© 1996 American Heart Association, Inc.
Articles |
Gemfibrozil Treatment of Combined Hyperlipoproteinemia
No Improvement of Fibrinolysis Despite Marked Reduction of Plasma Triglyceride Levels
From the Departments of Clinical Pharmacology (A.B., P.H.) and Clinical Chemistry (B.W.), Karolinska Hospital, Stockholm, and the Metabolism Unit (M.E., B.A.), Department of Medicine, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden.
Correspondence to Anders Bröijersen, Department of Clinical Pharmacology, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail broij@mb.ks.se.
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Abstract |
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Abstract Hypertriglyceridemia is linked to impaired fibrinolytic function, and lipid-lowering treatment with fibric acid derivatives could hypothetically improve fibrinolysis in this condition. We therefore conducted a double-blind, placebo-controlled, crossover study of gemfibrozil treatment on fibrinolytic function in 21 men with combined hyperlipoproteinemia. Measurements were performed at rest and during mental stress and after venous occlusion. The patients had clearly disturbed fibrinolytic function, with elevated plasminogen activator inhibitor–1 (PAI-1) activity at rest (
25 U/mL; reference, <15 U/mL).
Gemfibrozil reduced plasma total and VLDL cholesterol as
well as all triglyceride fractions, whereas HDL
cholesterol increased (P<.001 for all). Total
triglyceride levels were reduced by 57±4% (from 5.3 to
2.1 mmol/L). Fasting serum insulin levels were not altered by
gemfibrozil treatment. Plasma levels of PAI-1 activity and
tissue-type plasminogen activator (TPA)
activity or antigen were unaffected by gemfibrozil treatment both at
rest and during the provocations. The levels of D-dimer,
plasmin/antiplasmin complex, and fibrinogen were also uninfluenced by
gemfibrozil treatment. Mental stress elevated plasma TPA
(P=.0036) and lowered PAI-1 (P=.0012) activity
during placebo but not gemfibrozil treatment (P=.28 and
P=.17, respectively), but treatment effects did not differ
by ANOVA on 
values (ie, stress minus rest). Venous occlusion
reduced PAI-1 activity, whereas TPA and plasmin/antiplasmin complex
increased during both treatments. Thus, gemfibrozil treatment did not
improve fibrinolysis or lower fibrinogen levels in men
with combined hyperlipoproteinemia despite
marked reduction of plasma triglyceride levels. It seems
unlikely that improved fibrinolysis explains the
primary preventive effect of gemfibrozil.
Key Words: hyperlipoproteinemia • gemfibrozil • fibrinolysis • plasminogen activator inhibitor • tissue-type plasminogen activator
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Introduction |
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Impaired fibrinolytic function may predispose susceptible individuals to thrombosis and the development of coronary artery disease,1 and hypertriglyceridemia is associated with a global impairment of fibrinolytic function2 3 and an elevation of PAI-1.4 Thus, deranged fibrinolysis may be an important factor in patients with hypertriglyceridemia that could lead to an increased risk of coronary artery disease.
The primary preventive Helsinki Heart Study showed that lipid-lowering treatment with gemfibrozil, which markedly lowers plasma triglyceride levels, reduces the incidence of coronary heart disease in hyperlipidemic men.5 Retardation of lipid-dependent coronary atherosclerosis is one possible explanation for the favorable results, but beneficial effects on fibrinolysis may have contributed. Indeed, high concentrations of gemfibrozil decrease the release of PAI-1 from vascular endothelial cells in vitro.6 Furthermore, when given to patients with hypertriglyceridemia or survivors of myocardial infarction, gemfibrozil has been claimed to improve certain fibrinolytic parameters.7 8 9 10 11 However, these findings should be interpreted cautiously since two of the trials were uncontrolled,7 8 and another two relied on subgroup analysis to demonstrate effects.10 11 Moreover, the studies were limited in size.
The fibrinolytic system is usually studied at rest, but standardized provocations, such as mental stress or venous occlusion, may be used to obtain information on the dynamic regulation of the system. In other words, a fibrinolytic system that performs well at rest may not respond properly during stressful situations.
The present study was performed to clarify whether gemfibrozil alters the fibrinolytic function in men with combined hyperlipoproteinemia. A double-blind, placebo-controlled, crossover design was used, and measurements were performed both at rest and during provocation by mental stress and venous occlusion.
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Methods |
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Patients and Study Protocol
Twenty-one men aged 21 to 70 (mean, 47) years with total plasma cholesterol concentrations
6.4 mmol/L and
triglyceride levels 2.3 mmol/L participated in the study.
Patients with secondary hyperlipoproteinemia
due to hypothyroidism, diabetes mellitus, and nephrosis were excluded,
as were those who had experienced an acute myocardial infarction or
unstable angina pectoris during the preceding 12 months. Two patients
received concomitant anti-ischemic medication with
ß-blockers and a calcium antagonist. Another 3
patients had hypertension, for which they received diuretics,
ß-blockers, and an angiotensin-converting enzyme
inhibitor. In addition, 1 hypertensive patient was treated
with allopurinol, and another patient received clomipramine. All
nonstudy medication was kept constant during the study. Body weight and
BMI of the patients at randomization were 87±3 kg and 27.7±0.8
kg/m2 (mean±SEM), respectively. Six patients were
smokers.
The study design is shown in panel A of the Figure
. The
trial started with a dietary period of 4 to 6 weeks, during which the
patients were instructed to follow the AHA step I diet. Previous
lipid-lowering medication (six patients) was discontinued at the
onset of the diet period. After the dietary run-in phase the
patients were randomized to receive gemfibrozil 600 mg BID
(Parke-Davis) or placebo in a double-blind fashion. After 10 to 12
weeks of treatment the patients were switched to the alternate
treatment.
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The design of individual experiments is shown in panel B. The experiments were performed at the end of the treatment periods between 8:30 and 11:30 AM, while the subjects were in the fasting state. Venous blood was collected via 19G butterfly needles or evacuated tube systems (after venous occlusion) into trisodium citrate (Becton-Dickinson) or citric acid/citrate (Stabilyte, Biopool AB). Samples were obtained after a 1-hour rest, after 15 minutes of mental stress (a modified Stroop Color Word Conflict Test12 ), and again after 10 minutes of venous occlusion. The venous occlusion test was performed by inflating a BP cuff on the upper arm to 100 mm Hg for 10 minutes. Blood was then collected before the cuff was deflated. The samples were centrifuged at 4°C for 10 minutes at 1500g, and the plasma was divided into aliquots and stored frozen at -80°C until analysis.
Compliance was monitored by tablet count. The manufacturer randomized the treatment order (11 started on placebo), and the participants were instructed to abstain from smoking and caffeine-containing beverages on the experimental days.
The study was approved by the ethics committee of the Karolinska Institute. All patients gave their informed consent to participate.
Assessments of Fibrinolytic Variables and
Fibrinogen
PAI-1 activity and TPA antigen were determined on citrated
plasma samples by using commercially available kits (Spectrolyze PL and
TintElize tPA, respectively, Biopool AB). Determinations of TPA
activity (Spectrolyze fibrin, Biopool), fibrin degradation product
D-dimer (TintElize D-dimer, Biopool), and PAP
were performed on acidified plasma samples (Stabilyte, Biopool). Fibrin
D-dimer and PAP assays provide more dependable results in
acidified plasma samples than in normal citrated samples (B. Wiman, M.
Haegerstrand-Björkman, unpublished data, 1994). Because
significantly higher concentrations of these compounds were found in
citrated than in acidified samples, suggesting in vitro generation
during the handling of citrated samples, acidified plasma samples were
chosen for assays of PAP and fibrin D-dimer.
The method for determination of PAP in plasma was a double-antibody
enzyme-linked immunosorbent assay developed in our laboratory. The
acidified plasma samples were diluted 10-fold with 0.1 mol/L sodium
phosphate buffer and passed through small columns of lysine-Sepharose.
The adsorbed PAP and plasminogen were eluted with 0.1 mol/L
6-aminohexanoic acid in the phosphate buffer. Subsequently PAP was
determined by enzyme-linked immunosorbent assay with goat
antiplasmin IgG as catch antibodies and horseradish
peroxidase–conjugated antiplasminogen IgG for
detection. Reference values are 0.90±0.27 mg/L (mean±SD).
Intra-assay and interassay coefficients of variation were <10% at
PAP concentrations of 1 mg/L. The detection limit was 0.02 mg/L.
Accuracy, determined as analytical recovery of added pure PAP, was
>90% at a concentration of 1 mg/L.
Fibrinogen was determined as a modified thrombin time.13 Fasting serum insulin levels were determined by radioimmunoassay (Insulin RIA 100, Pharmacia).
Lipid and Lipoprotein Determinations
Plasma lipoproteins were quantified by using a combination of
preparative ultracentrifugation and precipitation
of apoB-containing lipoproteins with phosphotungstic
acid.14 15 The cholesterol and
triglyceride contents of the various lipoprotein fractions
were assessed by using standard enzymatic techniques
(Boehringer-Mannheim). ApoA-I and apoB were analyzed by
using immunoturbidimetric methods (Orion Diagnostica), and
apo(a) levels were determined by radioimmunoassay (Pharmacia
Diagnostics).
Other Measurements
The catecholamine concentrations in venous plasma
were determined by using cation-exchange
high-performance liquid chromatography with
amperometric detection.16 BPs and heart rates were
monitored with an Ohmeda 2300 FINAPRESS BP monitor (Ohmeda Monitoring
Systems).
Statistical Analysis
Data are presented as mean±SEM or as median with 25th
and 75th percentiles when skewed. Differences between the treatments
were evaluated by using a three-way ANOVA according to the standard
2x2 crossover model, controlling for subject and period effects.
Skewed data were log-transformed before this evaluation. Changes
induced by mental stress and venous occlusion during each treatment
were analyzed by using Wilcoxon's signed rank test
followed by Bonferroni corrections for multiple hypothesis testing.
Differences between the treatments for the provocation-induced
changes were analyzed by using values (ie, stress minus
rest). The subgroup analysis of obese (BMI25
kg/m2) versus nonobese (BMI<25 kg/m2) patients
was performed by using an unpaired Student's t test or a
Mann-Whitney U test. Tests to examine possible carryover
effects were applied according to standard procedures,17
and correlations were tested by calculation of Spearman's rank
correlation coefficient. Statistical evaluations were performed by
using SuperANOVA and StatView 4.0 software (Abacus Concepts Inc).
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Results |
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Two of the 21 patients did not complete the study, one because of noncompliance and the other because of an acute myocardial infarction. Compliance with medication treatment was good (94±1% of the tablets were consumed during placebo and 93±2% during gemfibrozil treatment). No significant carryover effects between treatment periods were noted for total triglyceride or PAI-1 levels.
Lipid, Lipoprotein, and Insulin Levels
Gemfibrozil treatment significantly lowered all plasma
triglyceride fractions as well as total and VLDL
cholesterol (Table 1). Total plasma
triglyceride concentrations were reduced by 57±4%,
whereas HDL cholesterol increased by 22±5%. LDL
cholesterol, apoA-I, apoB, and apo(a) levels were
unaltered. Fasting serum insulin levels were 14.9±2.5 mU/mL during
placebo and 13.2±2.2 mU/mL during gemfibrozil therapy
(P=.26).
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Fibrinolytic Function
No significant difference between the treatments was observed for
the levels of fibrinolytic variables or fibrinogen either at rest
or during mental stress or after venous occlusion (Table 2). Mental stress elevated plasma
catecholamine levels, heart rate, and BPs similarly during
the two treatments (Table 3). In addition, mental stress
elevated plasma TPA activity (P=.0036) and lowered PAI-1
activity (P=.0012) during placebo but not during gemfibrozil
(P=.28 and P=.17, respectively) treatment.
However, treatment effects did not differ by ANOVA (P=.14
and P=.10 between treatments for values; Table 2). The
levels of TPA antigen, D-dimer, PAP, and fibrinogen were
not altered by mental stress. Venous occlusion reduced PAI-1 activity
more clearly during placebo treatment (placebo, P=.0012;
gemfibrozil, P=.12), whereas TPA activity, TPA antigen, and
PAP increased significantly during both treatments. D-dimer
levels were unaltered during venous occlusion.
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Subgroup Analysis of Obese Versus Nonobese
Patients
A subgroup analysis was undertaken to compare obese and
nonobese (BMI, 29.4±0.7 and 23.6±0.6 kg/m2,
respectively) patients. Overweight was associated with higher insulin
(16.6±2.4 versus 7.0±1.1 mU/mL, P=.037) and increased
total triglyceride (6.4±0.9 versus 3.2±0.3 mmol/L,
P=.023) levels. Furthermore, the obese individuals had
higher PAI-1 and lower TPA activity levels during mental stress (Table 4). Gemfibrozil treatment did not, however, alter the
activities of PAI-1 or TPA in either obese or nonobese patients (Table 4). Individual data showed that gemfibrozil reduced PAI-1 activity in 7
of 12 obese patients at rest, in 6 of 12 during mental stress, and in 3
of 10 after venous occlusion. Corresponding data for TPA levels were
elevations in 7 of 12 at rest, 6 of 12 during mental stress, and 7 of
11 after venous occlusion. Thus, there were no significant effects in
obese patients.
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Correlations
PAI-1 activity at rest was positively correlated with total
triglyceride (placebo, r=.45 and
P=.044; gemfibrozil, r=.52 and
P=.027), VLDL triglyceride (placebo,
r=.45 and P=.046; gemfibrozil, r=.56
and P=.019), and fasting insulin (placebo, r=.78
and P=.001; gemfibrozil, r=.76 and
P=.0033) levels. In addition, TPA antigen was
positively correlated with total triglyceride
(placebo, r=.52 and P=.019; gemfibrozil,
r=.48 and P=.041) and VLDL
triglyceride (placebo, r=.52 and
P=.021; gemfibrozil, r=.50 and P=.034)
levels. The gemfibrozil-induced reductions of total and VLDL
triglyceride levels were positively correlated with changes
in TPA antigen at rest (r=.65, P=.0056 and
r=.67, P=.0046, respectively).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of this double-blind, placebo-controlled trial do not support the view that gemfibrozil treatment improves fibrinolysis in men with combined hyperlipoproteinemia, despite marked reductions of plasma triglycerides and clear-cut signs of disturbed fibrinolysis. Thus, a causal and direct link between plasma triglyceride levels and fibrinolysis is unlikely in this group of patients.
Case-control studies have shown that patients suffering from coronary artery disease exhibit elevated plasma PAI-1 activity18 19 and that increased PAI-1 levels are related to reinfarction in young survivors of myocardial infarction.20 Moreover, the PLAT study has shown that high PAI-1 levels increase the risk of experiencing thrombotic ischemic events in atherosclerotic patients.21
The reports that gemfibrozil treatment reduces plasma PAI-1 levels in patients with isolated hypertriglyceridemia both at rest7 8 9 and during venous occlusion9 are therefore interesting. Our results did not confirm this favorable effect of gemfibrozil on plasma PAI-1 levels in patients with combined hyperlipoproteinemia, either at rest or after mental stress or venous occlusion. If anything, the provocations lowered PAI-1 activity more consistently during placebo treatment than during active treatment, and the TPA increase after mental stress was significant only during the placebo phase. The discrepancy between the trials could be related to differing study populations or methodological differences. A noteworthy difference between the studies is that basal PAI-1 activity was in the normal range in the previous studies,7 8 9 whereas PAI-1 levels in our patient population were well above the upper reference limit (<15 U/mL). Our PAI-1 data agree with those of others on gemfibrozil-treated hypertriglyceridemic patients with histories of venous thrombosis22 or myocardial infarction.10
The idea that fibric acid derivatives could improve fibrinolysis originates from the fact that these drugs markedly lower plasma triglyceride levels and that a fairly strong positive correlation exists (also present in this study) between triglyceride and PAI-1 levels.18 23 24 It has been claimed that a reduction of plasma triglycerides to levels <2.8 mmol/L is necessary to reduce PAI-1 levels.11 Sixteen of the patients in the present trial met this criterion. Even though total triglyceride levels were reduced by almost 60% in these patients there was no consistent change in PAI-1 activity or any other fibrinolytic variable. In the entire study population gemfibrozil-induced reductions of total and VLDL triglyceride levels correlated positively with changes in TPA antigen at rest, but 8 patients increased their TPA levels during gemfibrozil therapy despite triglyceride reductions. A closer look at these individuals revealed no common features that could explain the results.
It has been convincingly shown that high plasma insulin levels and/or BMI are associated with elevated PAI-1 levels.23 Moreover, reductions of these variables are accompanied by reductions of plasma PAI-1.25 26 Thus, the links to insulin seem to be of major importance, and Juhan-Vague et al27 have suggested that insulin resistance is the key factor regulating plasma PAI-1 levels. As insulin levels are positively related to BMI,28 weight reduction is a plausible explanation for the beneficial effects noted during dietary reduction of triglycerides.2 29 30 Body weight was, unfortunately, not monitored throughout the present investigation, but the dietary background was kept constant, and there are no data showing that gemfibrozil alters body weight profoundly. Our subgroup analysis of obese versus nonobese patients confirmed findings showing that obesity is associated with elevated PAI-1 and insulin levels.25 Gemfibrozil treatment did not influence either insulin or PAI-1 levels or TPA activity in either subgroup, but the sample size is small, and firm conclusions cannot be drawn. Nonetheless, it is quite clear from the present and previous data that there is no simple link between triglyceride levels and PAI-1 activity.
Avellone et al7 report that euglobulin clot lysis time is shortened and fibrinogen levels are reduced in hypertriglyceridemic patients on gemfibrozil therapy. When evaluating these data, it should be borne in mind that the euglobulin clot lysis time method is sensitive to alterations in fibrinogen levels. In the postinfarction trial of Andersen et al10 fibrinogen levels and euglobulin clot lysis time measurements were unaltered, but a subgroup of patients with reduced fibrinolytic capacity normalized their D-dimer scores after desmopressin stimulation. In accordance with our findings of unaltered D-dimer levels, analysis of all subjects by Andersen et al10 revealed no effect. It is possible that subgroups of patients with reduced fibrinolytic function might benefit from gemfibrozil treatment, but this needs to be confirmed in studies specifically designed to test this hypothesis.
Elevated plasma levels of lipoprotein(a) are associated with ischemic heart disease.31 This lipoprotein contains apo(a), which is structurally related to plasminogen.32 It has therefore been suggested that elevated plasma apo(a) levels might impair fibrinolysis. The present study showed no alteration of plasma apo(a) levels during gemfibrozil treatment, nor were any associations found between fibrinolytic variables and apo(a) levels.
It may be argued that concomitant medication and the inclusion of patients both with and without cardiovascular disease could have limited the interpretation of the study results. However, all concomitant medication was kept constant throughout the trial, and the patients served as their own controls. Furthermore, the studied population is representative of the patient category that receives gemfibrozil therapy. Another possible limitation of the study is its crossover design, with inherent risks of carryover from the first to second treatment period. This possibility, however, seems very unlikely to have influenced our results as our treatment periods were long (2.5 to 3 months). Furthermore, the statistical evaluation showed no signs of carryover effects.
In conclusion, gemfibrozil given to men with combined hyperlipoproteinemia influences plasma lipoprotein levels favorably without influencing the fibrinolytic system or fibrinogen levels. In addition, the dynamic regulation of fibrinolysis after mental stress or venous occlusion did not improve during gemfibrozil treatment. Insulin levels were not found to be a confounder with regard to the lack of gemfibrozil effect on fibrinolysis. Our results indicate that the relationship between triglycerides and PAI-1 is complex and that mechanisms other than improved fibrinolysis may explain the primary preventive effects of gemfibrozil on coronary heart disease.
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Selected Abbreviations and Acronyms |
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2–antiplasmin complex
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Acknowledgments |
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This study was supported by grants from Parke-Davis, the Swedish Heart-Lung Foundation, the Swedish Medical Research Council (5930, 7137, and 5193), the Thuring Foundation, the Swedish Society of Medicine, King Gustaf V and Queen Victoria's Foundation, and the Karolinska Institute. We are indebted to Maud Daleskog, Maj-Christina Johansson, Lilian Larsson, Tova Dahlström, and Marie Haegerstrand-Björkman for expert technical assistance and to Pia Gustafsson for excellent patient care.
Received May 28, 1995; accepted November 2, 1995.
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