline to follow-up in the pravastatin group with 1.7±0.8 and in the placebo group with 1.9±0.9 (P=.52).
Clinical Events
Although this substudy was rather small, a remarkable number of
clinical events could be registered. In the placebo group, 13 of 34
patients had a total of 15 clinical events versus 7 clinical events in
5 of 35 patients in the pravastatin group
(2, 3.96; P<.05, with Yates'
correction). The clinical events were the main reason for loss of
follow-up in the medical management stratum.
Correlations and Regression Analysis in the Medical
Management Stratum
The change in MSD was correlated with the change in MOD (n=31,
r=.62, P<.001) but not with the change in
exercise parameters (n=24) or HMTT (n=25). The change in
MOD was correlated with the change in ST-segment depression (n=24,
r=-.52, P=.009). The change in percentage
stenosis was also correlated with the change in ST-segment
depression (n=24, r=.41, P=.046) and with the
time to 1-mm ST-segment depression (n=6, r=.89,
P=.017). The change in HMTT was correlated with the change
in exercise time (n=20, r=-.65, P=.002; see Fig 2) and with the maximal load (n=20, r=-.47,
P=.037) but not with the other exercise
parameters. In the stepwise multiple regression, the change
in HMTT was explained by the combination of changes in total exercise
time and MOD (n=19, multiple r=.76, F=0.0007).
The parameters included in this stepwise multiple
regression were change in exercise time, change in MOD, change in MSD,
and change in LDL level.
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Discussion |
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The results of this study show that in patients with coronary artery disease and a cholesterol level between 4 and 8 mmol/L, pravastatin had a favorable effect on regional myocardial perfusion compared with placebo. In the pravastatin group, there was a slight increase in regional myocardial perfusion in the absence of arteriographic evidence of regression. The results of the exercise tests and classification of angina pectoris, however, were concordant with the assessment of regional myocardial perfusion. The discrepancy between the improved myocardial perfusion and the progression of coronary artery disease in the pravastatin group might be explained by an improved endothelium-dependent relaxation.
Myocardial Perfusion
The baseline HMTT values in the placebo group were shorter than
those in the pravastatin group, although the difference was
not statistically significant. This phenomenon may be explained by the
small sample size and more right coronary artery regions in the
pravastatin than in the placebo group (13 versus 7,
respectively) . In general, HMTT values in the right coronary
artery region are about 1 second longer, which is the mean time
required for contrast passage from the ostium of the right
coronary artery to the crux. Because interventions such as CABG
and PTCA may also influence myocardial perfusion in remote
noninterventional regions, these strata were excluded from effect
analysis of pravastatin on myocardial
perfusion.21 22 The results of the determination of
myocardial perfusion were better related with exercise
parameters than with anatomic parameters. The
assessment of the relation of the change in QCA parameters
and the change in HMTT is hampered by a few problems. The QCA
analysis of progression and regression was a patient-based
comparison, whereas changes in MOD may be restricted to one segment.
The regional HMTT data were averaged to a mean value per patient on the
basis of a mean of 1.6 perfusion areas per patient. The areas of
regional HMTT do not necessarily correspond with the vessel segments
that were averaged for the per-patient QCA results. Finally, the
expected relation of change in myocardial perfusion and
coronary diameter is not linear.
Maximal myocardial perfusion is determined by the resistance in both the conductance vessels and the microcirculation. Because of the method of assessment of the HMTT (sublingual isosorbide dinitrate before the coronary angiography and intracoronary papaverine during the image acquisition), the hyperemia is induced by an endothelium-independent vasodilatation of the resistance vessels and a flow-mediated vasodilatation of the epicardial vessels. The flow-mediated response is endothelium dependent.23 The difference in myocardial perfusion between the pravastatin and placebo groups might be induced by an impaired flow-mediated vasodilatation in the epicardial vessels in response to the induced hyperemia in the resistance vessels in the placebo group. This hypothesis is adapted from Gould et al,24 who described this phenomenon in relation to dipyridamole infusion intravenously during PET for flow assessment in lipid-lowering therapy by diet. The administration of isosorbite dinitrate just before the coronary angiogram might have blunted the endothelium-dependent response. However, the difference in change between the pravastatin and placebo groups of regional myocardial reperfusion are remarkable.
Exercise Testing
Fixed atherosclerotic obstructions and
endothelium-dependent relaxation of the resistance and
epicardial vessels are determinants of exercise capacity and
exercise-induced ischemia. Although the number of patients
studied was relatively small, the group of patients on
pravastatin showed a trend toward less ischemia, a
lower heart rate at rest, and a better preserved exercise tolerance
compared with the placebo group. These effects may be due in part to a
preserved or improved endothelial function.
Classification of Angina Pectoris
As could be expected, baseline angina pectoris was worse in the
intervention strata (PTCA and CABG) compared with the medical
management stratum. Interventions have a major impact on the
classification of angina pectoris. No additional benefit of
pravastatin could be established in the intervention
strata. After 2 years of therapy, the results of the intervention
strata were actually better than the medical management stratum.
Nonscheduled interventions may cause a confounding effect on the
analysis of the classification of angina pectoris in the
medical management group. For that reason, the classification of angina
pectoris before the nonscheduled intervention was considered an end
point. The periods of unstable angina were not included because they
may represent acute plaque rupture and thrombosis rather than
progression of fixed coronary artery
atherosclerosis. Nevertheless, the clinical benefit of
pravastatin treatment in the medical management stratum is
evident.
Comparison With Other Studies
The number of studies evaluating lipid-lowering therapy with
assessment of myocardial perfusion is limited.24 25 26 27 28
Thallium-201 scintigraphy and PET were used for
semiquantitative evaluation. In these studies, myocardial perfusion
defects improved in the actively treated patient groups, without
significant changes in coronary anatomy, as measured or
supposed. In the "long-term intense risk factor modification
study," the change in dipyridamole PET images of
normalized counts worsened in control subjects by 13.5% and improved
in the experimental group by 4.2%, numbers that correspond very well
with our results.27 In some studies, patients in the
active treatment group were subjected to a regular exercise program.
The effect of training precludes a direct comparison of the effect of
lipid-lowering therapy on the exercise
parameters.25 26 In the short-term
lipid-lowering study with fluvastatin, the improvement of
perfusion defects is established after only 12 weeks of therapy. The
improvement was especially noticeable in areas of
ischemia.28 The positive effects of these studies
on myocardial perfusion are not elucidated. Suggested mechanisms are
improved endothelium-dependent vasodilation, improved
collateral circulation, and changes in blood viscosity. The data of the
effect of HMG-coenzyme A reductase inhibitors on blood
viscosity are conflicting.29 30 31 In studies with
lovastatin and simvastatin, no effect on blood
viscosity was observed, so it is unlikely that a change in blood
viscosity caused the changes in myocardial perfusion. Coronary
resistance vessels are spared from the development of overt
atherosclerosis, but the endothelial
function of the microcirculation can be disturbed in the presence of
hypercholesterolemia.9 Thus,
improved endothelial function remains the most likely
explanation for the improvement in myocardial perfusion, which also may
affect collateral circulation.
Study Limitations
Evaluation of exercise testing in the PTCA and CABG strata was
influenced largely by the intervention, so we decided not to include
these data in the effect analysis of pravastatin.
Follow-up parameters were not available in several patients
in the medical management stratum, mostly because of
cardiovascular complications. These dropouts occurred
predominantly in the placebo group and may have influenced the results
of this study. However, these dropouts most likely caused
underestimation rather than overestimation of the difference in
response between the pravastatin and placebo group.
Conclusions
In symptomatic men with coronary artery
disease and normal to moderately raised cholesterol levels,
pravastatin therapy for 2 years resulted in a preserved
regional myocardial perfusion, whereas this parameter
deteriorated in patients on placebo. The group of patients on
pravastatin had fewer clinical events and a trend toward
preserved exercise capacity. The change in myocardial perfusion was
better related with a change in exercise parameters than
with a change in anatomic parameters. In lipid-lowering
therapy, assessment of myocardial perfusion is advantageous because it
represents a combined measure of the resistance to flow by the
epicardial vessels and microcirculation. Functional evaluation of the
coronary circulation deserves further investigation as a tool
for evaluation of lipid-lowering therapy in patients with
coronary artery disease because it might better reflect the
clinical benefit for the patient.
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Selected Abbreviations and Acronyms |
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Footnotes |
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Presented in part at the 69th Annual Scientific Sessions of the American Heart Association, New Orleans, La, November 10-13, 1996.
Received October 10, 1996; revision received February 3, 1997; accepted February 11, 1997.
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