Prevention of the Angiographic Progression of Coronary and Vein-Graft Atherosclerosis by Gemfibrozil After Coronary Bypass Surgery in Men With Low Levels of HDL Cholesterol
Background Studies have shown that treatment of hyperlipidemia, especially lowering of plasma LDL levels, retards the progression of coronary atherosclerosis and prevents clinical cardiovascular events. No such studies have focused on subjects with low levels of HDL cholesterol.
Methods and Results We randomly assigned 395 post–coronary bypass men, who had an HDL cholesterol concentration ≤1.1 mmol/L and LDL cholesterol ≤4.5 mmol/L, to receive gemfibrozil 1200 mg/d or placebo. Coronary angiography was performed at baseline and after, on average, 32 months of therapy. Changes in coronary dimensions were assessed by computer-assisted analysis. Average on-trial serum triglyceride concentrations were 1.69±0.68 and 1.02±0.37, total cholesterol 5.48±0.68 and 4.83±0.63, LDL cholesterol 3.84±0.59 and 3.39±0.56, and HDL cholesterol 0.88±0.15 and 0.98±0.17 mmol/L in the placebo and gemfibrozil groups, respectively (mean±SD, each P<.001). The change in per-patient means of average diameters of native coronary segments was –0.04±0.11 mm in the placebo group and –0.01±0.10 mm in the gemfibrozil group (P=.009). The equivalent changes in minimum luminal diameters of stenoses were –0.09±0.18 and –0.04±0.15 mm, respectively (P=.002). A similar, albeit nonsignificant, trend toward treatment benefit was found in the predefined primary study end point, segments unaffected by grafts and those distal to graft insertions. In aortocoronary bypass grafts, 23 subjects (14%) assigned to placebo had new lesions in the follow-up angiogram, compared with 4 subjects (2%) assigned to gemfibrozil (P<.001).
Conclusions Gemfibrozil therapy retarded the progression of coronary atherosclerosis and the formation of bypass-graft lesions after coronary bypass surgery in men with low HDL cholesterol as their main lipid abnormality.
A number of clinical trials have shown benefit from lipid-modifying therapy in patients with established coronary atherosclerosis.1 These studies have used diverse therapeutic regimens, including diet and other lifestyle modifications,2 3 4 combined-drug therapy,5 6 7 8 single-drug therapy,4 9 10 11 12 13 a multifactorial prevention program,14 and partial ileal bypass surgery.15 With one exception,13 all successful secondary-prevention trials so far have lowered LDL cholesterol levels in the groups assigned to active therapy. The Scandinavian Simvastatin Survival Study16 and the CARE trial17 confirmed that lowering LDL cholesterol may be associated with reduced total and cardiovascular mortality and nonfatal cardiac events.
Another common feature in the published secondary-prevention studies is that they have enrolled hyperlipidemic subjects and aimed at reducing the levels of atherogenic lipoproteins, mainly LDL. One study included only subjects with lipid levels regarded as normal, but it did not show benefit from lipid lowering.18
A low plasma HDL level is associated with a high risk of atherosclerosis.19 20 21 Low HDL is a common dyslipidemia among patients with coronary artery disease.22 23 Gemfibrozil, a fibric acid derivative, was found to reduce the incidence of cardiovascular events in the Helsinki Heart Study,24 a primary-prevention trial in middle-aged dyslipidemic men. This beneficial result was associated with a gemfibrozil-induced increment of HDL levels.25 26 The present study, LOCAT, was designed to expand these findings to another population, men who have undergone coronary bypass surgery and who have low HDL cholesterol concentrations as their main lipid abnormality. The study was carried out in three university hospitals in Finland: Helsinki, Oulu, and Tampere. We compared gemfibrozil with placebo therapy in a double-blind, randomized study using end points based on computer-assisted quantitative interpretation of serial coronary angiograms.
Three hundred ninety-five men ≤70 years old were randomly assigned in a double-blind fashion to receive either slow-release gemfibrozil (Lopid SR) 1200 mg/d or a matching placebo. All patients had previously undergone coronary bypass surgery. They fulfilled the following lipid criteria at two consecutive screening visits: HDL cholesterol ≤1.1 mmol/L (42.5 mg/dL), LDL cholesterol ≤4.5 mmol/L (174 mg/dL), and serum triglycerides ≤4.0 mmol/L (354 mg/dL). In addition, they had blood pressure ≤160/95 mm Hg; body mass index ≤30 kg/m2; left ventricular ejection fraction ≥35%; no history of diabetes and fasting serum glucose concentration <7.8 mmol/L (140 mg/dL); and no conditions requiring therapy with calcium channel blockers, ACE inhibitors, or diuretics. Persons who smoked >20 cigarettes/wk were excluded. Details of the entry criteria and the screening process were described previously.27
All patients provided written informed consent. The study was approved by the ethics committees of the participating hospitals.
At baseline, all patients received detailed instructions to maintain a diet containing 30% of energy as fat, with polyunsaturated, monounsaturated, and saturated fat each contributing 10%; 50% of energy as carbohydrate, preferably complex carbohydrates; and <300 mg cholesterol/d.
Native coronary arteries and bypass grafts were imaged at baseline and at the end of the trial as described previously.27 28 Briefly, 0.5 mg nitroglycerin was given sublingually at the beginning of the procedure and every 20 minutes thereafter to control vasomotor tone. Angiographic views and other gantry settings were recorded at baseline and reproduced exactly at the follow-up study. Stringent quality control of all participating angiography laboratories was performed before the study and regularly during the study by an experienced third party.
Cineframes were selected for quantitative computer-assisted analysis in matching views and identical parts of the cardiac cycle, usually in end diastole or in the diastasis period, by projecting the baseline and follow-up films side by side. The images were analyzed with the Cardiovascular Measurement System (Medis)29 by a single trained technical analyst. The accuracy and precision of the angiographic analyses was shown to be comparable to those reported previously by other investigators.28 All angiographic analyses and handling of the data were done by persons blinded to the treatment group and the on-trial lipid values.
Clinic Visits and Laboratory Tests
Patients visited one of the three participating clinical centers 1 month, 3 months, 6 months, and 1 year after randomization; thereafter, the visit intervals did not exceed 6 months. An exercise test was performed at baseline and at the time of the follow-up angiography. Among the patients who underwent both angiograms, 24 subjects (placebo 8, gemfibrozil 16; P=.090) had major deviations from the protocol, defined as missing at least 30 days of study medication. These interruptions were due to intolerance of the study drug in 4 placebo and 10 gemfibrozil subjects, to concomitant medical conditions in 3 and 4 subjects, and to nonmedical reasons in 1 and 2 subjects, respectively.
Fasting serum triglycerides and cholesterol were measured at each visit with automated enzymatic methods.27 HDL cholesterol was measured in the supernatant after precipitation with phosphotungstic acid and magnesium chloride, and LDL cholesterol was calculated.27 Average values from three prerandomization visits were considered to represent baseline lipid levels; on-trial lipid values were averaged over first-year visits, visits after the first year, and the entire double-blind period. Extensive lipoprotein and other metabolic studies were performed at baseline and after 1 and 2 years of randomized therapy.27 The results of these studies will be reported separately.
End Points and Statistical Analysis
The change from the baseline to the follow-up angiogram in the ADS and MLD of the stenoses was assessed. Per-patient means of these variables were calculated in three types of native coronary segments differing in their relation to bypass grafts (unaffected, graft-affected [proximal to graft insertions and hemodynamically related], and graft-dependent [mainly distal to graft insertions])27 and in saphenous vein bypass grafts. Per-patient means were also calculated for ADS and MLD values in all native segments and in the “primary” segments, comprising unaffected and graft-dependent segments. Changes in the primary segments were predefined as the main end point of the study.27
New lesions were defined as stenoses in the follow-up angiogram causing at least 20% diameter reduction (or milder if clearly present by visual analysis) that were not present in the baseline angiogram. New lesions suggested by the computer-assisted analysis were verified by visual inspection of the paired angiograms.
The mean per-patient changes in ADS and MLD were compared in the randomized groups by ANOVA, adjusted for study center, the baseline value of the dependent variable, and the time interval between the baseline and follow-up angiograms. The number of patients showing new lesions was compared by the χ2 test. Differences in patient characteristics at baseline were evaluated by ANOVA or the χ2 test, as appropriate. Baseline and on-trial lipid levels were compared by ANOVA; triglycerides were transformed to their natural logarithms before statistical tests. A two-tailed value of P<.05 was considered statistically significant.
One hundred ninety-eight subjects were randomized to receive placebo and 197 subjects, gemfibrozil. The groups were well balanced at baseline (Table 1⇓). Of the 395 randomized subjects, 372 (94%) underwent the follow-up angiogram. The 187 subjects in the placebo group had 4.1±1.2 (mean±SD) distal bypass anastomoses, and the 185 subjects assigned to gemfibrozil had 4.0±1.3 anastomoses, indicating similar severity of coronary artery disease before bypass surgery. Reasons for missing the follow-up angiogram were concomitant illnesses (placebo 4, gemfibrozil 4), withdrawal of informed consent because of intolerance of the study drug (3 and 5), technical vascular access problems (2 and 1), and unwillingness (2 and 2 subjects, respectively). The 23 subjects who did not complete the trial had baseline characteristics similar to those of the subjects who underwent both angiograms (data not shown).
Changes in Lipid Levels
Fig 1⇓ shows the baseline and on-trial lipid levels in the randomized groups. Among the patients in the gemfibrozil group who completed the study, triglyceride levels were reduced on average by 36%, total and LDL cholesterol levels were reduced by 5.5% and 4.5%, respectively, and HDL cholesterol levels were increased by 21% from baseline to mean on-trial levels. In the placebo group, the corresponding changes were triglycerides +4.6%, total cholesterol +5.1%, LDL cholesterol +5.3%, and HDL cholesterol +7.0%. Average on-trial lipid levels in the placebo group were triglycerides, 1.69±0.68 mmol/L (154±62 mg/dL); cholesterol, 5.48±0.68 mmol/L (211±26 mg/dL); LDL cholesterol, 3.84±0.59 mmol/L (148±23 mg/dL); and HDL cholesterol, 0.88±0.15 mmol/L (34±6 mg/dL); and in the gemfibrozil group, 1.02±0.37 mmol/L (92±34 mg/dL); 4.83±0.63 mmol/L (186±24 mg/dL); 3.39±0.56 mmol/L (130±21 mg/dL); and 0.98±0.17 mmol/L (38±7 mg/dL), respectively (mean±SD). All between-group differences in on-trial lipid levels and in the changes from baseline were highly significant (P<.001).
Angiographic End Points
Time intervals between the two angiograms were 32±2 months for the placebo group (range, 27 to 41 months) and 32±3 months for the gemfibrozil group (range, 13 to 40 months). As shown in Table 2⇓, when coronary segments were analyzed separately according to their relation to bypass grafts, diffuse progression of coronary atherosclerosis, expressed as the per-patient mean reduction in the ADS, was significantly milder in the gemfibrozil group than in the placebo group in segments unaffected by grafts and in graft-affected segments. By contrast, there was no significant change in the ADS values of the graft-dependent segments either in the placebo group (P=.518, paired t test) or in the gemfibrozil group (P=.903) and therefore no difference between the randomized groups. In the primary segments (unaffected and graft-dependent segments combined), there was a trend in favor of gemfibrozil that was not statistically significant. When all types of native coronary segments (unaffected, graft-affected, and graft-dependent) were taken into account, there was significantly less progression in the gemfibrozil group compared with placebo. In these segments, the difference in mean changes of ADS was 0.03 mm (95% CI, 0.004 to 0.046 mm).
Table 2⇑ also shows that progression of focal coronary atherosclerosis, assessed as changes in the MLD of stenotic lesions, was reduced in patients randomized to gemfibrozil compared with those in the placebo group, although this difference was not statistically significant for the primary segments. In all native segments combined, the difference in mean changes of MLD was 0.05 mm (95% CI, 0.018 to 0.087 mm). Again, this overall difference was accounted for by the unaffected and the graft-affected segments, because there was on average virtually no progression in lesions located in the graft-dependent segments. Expressed as average per-patient change in percent diameter stenosis, lesion progression was milder in gemfibrozil than in placebo patients (1.2±6.4 versus 2.1±6.6, 1.6±7.4 versus 2.4±8.9, 0.8±8.5 versus 2.4±9.4, and 0.3±7.2 versus 1.3±7.7 percentage points in primary, unaffected, graft-affected, and graft-dependent segments, respectively), but these differences were not statistically significant.
The appearance of new lesions was not significantly affected by gemfibrozil therapy in unaffected segments (18 patients with one or more new lesions in the placebo group and 15 in the gemfibrozil group) or in graft-dependent segments (12 and 9, respectively). Thus, one of the predefined principal end points, appearance of new lesions in primary segments, did not show a significant difference between the groups (P=.578). In the graft-affected segments, however, 18 patients assigned to placebo had new lesions, compared with 6 of those assigned to gemfibrozil (P=.008).
We observed a marked reduction by active treatment in the number of new lesions in the venous aortocoronary bypass grafts (placebo, 23 of 161 patients with analyzable grafts; gemfibrozil, 4 of 165; P<.001). The mean diameter stenosis of these lesions was 37±13% and 32±12% in the placebo and gemfibrozil groups, respectively (P>.2). As expected in patients studied on average ≈2 years after bypass surgery, only 45% of the patients with analyzable vein grafts had stenotic graft lesions in their baseline angiograms (placebo, 73 and gemfibrozil, 74 patients). Thus, the study was underpowered to detect differences in changes of preexisting graft lesions; accordingly, none were found (data not shown).
Nine patients in the placebo group and 4 in the gemfibrozil group experienced a vein graft occlusion during the study (P=.185). Because altered flow conditions in graft-affected segments might influence diameters of these segments after graft closure, we performed ANOVAs of ADS and MLD changes in these segments after exclusion of patients with graft occlusions. The results were similar to those presented in Table 2⇑ (P=.005 and P=.008, respectively).
Clinical and Adverse Events
There were no deaths during the trial. Only 7 patients in each group had a major coronary event (myocardial infarction or a revascularization procedure). As in the baseline study, a minority of the patients had any signs of ischemia in the end-of-study exercise test (placebo, 66 and gemfibrozil, 63 subjects). Likewise, only 28 and 39 subjects assigned to placebo and gemfibrozil, respectively, reported any angina symptoms during the week preceding follow-up angiography.
Cancer was diagnosed during the study in 7 placebo patients and in 3 gemfibrozil patients. Eleven subjects assigned to placebo and 22 subjects assigned to gemfibrozil were found to have new or worsening diseases of the gastrointestinal tract (odds ratio, 2.137; 95% CI, 1.007 to 4.536; P=.044). This difference was due to upper gastrointestinal diseases (esophagitis, Helicobacter pylori gastritis, or ulcer; placebo, 4 and gemfibrozil, 11) and to gastrointestinal hemorrhages (2 and 6, respectively). Significant liver enzyme elevations were reported in 9 gemfibrozil patients and in none of the placebo patients (P=.002); all were reversible after discontinuation of the drug.
The results of the present study indicate that therapy with gemfibrozil, a fibric acid derivative, retards angiographic progression of coronary and vein-graft atherosclerosis in a group of post–coronary bypass men selected primarily on the basis of low HDL cholesterol levels at baseline. It is important to note that the patients were also selected to have relatively low LDL cholesterol levels (≤4.5 mmol/L) and that patients with hypertension not controlled by β-blocker monotherapy, with diabetes mellitus, and with poor left ventricular function were excluded. Thus, the results should not be generalized to other types of coronary patients.
So far, only one angiographic secondary-prevention trial has shown benefit from therapy with a fibric acid derivative.13 BECAIT found retarded progression of coronary atherosclerosis in a group of hyperlipidemic young male survivors of myocardial infarction randomized to receive bezafibrate compared with placebo. Although that study was smaller than the present one, it also showed significantly fewer clinical cardiovascular events in the bezafibrate group. Our trial was not designed to study the effect of gemfibrozil on clinical end points. On the contrary, we selected a group of men who had recently undergone a successful bypass operation and who were therefore expected to have a good prognosis for several years.30 Taken together, BECAIT13 and our study with gemfibrozil suggest a role for fibric acid derivatives in the secondary prevention of coronary artery disease. Two large, ongoing fibrate trials with clinical end points,31 32 when completed, will further help to define the role of this class of compounds in the management of coronary patients.
Fig 2⇓ compares angiographic outcomes in four studies that used the Cardiovascular Measurement System for quantitative angiographic analyses. Although there were differences in average or median per-patient MLD scores at baseline, lipid levels of the study populations, and study durations, the angiographic results were markedly similar: in each study there was a significant reduction in the progression of coronary atherosclerosis. Two of the studies, CCAIT10 and REGRESS,12 used statin therapy in patients with mild to moderate hypercholesterolemia, and the main lipid effect in these studies was reduction of LDL cholesterol. The two other studies, BECAIT13 and the present study (LOCAT), used a fibrate that mainly reduced triglyceride levels and raised HDL levels. A logical conclusion of these observations is that therapy of dyslipidemia, tailored to suit the lipoprotein phenotype of each patient, is beneficial in the retardation of atherosclerosis progression.
CLAS5 6 showed less progression and more regression of coronary atherosclerosis in a group of middle-aged post–coronary bypass men randomized to receive niacin and colestipol compared with placebo. When the changes in the native coronary arteries were studied in greater detail, the CLAS investigators found that much of the global benefit from active therapy was confined to the segments proximal to graft insertions.33 Although the importance of these bypassed proximal segments for myocardial blood flow may often be limited, clinical follow-up of the CLAS patients indicated that angiographic change in that study was a significant predictor of future clinical events,34 suggesting that disease progression in proximal segments serves as a valid surrogate end point for clinical events. As in CLAS, we found less progression and fewer new lesions in the proximal segments during gemfibrozil than during placebo therapy. Importantly, we also noted a significant treatment benefit in the nonbypassed coronary segments. By contrast, disease progression over 2.5 years in graft-dependent segments was minimal as assessed by computer-derived end points, in agreement with earlier studies based on visual interpretation of angiograms.35 Accordingly, no treatment effect could be found in these segments, which diluted the benefit observed in the primary end point of our study. Indeed, the treatment benefit was directly related to the propensity for progression in a given segment type: greatest in the graft-affected segments, moderate in nonbypassed segments, and nonexistent in distal segments (Fig 3⇓).
Also in accordance with CLAS, we found less disease progression, manifesting as fewer new lesions, in the venous aortocoronary bypass grafts in the active-therapy group. In fact, only 2% of our actively treated patients had new graft lesions, compared with 14% of the placebo-treated patients. Thus, our data support the conclusions of CLAS, namely that active treatment of dyslipidemia after bypass surgery retards the progression of atherosclerosis both in native coronary arteries and in bypass grafts.
Although in the present study, on-trial LDL cholesterol values were significantly lower in subjects assigned to gemfibrozil than in the placebo group, the decrease in LDL cholesterol in our study (–4.5%) was smaller than in most previous studies.2 3 4 5 6 7 8 9 10 11 12 14 15 16 17 In BECAIT,13 a treatment benefit was found, although there was no change in average LDL cholesterol levels. These two fibrate trials showed, as expected, a major decrease in serum triglyceride concentrations and an elevation in HDL cholesterol. Subgroup analyses in CLAS36 and in CCAIT10 suggested that triglyceride-rich lipoproteins and HDL assume an important role in the progression of atherosclerosis after elevated LDL levels have been lowered. In support of these data, the CARE study17 recently showed that LDL lowering was not beneficial in patients with baseline LDL cholesterol concentrations <3.2 mmol/L (125 mg/dL), in contrast to those with higher LDL levels, suggesting that other lipoprotein classes or nonlipid atherogenic insults may determine the progression of atherosclerosis in this subgroup of coronary patients. The results of the present study support the hypothesis that in patients with low HDL but normal or only mildly elevated LDL cholesterol levels, reduction of the atherogenic remnants of triglyceride-rich lipoproteins37 38 and enhancement of reverse cholesterol transport,39 40 by increasing levels of the antiatherogenic HDL,41 retard the progression of coronary artery disease.
Selected Abbreviations and Acronyms
|ADS||=||average diameter of segments|
|BECAIT||=||Bezafibrate Coronary Atherosclerosis Intervention Trial|
|CARE||=||Cholesterol and Recurrent Events|
|CCAIT||=||Canadian Coronary Atherosclerosis Intervention Trial|
|CLAS||=||Cholesterol Lowering Atherosclerosis Study|
|LOCAT||=||Lopid Coronary Angiography Trial|
|MLD||=||minimum luminal diameter|
|REGRESS||=||Regression Growth Evaluation Statin Study|
LOCAT Investigators and Staff
Principal Investigator: M. Heikki Frick, MD.
Steering Committee: M. Heikki Frick, MD, chairman (University of Helsinki); Vesa Manninen, MD (University of Helsinki); Y. Antero Kesäniemi, MD (University of Oulu); Amos Pasternack, MD (University of Tampere); James W. Nawrocki, MS (Parke-Davis, Ann Arbor, MI).
Safety Committee: Juhani Heikkilä, MD, chairman; Olli P. Heinonen, MD; Jussi K. Huttunen, MD.
Core Quantitative Angiography Laboratory: Mikko Syvänne, MD; Markku S. Nieminen, MD; Mervi Pietilä, QCA technician.
Core Lipid Laboratory: Marja-Riitta Taskinen, MD. Technicians: Hannele Hilden, Leena Lehikoinen, Ritva Marjanen, Helinä Perttunen-Nio, Sirpa Rannikko, Sirkka-Liisa Runeberg.
Clinical Investigators: Helsinki, Mikko Syvänne, MD. Oulu, Heikki Kauma, MD. Tampere, Silja Majahalme, MD; Vesa Virtanen, MD.
Senior Investigators: Oulu, Markku Savolainen, MD. Tampere, Kari Pietilä, MD.
Coronary Angiographers: Helsinki, Markku S. Nieminen, MD; Kari S. Virtanen, MD. Oulu, Markku Ikäheimo, MD; Heikki Huikuri, MD; Juhani Airaksinen, MD; Juhani Koistinen, MD. Tampere, Kari Niemelä, MD; Taisto Talvensaari, MD; Olli Anttonen, MD; Kaj Groundstroem, MD; Vesa Virtanen, MD.
Clinical Staff: Helsinki, Anita Leppämäki, RN. Oulu, Liisa Laine, RN; Leena Virkkala, RN. Tampere, Heidi Hällström, RN.
Study Secretaries: Päivi Närvä, Sirpa Koskela.
Dietitian: Kaisa Ketonen, RD.
Parke-Davis Monitor: Elina Jalkanen, CRA.
This study was supported by grants from Parke-Davis, a division of Warner Lambert; the Finnish Foundation for Cardiovascular Research; the Aarne Koskelo Foundation; and the Finnish Society of Angiology.
Reprint requests to Prof M.H. Frick, Department of Medicine, Division of Cardiology, Helsinki University Central Hospital, Haartmaninkatu 4, FIN-00290 Helsinki, Finland.
↵1 The institutions and investigators participating in the Lopid Coronary Angiography Trial are listed in the “Appendix.”
- Received December 23, 1996.
- Revision received May 12, 1997.
- Accepted May 20, 1997.
- Copyright © 1997 by American Heart Association
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