`Stent Thrombosis After Coronary Stent Implantation
`Issam Moussa, Mathew Oetgen, Gary Roubin, Antonio Colombo, Xangdong Wang, Sriram Iyer,
`Roberta Maida, Michael Collins, Edward Kreps and Jeffrey W. Moses
`
`Circulation
`
`Circulation.
`1999;99:2364-2366
`doi: 10.1161/01.CIR.99.18.2364
`is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
`Copyright © 1999 American Heart Association, Inc. All rights reserved.
`Print ISSN: 0009-7322. Online ISSN: 1524-4539
`
`The online version of this article, along with updated information and services, is located on the
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`Ex. 1018, p. 1 of 4
`
`
`
`Brief Rapid Communications
`
`Effectiveness of Clopidogrel and Aspirin Versus Ticlopidine
`and Aspirin in Preventing Stent Thrombosis After
`Coronary Stent Implantation
`
`Issam Moussa, MD; Mathew Oetgen, MS; Gary Roubin, MD; Antonio Colombo, MD;
`Xangdong Wang, MD; Sriram Iyer, MD; Roberta Maida, RN; Michael Collins, MD;
`Edward Kreps, MD; Jeffrey W. Moses, MD
`
`Background—Ticlopidine has been shown to reduce the incidence of stent thrombosis compared with warfarin, but it may
`cause serious hematological side effects. Clopidogrel, a new thienopyridine derivative, may be a safe alternative to
`ticlopidine. The aim of this study was to compare the safety and efficacy of clopidogrel and aspirin with those of
`ticlopidine and aspirin in patients undergoing coronary stent implantation.
`Methods and Results—The population of this study consisted of 2 groups: patients who underwent coronary stenting and
`were treated with ticlopidine and aspirin (TA group, n⫽1406), and patients who underwent coronary stenting followed
`by treatment with clopidogrel and aspirin (CA group, n⫽283). At 1-month follow-up, there was no difference in stent
`thrombosis (1.5% versus 1.4%, P⫽1.0) or major adverse cardiac events (3.1% versus 2.4%, P⫽0.85) between the TA
`and CA groups, respectively. The probability of any side effect (neutropenia, diarrhea, rash) was significantly higher in
`the TA group (10.6% versus 5.3%, P⫽0.006; relative risk, 0.53; CI, 0.32 to 0.86).
`Conclusions—These data suggest that clopidogrel may be an effective pharmacological regimen after coronary stent
`implantation. Furthermore, the simpler dosing regimen, the absence of neutropenia, and the lower frequency of other
`side effects make it a safe alternative to ticlopidine. (Circulation. 1999;99:2364-2366.)
`
`Key Words: clopidogrel 䡲 ticlopidine 䡲 stents
`
`C oronary stent implantation has become the dominant
`
`form of catheter-based coronary interventions on the
`basis of data demonstrating the efficacy and safety of coro-
`nary stenting when appropriate technique and postprocedure
`antiplatelet therapy are used.1,2 The combination of ticlopi-
`dine and aspirin has been confirmed to be superior to aspirin
`alone or aspirin and coumarin in randomized trials.3,4 Despite
`the effectiveness of ticlopidine, a small incidence of side
`effects remains,5 in particular hematological side effects that
`may occasionally be fatal.6
`Clopidogrel, a new thienopyridine derivative, was recently
`approved for use in patients with atherosclerotic vascular
`disease to reduce the incidence of ischemic events.7 This
`antiplatelet agent may potentially be of use after stent
`implantation to reduce stent thrombosis without the added
`risks of hematological toxicity. As of this writing, few data
`are available as to the effectiveness of this agent in preventing
`thrombosis after stenting. The purpose of this study was to
`compare the safety and effectiveness of clopidogrel and
`aspirin with those of ticlopidine and aspirin in a consecutive
`series of patients undergoing coronary stent implantation.
`
`Methods
`
`Patient Population, Stent Implantation, and
`Pharmacological Regimen
`Between September 1996 and June 1998, 2057 patients underwent
`stent implantation for obstructive coronary artery disease. Of these,
`368 were excluded from this study because of (1) requirement for
`oral anticoagulation (57 patients); (2) administration of abciximab
`(280 patients); (3) procedural failure: less than TIMI 3 flow (8
`patients), residual diameter stenosis ⬎50% (4 patients), emergency
`bypass surgery (3 patients), or intracerebral hemorrhage (1 patient);
`and (4) patients who received aspirin alone (14 patients) or ticlopi-
`dine alone (1 patient) because of known allergy to the other agent.
`The final study population consisted of patients who underwent
`coronary stenting between September 1996 and February 1998 and
`were treated with ticlopidine and aspirin (TA group: 1406 patients,
`1763 lesions) and patients who underwent coronary stenting between
`March 1998 and June 1998 and were treated with clopidogrel and
`aspirin (CA group: 283 patients, 376 lesions). Stent implantation was
`performed by use of techniques previously described,2 and quanti-
`tative angiographic analysis was performed with a computer-based
`system (CMS version 3.0, MEDIS).
`Ticlopidine was administered as a loading dose of 500 mg
`followed by 250 mg PO twice a day for 2 weeks.8 Clopidogrel was
`administered as a loading dose of 300 mg followed by 75 mg PO
`once a day for 4 weeks. Aspirin was administered as 325 mg PO
`
`Received December 12, 1998; revision received March 2, 1999; accepted March 9, 1999.
`From Lenox Hill Hospital, New York, NY, and Centro Cuore Columbus, Milan, Italy (A.C.).
`Correspondence to Jeffrey W. Moses, MD, Interventional Cardiology, Lenox Hill Hospital, 130 E 77th St, New York, NY 10021. E-mail
`jmoses@idt.net
`© 1999 American Heart Association, Inc.
`
`Circulation is available at http://www.circulationaha.org
`
`2364
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`Ex. 1018, p. 2 of 4
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`
`
`Moussa et al
`
`May 11, 1999
`
`2365
`
`TABLE 1. Patient Clinical and Angiographic Characteristics
`
`Patients
`
`Age, y
`
`Male, n (%)
`
`Diabetes mellitus, n (%)
`
`Unstable angina, n (%)
`
`TA Group
`(n⫽1406)
`
`CA Group
`(n⫽283)
`
`63⫾12
`
`951 (68)
`
`301 (21)
`
`490 (35)
`
`64⫾12
`
`193 (68)
`
`63 (22)
`
`97 (34)
`
`Lesions
`
`(n⫽1763)
`
`(n⫽376)
`
`Lesion complexity,* n (%)
`
`A
`
`190 (11)
`
`24 (6)
`
`96 (25)
`
`Incidence of Stent Thrombosis, Major Adverse
`TABLE 2.
`Cardiac Events, and Drug Side Effects at 1-Month Follow-Up
`
`P
`
`0.20
`
`0.89
`
`0.75
`
`0.89
`
`0.08
`
`Patients
`
`Stent thrombosis
`
`Myocardial infarction
`
`Non–Q-wave
`
`Q-wave
`
`Coronary artery bypass surgery
`
`Death
`
`Drug side effects
`
`TA Group
`(n⫽1390)
`
`CA Group
`(n⫽281)
`
`21 (1.5)
`
`25 (1.8)
`
`18 (1.3)
`
`7 (0.5)
`
`5 (0.4)
`
`12 (0.9)
`
`4 (1.4)
`
`2 (0.7)
`
`2 (0.7)
`
`0 (0)
`
`2 (0.7)
`
`3 (1)
`
`P
`
`1.0
`
`0.29
`
`0.33
`
`0.73
`
`B1
`
`B2
`
`C
`
`Quantitative angiography
`
`Preprocedure
`
`438 (25)
`
`586 (33)
`
`549 (31)
`
`130 (35)
`
`126 (34)
`
`Reference diameter, mm
`
`2.83⫾0.67
`
`2.78⫾0.59
`
`Minimum lumen diameter, mm
`
`0.84⫾0.47
`
`0.90⫾0.45
`
`Lesion length, mm
`
`10.93⫾5.59
`
`11.63⫾6.18
`
`Postprocedure
`
`Minimum lumen diameter, mm
`
`3.13⫾0.55
`
`3.08⫾0.48
`
`Diameter stenosis, %
`
`10⫾15
`
`10⫾3
`
`0.18
`
`0.02
`
`0.05
`
`1.0
`
`1.0
`
`A value of P⬍0.05 is considered significant.
`*AHA/ACC classification.
`
`once a day to both groups. All patients were instructed to follow up
`with their referring physician in 2 weeks for clinical assessment and
`blood count analysis. In addition, a dedicated nurse practitioner
`(R.M.) was performing telephonic follow-up evaluation at 1 month
`on an ongoing basis.
`
`Statistics
`Statistical analysis was performed with StatView software. Contin-
`uous normally distributed data were expressed as mean⫾SD and
`were compared by unpaired Student’s t test. Categorical variables
`were expressed as numbers and percentages and compared by the 2
`test. Differences were considered statistically significant at a value
`of P⬍0.05.
`
`Results
`
`Patient Characteristics and Procedural Data
`Patient characteristics and angiographic measurements are
`shown in Table 1. Similar numbers (1.3⫹0.6 versus 1.3⫹0.5,
`P⫽1.0) and types (slotted tube, 87% versus 88%; coil, 12%
`versus 12%; and Wallstent, 1% versus 0%, P⫽0.49) of stents
`were implanted in the TA and CA groups, respectively.
`Bailout stenting was performed with similar frequency in
`both groups (6% versus 7%, P⫽0.57).
`
`Medication Side Effects and Clinical Outcome
`During the period of this study, 16 patients in the TA group
`(1.1%) and 2 patients in the CA group (0.7%) were lost to
`follow-up. Of the study population, 46 patients (3.3%) in the
`TA group and 8 patients (2.8%) in the CA group (P⫽0.85)
`discontinued the study drug early for reasons other than the
`occurrence of an outcome event. Reasons for stopping ticlo-
`pidine were rash in 30 patients, diarrhea in 6 patients, rash
`and diarrhea in 5 patients, neutropenia in 4 patients, and
`noncompliance in 1 patient. Reasons for stopping clopidogrel
`
`Neutropenia
`
`Diarrhea
`
`Rash
`
`4 (0.3)
`
`61 (4.4)
`
`82 (6)
`
`0 (0)
`
`9 (3.2)
`
`6 (2)
`
`Any side effect
`
`147 (10.6)
`
`15 (5.3)
`
`Values are n (%). A value of P⬍0.05 is considered significant.
`
`1.0
`
`0.5
`
`0.008
`
`0.006
`
`were rash in 4 patients, diarrhea in 3 patients, and noncom-
`pliance in 1 patient. The incidence of stent
`thrombosis,
`cardiac events, and medication side effects at 1-month
`follow-up is shown in Table 2.
`
`Discussion
`
`Rationale for Use of Clopidogrel After
`Stent Implantation
`Clopidogrel is a thienopyridine derivative that inhibits plate-
`let aggregation by inhibiting the binding of ADP to its platelet
`receptor, which leads to direct inhibition of the binding of
`fibrinogen to the glycoprotein IIb/IIIa complex.9 Although
`both ticlopidine and clopidogrel prevent platelet aggregation
`evoked by shear stress, experimental studies suggest that
`clopidogrel is more effective than either aspirin or ticlopidine
`in preventing the high-shear-stress– dependent coronary stent
`thrombosis.10 Furthermore, clopidogrel has a favorable safety
`profile compared with ticlopidine, for which routine hemato-
`logical monitoring is mandatory to ensure early detection of
`potentially lethal hematological events. The incidence of
`neutropenia with ticlopidine is proportional to the duration of
`treatment (up to 2.4%), and it may resolve with drug
`cessation in most but not all cases.5 Another serious side
`effect of ticlopidine is thrombotic thrombocytopenic purpura
`(TTP). A recent review6 documented 60 cases of TTP among
`patients treated with ticlopidine, with an associated mortality
`rate of 33%. In this review, 12 patients developed TTP after
`receiving ticlopidine for ⱕ3 weeks after stent implantation.
`Other common but less morbid adverse effects reported to
`accompany ticlopidine use are gastrointestinal symptoms.5
`Clopidogrel was developed because it did not show bone
`marrow toxicity in tissue culture and animal models. In the
`large CAPRIE trial,7 the incidence of severe neutropenia with
`long-term use was only 0.05%, which was similar to the rate
`seen with aspirin (0.04%). In addition, the proportions of
`patients with severe rash and diarrhea while on clopidogrel in
`this trial were less than those reported with ticlopidine but
`twice as high as with aspirin. Therefore, the combination of a
`favorable safety profile and a proven experimental and
`
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`Ex. 1018, p. 3 of 4
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`
`
`2366
`
`Clopidogrel vs Ticlopidine After Coronary Stent
`
`clinical antiplatelet effect make clopidogrel an attractive
`alternative to ticlopidine after coronary stent implantation.
`
`Clopidogrel: Administration and Clinical Impact
`is
`The inhibition of platelet aggregation by clopidogrel
`concentration dependent.9 In this study, clopidogrel was
`administered as a loading dose of 300 mg, a dose that
`provides 80% platelet inhibition in 5 hours,11 followed by 75
`mg PO daily for 4 weeks. Aspirin was added to clopidogrel
`because this drug has no effect on the cyclooxygenase
`pathway, and therefore, both agents may work synergisti-
`cally, as is the case with ticlopidine.12 In this study, stent
`thrombosis occurred with similar frequency in the ticlopidine
`and clopidogrel groups (1.5% versus 1.4%, P⫽NS). Simi-
`larly,
`there was no difference between the 2 groups in
`incidence of major adverse cardiac events at 1-month
`follow-up (3.1% versus 2.4%, P⫽NS).
`With respect to side effects, neutropenia occurred in 4
`patients (0.3%) in the ticlopidine group but none of the
`patients in the clopidogrel group (0%). This rate of neutro-
`penia is similar to those in other stent
`trials in which
`ticlopidine was used for 4 weeks.3,4 In this study, rash
`occurred significantly more often in the ticlopidine group
`despite the short duration of administration. The incidence of
`diarrhea was also slightly higher, but not statistically signif-
`icant. Overall, patients in the ticlopidine group were at twice
`the risk of having any side effect compared with patients
`receiving clopidogrel.
`
`Study Limitations
`First, this is a nonrandomized comparison between the 2
`pharmacological regimens. However, these regimens were
`used in a chronologically consecutive manner, an approach
`that eliminates the potential for operator bias in selecting one
`specific regimen over the other. Second, because the inci-
`dence of stent thrombosis with antiplatelet therapy is very
`low, a higher number of patients is necessary to establish
`equivalence between clopidogrel and ticlopidine. Therefore, a
`large randomized trial is needed to establish the validity of
`these data.
`
`Conclusions
`These data suggest that clopidogrel may be an effective
`pharmacological regimen after coronary stent implantation.
`
`Furthermore, the simpler dosing regimen and the absence of
`hematological toxicity make it a potential safe alternative to
`ticlopidine.
`
`References
`1. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre
`K, Veltre L, Ricci D, Nobuyoshi M, Cleman M, Heuser R, Almond D,
`Teirstein P, Fish RD, Colombo A, Brinker J, Moses J, Shaknovich A,
`Hirschfeld J, Bailey S, Ellis S, Rake R, Goldberg S. A randomized
`comparison of coronary-stent placement and balloon angioplasty in the
`treatment of coronary artery disease. N Engl J Med. 1994;331:496 –501.
`2. Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G,
`Gaglione A, Goldberg SL, Tobis J. Intracoronary stenting without anti-
`coagulation accomplished with intravascular ultrasound guidance. Circu-
`lation. 1995;91:1676 –1688.
`3. Scho¨mig A, Neumann FJ, Kastrati A, Schu¨hlen H, Blasini R, Hadamitzky
`M, Walter H, Zitzmann-Roth EM, Richardt G, Alt E, Schmitt C, Ulm K.
`A randomized comparison of antiplatelet and anticoagulant therapy after
`the placement of coronary-artery stents. N Engl J Med. 1996;334:1084 –9.
`4. Leon MB, Baim DS, Popma JJ, Gordon P, Cutlip D, Ho KL,
`Giambotolomei A, Diver DD, Lasorda DM, Williams D, Pocock SJ,
`Kuntz RE. A clinical trial comparing three antithrombotic-drug regimens
`after coronary artery stenting. N Engl J Med. 1998;339:1665–1671.
`5. Moloney BA. An analysis of the side-effects of ticlopidine. In: Hass WK,
`Easton JD, eds. Ticlopidine, Platelets and Vascular Disease. New York,
`NY: Springer-Verlag; 1993:117–139.
`6. Bennett CL, Weinberg PD, Rosenberg Ben-Dror K, Yarnold P, Kwaan H,
`Green D. Thrombotic thrombocytopenic purpura associated with ticlo-
`pidine. Ann Intern Med. 1998;128:541–544.
`7. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel
`versus aspirin in patients at risk for ischemic events (CAPRIE). Lancet.
`1996;348:1329 –1339.
`8. Berger P, Melby S, Grill D, Bell M. How long should ticlopidine be
`administered to intracoronary stent patients not treated with coumadin?
`Circulation. 1996;94(suppl I):I-256. Abstract.
`9. Mills DC, Puri R, Hu CJ, Minniti C, Grana G, Freedman MD. Clopi-
`dogrel inhibits the binding of ADP analogues to the receptor mediating
`inhibition of platelet adenylate cyclase. Arterioscler Thromb. 1992;12:
`430 – 436.
`10. Makkar R, Eigler N, Kaul S, Zeng H, Herbert JM, Litvack F. Clopidogrel,
`a novel platelet ADP receptor antagonist inhibits aspirin and ticlopidine
`resistant stent thrombosis. J Am Coll Cardiol. 1997;29(suppl A):353A.
`Abstract.
`11. Bachmann F, Savcic M, Hauert J, Geudelin B, Kieffer G, Cariou R. Rapid
`onset of inhibition of ADP-induced platelet aggregation by a loading dose
`of clopidogrel. Eur Heart J. 1996;17:263. Abstract.
`12. Rupprecht HJ, Darius H, Borkowsky U, Voigtlander T, Nowak B, Genth
`S, Meyer J. Comparison of antiplatelet effects of aspirin, ticlopidine, or
`their combination after stent
`implantation. Circulation. 1998;97:
`1046 –1052.
`
`
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`Ex. 1018, p. 4 of 4
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