- Email: [email protected]
Statins do not affect platelet inhibition with clopidogrel during coronary stenting
Atherosclerosis 159 (2001) 239– 241 www.elsevier.com/locate/atherosclerosis
Letter to the Editors Statins do not affect platelet inhibition with clopidogrel during coronary stenting Dear Sir Platelets play an important role in the pathogenesis of acute coronary syndromes [1,2]. There is substantial evidence of impaired platelet function in patients with unstable angina, primarily due to plaque disruption and endothelial exposure of prothrombotic substances [3,4]. Coronary stenting has recently become a mainstay of interventional cardiology. Acquired platelet activation following stent implantation is well documented, and may affect both short- and long-term outcomes in such patients [5,6]. Clopidogrel, a novel thienopyridine, is a platelet ADP-receptor blocker, and a widely prescribed agent for sustained mild platelet inhibition during and after coronary stenting. In this patient population, statins have become the gold standard for treatment because of their beneficial effects on cholesterol and lipid metabolism in both primary and secondary prevention of coronary artery disease [7,8]. Obviously, certain clinical scenarios exist when treatment with clopidogrel is combined with the chronic use of statins. There are a few anecdotal reports that statins may selectively interfere with clopidogrel, limiting the ability of this ADP-receptor blocker to inhibit platelet function [9]. We retrospectively analyzed the data from the PRONTO (Plavix Reduction of New Thrombus Occurrence) trial comparing platelet inhibition with clopidogrel in patients who received statins with those who did not. One hundred patients who were loaded with 300 mg of clopidogrel 3–24 h prior to undergoing intracoronary NIR® stent placement, or received 75 mg of clopidogrel immediately prior to stent were analyzed. Patients were excluded if they had a history of bleeding diathesis, acute myocardial infarction within 48 h, stroke within 3 months, a history of drug or alcohol abuse, a prothiombin time greater than 1.5 times con* Corresponding author. Present address. Center for Thrombosis Research, Sinai Hospital of Baltimore, 2401 West Belvedere Avenue, Schapiro Research Building-R 202 Baltimore, MD 21215 USA. Tel.: +1-410-601-5266; fax: +1-410-601-9061.
trol, platelet count B 100,000/mm3, hematocrit B25%, or creatinine \ 4.0 mg/dl. All patients received aspirin (81 –325 mg) for at least 1 week before the interventional procedure, and intravenous heparin prior to stent implantation to achieve an activated clotting time \ 300 s. Platelet function was assessed at baseline, at discharge (day 2), and finally at day 5 following coronary intervention. Blood samples were obtained with a 19-gauge needle by direct venipuncture and drawn into two 7 ml vacutainer tubes at room temperature containing 3.8% trisodium citrate. The vacutainer tube was filled to capacity and gently inverted 3–5 times to ensure complete mixing of the anticoagulant. The blood –citrate mixture was centrifuged at 1200× g for 2.5 min. The resulting platelet-rich plasma was kept at room temperature for use within 1 h. The platelet count was determined in the plasma sample and adjusted to 3.5× 108/ml with homologous platelet-poor plasma. Platelets were stimulated with 5 mmol adenosine diphosphate (Chronolog, Inc., Hawerton, PA) and aggregation was assessed as previously described using a Chronolog Lumi-Aggregometer (model 560-Ca) with the AggroLink software package. Aggregation was expressed as the maximal percent change in light transmittance from baseline, using platelet-poor plasma as a reference. Curves were analyzed according to international standards [10]. The surface expression of platelet receptors was determined by flow cytometry using the following monoclonal antibodies: CD 41 (GP IIb/IIIa, aIIbb3 (DAKO Corporation, Carpenteria, CA), and CD 31 (platelet/ endothelial cell adhesion molecule [PECAM]-1), (PharMingen, San Diego, CA). The blood –citrate mixture (50 ml) was diluted with 450 ml Tris buffered saline (10 mmol/l Tris, 0.15 mol/l sodium chloride) and mixed by inverting an Eppendorf tube gently two times. The corresponding antibody was then added (5 ml) and incubated at room temperature for 30 min. After incubation, 400 ml of 2% buffered paraformaldehyde was added for fixation. The samples were analyzed on a Becton Dickinson FACScan flow cytometer set up to measure fluorescent light scatter as previously described [11]. All parameters were collected using four decade
0021-9150/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 0 1 ) 0 0 6 0 6 - 2
240
Letter to the Editors
logarithmic amplification. The data were collected in list mode files and then analyzed. The clinical characteristics of 100 patients with respect to statin use are shown in Table 1. Of the individuals analyzed, 25 patients received statin therapy (atorvastatin, nine patients [36%]; fluvastatin, six patients [24%]; pravastatin, four patients [16%]; cerivastatin, three patients [12%]; lovastatin, two patients [8%]; simvastatin, one patient [4%]) and 75 did not. The group receiving a statin had a higher mean age and had a greater proportion of white patients than those not given statin therapy. No age difference was observed Table 1 Characteristics of patients by statin use Characteristic
Patients receiving statin therapy (n = 25)
Age 72 9 7 (years-mean 9 S.D.) Gender n (%) Male Female
Patients not receiving statin therapy (n=75) 679 8
18 (72%) 7 (28%)
58 (77%) 17 (23%)
Ethnic group n (%) Caucasian 20 (80%) African-American 3 (12%)
43 (57%) 30 (40%)
Asian
2 (8%)
Risk factors n (%) Tobacco use 7 (28%) Systemic 14 (56%) hypertension Hypercholesterole 4 (16%) miaa Other cardio6ascular disease n (%) Stable angina 2 (8%) Unstable angina 23 (92%) Previous AMI 13 (52%) Peripheral 4 (16%) vascular disease Diabetes 9 (36%) mellitus History of 7 (28%) CABG Other medication n (%) Aspirin 25 (100%) Beta-blocker 10 (40%) ACE Inhibitor 6 (24%) Nitrates 7 (28%) Diuretics 6 (24%) Calcium 4 (16%) antagonist Anti-diabetic 9 (36%) agent
2 (3%) 32 (43%) 38 (51%) 41 (55%)
3 72 11 12
(4%) (96%) (15%) (16%)
26 (35%) 10 (13%)
75 41 16 32 26 25
(100%) (55%) (21%) (43%) (35%) (31%)
26 (35%)
a Hypercholesterolemia defined as total cholesterol \220 mg/dl and LDL cholesterol \130 mg/dl.
between the two groups. The statin users exhibited a higher incidence of previous acute myocardial infarction (AMI), and heart surgery. The distribution of medications was comparable between groups. Platelet data are expressed in Table 2. Platelet inhibition by clopidogrel was similar in patients receiving and those not receiving concomitant statin therapy. After 5 days, 35–40% inhibition of aggregation, more than 50% reduction of GP IIb/IIIa expression, and 40–45% of PECAM-1 expression compared with the baseline values were observed in both groups. Analysis according to individual statin use showed that none of the agents studied had any significant effect on clopidogrel activity. The data from the present study show that antecedent therapy with statins did not jeopardize the ability of clopidogrel to inhibit platelets among patients undergoing coronary stenting. Our patient population were treated with all six statins commonly prescribed in the United States representing the whole spectrum of these potent agents. These data concur with previous observations reporting that co-administration of clopidogrel did not interfere with the clinical control of hypertension or angina established with atenolol or nifedipine, or both [12]. Clopidogrel retained its full antiplatelet effect, and there were no safety problems caused by such combination therapy. Another study found no interaction when clopidogrel was added to digoxin for long-term management of patients with cardiac disease [13]. In summary, in a much larger patient group than previously described, we found no evidence of a clopidogrel– statin interaction and conclude that statin use is not an independent factor that may affect the ability of clopidogrel to achieve sustained platelet inhibition.
References [1] Harrington RA. Overview of clinical trials of glycoprotein IIb – IIIa inhibitors in acute coronary syndromes. Am Heart J 1999;138(4 Pt 2):276 – 86. [2] Cohen M. Treatment of unstable angina: the role of platelet inhibitors and anticoagulants. J Invasive Cardiol 1999;3:147 –59. [3] Golino P, Ragni M, Cirillo P, Buono C, Piro O, Chiariello M. Emerging antithrombotic treatments for acute coronary syndromes. Cardiologia 1999;44:969 – 80. [4] Libby P. Changing concepts of atherogenesis. J Intern Med 2000;247:349 – 58. [5] Mak KH, Belli G, Ellis SG, Moliterno DJ. Subacute stent thrombosis: evolving issues and current concepts. J Am Coll Cardiol 1996;27:494 – 503. [6] Eeckhout E, Kappenberger L, Goy JJ. Stents for intracoronary placement: status and future direction. J Am Coll Cardiol 1996;27:757 – 65. [7] Roberts WC. The underused miracle drugs: the statin drugs are to atherosclerosis what penicillin was to infectious disease. Am J Cardiol 1996;78:377 – 8.
241
Letter to the Editors Table 2 Platelet characteristics of patients by statin use Time point
Baseline Day 2 Day 5
5 mM ADP induced platelet aggregation (%)
GP IIb/IIIa expression (log fluorescence intensity)
PECAM-1 expression (log fluorescence intensity)
With statin (n = 25)
No statin (n= 75)
With statin (n =25)
No statin (n =75)
With statin (n =25)
No statin (n =75)
58.7 9 10.7 36.0 9 9.1 37.3 9 7.3
59.4 9 11.5 38.79 10.5 35.89 7.7
186 9 39 256 9 57 80 918
202 9 44 269 947 87 9 16
90 98 51 9 9 48 96
87 9 10 549 11 469 8
Data presented as mean 9 S.D. [8] Stenestrand U, Wallentin L. Early statin treatment following acute myocardial infarction and 1-year survival. J Am Med Assoc 2001;285:430 –6. [9] Lau WC, Waskell LA, Neer CJ, Carville DOM, Bates ER. The antiplatelet activity of clopidogrel is inhibited by atorvastatin but not by pravastatin, Circulation 2000;102( Suppl. 429). [10] Ruggeri ZM. New insights into the mechanisms of platelet adhesion and aggregation. Semin Hemat 1994;31:229 –39. [11] Ault KA. Flow cytometric measurement of platelet function and reticulated platelets. Ann NY Acad Sci 1993;677:293 –308. [12] Forbes CD, Lowe GD, MacLaren M, Shaw BG, Dickinson JP, Kieffer G. Clopidogrel compatibility with concomitant cardiac co-medications: a study of its interactions with a beta-blocker and a calcium uptake antagonist. Semin Thromb Hemost 1999;25(Suppl. 2):55 –60. [13] Peeters PA, Crijns HJ, Tamminga WJ, Jonkman JH, Dickinson
JP, Necciari J. Clopidogrel, a novel antiplatelet agent, and digoxin: absence of pharmacodynamic and pharmacokinetic interaction. Semin Thromb Hemost 1999;25(Suppl. 2):51 –4.
Victor L. Serebruany*, Alex I. Malinin, Kevin P. Callahan, Paul A. Gurbel Sinai Center for Thrombosis Research Johns Hopkins Uni6ersity Baltimore, MD, USA E-mail: [email protected] Steven R. Steinhubl Willford Hall Medical Center San Antonio, TX, USA
Letter to the Editors Statins do not affect platelet inhibition with clopidogrel during coronary stenting Dear Sir Platelets play an important role in the pathogenesis of acute coronary syndromes [1,2]. There is substantial evidence of impaired platelet function in patients with unstable angina, primarily due to plaque disruption and endothelial exposure of prothrombotic substances [3,4]. Coronary stenting has recently become a mainstay of interventional cardiology. Acquired platelet activation following stent implantation is well documented, and may affect both short- and long-term outcomes in such patients [5,6]. Clopidogrel, a novel thienopyridine, is a platelet ADP-receptor blocker, and a widely prescribed agent for sustained mild platelet inhibition during and after coronary stenting. In this patient population, statins have become the gold standard for treatment because of their beneficial effects on cholesterol and lipid metabolism in both primary and secondary prevention of coronary artery disease [7,8]. Obviously, certain clinical scenarios exist when treatment with clopidogrel is combined with the chronic use of statins. There are a few anecdotal reports that statins may selectively interfere with clopidogrel, limiting the ability of this ADP-receptor blocker to inhibit platelet function [9]. We retrospectively analyzed the data from the PRONTO (Plavix Reduction of New Thrombus Occurrence) trial comparing platelet inhibition with clopidogrel in patients who received statins with those who did not. One hundred patients who were loaded with 300 mg of clopidogrel 3–24 h prior to undergoing intracoronary NIR® stent placement, or received 75 mg of clopidogrel immediately prior to stent were analyzed. Patients were excluded if they had a history of bleeding diathesis, acute myocardial infarction within 48 h, stroke within 3 months, a history of drug or alcohol abuse, a prothiombin time greater than 1.5 times con* Corresponding author. Present address. Center for Thrombosis Research, Sinai Hospital of Baltimore, 2401 West Belvedere Avenue, Schapiro Research Building-R 202 Baltimore, MD 21215 USA. Tel.: +1-410-601-5266; fax: +1-410-601-9061.
trol, platelet count B 100,000/mm3, hematocrit B25%, or creatinine \ 4.0 mg/dl. All patients received aspirin (81 –325 mg) for at least 1 week before the interventional procedure, and intravenous heparin prior to stent implantation to achieve an activated clotting time \ 300 s. Platelet function was assessed at baseline, at discharge (day 2), and finally at day 5 following coronary intervention. Blood samples were obtained with a 19-gauge needle by direct venipuncture and drawn into two 7 ml vacutainer tubes at room temperature containing 3.8% trisodium citrate. The vacutainer tube was filled to capacity and gently inverted 3–5 times to ensure complete mixing of the anticoagulant. The blood –citrate mixture was centrifuged at 1200× g for 2.5 min. The resulting platelet-rich plasma was kept at room temperature for use within 1 h. The platelet count was determined in the plasma sample and adjusted to 3.5× 108/ml with homologous platelet-poor plasma. Platelets were stimulated with 5 mmol adenosine diphosphate (Chronolog, Inc., Hawerton, PA) and aggregation was assessed as previously described using a Chronolog Lumi-Aggregometer (model 560-Ca) with the AggroLink software package. Aggregation was expressed as the maximal percent change in light transmittance from baseline, using platelet-poor plasma as a reference. Curves were analyzed according to international standards [10]. The surface expression of platelet receptors was determined by flow cytometry using the following monoclonal antibodies: CD 41 (GP IIb/IIIa, aIIbb3 (DAKO Corporation, Carpenteria, CA), and CD 31 (platelet/ endothelial cell adhesion molecule [PECAM]-1), (PharMingen, San Diego, CA). The blood –citrate mixture (50 ml) was diluted with 450 ml Tris buffered saline (10 mmol/l Tris, 0.15 mol/l sodium chloride) and mixed by inverting an Eppendorf tube gently two times. The corresponding antibody was then added (5 ml) and incubated at room temperature for 30 min. After incubation, 400 ml of 2% buffered paraformaldehyde was added for fixation. The samples were analyzed on a Becton Dickinson FACScan flow cytometer set up to measure fluorescent light scatter as previously described [11]. All parameters were collected using four decade
0021-9150/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 0 1 ) 0 0 6 0 6 - 2
240
Letter to the Editors
logarithmic amplification. The data were collected in list mode files and then analyzed. The clinical characteristics of 100 patients with respect to statin use are shown in Table 1. Of the individuals analyzed, 25 patients received statin therapy (atorvastatin, nine patients [36%]; fluvastatin, six patients [24%]; pravastatin, four patients [16%]; cerivastatin, three patients [12%]; lovastatin, two patients [8%]; simvastatin, one patient [4%]) and 75 did not. The group receiving a statin had a higher mean age and had a greater proportion of white patients than those not given statin therapy. No age difference was observed Table 1 Characteristics of patients by statin use Characteristic
Patients receiving statin therapy (n = 25)
Age 72 9 7 (years-mean 9 S.D.) Gender n (%) Male Female
Patients not receiving statin therapy (n=75) 679 8
18 (72%) 7 (28%)
58 (77%) 17 (23%)
Ethnic group n (%) Caucasian 20 (80%) African-American 3 (12%)
43 (57%) 30 (40%)
Asian
2 (8%)
Risk factors n (%) Tobacco use 7 (28%) Systemic 14 (56%) hypertension Hypercholesterole 4 (16%) miaa Other cardio6ascular disease n (%) Stable angina 2 (8%) Unstable angina 23 (92%) Previous AMI 13 (52%) Peripheral 4 (16%) vascular disease Diabetes 9 (36%) mellitus History of 7 (28%) CABG Other medication n (%) Aspirin 25 (100%) Beta-blocker 10 (40%) ACE Inhibitor 6 (24%) Nitrates 7 (28%) Diuretics 6 (24%) Calcium 4 (16%) antagonist Anti-diabetic 9 (36%) agent
2 (3%) 32 (43%) 38 (51%) 41 (55%)
3 72 11 12
(4%) (96%) (15%) (16%)
26 (35%) 10 (13%)
75 41 16 32 26 25
(100%) (55%) (21%) (43%) (35%) (31%)
26 (35%)
a Hypercholesterolemia defined as total cholesterol \220 mg/dl and LDL cholesterol \130 mg/dl.
between the two groups. The statin users exhibited a higher incidence of previous acute myocardial infarction (AMI), and heart surgery. The distribution of medications was comparable between groups. Platelet data are expressed in Table 2. Platelet inhibition by clopidogrel was similar in patients receiving and those not receiving concomitant statin therapy. After 5 days, 35–40% inhibition of aggregation, more than 50% reduction of GP IIb/IIIa expression, and 40–45% of PECAM-1 expression compared with the baseline values were observed in both groups. Analysis according to individual statin use showed that none of the agents studied had any significant effect on clopidogrel activity. The data from the present study show that antecedent therapy with statins did not jeopardize the ability of clopidogrel to inhibit platelets among patients undergoing coronary stenting. Our patient population were treated with all six statins commonly prescribed in the United States representing the whole spectrum of these potent agents. These data concur with previous observations reporting that co-administration of clopidogrel did not interfere with the clinical control of hypertension or angina established with atenolol or nifedipine, or both [12]. Clopidogrel retained its full antiplatelet effect, and there were no safety problems caused by such combination therapy. Another study found no interaction when clopidogrel was added to digoxin for long-term management of patients with cardiac disease [13]. In summary, in a much larger patient group than previously described, we found no evidence of a clopidogrel– statin interaction and conclude that statin use is not an independent factor that may affect the ability of clopidogrel to achieve sustained platelet inhibition.
References [1] Harrington RA. Overview of clinical trials of glycoprotein IIb – IIIa inhibitors in acute coronary syndromes. Am Heart J 1999;138(4 Pt 2):276 – 86. [2] Cohen M. Treatment of unstable angina: the role of platelet inhibitors and anticoagulants. J Invasive Cardiol 1999;3:147 –59. [3] Golino P, Ragni M, Cirillo P, Buono C, Piro O, Chiariello M. Emerging antithrombotic treatments for acute coronary syndromes. Cardiologia 1999;44:969 – 80. [4] Libby P. Changing concepts of atherogenesis. J Intern Med 2000;247:349 – 58. [5] Mak KH, Belli G, Ellis SG, Moliterno DJ. Subacute stent thrombosis: evolving issues and current concepts. J Am Coll Cardiol 1996;27:494 – 503. [6] Eeckhout E, Kappenberger L, Goy JJ. Stents for intracoronary placement: status and future direction. J Am Coll Cardiol 1996;27:757 – 65. [7] Roberts WC. The underused miracle drugs: the statin drugs are to atherosclerosis what penicillin was to infectious disease. Am J Cardiol 1996;78:377 – 8.
241
Letter to the Editors Table 2 Platelet characteristics of patients by statin use Time point
Baseline Day 2 Day 5
5 mM ADP induced platelet aggregation (%)
GP IIb/IIIa expression (log fluorescence intensity)
PECAM-1 expression (log fluorescence intensity)
With statin (n = 25)
No statin (n= 75)
With statin (n =25)
No statin (n =75)
With statin (n =25)
No statin (n =75)
58.7 9 10.7 36.0 9 9.1 37.3 9 7.3
59.4 9 11.5 38.79 10.5 35.89 7.7
186 9 39 256 9 57 80 918
202 9 44 269 947 87 9 16
90 98 51 9 9 48 96
87 9 10 549 11 469 8
Data presented as mean 9 S.D. [8] Stenestrand U, Wallentin L. Early statin treatment following acute myocardial infarction and 1-year survival. J Am Med Assoc 2001;285:430 –6. [9] Lau WC, Waskell LA, Neer CJ, Carville DOM, Bates ER. The antiplatelet activity of clopidogrel is inhibited by atorvastatin but not by pravastatin, Circulation 2000;102( Suppl. 429). [10] Ruggeri ZM. New insights into the mechanisms of platelet adhesion and aggregation. Semin Hemat 1994;31:229 –39. [11] Ault KA. Flow cytometric measurement of platelet function and reticulated platelets. Ann NY Acad Sci 1993;677:293 –308. [12] Forbes CD, Lowe GD, MacLaren M, Shaw BG, Dickinson JP, Kieffer G. Clopidogrel compatibility with concomitant cardiac co-medications: a study of its interactions with a beta-blocker and a calcium uptake antagonist. Semin Thromb Hemost 1999;25(Suppl. 2):55 –60. [13] Peeters PA, Crijns HJ, Tamminga WJ, Jonkman JH, Dickinson
JP, Necciari J. Clopidogrel, a novel antiplatelet agent, and digoxin: absence of pharmacodynamic and pharmacokinetic interaction. Semin Thromb Hemost 1999;25(Suppl. 2):51 –4.
Victor L. Serebruany*, Alex I. Malinin, Kevin P. Callahan, Paul A. Gurbel Sinai Center for Thrombosis Research Johns Hopkins Uni6ersity Baltimore, MD, USA E-mail: [email protected] Steven R. Steinhubl Willford Hall Medical Center San Antonio, TX, USA