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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:425-430.)
© 1996 American Heart Association, Inc.

Articles

Evidence for a Synergistic Effect of Calcium Channel Blockers With Lipid-Lowering Therapy in Retarding Progression of Coronary Atherosclerosis in Symptomatic Patients With Normal to Moderately Raised Cholesterol Levels

J. Wouter Jukema; Aeilko H. Zwinderman; Ad J. van Boven; Johan H.C. Reiber; Arnoud Van der Laarse; Kong I. Lie; Albert V.G. Bruschke; for the REGRESS Study Group

From the Department of Cardiology (J.W.J., A. Van der L., A.V.G.B.) and the Department of Diagnostic Radiology and Nuclear Medicine (J.H.C.R.), University Hospital, Leiden; the Department of Medical Statistics, Leiden University (A.H.Z.); and the Department of Cardiology, University Hospital, Groningen (A.J. van B., K.I.L.), The Netherlands.

Correspondence to J.W. Jukema, MD, Department of Cardiology, University Hospital, Leiden, Bldg 1, C5-P, Rijnsburgerweg 10, 2333 AA Leiden, the Netherlands.

	Abstract

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Abstract To date, lipid-lowering therapy appears to be the most effective medical intervention to retard progression of coronary atherosclerosis. In spite of promising experimental results, clinical trials completed so far have failed to demonstrate that calcium channel blockers (CCBs) alone influence the evolution of established coronary atherosclerosis. To assess whether the two therapies may have an additive or synergistic beneficial effect on human atherosclerosis, we reviewed in this regard the data of the angiographic Regression Growth Evaluation Statin Study (REGRESS) trial. REGRESS was designed to determine the effect of lipid-lowering therapy with pravastatin in symptomatic patients with normal to moderately raised cholesterol levels. Angiographically, with respect to the minimum obstruction diameter, in the pravastatin group, patients had on average 0.05 mm (95% confidence interval [CI]: 0.01-0.09) less progression if cotreated with CCBs compared with no CCB cotreatment, whereas in the placebo (no pravastatin) group, no effect of CCB treatment was observed (interaction test for differential effect of CCB treatment in patients with pravastatin compared with patients receiving placebo: P=.0016). With respect to the mean segment diameter, similar although not significant (P=.33) results were found. With respect to new lesion formation, in the pravastatin group, there were 50% (CI: 25-83) fewer patients with new angiographic lesions if cotreated with CCBs compared with no CCB cotreatment, whereas in the placebo (no pravastatin) group, no significant effect of CCB treatment was observed (interaction test: P=.0026). No beneficial effects of CCB treatment on clinical events were observed. Although the REGRESS trial was not designed to evaluate combination therapy, the results suggest strongly that addition of CCBs to 3-hydroxy-3-methylglutaryl–coenzyme reductase inhibitor therapy (pravastatin) acts synergistically in retarding the progression of established coronary atherosclerosis.

Key Words: calcium channel blockers • pravastatin • lipids • atherosclerosis • clinical trials

	Introduction

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In patients with coronary atherosclerosis, progression of the disease is one of the major factors that determine clinical prognosis.¹ At present, lipid lowering appears to be the most effective therapeutic modality to retard progression of coronary atherosclerosis.^{2 3 4 5 6 7} However, in spite of intensive LDL cholesterol reduction and HDL cholesterol elevation, a substantial percentage of the treated patients still show progression. For example, in the Familial Atherosclerosis Treatment Study (FATS),³ one quarter of the patients treated with colestipol plus niacin experienced progression of coronary atherosclerosis in a period of 2.5 years despite a reduction of 32% in LDL cholesterol and an increase of 43% in HDL cholesterol. The introduction of a powerful class of lipid-lowering agents, the HMG-CoA reductase inhibitors, has not led to complete control of progression either.^{5 6 7}

In the 1980s it was demonstrated that plasma membrane calcium transport in the aortic wall of rabbits with experimental atherosclerosis was increased fivefold and that CCBs were able to suppress such experimental atherosclerosis.^{8 9 10} Since then, CCBs have been evaluated for their antiatherosclerotic effect in humans. Loaldi et al¹¹ demonstrated a reduction in progression of preexisting stenoses and reduction of new lesion formation in patients treated with nifedipine compared with patients treated with propranolol or isosorbide dinitrate. However, in two placebo-controlled randomized clinical trials, CCBs did not influence the overall rate of progression and regression of coronary atherosclerosis,^{12 13} although these trials also showed less progression of minimal lesions and less new lesion formation in the patients treated with CCBs.

To our knowledge, clinical data on the antiatherosclerotic effects of the combination of lipid-lowering drugs and CCBs are lacking.¹⁴ It is conceivable that these drugs have an additive or synergistic effect, because the mechanisms of action of the two classes of drugs and their role in preventing progression of atherosclerosis differ. To assess whether this supposition is corroborated by clinical evidence, we reviewed the data of the angiographic regression trial, Regression Growth Evaluation Statin Study (REGRESS), in this regard.

	Methods

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The REGRESS study and design have been described elsewhere.⁷ In brief, REGRESS is a randomized, placebo-controlled multicenter study to assess the effect of 2 years of treatment with pravastatin 40 mg, on progression and regression of angiographically documented coronary atherosclerosis in 885 male patients with a normal to moderately raised serum cholesterol, ie, between 4 and 8 mmol/L (155 to 310 mg/dL). Coronary arteriograms were analyzed by quantitative computer analysis (Cardiovascular Measurement System). To standardize vasomotor tone, 5 to 10 minutes before coronary angiography 5 to 10 mg isosorbide dinitrate was administered sublingually. Primary end points were (1) change in average MSD and (2) change in average MOD per patient. If a segment or lesion was adequately visualized in two (preferably orthogonal) projections and free of significant foreshortening in both views, the average values of the parameters in both projections were calculated. To calculate average MSD and MOD per patient, the MSDs and MODs of all qualifying segments or obstructions were added and divided by the number of contributing segments or obstructions.⁷ The following clinical events (according to prespecified criteria) were analyzed: (1) MI (fatal or nonfatal), (2) coronary heart disease death (other than known fatal MI), (3) nonscheduled PTCA or CABG, (4) stroke and TIA, and (5) death (all other causes).

Development of angiographic new lesions was a predefined secondary end point in the REGRESS study. New lesions were prospectively analyzed together with the primary angiographic end points. Angiographic new lesions were defined as the absence of a stenosis narrowing the lumen by 20% on the first angiogram, in combination with a progression of 0.4 mm (2 times medium term variability), leading to a stenosis narrowing the lumen by 20% on the second angiogram. This definition has been reviewed before.¹³ We recognize that the term "new lesion" may be inaccurate because an angiographically normal–looking vessel wall may have early atherosclerotic changes, and quantitative angiography is not ideally suited to assess minor vessel wall irregularities. However, we included the angiographically defined term "new lesion" to be able to compare our results with results of the earlier reported CCB trials.^{11 12 13}

Statistics
Differences on quantitative variables between patient groups were assessed with Student's t test or the Mann-Whitney U statistic, and differences on categorical variables with the ² test. The differential effect of CCB treatment in patients treated with pravastatin compared with patients receiving placebo (no pravastatin) was assessed with the test for interaction in two-way ANOVA, logistic regression, or Cox regression, where appropriate, all with baseline covariate adjustment. A value of P<.05 was considered significant.

	Results

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Of 1068 patients who were considered for entry in the study, 885 were randomized to pravastatin therapy (450) or placebo (435).⁷ All patients were admitted to the hospitals for cardiac catheterization because of anginal complaints. One patient withdrew his informed consent and was therefore excluded from the analysis. Hence, the effect of pravastatin treatment on lipid lowering, cardiac events, and survival during follow-up was evaluated in 884 patients. In 5 patients, the baseline angiogram was lost or could not be used. Of the 879 patients with a baseline angiogram, 101 had no follow-up angiogram (12 deaths) and for 125 patients, the follow-up angiogram was not informative owing to the fact that all analyzable segments were considered to be influenced by CABG or PTCA procedures and therefore were excluded from quantitative angiographic analysis, according to the protocol.⁷ Hence, the effect of pravastatin treatment on angiographic progression was evaluated in 653 patients: in 641 patients, quantitative data on the change of the MOD and the occurrence of new lesions, and in 635 patients, quantitative data on change of the MSD were available. In the pravastatin group, total cholesterol decreased by 20%, LDL cholesterol decreased by 29%, and triglycerides decreased by 7%, whereas HDL cholesterol increased by 10% (all P<.001). There were no significant changes of serum lipids in the placebo group. The primary end points of the study, ie, change in MSD and change in MOD averaged per patient, showed significantly less progression in the pravastatin group compared with the placebo group. Change in MSD in the pravastatin group was -0.06 mm versus -0.10 mm in the placebo group (P=.019), and change in MOD in the pravastatin group was -0.03 mm versus -0.09 mm in the placebo group (P=.001). Furthermore, the incidence of clinical events during the 2-year follow-up was 11% in the pravastatin group and 19% in the placebo group (P=.002).⁷

Calcium Channel Blocker Comedication Results
At baseline, 536 patients received CCBs as comedication: 260 (60%) in the placebo group and 276 (61%) in the pravastatin group (P=.66). During the study, the number of patients receiving CCBs and the dosage hardly changed. The following CCBs (median dose and range) were used: 175 patients (32.6%) used nifedipine (40, 10 to 60 mg), 35 patients (6.5%) used amlodipine (6, 5 to 10 mg), 36 patients (6.7%) used another dihydropyridine CCB (20, 10 to 60 mg), 269 patients (49.3%) used diltiazem (180, 120 to 360 mg), and 26 patients (4.9%) used verapamil (240, 160 to 300 mg). Baseline characteristics of patients with CCBs are reported in Table 1 and compared with patients not using CCBs. Patients using CCBs were slightly older (1 year: P=.04), had slightly fewer previous MIs (P=.04), received long-acting nitrates more often (P<.0001), and ß-blocking agents less often (P=.0006).

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Patients With and Without Calcium Channel Blocker

After 2 years' follow-up, in the pravastatin group, 93% of the patients without CCBs and 86% of the patients with CCBs were event-free and alive, whereas in the placebo group, these numbers were 82% and 81%, respectively. In patients treated with pravastatin, there was no significant differential effect of CCB treatment on coronary events and survival compared with patients receiving placebo (interaction test: P=.11). In 390 patients (73%) with CCBs, the angiograms were informative, 77 (14%) had noninformative (see first part of "Results" section) angiograms, and 69 (13%) had no second angiogram. In the group of patients without CCB, these numbers were 263 (76%), 48 (14%), and 37 (11%), respectively (P=.56).

Changes of lipids, MSD, MOD, and the percent of patients with new lesions are reported in Table 2. The effect of pravastatin on serum lipid levels was not influenced by the use of CCBs (all P>.10).

View this table: [in this window] [in a new window]   Table 2. Change (Follow-up Minus Baseline Measurement) of Lipid Levels and Angiographic Parameters During the Study With Regard to Calcium Channel Blockers

Angiographically, with respect to MOD, patients in the pravastatin group had on average 0.05 mm (95% confidence interval [CI]: 0.01-0.09) less progression if cotreated with CCBs compared with no CCB cotreatment (P=.0078), whereas in the placebo (no pravastatin) group, no effect of CCB treatment was observed (interaction test for differential effect of CCB treatment in patients with pravastatin compared with patients receiving placebo: P=.0016). With respect to MSD, similar trends were observed, although the effect of CCB treatment was statistically not significant (P=.33). With respect to new lesion formation, in the pravastatin group, there were 50% (CI: 25%-83%) fewer patients with new lesions if cotreated with CCBs compared with no CCB cotreatment (P=.0015), whereas in the placebo (no pravastatin) group, no significant effect of CCB treatment was observed (interaction test: P=.0026).

The statistical significance of the differential effects of CCB treatment in patients treated with or without pravastatin remained after correction for the significant baseline differences (age, previous MI, long-acting nitrate and ß-blocking medication, see Table 1) between patients with and without CCBs.

Subgroups of Calcium Channel Blockers
To analyze whether the results differed for different kinds of CCBs, we divided the CCBs into two subgroups. The first group contained the dihydropyridine CCBs (nifedipine and second- and third-generation dihydropyridines) and the second group contained the nondihydropyridine CCBs (diltiazem and verapamil).

Changes in MOD, percent of patients with new lesions, and 2-year event-free survival with regard to type of CCB treatment (no CCB, nondihydropyridine CCB, and dihydropyridine CCB) are reported in Table 3. Changes in MSD with regard to type of CCB treatment showed similar results as reported for changes in MOD. A beneficial effect of CCB treatment together with pravastatin therapy was evident for both nondihydropyridine CCBs and dihydropyridine CCBs regarding the effect on MOD and percent of patients with new lesions (interaction test: P=.03 and P=.01, respectively). No beneficial effect was found for either type of CCB treatment on 2-year event-free survival. If there was any effect on event-free survival, it was in favor of no CCB treatment; however, this was not statistically significant (interaction test: P=.25). Thus, neither in the placebo group nor in the pravastatin group did there appear to be a difference in effectiveness between nondihydropyridine CCBs and dihydropyridine CCBs. If any difference could be observed, the dihydropyridine CCBs in general seemed to do slightly better than the nondihydropyridine CCBs (in the placebo group, -0.07 versus -0.12 mm MOD change, and in the pravastatin group -0.00 versus -0.04 mm MOD change and 88% versus 85% event-free survival), but these differences were by no means statistically significant (all P>.20).

View this table: [in this window] [in a new window]   Table 3. Changes in MOD, Percent of Patients With New Lesions, and 2-Year Event-Free Survival With Regard to Type of CCB Treatment (No CCB, Nondihydropyridine CCB, and Dihydropyridine CCB)

In Table 4, the clinical events are shown according to type of CCB treatment. As can be seen from this table, any trend to more clinical events in the CCB groups can largely be explained by the higher number of unscheduled CABG procedures in the nondihydropyridine CCB group. None of the other clinical events had a clearly higher incidence in any of the CCB groups, especially not MI, which had the highest incidence in the no CCB/placebo group.

View this table: [in this window] [in a new window]   Table 4. Number of Clinical Events With Regard to CCB Treatment (No CCB, Nondihydropyridine CCB, and Dihydropyridine CCB)

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
To our knowledge, the combined effect of lipid-lowering therapy and CCBs on human coronary atherosclerosis has not been reported earlier. In REGRESS, we observed a significant beneficial effect on progression of CCBs in patients treated with pravastatin with regard to MOD and new lesion formation, whereas there was no effect of CCB treatment in the placebo (no pravastatin) group. No beneficial effects of CCBs on clinical events were observed. The trend to more clinical events in the CCB groups in our study is largely due to a higher number of unscheduled CABG procedures in the nondihydropyridine CCB/pravastatin group. In the CCB/placebo group, no trend to more clinical events was observed. None of the other clinical events, such as (coronary) death or stroke had a clearly higher incidence in any of the CCB groups. Some studies have shown a possible adverse effect of CCBs, especially in patients with hypertension or heart failure.^{15 16} In the Holland Interuniversity Nifedipine/Metoprolol Trial (HINT), coronary events were more common in patients with unstable angina receiving nifedipine monotherapy,¹⁷ and in the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT), mortality was slightly higher in patients randomized to nifedipine.¹² In the Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT), no beneficial effect of nifedipine post-MI was observed.¹⁸ In contrast, beneficial effects of diltiazem on survival and prevention of reinfarction have been reported in patients with MI without left ventricular dysfunction and in patients with non–Q-wave infarction.^{19 20} Comparison of our results with these studies is difficult because of differences in study design and patient selection. REGRESS mainly included patients with stable anginal complaints and excluded patients with recent MI, severe hypertension, or marked left ventricular dysfunction.⁷ The apparent paradox between the findings of a reduction of anatomic progression of coronary atherosclerosis and the lack of a reduction of clinical events (even an insignificant increase) in the CCB groups may be influenced by the remarkable low incidence of events in the REGRESS population (eg, less than 1% cardiac mortality in 2 years). In view of the correlation between angiographic progression and subsequent clinical events, as demonstrated by Buchwald et al¹ and Waters et al,²¹ it is not unrealistic to anticipate also in our population a beneficial effect on clinical events with longer follow-up.

In the placebo (no pravastatin) groups, we found no effect of CCBs on new lesion formation. This is not in line with the results of the three CCB trials mentioned.^{11 12 13} Differences in study design and patient selection of the trials may play a role in explaining this dissimilarity.

We can only hypothesize about the mechanism by which CCBs may augment the beneficial effects of lipid lowering by pravastatin. The mechanisms that may contribute to this effect include stimulation of cholesteryl ester hydrolase activity in vascular smooth muscle cells, amelioration of hypercholesterolemia-induced endothelial dysfunction, and inhibition of vascular smooth muscle cell proliferation and migration.^{14 22} Furthermore, an increased resistance to oxidation of LDL cholesterol is associated with diminished atherogenicity.²³ Antioxidants are considered to protect LDL cholesterol from oxidation. Several investigators have demonstrated that certain CCBs have antioxidant properties.²⁴ Lower concentrations of LDL in plasma and an improved protection against its oxidation may act synergistically in preventing progression of atherosclerosis.

Whether all CCBs or only some of these drugs are capable of extending the antiatherosclerotic effect of pravastatin is not yet known. In our study, neither in the placebo group nor in the pravastatin group did there appear to be a difference in antiatherogenic effects between nondihydropyridine CCBs and dihydropyridine CCBs.

The REGRESS trial was not designed to study the effect of CCB administration. In this regard, it is a retrospective analysis and therefore no definite conclusions can be drawn concerning the beneficial effect of adding a CCB to lipid-lowering therapy. It is also possible that patients in whom an indication for CCB treatment was present represent a select group, although such a selection was not reflected by the baseline characteristics that were recorded.

Recognizing these limitations, it may be stated that this is the first report to provide substantial evidence that CCBs may have a beneficial effect on the evolution of coronary atherosclerosis in patients treated with lipid-lowering therapy. Our results appear to warrant a prospective randomized trial to determine in a more definitive manner the merits of this combination in the prevention of progression of coronary atherosclerosis.

	Selected Abbreviations and Acronyms

 

CABG = coronary artery bypass graft surgery CCB(s) = calcium channel blocking agent(s) CoA = coenzyme A MI = myocardial infarction MOD = minimum obstruction diameter MSD = mean segment diameter PTCA = percutaneous transluminal coronary angioplasty TIA = transient ischemic attack

	Acknowledgments

 
The REGRESS trial was sponsored by Bristol-Myers Squibb Company, Princeton, NJ.

Received May 12, 1995; accepted November 8, 1995.

	References

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