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J Am Coll Cardiol, 1999; 33:1294-1304
© 1999 by the American College of Cardiology Foundation
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CLINICAL STUDIES

Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile

George Dangas, MDa, Juan J. Badimon, PhDa, Donald A. Smith, MDa, Allen H. Unger, MD, FACCa, Daniel Levine, PhD*, John H. Shao, BSa, Perwaiz Meraj, BSa, Carl Fier, MDa, John T. Fallon, MD, PhDa and John A. Ambrose, MD, FACCa

a Cardiovascular Institute and the Departments of Medicine and Pathology, Mount Sinai School of Medicine, New York, New York, USA
* Rogosin Institute, Cornell University Medical College, New York, New York, USA

Manuscript received June 12, 1998; revised manuscript received October 29, 1998, accepted January 5, 1999.

Reprint requests and correspondence: Dr. John A. Ambrose, Chief of Cardiology (Cronin 553), Saint Vincent’s Hospital and Medical Center, 153 West 11th Street, New York, New York 10011


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

The study sought to determine the effects of lipid-lowering with pravastatin on the systemic fibrinolytic profile and on thrombus formation under dynamic flow conditions.

BACKGROUND

Lowering cholesterol (C) decreases clinical events in coronary artery disease (CAD) patients, but an analysis of the effects of lipid-lowering on the entire hemostatic and thrombotic profile has not been conducted.

METHODS

We prospectively studied 93 stable patients with untreated low-density lipoprotein cholesterol (LDL-C) >145 mg/dl. The CAD patients received pravastatin, and non-CAD patients were randomized to pravastatin versus placebo (double-blind). Thrombus formation upon an injured vascular surface was assessed in a substudy of 40 patients with a previously validated ex vivo perfusion chamber system. Systemic hemostatic markers and thrombus formation were evaluated at baseline, three and six months.

RESULTS

Placebo produced no changes in either the lipid profile, any of the hemostatic markers, or the ex vivo thrombus formation. Both pravastatin groups (CAD and non-CAD) showed decreased LDL-C by 30% within 6 weeks (188 to 126 mg/dl, p < 0.001 vs. baseline), and decreased plasminogen activator inhibitor-1 at 3- and 6-month follow-up compared to baseline (15% to 18% decrease at 3 months and 21% to 23% at 6 months). For the tissue plasminogen activator antigen, CAD and non-CAD groups showed significant decreases at 6 months compared to baseline (10% and 13%, respectively). No significant changes were observed with treatment in d-dimer, fibrinopeptide A, prothrombin fragment F1.2, factor VIIa, von Willebrand factor, or C-reactive protein. Fibrinogen levels were significantly increased at 6 months compared to baseline, though still below the upper normal limit. In the perfusion chamber substudy, there was a decrease in thrombus area in non-CAD patients treated with pravastatin at both 3 and 6 months compared to baseline (by 21% and 34%, respectively). The CAD patients showed decreases in thrombus formation by 13% at 3 months, and by 16% at 6 months. The change in LDL-C- correlated modestly with the change in thrombus formation (r = 0.49; p < 0.01).

CONCLUSIONS

Pravastatin therapy significantly decreased thrombus formation and improved the fibrinolytic profile in patients with and without CAD. These early effects may, in part, explain the benefit rendered in primary and secondary prevention of CAD.

Abbreviations and Acronyms
  ALT = alanine aminotransferase
  AST = aspartate aminotransferase
  CAD = coronary artery disease
  CRP = C-reactive protein
  HDL-C = high-density lipoprotein cholesterol
  LDL-C = low-density lipoprotein cholesterol
  PAI-1 = plasminogen activator inhibitor-1
  t-PA = tissue plasminogen activator

Hyperlipidemia has been identified as a major risk factor for the development of coronary artery disease (CAD) (1), and lipid-lowering has been proven beneficial for the primary and secondary prevention of CAD (2–4). Reduction of low-density lipoprotein cholesterol (LDL-C) has been associated with decreased progression and occasionally with regression of CAD (5–10), but the most profound effect of such intervention is the marked decrease in ischemic events (2–4,11,12).

The development of acute coronary syndromes has mainly been attributed to thrombus formation upon a fissured, disrupted, or eroded plaque (13–15). The lipid-core is a very strong thrombogenic stimulus when exposed to the bloodstream (16,17). Elevated cholesterol contributes to the pathogenesis of endothelial dysfunction, even before the development of typical atherosclerotic lesions (18). Occurrence of an acute coronary event may also be due to an inflammatory and prothrombotic systemic state (19–22). Previous data suggest that the clinical improvement and prevention of coronary events with cholesterol lowering may be achieved by diminishing the plaque lipid content, by affecting the systemic hemostatic profile or by improving endothelial function (23–25).

Concerning its effects on thrombosis, treatment of hypercholesterolemia with pravastatin has been reported to decrease platelet aggregation and ex vivo thrombus formation in CAD patients (26). The effects of several lipid-lowering agents on certain systemic thrombotic parameters have also been described in observational studies (27–30). However, a systemic analysis of the effects of lipid-lowering on the entire hemostatic and thrombotic profile has not been conducted in patients with and without CAD.

We prospectively investigated in a randomized, double-blind, placebo-controlled trial the effects of lowering LDL-C with pravastatin on thrombus formation, and parameters that evaluate the entire thrombotic and hemostatic profile, in a target population without CAD, and a nonrandomized group with CAD.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Patient population and study protocol.   Outpatients were evaluated for possible enrollment at the lipid clinic of the Mount Sinai Medical Center over a period of 6 months (December 15, 1995, to June 30, 1996), according to their fasting lipid profile in the absence of lipid-lowering therapy for at least 2 months. Patients with LDL-C >145 mg/dl and triglycerides <275 mg/dl were considered for enrollment. The presence of CAD was evidenced by a prior angiogram, or a positive stress test and typical angina, or a prior myocardial infarction. Patients without CAD had a negative Rose angina questionnaire (31), as well as no prior carotid or peripheral atherosclerotic disease. Exclusion criteria were major surgery, major infection, anti-inflammatory medications, or anticoagulants for the last six months prior to enrollment. The CAD patients had no history of unstable angina, myocardial infarction, stroke, angioplasty or bypass surgery for at least six months prior to enrollment.

Patients with coronary disease were treated with open-label pravastatin, whereas patients without evidence of CAD were randomized to pravastatin or placebo. All patients received an American Heart Association (AHA) step I diet. No change in cardiac medications was made during the study period. Diabetics in good glucose control, as evidenced by fasting blood glucose <180 mg/dl and hemoglobin A1c <8 g%, were included in the study, and the randomization prospectively stratified their distribution between the pravastatin and placebo groups in the non-CAD population. Randomization was done according to a table of random numbers, kept by the unblinded investigator (D.A.S.), who was the only one aware of the treatment assignment and made all decisions regarding the dose of pravastatin or placebo based on the lipid profile results. The pre-specified goal was at least a 30% relative reduction of LDL-C, or an achievement of LDL-C <125 mg/dl. Patients were started on 20 mg of pravastatin at bedtime, and were evaluated at six weeks to assess the efficacy of LDL-C lowering, and to exclude possible hepatotoxicity. In case that LDL-C was not 30% lower than baseline or <125 mg/dl, the pravastatin dose was increased to 40 mg per day. Placebo patients were evaluated in a similar fashion, took placebo capsules that were identical to pravastatin, and their dosage was in equivalent proportion to the pravastatin patients who required an increased dose.

The Institutional Review Board approved the study, and all patients granted written informed consent. All patients had blood drawing (30 ml) for lipid profile, thrombotic and hemostatic profile (see below) at baseline and after three and six months of therapy. The patient subset specifically consenting to participate in the thrombus formation substudy had an additional 50 ml of blood withdrawn during direct ex vivo perfusion through the Badimon chamber (32) at the same three time points.

Chemical determinations.   A complete 12-h fasting lipid profile was measured at baseline, 6 weeks, 3 and 6 months after beginning of therapy. Serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) were also monitored at the same time intervals. The determinations were performed on a Technicon Chem 1 system (Bayer Diagnostics, Tarrytown, New York) according to the manufacturer’s recommendations. Only the unblinded investigator had access to these results so as to ensure patient safety and appropriate therapeutic response to pravastatin. Serum Lp(a), C-reactive protein (CRP), and apoproteins A and B were measured with immuno-turbinometric systems (INCSTAR, Minneapolis, Minnesota), and homocysteine was measured with a fluorescence detection method. Both Lp(a) and homocysteine levels were measured only at baseline, as they were unlikely to change with pravastatin therapy.

Thrombotic and hemostatic profile.   Several sites of the coagulation cascade and the hemostatic mechanism were also evaluated. All blood drawings were performed between 9:00 and 11:30 AM. The patient remained seated for 20 min; with a tourniquet in place, a 20G cannula was inserted into an antecubital vein of the patient, and then the tourniquet was immediately removed. The first 10 ml of blood were discarded, and then blood was collected for all determinations. Fibrinogen was determined with a heat precipitation method, prothrombin time/International normalized ratio was performed on a MLA 900/900C/1000 instrument (Medical Laboratory Automation, Pleasantville, New York) and the complete blood count on a Coulter STKS (Coulter, Hialeah, Florida). Thrombin generation and activity were assessed by measurement of prothrombin fragment F1.2, and fibrinopeptide A (FPA) in plasma using commercially available ELISA kits (Behring Diagnostics, Westwood, Massachusetts, and Diagnostica Stago, Asnieres-sur-Seine, France, respectively). Fibrin formation was assessed in citrated plasma with the d-dimer levels (Diagnostica Stago, France), and the extrinsic coagulation cascade with factor VIIa assay as previously described (33). Endothelial markers were measured with ELISA (American Diagnostica, Greenwich, Connecticut): plasminogen activator inhibitor-1 (PAI-1) antigen, tissue plasminogen activator (t-PA) antigen; von Willebrand factor activity (the latter only in the CAD group) with a standard assay (Biodata, Philadelphia, Pennsylvania). Specimens were centrifuged at 3000g for 20 min, and then separated and shock-frozen at –75°C. Blood was unfrozen only once for the determinations, after completion of the study. Only investigators blinded to the patients’ clinical group conducted these analyses.

Thrombus formation substudy.   Ex vivo perfusion chamber
The perfusion chamber system has been described elsewhere by Badimon et al. and other investigators (26,32,34,35). It consists of a cylindrical flow channel, which allows the blood, pumped directly from the patient to flow over the exposed thrombogenic substrate. Local flow conditions, mimicking mild arterial stenosis, were kept constant: shear rate 1690 s–1, Re = 60, flow rate 10 ml/min, velocity 21.2 cm/s.

Thrombogenic substrates
Fresh frozen porcine aorta was surgically prepared to simulate arterial injury, as previously described (26,32,34,35). Segments were prepared by first removing excess adventitia, and after opening the aorta longitudinally, by peeling off the intima and a thin portion of the media. Segments were stored at –20°C in 0.1 mol/liter NaCl, 0.01 mol/liter Na3PO4, pH = 7.4.

Perfusion studies
During each perfusion study, blood was circulated through three chambers, connected in series. The system was connected with polyethylene tubing to the intravenous line and to a peristaltic pump (Masterflex model 7013, Cole-Palmer Instruments, Denver, Colorado) positioned distal to the chambers, and flushed with 0.9% NaCl for 30 s. With a tourniquet in place, a 20G cannula was inserted into an antecubital vein of the patient, and then the tourniquet was immediately removed. The first 10 ml of blood were discarded, and then the ensuing blood was passed directly from the patient through the chamber system for 5 min, after which the chambers were flushed with 0.9% NaCl for 1 min at the same rheologic conditions. The perfused substrates were then removed from the chambers and placed in formalin at 4°C for 48 to 72 h, and then processed for immunocytochemistry and light microscopy. All 50 ml of blood was discarded after perfusion through the chamber system, and no blood was returned to the patient.

Evaluation of thrombus formation
As previously described, serial sections were cut from each formalin-fixed specimen, and embedded in paraffin. Thin sections were prepared and stained with 1) combined Mason-elastin stain and 2) a rabbit polyclonal anti-human fibrinogen antibody (A080, Dako) at 3.6 µg/ml. For immunohistochemical staining, the primary antibody was reacted with a biotin-conjugated secondary antibody, which in turn was reacted with streptavidin conjugated with peroxidase (BioGenex, San Ramon, California). Peroxidase activity was detected with 3-3'-diaminobenzidine. Microscopic analyses were conducted at 100-fold magnification and images were digitized using a Sony DKC-5000 camera and Adobe Photoshop 3.0.5 software on a PowerMacintosh 8500 computer. Thrombus areas were measured on each section with computerized planimetry using NIH Image 1.60 cc software. The results from the three sections were averaged to determine the thrombus area for each chamber substrate, and then the results from the three chambers were averaged (i.e., a total of nine sections per perfusion study). All measurements were done by the same investigator (G.D.), blinded as to the treatment assignment.

Statistical analysis.   Patients with CAD formed an individual group (open-label pravastatin), whereas non-CAD patients were randomized into pravastatin and placebo groups (double-blind treatment and follow-up). The primary method of comparison, as part of the study design, was to allow each patient to serve as his or her own control, with the baseline measurements compared to values at three or six months’ posttreatment within each group. Analysis of variance (ANOVA) with Bonferroni correction for multiple comparisons was used, and significance was defined at the level p < 0.045. Correlations between continuous variables were conducted with linear regression analysis. Continuous variables were expressed as mean ± SE; categorical variables were expressed as n(%) and compared with the Fisher exact test. We also conducted an analysis of covariance between the placebo group and all pravastatin-treated patients (both CAD and non-CAD combined) to evaluate differences in the three-month and six-month follow-up values controlling for the respective values obtained at baseline. This was performed by entering in a multivariate logistic regression model the observed three- or six-month to baseline changes as the outcome, and entering the pravastatin versus placebo treatment group and the baseline value of the respective parameter as the two variables. The software JMP 3.2 (SAS Institute, Cary, North Carolina) was used, and statistical significance was defined at the level p < 0.05 in other than ANOVA comparisons.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
A total of 226 hyperlipidemic patients without lipid-lowering therapy for the previous 2 months were evaluated for possible enrollment in the study. Of those, 88 were excluded because of their lipid values, 8 for insufficiently controlled diabetes, 10 for prior angioplasty within 6 months, 5 for prior surgery within 3 months and 3 for hematocrit <30%; 9 patients refused to grant consent. The remaining 103 patients comprised our preliminary study population: CAD group n = 32, non-CAD group n = 71. Ten did not wish to continue with the study after the first blood drawing; thus, the final number of participants incorporated to the analyses was 93: CAD group n = 31, non-CAD group n = 62, divided into pravastatin n = 26 and placebo n = 36. Forty of these patients were in the thrombus formation substudy as well: CAD group n = 16; non-CAD group n = 24, divided into pravastatin n = 12 and placebo n = 12.

Baseline patient characteristics are demonstrated in Table 1. The CAD patients were more frequently on aspirin, and were older, with lower high-density lipoprotein cholesterol (HDL-C), and were more frequently hypertensive and male compared to non-CAD patients. Non-CAD pravastatin versus placebo patients had no differences. There were no significant baseline differences between the entire population and the participants in the thrombus formation substudy.


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  		Table 1 Baseline Characteristics in the Entire Study Population (n = 93)

 
In 64.5% of patients, 20 mg of pravastatin resulted in appropriate LDL-C reduction within 6 weeks, while the remaining patients reached the set goal by 3 months, after an increase in their dose to 40 mg. The response to pravastatin did not differ among the groups. No patient had side effects due to pravastatin therapy, or demonstrated an increase in AST or ALT levels warranting discontinuation of therapy. The Lp(a) levels were similar in all groups, and homocysteine levels were slightly higher in the CAD patients (Table 1).

Changes in lipids, and the thrombotic and hemostatic profile.   Pravastatin therapy decreased both total and LDL-C at follow-up compared to baseline (Table 2). These changes were apparent in both patients with and without CAD. Patients’ weight at follow-up was not significantly different from baseline for any group. Placebo had no significant effect on the lipid profile, or in any of the systemic markers. Hematocrit, CRP and prothrombin time d-dimer, FPA, F1.2, von Willebrand factor activity, and factor VIIa did not change significantly with time in any group. Fibrinogen levels were significantly increased at six months compared to baseline, in both pravastatin patients with CAD (11%) and without CAD (21%), but remained within normal limits, according to laboratory specifications.


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  		Table 2 Hemostatic Factors in the Entire Study Population (n = 93)

 
In the non-CAD pravastatin-treated group, PAI-1 antigen showed a significant decrease both at three and six months of follow-up compared to baseline (by 18% and 23%, respectively, p < 0.04). Similarly, a significant decrease at 6 months compared to baseline occurred in t-PA levels of the same group (by 13%, p < 0.04). In the CAD patients treated with open-label pravastatin, PAI-1 was significantly reduced at 3 months compared to baseline (by 15%, p < 0.04), and both t-PA and PAI-1 were significantly decreased compared to baseline at the 6-month follow-up (by 10% and 21%, respectively, p < 0.04).

Effect on thrombus formation.   At baseline, non-CAD patients randomized to pravastatin had somewhat larger thrombus cross-sectional area as compared to CAD patients or to placebo patients. In response to pravastatin therapy, there was a significant decrease in thrombus area in non-CAD patients at both three and six months compared to baseline (21% and 34%, respectively, p < 0.04). Compared to baseline, CAD patients showed a trend to decreased thrombus formation at three months (by 13%, p < 0.09), and a significant decrease at six months of therapy (by 16%, p < 0.04). Placebo produced no significant changes in thrombus formation at either time point (Fig. 1). Changes in thrombus formation that occurred in either pravastatin group were significantly different compared to changes in the placebo group.



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  		Figure 1 Changes of total thrombus area in the three study groups (perfusion chamber substudy). Significant changes (p < 0.04) compared to baseline are indicated by asterisk (*).

 
We found no significant correlation between LDL-C (also total cholesterol) and total thrombus area in all patients studied at baseline. However, a direct linear correlation existed between change in LDL-C and change in thrombus formation (Fig. 2), with an r value of 0.47 for the three-month-to-baseline change, and an r value of 0.48 for the six-month-to-baseline change (p < 0.01). Reduction in LDL-C accounted for 23% in the reduction observed in thrombus formation under dynamic flow conditions.



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  		Figure 2 Perfusion chamber substudy (n = 40): correlation between change in LDL-cholesterol and total thrombus area after 6 months of therapy.

 
Patients included in the perfusion chamber substudy demonstrated similar trends in their hemostatic profile as the entire study population. The non-CAD as well the CAD pravastatin-treated patients had significant decreases (vs. baseline) in PAI-1 and t-PA after 6 months of therapy, whereas no significant changes were observed with placebo: CAD patients’ PAI-1 from 40.2 ± 4.4 to 31.3 ± 2.9 ng/ml, and t-PA from 11.7 ± 1.1 to 9.7 ± 1.0 ng/ml; non-CAD patients’ PAI-1 from 42.8 ± 6.3 to 30.0 ± 5.4 ng/ml, and t-PA from 9.5 ± 0.9 to 8.6 ± 0.9 ng/ml, p < 0.045 for all.

Analysis of covariance.   This analysis provided the adjusted mean values of patients treated with placebo (n = 36) versus pravastatin (n = 57), controlling for the baseline between-group differences in the examined values; for the perfusion chamber substudy, the corresponding numbers were n = 28 for pravastatin, n = 12 for placebo (Table 3). At the three-month follow-up visit, PAI-1 was significantly lower and thrombus formation was borderline lower in pravastatin-treated patients compared to placebo. At the six-month follow-up, values of thrombus formation and t-PA were significantly lower, and PAI-1 was borderline lower in pravastatin-treated patients compared to placebo.


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  		Table 3 Analysis of Covariance: Values Adjusted for Baseline Differences

 
Effect of aspirin on the response to pravastatin.   In a secondary analysis, we investigated the possible correlation of the use of aspirin to the changes in thrombus formation that occurred in the entire pravastatin-treated patient population (n = 57). Decreases in thrombus formation tended to be somewhat greater and occurred earlier in the non-CAD patients. Thrombus formation in the perfusion chamber was greater at baseline in patients not receiving aspirin (Fig. 3), and six-month-to-baseline decreases in thrombus area with pravastatin were significantly greater in patients not treated with aspirin versus those treated with aspirin: 5.3 ± 1.0 vs. 1.7 ± 0.9 µm2 x 103, respectively, p < 0.04 (Fig. 4).



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  		Figure 3 Perfusion chamber substudy (n = 40): baseline total thrombus formation was significantly lower (*p < 0.04) in patients receiving aspirin compared to those who were not treated with aspirin.

 


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  		Figure 4 Perfusion chamber substudy, pravastatin-treated patients (n = 28): the decrease in total thrombus formation was significantly greater (*p < 0.04) in patients not treated with aspirin compared to those who were receiving aspirin.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Several studies have assessed the effects of cholesterol-lowering agents on platelet function, endogenous fibrinolysis and fibrinogen, showing decreased platelet reactivity and aggregability with cholesterol-lowering therapy (30). Lacoste et al. (26) reported a reduction of the increased thrombogenic potential of hypercholesterolemic CAD patients after 3 months of pravastatin therapy. The present study reports for the first time a direct correlation between reduction in LDL-C and reduction in thrombus formation (Fig. 2). The reduction in LDL-C explained only 23% of that change in thrombus formation (r2 = 0.23). This suggests that the decrease in thrombus formation and the improvement in the systemic fibrinolytic profile may not be exclusively related to lipid reduction.

The effects of lipid-lowering on fibrinogen have been variable, with studies showing a decrease, no change, or an increase with statin therapy (28,36,37). In the present study, there was an increase in fibrinogen that was, however, not associated with changes in markers of thrombin generation and activity and fibrinogen levels remained below the upper limit of normal. Lipid-lowering may render the plaques less prone to rupture, or render them less thrombogenic when exposed to flowing blood after rupture (38). Treatment of hypercholesterolemia has been shown to improve endothelium-dependent coronary vasomotion (24,25,39), implying a beneficial effect at the early stages of atherogenesis.

Elevated t-PA levels have been demonstrated in conditions related to endothelial cell damage (40), and may also occur in relation to intravascular thrombus formation (41). Several studies, most showing a decrease, have evaluated the effects of lipid-lowering on endogenous fibrinolysis by measuring systemic levels of t-PA and PAI-1. As these substances are produced by endothelial cells, the decrease in their plasma levels reflects improved intrinsic fibrinolysis, and is also likely to represent an improvement in endothelial function and a "decreased thrombotic potential." In fact, most of the t-PA in the plasma circulates bound to PAI-1 molecules (42); therefore, higher t-PA and PAI-1 levels likely reflect an attenuated fibrinolytic state, and a decrease in both parameters represents an enhancement of intrinsic fibrinolysis (43) related to improved endothelial function with pravastatin therapy.

We systematically evaluated the thrombotic and hemostatic profile of hyperlipidemic patients with and without evidence of CAD. Our results support an inhibitory effect of pravastatin therapy on platelet thrombus formation, and the systemic hemostatic profile. Thrombin generation, thrombin activity and the intrinsic coagulation cascade were not affected by treatment in this study. The levels of CRP were uniformly low in all patient groups at baseline and remained so throughout the study duration. It is possible that induced changes in these parameters may be too small to detect with the present sample size and the given parameter variability (20). Nonetheless, the importance of platelet and fibrinolytic/endothelial function in arterial thrombosis has recently received greater attention than the coagulation cascade (19,44). In that respect, small changes in coagulation parameters may not have as great an implication concerning the occurrence of coronary events compared to changes in platelet reactivity and an improved hemostatic profile related to endothelial function (45–51).

These effects on thrombus formation were apparent in both CAD and non-CAD patients treated with pravastatin, and the effects of therapy were more accentuated in the non-CAD group. This might have been related to the greater number of risk factors for vascular disease in the CAD group (i.e., lower HDL-C, higher age, more male, and more hypertension). Additionally, CAD versus non-CAD patients had a significantly greater use of aspirin. Because pravastatin therapy appeared to improve the platelet/endothelium relationship and to diminish the formation of platelet thrombus, preexisting aspirin therapy might have limited the window of expected benefit from pravastatin, which was fully demonstrated in our hyperlipidemic patients with CAD.

Our results offer insights into possible mechanisms for the reduction in clinical events with pravastatin therapy in the prevention of CAD. Thrombus formation upon an injured vascular surface and the endothelial hemostatic markers changed favorably with pravastatin. Along with the reduction in LDL-C and the potential for plaque stabilization, pravastatin appears to affect significantly platelet reactivity, platelet–vessel wall interaction, endothelial function and intrinsic fibrinolysis. Recently, treatment with pravastatin in the West of Scotland primary prevention study was reported to be equivalent in reducing coronary events at all levels of LDL reduction greater than 23%, implying that the magnitude of LDL-lowering was not the sole determinant for the observed clinical benefit in the treatment arm (52). A similar effect was also evident in the CARE trial (53), which demonstrated no additional benefit from LDL-lowering below a treatment level of 125 mg/dl, and no relationship between LDL reduction and cardiac events.

The present investigation does not provide comparative information regarding different statins and their individual effect on platelet–vessel wall interaction and the thrombotic and hemostatic profile. Preliminary reports have indicated that these properties may differ among the statins, as simvastatin failed to show such effects on platelet thrombus formation in one pilot study, while it decreased thrombus formation in another (54,55). The interrelation between aspirin and pravastatin therapies on thrombus formation should be further investigated, as should differences among statins in thrombus formation and the systemic hemostatic profile.

Conclusions.   Treatment of hyperlipidemic patients with pravastatin correlated with a reduction in thrombus formation upon an injured vascular surface under dynamic flow conditions, and with an improvement in fibrinolytic markers. The modest correlation between the change in LDL-C and the changes in these markers suggests that the observed changes in the thrombotic markers were only in part due to the reduction of LDL-C.


   Footnotes
 
This work was supported in part by a grant from Bristol-Myers Squibb, Princeton, New Jersey, and by grant 5 M01 RR00071 to the Mount Sinai General Clinical Research Center from the National Center for Research Resources, National Institutes of Health, Bethesda, Maryland.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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