© 1997 American Heart Association, Inc.
Articles |
No Influence of Simvastatin Treatment on Platelet Function In Vivo in Patients With Hypercholesterolemia
the Department of Clinical Pharmacology, Karolinska Hospital (A.B., P.H.); the Metabolism Unit, Department of Medicine, Karolinska Institute at Huddinge University Hospital (M.E., B.A.); and the Department of Medicine, St Gorans Hospital (B.L.), Stockholm, Sweden.
Correspondence to Anders Broijersen, 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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Hypercholesterolemia is associated with platelet activation. Reduction of plasma cholesterol levels by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin has been found to improve certain aspects of platelet function in vitro and in vivo, but controlled trials are largely lacking. The present randomized, double-blind, crossover study was performed to evaluate whether 10- to 12-week treatment with simvastatin or placebo affects platelet function in vivo in 23 hypercholesterolemic men. Measurements were performed at rest and during mental stress. Simvastatin treatment reduced plasma total cholesterol levels by 18±2% and low density lipoprotein cholesterol levels by 26±2% (P<.001 for both), whereas high density liproprotein cholesterol levels increased slightly (6±2%, P<.05). Platelet aggregability as assessed by filtragometry ex vivo was unaffected by simvastatin treatment both at rest and during mental stress. Plasma ß-thromboglobulin levels, which reflect platelet secretion, were also unaltered by simvastatin treatment both at rest (antilog of the mean: 20.2 versus 20.0 ng/mL during placebo) and during mental stress. Moreover, nocturnal excretion of 11-dehydrothromboxane B2 in urine did not differ between placebo and active treatment: 218 versus 216 ng/mmol creatinine, respectively. The corresponding values for urinary excretion of high-molecular-weight ß-thromboglobulin were 1.78 versus 1.92 ng/mmol creatinine. Thus, simvastatin treatment had no clear-cut effect on platelet function, as assessed by four different in vivo related platelet function variables, in hypercholesterolemic men.
Key Words: hyperlipoproteinemia • simvastatin • platelet function • thromboxane • ß-thromboglobulin
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Introduction |
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Blood cholesterol levels are of fundamental importance in the pathogenesis of CAD.1 2 Elevations of LDL levels are not only linked to an increased risk for atherosclerosis but may also exert prothrombotic effects via platelet activation. When challenged with platelet-activating substances in vitro, platelets from hypercholesterolemic patients aggregate more readily3 4 and generate greater amounts of the vasoconstrictive and platelet-stimulating eicosanoid TxA2 (as reflected by measurement of TxB2).4 5 Furthermore, in vivo data indicate that urinary excretion of the thromboxane metabolite 11-dehydro-TxB26 and plasma levels of ßTG7 are elevated in hypercholesterolemic patients compared with normocholesterolemic individuals.
Lipid-lowering therapy with the HMG-CoA reductase inhibitor simvastatin reduces the occurrence of CAD in patients with preexisting cardiovascular disease.8 Interestingly, data from the 4S Study8 showed that the simvastatin-induced reduction of CAD was observed early in the trial, suggesting that mechanisms other than regression of atherosclerosis might have contributed. Indeed, administration of simvastatin to hypercholesterolemic patients has been found to attenuate platelet aggregation in vitro4 9 10 11 and the generation of TxB2 in vitro4 9 10 11 and in vivo.6 11 Thus, circumstantial evidence suggests a beneficial effect of simvastatin on platelet function, but all studies except one11 have had open study designs. To confirm the hypothesis that simvastatin therapy attenuates platelet activity in vivo, there is an obvious need for randomized, placebo-controlled trials as well as for data on in vivo related platelet function variables other than thromboxane generation.
The placebo-controlled study reported herein was undertaken to determine whether simvastatin treatment of hypercholesterolemic men influences platelet function in vivo. Measurements of several aspects of platelet function were performed at rest and during mental stress, the latter because sympathoadrenal activation seems to be implicated in the pathogenesis of coronary heart disease,12 and platelet activation could be of importance in this respect.13
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Methods |
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Study Subjects
Twenty-three patients with total plasma cholesterol levels >6.5 mmol/L were recruited from the Metabolism Unit at Huddinge University Hospital and from the Department of Medicine at St Goran's Hospital. Fifteen patients had isolated hypercholesterolemia (phenotype IIa), whereas 8 had combined hyperlipoproteinemia (type IIb, 6 with the familial form). Twelve of the type IIa patients had familial hypercholesterolemia with tendinous xanthomas, elevated LDL cholesterol levels, and affected first-degree relatives.14 Familial combined hyperlipidemia was considered to be present when multiple phenotypes (ie, IIa, IIb, and IV) were found in the family and also within the individual when examined on different occasions.15 Patients with secondary hyperlipidemia, diabetes mellitus, and a history of acute myocardial infarction or unstable angina during the preceding 12 months were excluded. Eleven patients had never been treated for their lipid disorder, whereas 12 patients had previously received lipid-lowering treatment with simvastatin, pravastatin, cholestyramine, gemfibrozil, or combinations thereof. One patient had experienced an acute myocardial infarction 8 years previously and was being treated with the ß-adrenoreceptor antagonist sotalol (this was kept constant throughout the study). Six patients were current smokers. The Ethics Committee of the Karolinska Institute approved the study, and all subjects gave their informed consent to participate.
Study Design
A double-blind, randomized, placebo-controlled, crossover design was applied. Previous hypolipidemic therapy was terminated 4 to 6 weeks before randomization, and dietary advice according to the American Heart Association Step 1 diet was given during this period. The randomization (performed by the manufacturer) selected 11 patients to start on simvastatin (20 mg/d) and 12 patients to start on placebo. After a 10- to 12-week treatment, the patient crossed over to the alternate treatment. Platelet function was assessed after an overnight fast at the end of each treatment period. Blood samples were collected after 60 minutes of rest and again after 15 minutes of mental stress (a modified version of Stroop's Color Word Conflict Test.16 Compliance was checked by counts of returned tablets.
Filtragometry Ex Vivo
Filtragometry ex vivo developed by Hornstra and ten Hoor17 measures platelet aggregates in blood continuously drawn from a forearm vein. In brief, each measurement requires venipuncture without stasis by use of a 19G butterfly needle. The needle is connected to a siliconized plastic tubing system that allows blood to flow at a constant speed (2 mL/min) through a siliconized nickel filter (pore size, 20 µm; filter diameter, 2.0 mm). Solitary platelets traverse the filter, whereas platelet aggregates are retained. The time (tA) taken to occlude 25% of the filter pore area (defined as a 5–mm Hg pressure differential across the filter) is inversely related to platelet aggregability in vivo. Thus, a short reading implies high aggregability. Heparin (final concentration, 5 IU/mL) is infused into the filtragometer to prevent clotting but does not influence filtragometry readings.17 Validation by scanning electron microscopy has revealed that filter occlusion is caused by retained platelet aggregates.17 Further evidence for platelet-dependent filter occlusion has been obtained from experiments in which acetylsalicylic acid has been shown to prolong the filtragometry readings.18 The intraindividual between-day reproducibility of the technique in our laboratory is 6% to 10% for log tA values (N.H. Wallen and J. Albert, unpublished data, 1994 and 1995).
Measurements of ßTG in Plasma and Urine
Venous blood was sampled without stasis in the arm not used for filtragometry measurements. The venipunctures were performed with the Vacutainer technique (21G needles), and the blood was collected into tubes (Becton Dickinson) prefilled with a platelet-stabilizing and anticoagulating solution consisting of EDTA (final concentration, 9 mmol/L), iloprost (20 µg/L), and theophylline (1 mmol/L). The samples were immediately spun at 15 000g (30 minutes at 4°C), and an aliquot of the midportion of plasma was taken and stored at -80°C until analysis. Urinary excretion (adjusted for creatinine excretion) of HMW ßTG was determined in urine voided during the night before each experiment (night urine) and after the mental stress test (day urine). The bladder was always emptied immediately before the rest period started. The levels of plasma ßTG and urinary HMW ßTG were analyzed with a commercially available radioimmunoassay kit (IM-88, Amersham) as described elsewhere.19 Urinary creatinine was measured by the Jaffe reaction with a Hitachi 717 analyzer (Boehringer Mannheim) and the HiCo creatinine reagent from Boehringer Mannheim.
Urinary Excretion of 11-Dehydro-TxB2
Determination of urinary 11-dehydro-TxB2 was based on a commercially available EIA (Cayman Chemical) and a sample work-up procedure developed by us (unpublished data, 1995). After thawing and centrifugation (5 minutes at 1400g), the urine was diluted 1:2 (vol/vol) with 0.063 mol/L NH4HCO3 buffer, pH 8.6, and left overnight at room temperature to convert 11-dehydro-TxB2 to its open-ring form.20 The samples were then purified by modified solid-phase extraction (Bond-Elut Certify II, Analytichem International) and eluted with 2% formic acid in methanol. The samples were taken to dryness overnight in a vacuum centrifuge and resuspended in an EIA buffer prepared according to the manufacturer's instruction. After overnight incubation, the samples were diluted again with the EIA buffer (1:11, vol/vol) and applied to a Maxisorb plate (Nunc immunoplate) precoated with mouse monoclonal antibodies. The analysis was then performed according to instructions from the manufacturer. Samples from patients and control subjects were intermingled in each assay to assure comparability. Coefficients of variation within and between assays were 8.9% (n=18) and 13.2% (50 samples from 4 assays), respectively. A comparison of this technique with gas chromatography–mass spectrometry (kindly performed by Prof D. Fitzgerald, Department of Clinical Pharmacology, Royal College of Surgeons, Dublin, Ireland) revealed that the two techniques correlated well (r2=.94, n=29; authors' unpublished data), although the EIA yielded somewhat higher absolute values.
Plasma Lipids, Lipoproteins, and Apolipoproteins
Lipoprotein quantitation was performed by a combination of ultracentrifugation and precipitation.21 22 The cholesterol and triglyceride contents of the various lipoprotein fractions were determined by standard enzymatic techniques (Boehringer Mannheim). Immunoturbidimetric methods were used for analyses of apo A-I and B (Orion Diagnostica), and apo(a) levels were determined by radioimmunoassay (Pharmacia Diagnostics).
Other Measurements
Platelet counts and median platelet volumes were determined in venous blood anticoagulated with EDTA (final concentration, 10 mmol/L) by use of a semiautomated cell analyzer (Medonic CA 460). Measurements were performed after 2 hours in EDTA to standardize swelling of the cells. Heart rate and blood pressure were monitored with an Ohmeda 2300 Finapress blood pressure monitor (Ohmeda Monitoring Systems). The catecholamine concentrations in venous plasma were determined by cation-exchange high-performance liquid chromatograpy with amperometric detection.23 Plasma fibrinogen levels were determined as modified thrombin time,24 whereas vWf:Ag levels were assessed with a commercially available enzyme-linked immunosorbent assay kit (Diagnostica Stago).
Statistical Analysis
On the basis of power calculations using pooled data from repeated filtragometry measurements in 28 healthy male volunteers at rest, it was found that a sample size of 15 individuals was required to detect a 20% difference in resting filtragometry measurements at the 5% significance level (
=.05, ß=.20). Results are presented as mean±SEM or as the median with interquartile ranges for skewed variables. Differences between treatments were analyzed with three-way ANOVAs according to the standard 2x2 crossover model, controlling for subject and period effects. Stress-induced changes for each variable were analyzed by Student's paired t test, and treatment effects for stress-induced changes were analyzed by 
values (ie, stress minus rest). Skewed data were logarithmically transformed before the statistical evaluation. Tests for carryover effects were applied according to standard procedures.25 The means and 95% confidence intervals for the ratios between treatments (simvastatin and placebo) were calculated. Correlations were tested with Pearson's correlation coefficient. The statistics were calculated on a Macintosh computer using SUPERANOVA version 1.02 and StatView 4.5 (Abacus Concepts Inc.).
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Results |
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Two patients were excluded from the statistical evaluation, one because of a vasovagal reaction and the other because of aspirin intake 6 days before the second experiment. Compliance with the study medication was judged to be good, with a consumption (according to pill count) of 90±2% and 89±2% of placebo and simvastatin tablets, respectively. No carryover effects between treatment periods were observed for total cholesterol, LDL cholesterol, or platelet function variables.
Plasma Lipids, Lipoproteins, and Apolipoproteins
Simvastatin treatment had the expected beneficial effect on the plasma lipid profile, as shown in Table 1.
Total and LDL cholesterol levels were reduced by 18±2% and 26±2%, respectively, whereas HDL cholesterol increased by 6±2%. Triglyceride and VLDL cholesterol levels were, however, unaffected by simvastatin therapy. Apo B and apo A-I levels decreased and increased, respectively, during simvastatin treatment, whereas apo(a) levels were unaffected.
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Filtragometry Ex Vivo
Platelet aggregability was not altered by simvastatin treatment (Fig 1). Filtragometry readings (antilog of the mean) at rest during placebo and simvastatin treatments were 173 and 169 seconds, respectively (P=.89, n=20). Corresponding values during mental stress were 131 and 143 seconds (P=.66, n=16). Mental stress per se did not significantly alter filtragometry measurements during either treatment, and there was no difference in stress-induced changes between treatments (ANOVA on values, ie, stress minus rest).
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Plasma ßTG
Two ßTG values obtained during mental stress were excluded before the treatment code was broken because they were extremely high (161 and 87 ng/mL) in combination with poor blood flow. Plasma ßTG levels were low and did not differ between treatments, either at rest (20.0 versus 20.2 ng/mL during placebo versus simvastatin treatment; P=.84, n=18) or during mental stress (23.9 versus 20.2 ng/mL during placebo versus simvastatin, respectively; P=.12, n=12) (Fig 1).
Plasma ßTG levels tended to be raised by mental stress during placebo treatment (from 19.4 to 23.2 ng/mL; P=.08, n=13) but not during active treatment (from 20.5 to 21.7 ng/mL; P=.61, n=15).
Urinary Excretion of ßTG and 11-Dehydro-TxB2
Urinary excretion values of HMW ßTG and 11-dehydro-TxB2 were unaffected by simvastatin treatment (Fig 1). The mean antilog values for night and day excretion of HMW ßTG were 1.78 and 1.93 ng/mmol creatinine during placebo therapy versus 1.92 and 2.24 ng/mmol creatinine during simvastatin treatment (P=.42 and P=.20, respectively). The corresponding night and day excretion values of 11-dehydro-TxB2 were 218 and 177 ng/mmol creatinine for placebo versus 216 and 163 ng/mmol creatinine for simvastatin (P=.91 and P=.53, respectively).
Subgroup Analysis of Type IIa Patients
A separate statistical analysis of patients with isolated hypercholesterolemia revealed that simvastatin treatment had no significant impact on the measured platelet function variables in this subgroup of patients (Table 2).
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Other Variables
Table 3 shows that platelet counts, median platelet volumes, plasma vWF:Ag, and fibrinogen levels were unaffected by simvastatin therapy. Moreover, heart rate, blood pressure, and plasma catecholamine levels did not differ during the two treatments (Table 4). Mental stress elevated heart rate and blood pressures similarly during the two treatments. Plasma norepinephrine levels increased during stress, while plasma epinephrine did not change significantly in response to the stress test.
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Correlations
No correlations were found between platelet function variables at rest and the different cholesterol fractions or total triglycerides. Neither were the simvastatin-induced reductions in plasma total cholesterol or LDL cholesterol levels associated with changes in platelet function indices.
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Discussion |
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Lipid-lowering therapy with simvastatin and other HMG CoA reductase inhibitors has been considered to improve platelet function26 by preferentially lowering generation of the vasoconstrictive and platelet-activating eicosanoid TxA2. The present placebo-controlled study in hypercholesterolemic men, however, failed to demonstrate any reduction in the urinary excretion of the stable TxA2 metabolite 11-dehydro-TxB2 during simvastatin treatment. Similarly, we found no evidence for reduced platelet aggregability or platelet secretion in vivo.
Uncontrolled clinical trials have shown that simvastatin treatment of hypercholesterolemic patients reduces generation of thromboxane in vitro4 9 10 11 and urinary excretion of 11-dehydro-TxB2.6 Moreover, Notarbartolo et al11 found a 50% reduction in excretion of 11-dehydro-TxB2 after simvastatin treatment in a recent placebo-controlled trial. The present findings of unaltered excretion of 11-dehydro-TxB2 are therefore somewhat surprising, although previous reports on thromboxane excretion during treatment with pravastatin have yielded similar results.27 28 We cannot explain the discrepancy between the study of Notarbartolo et al11 and the present trial, but there were obvious differences with regard to study design, gender, and diagnosis of the patients as well as to the thromboxane assay methodology.
We employed a crossover design and studied 15 men with type IIa and 8 men with type IIb hyperlipoproteinemia, whereas Notarbartolo et al11 investigated 24 type IIa patients (14 women and 10 men) in a parallel-design trial. Thus, our study was confined to male patients, a factor that rules out potential confounding by sex differences (women were overrepresented in the simvastatin group in11 ). Furthermore, we used a crossover design, which increases statistical power, because each patient served as his own control; this characteristic may be particularly important when biological markers with high interindividual variability are measured.29 Our inclusion of men with combined hyperlipidemia is potentially confounding, but a separate analysis of those with isolated hypercholesterolemia revealed similar results in this subgroup. Other minor differences between the trials were that plasma cholesterol and triglyceride levels were slightly higher in our patients and that simvastatin reduced LDL cholesterol levels by 26% in the present trial compared with 36% in the Notarbartolo study. We determined 11-dehydro-TxB2 by solid-phase extraction of samples followed by EIA, whereas Notarbartolo et al11 used a radioimmunoassay and a different extraction procedure. Immunological thromboxane metabolite assays usually overestimate true values due to cross-reactivity with structurally related substances in the urine. We have compared our method with gas chromatography–mass spectrometry (unpublished data obtained in collaboration with D. Fitzgerald, Dublin). Although this comparison confirmed such an overestimation, it also showed excellent correlation between the two techniques (r2=.94, n=29). The validity of our method is further supported by the fact that we can confirm (A.B. et al, unpublished data, 1996) previous findings6 of increased urinary excretion of 11-dehydro-TxB2 in hypercholesterolemic patients.
Measurements of the platelet-specific protein ßTG in plasma reflect platelet secretion in vivo. Again, our results differ from previous data that showed that simvastatin treatment reduced resting plasma ßTG levels in hypercholesterolemic individuals.30 Our stress data, however, suggest a trend toward lower plasma ßTG values during simvastatin therapy. Thus, a minor positive effect of simvastatin on stress-induced platelet release cannot be ruled out. Measurements of the urinary excretion of HMW ßTG, which has been found to predict future development of cardiovascular disease in women,31 supported the lack of a significant effect of simvastatin on platelet secretion in vivo.
We recently reported that pravastatin therapy had a clear-cut enhancing effect on platelet aggregability as measured by filtragometry ex vivo in patients with familial hypercholesterolemia.28 In fact, pravastatin markedly shortened (by 60%) filtragometry readings, an effect seen in all 10 patients studied.28 Such an adverse effect was not observed in the present study, but no beneficial alteration was observed either, in agreement with our data on platelet secretion and thromboxane generation. Whether a true difference exists between these closely related compounds is, however, uncertain, since our pravastatin study was uncontrolled and of shorter duration (4 weeks). Our findings of unaltered aggregability during simvastatin therapy contrast with previous trials that have shown reduced aggregation in vitro.4 9 11 The filtragometry technique measures unstimulated platelet aggregability in whole blood continuously drawn from a forearm vein, whereas traditional aggregometry is performed on isolated platelet suspensions stimulated by platelet agonists in vitro.32 Thus, there are important methodological differences, and filtragometry findings and data obtained with traditional in vitro aggregometry cannot be directly compared.
Awareness of high blood pressure33 and public speaking34 are stressful situations associated with increased plasma ßTG levels. Recently we reported that the stress test used in this study raises plasma ßTG levels in placebo-treated patients with combined hyperlipidemia, and that this effect was not observed during gemfibrozil treatment.35 The present data are similar, with a trend toward stress-induced elevations of plasma ßTG only during placebo treatment. The stress-induced enhancement of platelet aggregability previously observed in healthy young volunteers13 36 was not found in this middle-aged population. This difference could possibly be related to the age difference, less pronounced hemodynamic responses, or the fact that plasma ephinephrine levels did not increase significantly in the present population. Thus, the question of whether short-term stress influences platelet function in vivo in patients with hypercholesterolemia remains unsettled. Lipid-lowering treatment might attenuate platelet activation by intense stress (eg, physical exercise) more clearly than in connection with the milder form of stress studied herein.
Experimental and clinical studies have clearly shown that hypercholesterolemia is associated with platelet hyperactivity (reviewed in Reference 37). Whether this hyperactivity is due to direct effects of cholesterol-rich lipoproteins on platelets or to indirect influences, eg, endothelial dysfunction, is unclear. Positive correlations have occasionally been found between platelet function markers and plasma cholesterol levels,6 35 38 but this has not been a consistent finding.5 39 Moreover, short-term cholesterol-lowering trials have not convincingly demonstrated that a fall in plasma cholesterol levels is accompanied by reduced platelet activity. Simvastatin and other HMG-CoA reductase inhibitors have been thought to hold a unique position with beneficial effects on platelet function, but the present observations of four different in vivo related markers of platelet function do not support this view. Thus, the association between blood cholesterol and platelet function is far from straightforward. Simvastatin may nonetheless influence the thrombotic risk of patients via other mechanisms. Further investigations of the indirect links between plasma lipoproteins and platelet function should be encouraged.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from Merck Sharp and Dohme (European School Grant), the Swedish Heart-Lung Foundation, the Swedish Medical Research Council (5930 and 7137), the Karolinska Institute, the Thuring and Axson Johnson Foundations, and the Lars Hiertas Foundation. Maud Daleskog, Maj-Christina Johansson, Wiveka Ring-Persson, Christina Perneby, and Lilian Larsson are gratefully acknowledged for expert technical assistance. Appreciation is also given to Chatarina Sjoberg for excellent care of the patients at Huddinge University Hospital.
Received May 7, 1996; accepted May 28, 1996.
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