Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel‐Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events
Background Type 2 diabetes mellitus is a risk factor for lower extremity arterial disease. Cilostazol expresses antiplatelet, anti‐inflammatory, and vasodilator actions and improves the claudication intermittent symptoms. We investigated the efficacy and safety of adjunctive cilostazol to clopidogre...
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Wiley
2021-01-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.018184 |
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| author | Kallirroi Kalantzi Nikolaos Tentolouris Andreas J. Melidonis Styliani Papadaki Michail Peroulis Konstantinos A. Amantos George Andreopoulos George I. Bellos Dimitrios Boutel Magdalini Bristianou Dimitrios Chrisis Nikolaos A. Dimitsikoglou John Doupis Chrysoula Georgopoulou Stergios A. Gkintikas Styliani Iraklianou Κonstantinos Kanellas Kalliopi Kotsa Theocharis Koufakis Maria Kouroglou Anastasios G. Koutsovasilis Leonidas Lanaras Eirini Liouri Charalampos Lixouriotis Akrivi Lykoudi Efthymia Mandalaki Evanthia Papageorgiou Nikolaos Papanas Spyridon Rigas Maria I. Stamatelatou Ioannis Triantafyllidis Aikaterini Trikkalinou Aikaterini N. Tsouka Ourania Zacharopoulou Christos Zoupas Ioannis Tsolakis Alexandros D. Tselepis |
| author_facet | Kallirroi Kalantzi Nikolaos Tentolouris Andreas J. Melidonis Styliani Papadaki Michail Peroulis Konstantinos A. Amantos George Andreopoulos George I. Bellos Dimitrios Boutel Magdalini Bristianou Dimitrios Chrisis Nikolaos A. Dimitsikoglou John Doupis Chrysoula Georgopoulou Stergios A. Gkintikas Styliani Iraklianou Κonstantinos Kanellas Kalliopi Kotsa Theocharis Koufakis Maria Kouroglou Anastasios G. Koutsovasilis Leonidas Lanaras Eirini Liouri Charalampos Lixouriotis Akrivi Lykoudi Efthymia Mandalaki Evanthia Papageorgiou Nikolaos Papanas Spyridon Rigas Maria I. Stamatelatou Ioannis Triantafyllidis Aikaterini Trikkalinou Aikaterini N. Tsouka Ourania Zacharopoulou Christos Zoupas Ioannis Tsolakis Alexandros D. Tselepis |
| author_sort | Kallirroi Kalantzi |
| collection | DOAJ |
| description | Background Type 2 diabetes mellitus is a risk factor for lower extremity arterial disease. Cilostazol expresses antiplatelet, anti‐inflammatory, and vasodilator actions and improves the claudication intermittent symptoms. We investigated the efficacy and safety of adjunctive cilostazol to clopidogrel‐treated patients with type 2 diabetes mellitus exhibiting symptomatic lower extremity arterial disease, in the prevention of ischemic vascular events and improvement of the claudication intermittent symptoms. Methods and Results In a prospective 2‐arm, multicenter, open‐label, phase 4 trial, patients with type 2 diabetes mellitus with intermittent claudication receiving clopidogrel (75 mg/d) for at least 6 months, were randomly assigned in a 1:1 ratio, either to continue to clopidogrel monotherapy, without receiving placebo cilostazol (391 patients), or to additionally receive cilostazol, 100 mg twice/day (403 patients). The median duration of follow‐up was 27 months. The primary efficacy end point, the composite of acute ischemic stroke/transient ischemic attack, acute myocardial infarction, and death from vascular causes, was significantly reduced in patients receiving adjunctive cilostazol compared with the clopidogrel monotherapy group (sex‐adjusted hazard ratio [HR], 0.468; 95% CI, 0.252–0.870; P=0.016). Adjunctive cilostazol also significantly reduced the stroke/transient ischemic attack events (sex‐adjusted HR, 0.38; 95% CI, 0.15–0.98; P=0.046) and improved the ankle‐brachial index and pain‐free walking distance values (P=0.001 for both comparisons). No significant difference in the bleeding events, as defined by Bleeding Academic Research Consortium criteria, was found between the 2 groups (sex‐adjusted HR, 1.080; 95% CI, 0.579–2.015; P=0.809). Conclusions Adjunctive cilostazol to clopidogrel‐treated patients with type 2 diabetes mellitus with symptomatic lower extremity arterial disease may lower the risk of ischemic events and improve intermittent claudication symptoms, without increasing the bleeding risk, compared with clopidogrel monotherapy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02983214. |
| first_indexed | 2024-12-18T10:48:59Z |
| format | Article |
| id | doaj.art-ccf9f7f76345473297cda19de127de91 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-18T10:48:59Z |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-ccf9f7f76345473297cda19de127de912022-12-21T21:10:29ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802021-01-0110110.1161/JAHA.120.018184Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel‐Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular EventsKallirroi Kalantzi0Nikolaos Tentolouris1Andreas J. Melidonis2Styliani Papadaki3Michail Peroulis4Konstantinos A. Amantos5George Andreopoulos6George I. Bellos7Dimitrios Boutel8Magdalini Bristianou9Dimitrios Chrisis10Nikolaos A. Dimitsikoglou11John Doupis12Chrysoula Georgopoulou13Stergios A. Gkintikas14Styliani Iraklianou15Κonstantinos Kanellas16Kalliopi Kotsa17Theocharis Koufakis18Maria Kouroglou19Anastasios G. Koutsovasilis20Leonidas Lanaras21Eirini Liouri22Charalampos Lixouriotis23Akrivi Lykoudi24Efthymia Mandalaki25Evanthia Papageorgiou26Nikolaos Papanas27Spyridon Rigas28Maria I. Stamatelatou29Ioannis Triantafyllidis30Aikaterini Trikkalinou31Aikaterini N. Tsouka32Ourania Zacharopoulou33Christos Zoupas34Ioannis Tsolakis35Alexandros D. Tselepis36Atherothrombosis Research Center Laboratory of Biochemistry Department of Chemistry University of Ioannina Greece1st Department of Propaedeutic Internal Medicine Medical School National and Kapodistrian University of Athens GreeceDiabetes Center Metropolitan Hospital Athens GreeceAtherothrombosis Research Center Laboratory of Biochemistry Department of Chemistry University of Ioannina GreeceAtherothrombosis Research Center Laboratory of Biochemistry Department of Chemistry University of Ioannina GreeceDiabetes Center Metropolitan Hospital Athens GreeceDiabetes Center Metropolitan Hospital Athens GreeceKoropi Health Center Attica GreeceGeneral Hospital of Giannitsa GreeceDepartment of Internal Medicine General Hospital of Lamia Greece3rd Internal Medicine Department and Diabetes Center General Hospital of Nikaia Athens GreeceAtherothrombosis Research Center Laboratory of Biochemistry Department of Chemistry University of Ioannina GreeceAtherothrombosis Research Center Laboratory of Biochemistry Department of Chemistry University of Ioannina GreeceDiabetes Center Metropolitan Hospital Athens GreeceDivision of Endocrinology and Metabolism and Diabetes Center First Department of Internal Medicine Medical School Aristotle University of ThessalonikiAHEPA University Hospital Thessaloniki Greece3rd Department of Internal Medicine Center General Hospital "Tzaneio," Piraeus Greece3rd Department of Internal Medicine Center General Hospital "Tzaneio," Piraeus GreeceDivision of Endocrinology and Metabolism and Diabetes Center First Department of Internal Medicine Medical School Aristotle University of ThessalonikiAHEPA University Hospital Thessaloniki GreeceDivision of Endocrinology and Metabolism and Diabetes Center First Department of Internal Medicine Medical School Aristotle University of ThessalonikiAHEPA University Hospital Thessaloniki GreeceGeneral Regional Hospital of Mytilene Greece3rd Internal Medicine Department and Diabetes Center General Hospital of Nikaia Athens GreeceDepartment of Internal Medicine General Hospital of Lamia Greece3rd Internal Medicine Department and Diabetes Center General Hospital of Nikaia Athens GreeceHealth Center of Distomo Voiotia Greece3rd Internal Medicine Department and Diabetes Center General Hospital of Nikaia Athens GreeceAtherothrombosis Research Center Laboratory of Biochemistry Department of Chemistry University of Ioannina Greece3rd Internal Medicine Department and Diabetes Center General Hospital of Nikaia Athens GreeceSecond Department of Internal Medicine Democritus University of Thrace Alexandroupolis Greece3rd Internal Medicine Department and Diabetes Center General Hospital of Nikaia Athens GreeceInternal Medicine Clinic General Hospital of Sitia Crete GreeceAtherothrombosis Research Center Laboratory of Biochemistry Department of Chemistry University of Ioannina GreeceDiabetes Center Metropolitan Hospital Athens GreeceAtherothrombosis Research Center Laboratory of Biochemistry Department of Chemistry University of Ioannina GreeceDiabetes Center Metropolitan Hospital Athens GreeceDiabetes Center Metropolitan Hospital Athens GreeceVascular Surgery Department University of Patras GreeceAtherothrombosis Research Center Laboratory of Biochemistry Department of Chemistry University of Ioannina GreeceBackground Type 2 diabetes mellitus is a risk factor for lower extremity arterial disease. Cilostazol expresses antiplatelet, anti‐inflammatory, and vasodilator actions and improves the claudication intermittent symptoms. We investigated the efficacy and safety of adjunctive cilostazol to clopidogrel‐treated patients with type 2 diabetes mellitus exhibiting symptomatic lower extremity arterial disease, in the prevention of ischemic vascular events and improvement of the claudication intermittent symptoms. Methods and Results In a prospective 2‐arm, multicenter, open‐label, phase 4 trial, patients with type 2 diabetes mellitus with intermittent claudication receiving clopidogrel (75 mg/d) for at least 6 months, were randomly assigned in a 1:1 ratio, either to continue to clopidogrel monotherapy, without receiving placebo cilostazol (391 patients), or to additionally receive cilostazol, 100 mg twice/day (403 patients). The median duration of follow‐up was 27 months. The primary efficacy end point, the composite of acute ischemic stroke/transient ischemic attack, acute myocardial infarction, and death from vascular causes, was significantly reduced in patients receiving adjunctive cilostazol compared with the clopidogrel monotherapy group (sex‐adjusted hazard ratio [HR], 0.468; 95% CI, 0.252–0.870; P=0.016). Adjunctive cilostazol also significantly reduced the stroke/transient ischemic attack events (sex‐adjusted HR, 0.38; 95% CI, 0.15–0.98; P=0.046) and improved the ankle‐brachial index and pain‐free walking distance values (P=0.001 for both comparisons). No significant difference in the bleeding events, as defined by Bleeding Academic Research Consortium criteria, was found between the 2 groups (sex‐adjusted HR, 1.080; 95% CI, 0.579–2.015; P=0.809). Conclusions Adjunctive cilostazol to clopidogrel‐treated patients with type 2 diabetes mellitus with symptomatic lower extremity arterial disease may lower the risk of ischemic events and improve intermittent claudication symptoms, without increasing the bleeding risk, compared with clopidogrel monotherapy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02983214.https://www.ahajournals.org/doi/10.1161/JAHA.120.018184cilostazolclopidogrelcoronary artery diseasediabetes mellitusintermittent claudicationischemic stroke |
| spellingShingle | Kallirroi Kalantzi Nikolaos Tentolouris Andreas J. Melidonis Styliani Papadaki Michail Peroulis Konstantinos A. Amantos George Andreopoulos George I. Bellos Dimitrios Boutel Magdalini Bristianou Dimitrios Chrisis Nikolaos A. Dimitsikoglou John Doupis Chrysoula Georgopoulou Stergios A. Gkintikas Styliani Iraklianou Κonstantinos Kanellas Kalliopi Kotsa Theocharis Koufakis Maria Kouroglou Anastasios G. Koutsovasilis Leonidas Lanaras Eirini Liouri Charalampos Lixouriotis Akrivi Lykoudi Efthymia Mandalaki Evanthia Papageorgiou Nikolaos Papanas Spyridon Rigas Maria I. Stamatelatou Ioannis Triantafyllidis Aikaterini Trikkalinou Aikaterini N. Tsouka Ourania Zacharopoulou Christos Zoupas Ioannis Tsolakis Alexandros D. Tselepis Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel‐Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease cilostazol clopidogrel coronary artery disease diabetes mellitus intermittent claudication ischemic stroke |
| title | Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel‐Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events |
| title_full | Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel‐Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events |
| title_fullStr | Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel‐Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events |
| title_full_unstemmed | Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel‐Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events |
| title_short | Efficacy and Safety of Adjunctive Cilostazol to Clopidogrel‐Treated Diabetic Patients With Symptomatic Lower Extremity Artery Disease in the Prevention of Ischemic Vascular Events |
| title_sort | efficacy and safety of adjunctive cilostazol to clopidogrel treated diabetic patients with symptomatic lower extremity artery disease in the prevention of ischemic vascular events |
| topic | cilostazol clopidogrel coronary artery disease diabetes mellitus intermittent claudication ischemic stroke |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.018184 |
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