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Ozaki Y, Tobe A, Onuma Y, Kobayashi Y, Amano T, Muramatsu T, Ishii H, Yamaji K, Kohsaka S, Ismail TF, Uemura S, Hikichi Y, Tsujita K, Ako J, Morino Y, Maekawa Y, Shinke T, Shite J, Igarashi Y, Nakagawa Y, Shiode N, Okamura A, Ogawa T, Shibata Y, Tsuji T, Hayashida K, Yajima J, Sugano T, Okura H, Okayama H, Kawaguchi K, Zen K, Takahashi S, Tamura T, Nakazato K, Yamaguchi J, Iida O, Ozaki R, Yoshimachi F, Ishihara M, Murohara T, Ueno T, Yokoi H, Nakamura M, Ikari Y, Serruys PW, Kozuma K. CVIT expert consensus document on primary percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) in 2024. Cardiovasc Interv Ther 2024; 39:335-375. [PMID: 39302533 PMCID: PMC11436458 DOI: 10.1007/s12928-024-01036-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 08/04/2024] [Indexed: 09/22/2024]
Abstract
Primary Percutaneous Coronary Intervention (PCI) has significantly contributed to reducing the mortality of patients with ST-segment elevation myocardial infarction (STEMI) even in cardiogenic shock and is now the standard of care in most of Japanese institutions. The Task Force on Primary PCI of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) proposed an expert consensus document for the management of acute myocardial infarction (AMI) focusing on procedural aspects of primary PCI in 2018 and updated in 2022. Recently, the European Society of Cardiology (ESC) published the guidelines for the management of acute coronary syndrome in 2023. Major new updates in the 2023 ESC guideline include: (1) intravascular imaging should be considered to guide PCI (Class IIa); (2) timing of complete revascularization; (3) antiplatelet therapy in patient with high-bleeding risk. Reflecting rapid advances in the field, the Task Force on Primary PCI of the CVIT group has now proposed an updated expert consensus document for the management of ACS focusing on procedural aspects of primary PCI in 2024 version.
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Affiliation(s)
- Yukio Ozaki
- Department of Cardiology, Fujita Health University Okazaki Medical Center, Fujita Health University School of Medicine, 1-98 Dengaku, Kutsukake, Toyoake, Aichi, 470-1192, Japan.
| | - Akihiro Tobe
- Department of Cardiology, University of Galway, Galway, Ireland
| | - Yoshinobu Onuma
- Department of Cardiology, University of Galway, Galway, Ireland
| | - Yoshio Kobayashi
- Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Tetsuya Amano
- Department of Cardiology, Aichi Medical University, Nagakute, Japan
| | - Takashi Muramatsu
- Department of Cardiology, Fujita Health University Okazaki Medical Center, Fujita Health University School of Medicine, 1-98 Dengaku, Kutsukake, Toyoake, Aichi, 470-1192, Japan
| | - Hideki Ishii
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Kyohei Yamaji
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shun Kohsaka
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Tevfik F Ismail
- King's College London, London, UK
- Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Shiro Uemura
- Cardiovascular Medicine, Kawasaki Medical School, Kurashiki, Japan
| | | | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Junya Ako
- Department of Cardiology, Kitasato University Hospital, Sagamihara, Japan
| | - Yoshihiro Morino
- Department of Cardiology, Iwate Medical University Hospital, Shiwa, Japan
| | - Yuichiro Maekawa
- Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Toshiro Shinke
- Division of Cardiology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Junya Shite
- Cardiology Division, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
| | - Yasumi Igarashi
- Division of Cardiology, Sapporo-Kosei General Hospital, Sapporo, Japan
| | - Yoshihisa Nakagawa
- Division of Cardiovascular Medicine, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Nobuo Shiode
- Division of Cardiology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Atsunori Okamura
- Division of Cardiology, Sakurabashi Watanabe Advanced Healthcare Hospital, Osaka, Japan
| | - Takayuki Ogawa
- Division of Cardiology, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshisato Shibata
- Division of Cardiology, Miyazaki Medical Association Hospital, Miyazaki, Japan
| | | | - Kentaro Hayashida
- Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
| | - Junji Yajima
- Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan
| | - Teruyasu Sugano
- Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan
| | - Hiroyuki Okura
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hideki Okayama
- Division of Cardiology, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | | | - Kan Zen
- Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Saeko Takahashi
- Division of Cardiology, Tokushukai Shonan Oiso Hospital, Oiso, Japan
| | | | - Kazuhiko Nakazato
- Department of Cardiology, Fukushima Medical University Hospital, Fukushima, Japan
| | - Junichi Yamaguchi
- Department of Cardiology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Osamu Iida
- Cardiovascular Division, Osaka Police Hospital, Osaka, Japan
| | - Reina Ozaki
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fuminobu Yoshimachi
- Department of Cardiology, Tokai University Hachioji Hospital, Hachioji, Japan
| | - Masaharu Ishihara
- Department of Cardiovascular and Renal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takafumi Ueno
- Division of Cardiology, Marin Hospital, Fukuoka, Japan
| | - Hiroyoshi Yokoi
- Cardiovascular Center, Fukuoka Sanno Hospital, Fukuoka, Japan
| | - Masato Nakamura
- Division of Cardiovascular Medicine, Ohashi Medical Center, Toho University School of Medicine, Tokyo, Japan
| | - Yuji Ikari
- Department of Cardiology, Tokai University School of Medicine, Isehara, Japan
| | | | - Ken Kozuma
- Department of Cardiology, Teikyo University Hospital, Tokyo, Japan
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Seecheran N, McCallum P, Grimaldos K, Ramcharan P, Kawall J, Katwaroo A, Seecheran V, Jagdeo CL, Rafeeq S, Seecheran R, Quert AL, Ali N, Peram L, Khan S, Ali F, Motilal S, Bhagwandass N, Giddings S, Ramlackhansingh A, Sandy S. Pharmacodynamic Comparison of Two Aspirin Formulations in the Caribbean: The ARC Study. Cardiol Ther 2024; 13:593-602. [PMID: 39008026 PMCID: PMC11333668 DOI: 10.1007/s40119-024-00373-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/05/2024] [Indexed: 07/16/2024] Open
Abstract
INTRODUCTION This prospective, single-arm, crossover pharmacodynamic study assessed the effect of Bayer® low-dose enteric-coated aspirin 81 mg tablets (LD EC-ASA) (Bayer AG, Leverkusen, North Rhine-Westphalia, Germany) compared to Vazalore® low-dose phospholipid-aspirin liquid-filled 81 mg capsules (LD PL-ASA) (PLx Pharma Inc., Sparta, NJ, USA) on platelet reactivity with respect to aspirin reaction units (ARU). METHODS Forty-seven healthy volunteers were recruited. Platelet function was evaluated with the VerifyNow™ ARU assay (Werfen, Bedford, MA, USA) and assessed post-initiation of Bayer® LD EC-ASA daily for 14 days, with a washout period of 28 days, followed by Vazalore® LD PL-ASA daily for 14 days, again followed by ARU testing. RESULTS Participants on LD EC-ASA had a mean ARU score of 426, with 19.1% of participants having an ARU > 550; patients on LD PL-ASA derived a mean ARU score of 435, with 14.9% achieving an ARU > 550. There were no significant differences in aspirin resistance (ARU > 550) according to the formulation (Bayer® LD EC-ASA vs. Vazalore® LD PL-ASA) used. Aspirin resistance was independent of ethnicity regardless of the formulation used. In addition, there were no significant associations between body surface area (BSA) and Bayer® LD EC-ASA ARU value (p value 0.788) or Vazalore® LD PL-ASA ARU value (p value 0.477). No patients experienced any serious adverse events or treatment-emergent adverse events. CONCLUSIONS There were no significant differences in aspirin resistance between Bayer® LD EC-ASA and Vazalore® LD PL-ASA. This dedicated pharmacodynamic study could potentially be informative and applicable for Trinidadian patients on dual antiplatelet therapy (DAPT). Further studies are required to confirm these exploratory findings. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT06228820, prospectively registered 1/18/2024.
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Affiliation(s)
- Naveen Seecheran
- Department of Clinical Medical Sciences, Faculty of Medical Sciences, The University of the West Indies, 2nd Floor, Building #67, Eric Williams Medical Sciences Complex, Mt. Hope, Trinidad and Tobago.
| | - Penelope McCallum
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Kathryn Grimaldos
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Priya Ramcharan
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Jessica Kawall
- Department of Medicine, Trinidad Institute of Medical Technology, St. Augustine, Trinidad and Tobago
| | - Arun Katwaroo
- Department of Medicine, Trinidad Institute of Medical Technology, St. Augustine, Trinidad and Tobago
| | - Valmiki Seecheran
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Cathy-Lee Jagdeo
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Salma Rafeeq
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Rajeev Seecheran
- Department of Medicine, Kansas University Medical Center, Wichita, KS, USA
| | - Abel Leyva Quert
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Nafeesah Ali
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Lakshmipathi Peram
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Shari Khan
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Fareed Ali
- Department of Medicine, North Central Regional Health Authority, Mt. Hope, Trinidad and Tobago
| | - Shastri Motilal
- Department of Clinical Medical Sciences, Faculty of Medical Sciences, The University of the West Indies, 2nd Floor, Building #67, Eric Williams Medical Sciences Complex, Mt. Hope, Trinidad and Tobago
| | - Neal Bhagwandass
- Department of Clinical Medical Sciences, Faculty of Medical Sciences, The University of the West Indies, 2nd Floor, Building #67, Eric Williams Medical Sciences Complex, Mt. Hope, Trinidad and Tobago
| | - Stanley Giddings
- Department of Clinical Medical Sciences, Faculty of Medical Sciences, The University of the West Indies, 2nd Floor, Building #67, Eric Williams Medical Sciences Complex, Mt. Hope, Trinidad and Tobago
| | - Anil Ramlackhansingh
- Department of Clinical Medical Sciences, Faculty of Medical Sciences, The University of the West Indies, 2nd Floor, Building #67, Eric Williams Medical Sciences Complex, Mt. Hope, Trinidad and Tobago
| | - Sherry Sandy
- Department of Clinical Medical Sciences, Faculty of Medical Sciences, The University of the West Indies, 2nd Floor, Building #67, Eric Williams Medical Sciences Complex, Mt. Hope, Trinidad and Tobago
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Talasaz AH, Sadeghipour P, Ortega-Paz L, Kakavand H, Aghakouchakzadeh M, Beavers C, Fanikos J, Eikelboom JW, Siegal DM, Monreal M, Jimenez D, Vaduganathan M, Castellucci LA, Cuker A, Barnes GD, Connors JM, Secemsky EA, Van Tassell BW, De Caterina R, Kurlander JE, Aminian A, Piazza G, Goldhaber SZ, Moores L, Middeldorp S, Kirtane AJ, Elkind MSV, Angiolillo DJ, Konstantinides S, Lip GYH, Stone GW, Cushman M, Krumholz HM, Mehran R, Bhatt DL, Bikdeli B. Optimizing antithrombotic therapy in patients with coexisting cardiovascular and gastrointestinal disease. Nat Rev Cardiol 2024; 21:574-592. [PMID: 38509244 DOI: 10.1038/s41569-024-01003-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/21/2024] [Indexed: 03/22/2024]
Abstract
Balancing the safety and efficacy of antithrombotic agents in patients with gastrointestinal disorders is challenging because of the potential for interference with the absorption of antithrombotic drugs and for an increased risk of bleeding. In this Review, we address considerations for enteral antithrombotic therapy in patients with cardiovascular disease and gastrointestinal comorbidities. For those with gastrointestinal bleeding (GIB), we summarize a general scheme for risk stratification and clinical evidence on risk reduction approaches, such as limiting the use of concomitant medications that increase the risk of GIB and the potential utility of gastrointestinal protection strategies (such as proton pump inhibitors or histamine type 2 receptor antagonists). Furthermore, we summarize the best available evidence and potential gaps in our knowledge on tailoring antithrombotic therapy in patients with active or recent GIB and in those at high risk of GIB but without active or recent GIB. Finally, we review the recommendations provided by major medical societies, highlighting the crucial role of teamwork and multidisciplinary discussions to customize the antithrombotic regimen in patients with coexisting cardiovascular and gastrointestinal diseases.
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Affiliation(s)
- Azita H Talasaz
- Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Department of Pharmacy Practice, Long Island University, New York, NY, USA
- Division of Pharmacy, New York-Presbyterian/Columbia University Irvine Medical Center, New York, NY, USA
- Department of Pharmacotherapy and Outcome Sciences, Virginia Commonwealth University, Richmond, VA, USA
| | - Parham Sadeghipour
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Luis Ortega-Paz
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Hessam Kakavand
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Clinical Pharmacy, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran
| | | | - Craig Beavers
- University of Kentucky College of Pharmacy, Lexington, KY, USA
| | - John Fanikos
- Department of Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - John W Eikelboom
- Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Deborah M Siegal
- Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Manuel Monreal
- Department of Internal Medicine, Hospital Universitari Germans Trials i Pujol, Universidad Católica San Antonio de Murcia, Barcelona, Spain
| | - David Jimenez
- Respiratory Department, Hospital Ramón y Cajal and Medicine Department, Universidad de Alcalá (IRYCIS), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, ISCIII, Madrid, Spain
| | - Muthiah Vaduganathan
- Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Lana A Castellucci
- Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Ontario, Canada
| | - Adam Cuker
- Department of Medicine and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Geoffrey D Barnes
- Frankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jean M Connors
- Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Eric A Secemsky
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Penn Cardiovascular Outcomes, Quality, & Evaluative Research Center, Cardiovascular Medicine Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Benjamin W Van Tassell
- Department of Pharmacotherapy and Outcome Sciences, Virginia Commonwealth University, Richmond, VA, USA
| | - Raffaele De Caterina
- Cardiology Division, Pisa University Hospital, Pisa, Italy
- Fondazione Villa Serena per la Ricerca, Città Sant'Angelo, Pescara, Italy
| | - Jacob E Kurlander
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA
- VA Ann Arbor Center for Clinical Management Research, Ann Arbor, MI, USA
| | - Ali Aminian
- Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Gregory Piazza
- Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Samuel Z Goldhaber
- Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Thrombosis Research Group, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Lisa Moores
- F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Saskia Middeldorp
- Department of Internal Medicine, Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, Netherlands
| | - Ajay J Kirtane
- Cardiovascular Research Foundation, New York, NY, USA
- Division of Cardiology, New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, NY, USA
| | - Mitchell S V Elkind
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Dominick J Angiolillo
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Stavros Konstantinides
- Center for Thrombosis and Hemostasis, Johannes Gutenberg, University of Mainz, Mainz, Germany
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart and Chest Hospital, Liverpool, UK
- Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Gregg W Stone
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mary Cushman
- University of Vermont Medical Center, Burlington, VT, USA
| | - Harlan M Krumholz
- Yale New Haven Hospital/Yale Center for Outcomes Research and Evaluation, New Haven, CT, USA
- Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Roxana Mehran
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Deepak L Bhatt
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Behnood Bikdeli
- Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- VA Ann Arbor Center for Clinical Management Research, Ann Arbor, MI, USA.
- Yale New Haven Hospital/Yale Center for Outcomes Research and Evaluation, New Haven, CT, USA.
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Marquis‐Gravel G, Stebbins A, Wruck LM, Roe MT, Effron MB, Hammill BG, Whittle J, VanWormer JJ, Robertson HR, Alikhaani JD, Kripalani S, Farrehi PM, Girotra S, Benziger CP, Polonsky TS, Merritt JG, Gupta K, McCormick TE, Knowlton KU, Jain SK, Kochar A, Rothman RL, Harrington RA, Hernandez AF, Jones WS. Age and Aspirin Dosing in Secondary Prevention of Atherosclerotic Cardiovascular Disease. J Am Heart Assoc 2024; 13:e026921. [PMID: 38348779 PMCID: PMC11010083 DOI: 10.1161/jaha.122.026921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 01/04/2024] [Indexed: 02/21/2024]
Abstract
BACKGROUND In patients with atherosclerotic cardiovascular disease, increasing age is concurrently associated with higher risks of ischemic and bleeding events. The objectives are to determine the impact of aspirin dose on clinical outcomes according to age in atherosclerotic cardiovascular disease. METHODS AND RESULTS In the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) trial, patients with atherosclerotic cardiovascular disease were randomized to daily aspirin doses of 81 mg or 325 mg. The primary effectiveness end point was death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke. The primary safety end point was hospitalization for bleeding requiring transfusion. A total of 15 076 participants were randomized to aspirin 81 mg (n=7540) or 325 mg (n=7536) daily (median follow-up: 26.2 months; interquartile range: 19.0-34.9 months). Median age was 67.6 years (interquartile range: 60.7-73.6 years). Among participants aged <65 years (n=5841 [38.7%]), a primary end point occurred in 226 (7.54%) in the 81 mg group, and in 191 (6.80%) in the 325 mg group (adjusted hazard ratio [HR], 1.23 [95% CI, 1.01-1.49]). Among participants aged ≥65 years (n=9235 [61.3%]), a primary end point occurred in 364 (7.12%) in the 81 mg group, and in 378 (7.96%) in the 325 mg group (adjusted HR, 0.95 [95% CI, 0.82-1.10]). The age-dose interaction was not significant (P=0.559). There was no significant interaction between age and the randomized aspirin dose for the secondary effectiveness and the primary safety bleeding end points (P>0.05 for all). CONCLUSIONS Age does not modify the impact of aspirin dosing (81 mg or 325 mg daily) on clinical end points in secondary prevention of atherosclerotic cardiovascular disease.
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Affiliation(s)
- Guillaume Marquis‐Gravel
- Duke Clinical Research InstituteDurhamNC
- Montreal Heart Institute, Université de MontréalQCCanada
| | | | | | - Matthew T. Roe
- Duke Clinical Research InstituteDurhamNC
- Duke University Medical CenterDurhamNC
| | - Mark B. Effron
- Ochsner Clinical School, John Ochsner Heart and Vascular Institute, University of Queensland School of MedicineNew OrleansLA
| | - Bradley G. Hammill
- Duke Clinical Research InstituteDurhamNC
- Department of Population Health SciencesDuke School of MedicineDurhamNC
| | - Jeff Whittle
- Department of Medicine, Division of General Internal MedicineMedical College of WisconsinMilwaukeeWI
- Center for Advancing Population Science, Medical College of WisconsinMilwaukeeWI
| | | | | | | | - Sunil Kripalani
- Vanderbilt Institute for Medicine and Public HealthVanderbilt University Medical CenterNashvilleTN
| | - Peter M. Farrehi
- Division of Cardiovascular MedicineUniversity of MichiganAnn ArborMI
| | - Saket Girotra
- University of Iowa Carver College of Medicine and Comprehensive Access and Delivery Research and Evaluation, Iowa City Veterans Affairs Medical CenterIowa CityIA
| | | | | | - J. Greg Merritt
- Patient‐Centered Network of Learning Health Systems (LHSNet)Ann ArborMI
| | - Kamal Gupta
- University of Kansas Medical Center and HospitalKS
| | | | | | - Sandeep K. Jain
- University of Pittsburgh School of Medicine, UPMC Heart and Vascular InstitutePittsburghPA
| | | | - Russell L. Rothman
- Vanderbilt Institute for Medicine and Public HealthVanderbilt University Medical CenterNashvilleTN
| | | | - Adrian F. Hernandez
- Duke Clinical Research InstituteDurhamNC
- Duke University Medical CenterDurhamNC
| | - W. Schuyler Jones
- Duke Clinical Research InstituteDurhamNC
- Duke University Medical CenterDurhamNC
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Zoungas S, Zhou Z, Owen AJ, Curtis AJ, Espinoza SE, Ernst ME, Woods RL, Orchard SG, McNeil JJ, Murray AM, Nelson MR, Reid CM, Ryan J, Wolfe R. Daily low-dose aspirin and incident type 2 diabetes in community-dwelling healthy older adults: a post-hoc analysis of efficacy and safety in the ASPREE randomised placebo-controlled trial. Lancet Diabetes Endocrinol 2024; 12:98-106. [PMID: 38142708 DOI: 10.1016/s2213-8587(23)00327-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 11/03/2023] [Accepted: 11/03/2023] [Indexed: 12/26/2023]
Abstract
BACKGROUND Inflammation has been implicated in the pathogenesis of diabetes. This study investigated the randomised treatment effect of low-dose aspirin on incident type 2 diabetes and fasting plasma glucose (FPG) concentrations among older adults. METHODS ASPREE was a double-blind, placebo-controlled trial of daily oral low-dose aspirin. The study population included community-dwelling individuals aged 70 years or older (≥65 years for US minority ethnic groups) in the USA and Australia who were free of cardiovascular disease, independence-limiting physical disability, or dementia. For the post-hoc analysis, we excluded participants with diabetes at baseline or with incomplete or missing incident diabetes data during follow-up. Participants were randomly assigned 1:1 to oral 100 mg daily enteric-coated aspirin or placebo. Incident diabetes was defined as self-reported diabetes, commencement of glucose-lowering medication, or a FPG concentration of 7·0 mmol/L or more assessed at annual follow-up visits among participants with no diabetes at baseline. We used Cox proportional hazards models and mixed-model repeated measures to assess the effect of aspirin on incident diabetes and FPG concentrations in the intention-to-treat population. We assessed major bleeding in participants who had taken at least one dose of study medication. FINDINGS Between March 10, 2010, and Dec 24, 2014, a total of 16 209 participants were included (8086 [49·9%] randomly assigned to aspirin and 8123 [50·1%] randomly assigned to placebo). During a median follow-up of 4·7 years (IQR 3·6-5·7), 995 (in 6·1% individuals) incident cases of type 2 diabetes were recorded (459 in the aspirin group and 536 in the placebo group). Compared with placebo, the aspirin group had a 15% reduction in risk of incident diabetes (hazard ratio 0·85 [95% CI 0·75 to 0·97]; p=0·013) and a slower rate of increase in FPG concentration at year 5 (between-group difference estimate -0·048 mmol/L [95% CI -0·079 to -0·018]; p=0·0017). Major bleeding (major gastrointestinal bleeding, intracranial bleeding, and clinically significant bleeding at other sites) occurred in 510 (3·2%) of 16 104 participants (300 [3·7%] in the aspirin group and 210 [2·6%] in the placebo group). Compared with placebo, the aspirin group had a 44% increase in risk of major bleeding (hazard ratio 1·44 [95% CI 1·21 to 1·72]; p<0·0001). INTERPRETATION Aspirin treatment reduced the incidence of type 2 diabetes and slowed the increase in FPG concentration but increased major bleeding among community-dwelling older adults. Given the increasing prevalence of type 2 diabetes among older adults, the potential for anti-inflammatory agents such as aspirin to prevent type 2 diabetes or improve glucose levels warrants further study with a comprehensive assessment of all potential safety events of interest. FUNDING US National Institute on Aging, US National Cancer Institute, National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency.
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Affiliation(s)
- Sophia Zoungas
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
| | - Zhen Zhou
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Alice J Owen
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Andrea J Curtis
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Sara E Espinoza
- Sam and Ann Barshop Institute, UT Health San Antonio, San Antonio, TX, USA; Geriatrics Research, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Michael E Ernst
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Iowa, Iowa City, IA, USA; Department of Family Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Robyn L Woods
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Suzanne G Orchard
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - John J McNeil
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Anne M Murray
- Department of Medicine, Geriatrics Division, Hennepin HealthCare and Berman Centre for Clinical Research, Hennepin Healthcare Research Institute, Minneapolis, MN, USA
| | - Mark R Nelson
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | | | - Joanne Ryan
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Rory Wolfe
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
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6
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Tantry US, Duhan S, Navarese E, Ramotowski B, Kundan P, Bliden KP, Gurbel P. An update on novel therapies for treating patients with arterial thrombosis. Expert Rev Hematol 2023; 16:593-605. [PMID: 37335893 DOI: 10.1080/17474086.2023.2227788] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 06/16/2023] [Indexed: 06/21/2023]
Abstract
INTRODUCTION Antithrombotic therapy field is undergoing rapid and significant changes during the past decade. In addition to new therapeutic strategies with existing targets, investigators are exploring the potential use of new targets to address unmet needs to treat patients with arterial diseases. AREAS COVERED We aim to provide an update on and a comprehensive review of the antithrombic agents that are being explored in patients with arterial diseases. We discuss latest developments with respect to upstream antiplatelet agents, and collagen and thrombin pathway inhibitors. We searched PubMed databases for English language articles using keywords: antiplatelet agents, thrombin pathway inhibitors, collagen receptors, arterial disease. EXPERT OPINION Despite implementation of potent P2Y12 inhibitors, there are numerous unmet needs in the treatment of arterial diseases including ceiling effect of currently available antiplatelet agents along with and an elevated risk of bleeding. The latter observations encouraged investigators to explore new targets that can attenuate the generation of platelet-fibrin clot formation and subsequent ischemic event occurrences with minimal effect on bleeding. These targets include collagen receptors on platelets and thrombin generation including FXa, FXIa, and FXIIa. In addition, investigators are studying novel antiplatelet agents/strategies to facilitate upstream therapy in high-risk patients.
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Affiliation(s)
- Udaya S Tantry
- Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, MD, USA
| | - Sanchit Duhan
- Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, MD, USA
| | - Eliano Navarese
- Interventional Cardiology and Cardiovascular Medicine Research, Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Bogumil Ramotowski
- Department of Cardiology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Parshotam Kundan
- Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, MD, USA
| | - Kevin P Bliden
- Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, MD, USA
| | - Paul Gurbel
- Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, MD, USA
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7
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Muramatsu T, Masuda S, Kotoku N, Kozuma K, Kawashima H, Ishibashi Y, Nakazawa G, Takahashi K, Okamura T, Miyazaki Y, Tateishi H, Nakamura M, Kogame N, Asano T, Nakatani S, Morino Y, Katagiri Y, Ninomiya K, Kageyama S, Takahashi H, Garg S, Tu S, Tanabe K, Ozaki Y, Serruys PW, Onuma Y. Prasugrel Monotherapy After Percutaneous Coronary Intervention With Biodegradable-Polymer Platinum-Chromium Everolimus Eluting Stent for Japanese Patients With Chronic Coronary Syndrome (ASET-JAPAN). Circ J 2023; 87:857-865. [PMID: 36908118 DOI: 10.1253/circj.cj-23-0051] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
BACKGROUND P2Y12 inhibitor monotherapy without aspirin immediately after percutaneous coronary intervention (PCI) has not been tested in East Asian patients, so in this study we aimed to assess the safety and feasibility of reduced dose (3.75 mg/day) prasugrel monotherapy in Japanese patients presenting with chronic coronary syndrome (CCS). METHODS AND RESULTS ASET-JAPAN is a prospective, multicenter, single-arm pilot study that completed enrolment of 206 patients from 12 Japanese centers in September 2022. Patients with native de-novo coronary lesions and a SYNTAX score <23 were treated exclusively with biodegradable-polymer platinum-chromium everolimus-eluting stent(s). Patients were loaded with standard dual antiplatelet therapy (DAPT) and following successful PCI and optimal stent deployment, they received low-dose prasugrel (3.75 mg/day) monotherapy for 3 months. The primary ischemic endpoint was a composite of cardiac death, spontaneous target-vessel myocardial infarction, or definite stent thrombosis. The primary bleeding endpoint was Bleeding Academic Research Consortium (BARC) type 3 or 5. At 3-month follow-up, there were no primary bleeding or ischemic events, or any stent thrombosis. CONCLUSIONS This pilot study showed the safety and feasibility of prasugrel monotherapy in selected low-risk Japanese patients with CCS. This "aspirin-free" strategy may be a safe alternative to traditional DAPT following PCI.
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Affiliation(s)
| | - Shinichiro Masuda
- Cardiovascular Research Centre for Advanced Imaging and Core Laboratory (CORRIB), University of Galway
| | - Nozomi Kotoku
- Cardiovascular Research Centre for Advanced Imaging and Core Laboratory (CORRIB), University of Galway
| | | | | | - Yuki Ishibashi
- Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine
| | - Gaku Nakazawa
- Department of Cardiology, Kindai University Faculty of Medicine
| | | | - Takayuki Okamura
- Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine
| | - Yosuke Miyazaki
- Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine
| | - Hiroki Tateishi
- Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine
- Department of Cardiology, Shibata Hospital
| | - Masato Nakamura
- Division of Cardiovascular Medicine, Toho University Ohashi Medical Center
| | - Norihiro Kogame
- Division of Cardiovascular Medicine, Toho University Ohashi Medical Center
- Department of Cardiology, Tokyo Rosai Hospital
| | - Taku Asano
- Department of Cardiology, St. Luke's International Hospital
| | | | | | - Yuki Katagiri
- Department of Cardiology, Sapporo Higashi Tokushukai Hospital
| | - Kai Ninomiya
- Cardiovascular Research Centre for Advanced Imaging and Core Laboratory (CORRIB), University of Galway
| | - Shigetaka Kageyama
- Cardiovascular Research Centre for Advanced Imaging and Core Laboratory (CORRIB), University of Galway
| | | | - Scot Garg
- Department of Cardiology, Royal Blackburn Hospital
| | - Shengxian Tu
- Biomedical Instrument Institute, School of Biomedical Engineering, Shanghai Jiao Tong University and Shanghai Med-X Engineering Research Center, Shanghai Jiao Tong University
| | - Kengo Tanabe
- Division of Cardiology, Mitsui Memorial Hospital
| | - Yukio Ozaki
- Department of Cardiology, Fujita Health University Okazaki Medical Center
| | - Patrick W Serruys
- Cardiovascular Research Centre for Advanced Imaging and Core Laboratory (CORRIB), University of Galway
| | - Yoshinobu Onuma
- Cardiovascular Research Centre for Advanced Imaging and Core Laboratory (CORRIB), University of Galway
- Galway University Hospital
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8
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Clerici B, Cattaneo M. Pharmacological Efficacy and Gastrointestinal Safety of Different Aspirin Formulations for Cardiovascular Prevention: A Narrative Review. J Cardiovasc Dev Dis 2023; 10:jcdd10040137. [PMID: 37103016 PMCID: PMC10145431 DOI: 10.3390/jcdd10040137] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/18/2023] [Accepted: 03/20/2023] [Indexed: 04/28/2023] Open
Abstract
Aspirin inhibits platelet function by irreversibly inhibiting the synthesis of thromboxane A2 (TxA2). Aspirin, at low doses, is widely used for cardiovascular prevention. Gastrointestinal discomfort, mucosal erosions/ulcerations and bleeding are frequent complications of chronic treatment. To reduce these adverse effects, different formulations of aspirin have been developed, including enteric-coated (EC) aspirin, the most widely used aspirin formulation. However, EC aspirin is less effective than plain aspirin in inhibiting TxA2 production, especially in subjects with high body weight. The inadequate pharmacological efficacy of EC aspirin is mirrored by lower protection from cardiovascular events in subjects weighing >70 kg. Endoscopic studies showed that EC aspirin causes fewer erosions of the gastric mucosa compared to plain aspirin (which is absorbed in the stomach) but causes mucosal erosions in the small intestine, where it is absorbed. Several studies demonstrated that EC aspirin does not reduce the incidence of clinically relevant gastrointestinal ulceration and bleeding. Similar results were found for buffered aspirin. Although interesting, the results of experiments on the phospholipid-aspirin complex PL2200 are still preliminary. Considering its favorable pharmacological profile, plain aspirin should be the preferred formulation to be used for cardiovascular prevention.
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Affiliation(s)
- Bianca Clerici
- Divisione di Medicina Generale II, ASST Santi Paolo e Carlo, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via Di Rudinì 8, 20142 Milano, Italy
| | - Marco Cattaneo
- Fondazione Arianna Anticoagulazione, Via Paolo Fabbri 1/3, 40138 Bologna, Italy
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9
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Masuda S, Muramatsu T, Ishibashi Y, Kozuma K, Tanabe K, Nakatani S, Kogame N, Nakamura M, Asano T, Okamura T, Miyazaki Y, Tateishi H, Ozaki Y, Nakazawa G, Morino Y, Katagiri Y, Garg S, Hara H, Ono M, Kawashima H, Lemos PA, Serruys PW, Onuma Y. Reduced-dose prasugrel monotherapy without aspirin after PCI with the SYNERGY stent in East Asian patients presenting with chronic coronary syndromes or non-ST-elevation acute coronary syndromes: rationale and design of the ASET Japan pilot study. ASIAINTERVENTION 2023; 9:39-48. [PMID: 36936091 PMCID: PMC10018289 DOI: 10.4244/aij-d-22-00033] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 09/01/2022] [Indexed: 06/18/2023]
Abstract
The Acetyl Salicylic Elimination Trial (ASET) Japan pilot study is a multicentre, single-arm, open-label, proof-of-concept study with a stopping rule based on the occurrence of definite stent thrombosis. This study aims to demonstrate the feasibility and safety of low-dose prasugrel monotherapy following percutaneous coronary intervention (PCI) in Japanese patients presenting with chronic coronary syndromes (CCS) or non-ST-elevation acute coronary syndromes (NSTE-ACS). Four hundred patients with a SYNTAX score <23 requiring PCI due to CCS or NSTE-ACS will be screened and considered eligible for the study. The enrolment is planned in two phases: 1) 200 patients presenting with CCS, followed by 2) 200 patients presenting with NSTE-ACS. After optimal PCI with implantation of a SYNERGY (Boston Scientific) stent, patients will be enrolled and loaded with prasugrel 20 mg, followed by a maintenance dose of prasugrel 3.75 mg once daily without aspirin continued for 3 months in Phase 1 (CCS patients), and for 12 months in Phase 2 (NSTE-ACS patients). After these follow-up periods, prasugrel will be replaced by standard antiplatelet therapy according to local practice. The primary endpoint is a composite of cardiac death, target vessel myocardial infarction, or definite stent thrombosis after the index procedure. The primary bleeding endpoint is any Bleeding Academic Research Consortium type 3 or 5 bleeding occurring within 3 months of the index PCI for CCS patients, or 12 months for NSTE-ACS patients. The ASET Japan study is designed to demonstrate the feasibility and safety of reduced-dose prasugrel monotherapy after PCI in East Asian patients with acute and chronic coronary syndromes.
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Affiliation(s)
- Shinichiro Masuda
- Department of Cardiology, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Takashi Muramatsu
- Department of Cardiology, Fujita Health University Hospital, Toyoake, Japan
| | - Yuki Ishibashi
- Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Ken Kozuma
- Department of Cardiology, Teikyo University Hospital, Tokyo, Japan
| | - Kengo Tanabe
- Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan
| | - Shimpei Nakatani
- Department of Cardiology, JCHO Hoshigaoka Medical Center, Osaka, Japan
| | - Norihiro Kogame
- Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Masato Nakamura
- Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Taku Asano
- Department of Cardiology, St. Luke's International Hospital, Tokyo, Japan
| | - Takayuki Okamura
- Division of Cardiology, Department of Clinical Science and Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Yosuke Miyazaki
- Division of Cardiology, Department of Clinical Science and Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Hiroki Tateishi
- Division of Cardiology, Department of Clinical Science and Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
- Department of Cardiology, Shibata Hospital, Aichi, Japan
| | - Yukio Ozaki
- Department of Cardiology, Fujita Health University Okazaki Medical Center, Aichi, Japan
| | - Gaku Nakazawa
- Department of Cardiology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yoshihiro Morino
- Department of Cardiology, Iwate Medical University Hospital, Iwate, Japan
| | - Yuki Katagiri
- Department of Cardiology, Sapporo Higashi Tokushukai Hospital, Hokkaido, Japan
| | - Scot Garg
- Department of Cardiology, Royal Blackburn Hospital, Blackburn, UK
| | - Hironori Hara
- Department of Cardiology, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Masafumi Ono
- Department of Cardiology, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Hideyuki Kawashima
- Department of Cardiology, National University of Ireland Galway (NUIG), Galway, Ireland
- Department of Cardiology, Teikyo University Hospital, Tokyo, Japan
| | - Pedro A Lemos
- Heart Institute (InCor), University of São Paulo, São Paulo, Brazil
- Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Patrick W Serruys
- Department of Cardiology, National University of Ireland Galway (NUIG), Galway, Ireland
| | - Yoshinobu Onuma
- Department of Cardiology, National University of Ireland Galway (NUIG), Galway, Ireland
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10
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Thiruchenthooran V, Sánchez-López E, Gliszczyńska A. Perspectives of the Application of Non-Steroidal Anti-Inflammatory Drugs in Cancer Therapy: Attempts to Overcome Their Unfavorable Side Effects. Cancers (Basel) 2023; 15:cancers15020475. [PMID: 36672424 PMCID: PMC9856583 DOI: 10.3390/cancers15020475] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/30/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) express anti-tumoral activity mainly by blocking cyclooxygenase-2 involved in the synthesis of prostaglandins. Therefore, in the last few decades, many have attempted to explore the possibilities of applying this group of drugs as effective agents for the inhibition of neoplastic processes. This review summarizes the evidence presented in the literature regarding the anti-tumoral actions of NSAIDs used as monotherapies as well as in combination with conventional chemotherapeutics and natural products. In several clinical trials, it was proven that combinations of NSAIDs and chemotherapeutic drugs (CTDs) were able to obtain suitable results. The combination with phospholipids may resolve the adverse effects of NSAIDs and deliver derivatives with increased antitumor activity, whereas hybrids with terpenoids exhibit superior activity against their parent drugs or physical mixtures. Therefore, the application of NSAIDs in cancer therapy seems to be still an open chapter and requires deep and careful evaluation. The literature's data indicate the possibilities of re-purposing anti-inflammatory drugs currently approved for cancer treatments.
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Affiliation(s)
- Vaikunthavasan Thiruchenthooran
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
| | - Elena Sánchez-López
- Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, University of Barcelona, 08028 Barcelona, Spain
- Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain
- Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, 08034 Barcelona, Spain
- Correspondence: (E.S.-L.); or (A.G.)
| | - Anna Gliszczyńska
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
- Correspondence: (E.S.-L.); or (A.G.)
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11
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Lichtenberger LM. Development of the PC-NSAID technology: From contact angle to Vazalore®. Drug Discov Today 2023; 28:103411. [PMID: 36270473 DOI: 10.1016/j.drudis.2022.103411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/10/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022]
Abstract
We describe strategies in drug development to reduce the gastrointestinal (GI) toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs). We then provide an overview of the experiments that led to the development of PC-NSAIDs, a novel family of NSAIDs associated with phosphatidylcholine (PC) that have reduced GI toxicity and full therapeutic activity. Furthermore, we describe the evidence showing: that the stomach possesses hydrophobic properties that are attributable to phospholipids lining the mucus gel layer; and that NSAIDs chemically associate with intrinsic PC, thereby attenuating the tissue's hydrophobic properties. Further, pre-associating NSAIDs with PC reduces the GI toxicity of these drugs, both in rodent ulcer models and in human subjects, without affecting the drugs' therapeutic activity. Finally, we discuss the commercialization and launch of Aspirin-PC, an over-the-counter (OTC) drug with the brand name Vazalore®.
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Affiliation(s)
- Lenard M Lichtenberger
- Department of Integrative Biology & Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
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12
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Hofling U, Tacconelli S, Contursi A, Bruno A, Mucci M, Ballerini P, Cohen S, Patrignani P. Characterization of the acetylation of cyclooxygenase-isozymes and targeted lipidomics of eicosanoids in serum and colon cancer cells by the new aspirin formulation IP1867B versus aspirin in vitro. Front Pharmacol 2022; 13:1070277. [PMID: 36588714 PMCID: PMC9795017 DOI: 10.3389/fphar.2022.1070277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/25/2022] [Indexed: 12/15/2022] Open
Abstract
Background: Aspirin(acetylsalicylic acid, ASA) is recommended for the secondary prevention of atherothrombotic events and has shown anticancer effects. The current enteric-coated drug formulation may reduce aspirin bioavailability. Liquid formulations could improve aspirin pharmacokinetics and pharmacodynamics. IP1867B is a liquid-aspirin formulation that combines three ingredients, ASA/triacetin/saccharin. Methods: ASA and IP1867B(L-ASA) were assessed in human serum(obtained by allowing to clot human whole blood at 37 °C for 1h), washed platelets, and colonic adenocarcinoma HCA7 cells on eicosanoid generation and COX-isozyme acetylation at Serine529 and 516 by LC-MS/MS. Results: In serum, ASA and L-ASA acted by selectively affecting COX-1-derived eicosanoids, including thromboxane(TX)B2. L-ASA was more potent in inhibiting serum TXB2, a known biomarker of aspirin antiplatelet effect, than ASA. However, ASA and L-ASA were equipotent to acetylate COX-1 in washed platelets and COX-2 in HCA7 cells. In HCA7 cells, ASA and L-ASA acted by inhibiting prostaglandin(PG)E2(the most abundant prostanoid) and TXB2 biosynthesis. In the presence of a high arachidonic acid concentration(100 μM), 15R-hydroxyeicosatetraenoic acid(HETE) was generated at baseline by cancer cell COX-2 and was only slightly enhanced by supratherapeutic concentrations of ASA(1 mM). In whole blood and HCA7 cells treated with ASA or L-ASA, 15-epi-lipoxin(LX)A4 were undetectable. Conclusion: IP1867B was more potent in affecting serum TXB2 generation than ASA. The relevance of this finding deserves evaluation in vivo in humans. In cancer cells, ASA and IP1867B acted by inhibiting PGE2 and TXB2 generation via the acetylation of COX-2. ASA and IP867B at clinically relevant concentrations did not substantially induce the biosynthesis of 15R-HETE and 15-epi-LXA4.
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Affiliation(s)
- Ulrika Hofling
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, Medical School, “G. D’Annunzio” University, Chieti, Italy
| | - Stefania Tacconelli
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, Medical School, “G. D’Annunzio” University, Chieti, Italy
| | - Annalisa Contursi
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, Medical School, “G. D’Annunzio” University, Chieti, Italy
| | - Annalisa Bruno
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, Medical School, “G. D’Annunzio” University, Chieti, Italy
| | - Matteo Mucci
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, Medical School, “G. D’Annunzio” University, Chieti, Italy
| | - Patrizia Ballerini
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, “G. D’Annunzio” University, Chieti, Italy
| | - Simon Cohen
- Innovate Pharmaceuticals, Manchester, United Kingdom
| | - Paola Patrignani
- Center for Advanced Studies and Technology (CAST), “G. D’Annunzio” University, Chieti, Italy
- Department of Neuroscience, Imaging and Clinical Science, Medical School, “G. D’Annunzio” University, Chieti, Italy
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13
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Franchi F, Schneider DJ, Prats J, Fan W, Rollini F, Been L, Taatjes-Sommer HS, Bhatt DL, Deliargyris EN, Angiolillo DJ. Pharmacokinetic and pharmacodynamic profiles of a novel phospholipid-aspirin complex liquid formulation and low dose enteric-coated aspirin: results from a prospective, randomized, crossover study. J Thromb Thrombolysis 2022; 54:373-381. [PMID: 36036856 PMCID: PMC9421621 DOI: 10.1007/s11239-022-02687-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/16/2022] [Indexed: 11/25/2022]
Abstract
Low dose enteric-coated aspirin (EC-ASA) is routinely used for secondary cardiovascular event prevention. However, absorption of EC tablets is poor, which can result in subtherapeutic antiplatelet effects. Phospholipid-aspirin liquid filled capsules (PL-ASA) are a novel FDA-approved immediate-release formulation designed to reduce gastrointestinal (GI) injury by limiting direct contact with the stomach lining. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of PL-ASA versus EC-ASA at a low dose. This randomized, open-label, crossover study assessed PK and PD following a single 81-mg dose of PL-ASA versus EC-ASA under fasting conditions in 36 volunteers without cardiovascular disease between 18 and 75 years of age. Volunteers were randomly assigned 1:1 to either PL-ASA then EC-ASA or vice versa with a minimum 14-day washout. Assessments included PK parameters for acetylsalicylic acid and salicylic acid, platelet aggregation in response to arachidonic acid (AA), and serum thromboxane B2 (TxB2) assessments over 24 h. PL-ASA was rapidly absorbed. PL-ASA reached Tmax 3 h earlier (1.01 vs. 4.00 h, p < 0.0001), with almost double the Cmax (720 vs. 368 ng/mL, p < 0.0001) and overall 44% higher exposure of acetylsalicylic acid (AUC0-t: 601 vs. 416 h*ng/mL, p = 0.0013) compared with EC-ASA. Within 1 h of dosing, PL-ASA achieved significantly lower residual platelet aggregation, which persisted for the full 24 h (median AA-LTA was 47% with PL-ASA vs. 80.5% with EC-ASA; p = 0.0022 at hour-24). Treatment with PL-ASA also resulted in significantly lower serum TxB2 concentrations at each time point compared with EC-ASA (all p-values < 0.05). PL-ASA resulted in faster and more complete aspirin absorption paralleled by more prompt and potent platelet inhibition compared with EC-ASA after a single 81 mg dose. PL-ASA represents an attractive novel aspirin formulation for the secondary prevention of cardiovascular events. Clinical Trial Registration ClinicalTrials.gov identifier: NCT04811625.
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Affiliation(s)
- Francesco Franchi
- Division of Cardiology, University of Florida College of Medicine - Jacksonville, 655 West 8th Street, Jacksonville, FL, 32209, USA
| | - David J Schneider
- Department of Medicine, Cardiovascular Research Institute, The University of Vermont, Burlington, VT, USA
| | | | | | - Fabiana Rollini
- Division of Cardiology, University of Florida College of Medicine - Jacksonville, 655 West 8th Street, Jacksonville, FL, 32209, USA
| | - Latonya Been
- Division of Cardiology, University of Florida College of Medicine - Jacksonville, 655 West 8th Street, Jacksonville, FL, 32209, USA
| | - Heidi S Taatjes-Sommer
- Department of Medicine, Cardiovascular Research Institute, The University of Vermont, Burlington, VT, USA
| | - Deepak L Bhatt
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Dominick J Angiolillo
- Division of Cardiology, University of Florida College of Medicine - Jacksonville, 655 West 8th Street, Jacksonville, FL, 32209, USA.
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14
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Lichtenberger LM, Szabo S. A closer look at endothelial injury-induced platelet hyperactivity and the use of aspirin in the treatment of COVID infection. Inflammopharmacology 2022; 30:1475-1476. [PMID: 35729443 PMCID: PMC9213171 DOI: 10.1007/s10787-022-01015-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 05/30/2022] [Indexed: 11/29/2022]
Abstract
In this commentary, we make a case that the mechanism of COVID pathogenesis is related to virus-induced endothelial injury resulting in platelet activation and the formation of microthrombi both systemically and in cardiac and pulmnonary circulation which result in major causes of COVID morbidity and mortality. Aspirin by virtue of its irreversible inhibition of platelet COX-1, should reverse these platelet-induced pathogenic changes associated with COVID infection for the 6-9 day lifetime of the platelet. We also cite recent findings of a retrospective analysis that supports the use of low-dose (81 mg) aspirin to treat the symptoms associated with the early stages of COVID infection.
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Affiliation(s)
- Lenard M Lichtenberger
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, USA.
- American University of Health Sciences, Signal Hill/Long Beach, CA, USA.
| | - Sandor Szabo
- American University of Health Sciences, Signal Hill/Long Beach, CA, USA
- University of California, Irvine, Irvine, USA
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15
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Lopez-Candales A, Norgard N. Will the new pharmaceutical lipid-aspirin complex formulation restore the once lost trust of aspirin on cardiovascular protection? Postgrad Med 2022; 134:573-575. [DOI: 10.1080/00325481.2022.2082716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Angel Lopez-Candales
- Cardiovascular Medicine Division, University Health Truman Medical Center, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Nicholas Norgard
- University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
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16
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Angiolillo DJ, Galli M, Collet JP, Kastrati A, O'Donoghue ML. Antiplatelet therapy after percutaneous coronary intervention. EUROINTERVENTION 2022; 17:e1371-e1396. [PMID: 35354550 PMCID: PMC9896394 DOI: 10.4244/eij-d-21-00904] [Citation(s) in RCA: 146] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/16/2021] [Indexed: 11/23/2022]
Abstract
Antiplatelet therapy is key to reducing local thrombotic complications and systemic ischaemic events among patients undergoing percutaneous coronary interventions (PCI), but it is inevitably associated with increased bleeding. The continuous refinement in stent technologies, together with the high incidence of ischaemic recurrences after PCI and the understanding of prognostic implications associated with bleeding, have led to a substantial evolution in antiplatelet treatment regimens over the past decades. Numerous investigations have been conducted to better stratify patients undergoing PCI according to their ischaemic and bleeding risks and to implement antithrombotic regimens accordingly. Evidence from these investigations have resulted in a number of antithrombotic treatment options as recommended by recent guidelines. In this State-of-the-Art review we provide the rationale, summarise the evidence, and discuss current and future directions of antiplatelet treatment regimens after PCI.
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Affiliation(s)
- Dominick J Angiolillo
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Mattia Galli
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Jean-Philippe Collet
- ACTION Study Group, Institut de Cardiologie, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Adnan Kastrati
- Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
| | - Michelle L O'Donoghue
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA
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17
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Angiolillo DJ, Prats J, Deliargyris EN, Schneider DJ, Scheiman J, Kimmelstiel C, Steg PG, Alberts M, Rosengart T, Mehran R, Bhatt DL. Pharmacokinetic and Pharmacodynamic Profile of a Novel Phospholipid Aspirin Formulation. Clin Pharmacokinet 2022; 61:465-479. [PMID: 35060092 PMCID: PMC8773391 DOI: 10.1007/s40262-021-01090-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/01/2021] [Indexed: 12/25/2022]
Abstract
Aspirin is one of the most widely used medicines. Although aspirin is commonly utilized for the treatment of several medical conditions, its broadest uptake is for the prevention of recurrent ischemic events in patients with atherosclerotic disease. Its mechanism of action of inhibiting platelet activation via blockade of thromboxane A2 production is unique and is not covered by any other antiplatelet agents. While plain, uncoated, immediate-release aspirin is used in acute settings to help assure rapid absorption, enteric-coated aspirin formulations dominate current chronic use, particularly in North America, including for secondary prevention of cardiovascular events. The unmet needs with current aspirin formulations include a high risk of gastrointestinal (GI) adverse events with plain aspirin, which enteric-coated formulations are not able to overcome, and subject to erratic absorption leading to reduced drug bioavailability. These observations underscore the need for aspirin formulations with a more favorable safety and efficacy profile. Phospholipid-aspirin complex (PL-ASA) is a novel formulation designed to address these needs. It is associated with reduced local acute GI injury compared with plain aspirin, and predictable absorption resulting in more reliable platelet inhibition compared with enteric-coated tablets. This review explores the rationale and pharmacologic profile of PL-ASA intended to address the unmet needs for aspirin therapy.
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Affiliation(s)
- Dominick J Angiolillo
- Division of Cardiology, University of Florida College of Medicine, 655 West 8th street, Jacksonville, FL, 32209, USA.
| | | | | | - David J Schneider
- Cardiovascular Division Department of Medicine and Cardiovascular Research Institute, University of Vermont Burlington, Burlington, VT, USA
| | - James Scheiman
- iDivision of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA, USA
| | - Carey Kimmelstiel
- Division of Cardiology, Tufts Medical Center Boston, Boston, MA, USA
| | - Ph Gabriel Steg
- Université de Paris, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, INSERM-U1148, Paris, France
| | - Mark Alberts
- Department of Neurology, Hartford Hospital, Hartford, CT, USA
| | - Todd Rosengart
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Roxana Mehran
- Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Deepak L Bhatt
- Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, USA
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18
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Del Bianco-Rondeau M, Robert-Halabi M, Bloom S, Rabasa-Lhoret R, Tardif JC, Lordkipanidzé M, Marquis-Gravel G. Aspirin for Primary Cardiovascular Prevention in Patients with Diabetes: Uncertainties and Opportunities. Thromb Haemost 2022; 122:1443-1453. [DOI: 10.1055/s-0042-1743469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
AbstractThe use of the antiplatelet agent aspirin (acetylsalicylic acid) was previously routinely recommended for the primary prevention of cardiovascular (CV) events in patients with diabetes, but recent large-scale randomized trials have failed to demonstrate a sizeable net clinical benefit with a once-daily, low-dose (81–100 mg) regimen in this population. Previous pharmacokinetic and pharmacodynamic studies have suggested that the aspirin formulation (enteric-coated) and dosing schedule (once daily) studied in randomized trials for primary prevention of CV events defining contemporary clinical practice may not leverage the full potential of the drug, particularly in patients with diabetes. Indeed, the diabetic platelets bear characteristics that increase their thrombotic potential and alter their pharmacologic response to the drug. Consequently, the appropriateness of studying a uniform aspirin regimen in landmark primary prevention trials needs to be revisited. In this review, we present the evidence showing that diabetes not only increases baseline platelet reactivity, but also alters platelet response to aspirin through different mechanisms including a faster platelet turnover rate. Obesity, which is frequently associated with diabetes, also impacts its pharmacokinetics via an increase in distribution volume. Small-scale pharmacokinetic and pharmacodynamic studies have suggested that the relative aspirin resistance phenotype observed in patients with diabetes may be reversed with a twice-daily dosing schedule, and with nonenteric-coated aspirin formulations. Properly powered randomized controlled trials investigating the efficacy and safety of aspirin dosing schedules and formulations tailored to the population of patients with diabetes are urgently required to optimize patient care.
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Affiliation(s)
| | - Maxime Robert-Halabi
- Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada
- Department of Medicine, Montreal Heart Institute, Montreal, Québec, Canada
| | - Samara Bloom
- Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada
- Research Center, Montreal Heart Institute, Montreal, Québec, Canada
| | | | - Jean-Claude Tardif
- Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada
- Department of Medicine, Montreal Heart Institute, Montreal, Québec, Canada
- Research Center, Montreal Heart Institute, Montreal, Québec, Canada
| | - Marie Lordkipanidzé
- Faculty of Pharmacy, Université de Montréal, Montreal, Québec, Canada
- Research Center, Montreal Heart Institute, Montreal, Québec, Canada
| | - Guillaume Marquis-Gravel
- Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada
- Department of Medicine, Montreal Heart Institute, Montreal, Québec, Canada
- Research Center, Montreal Heart Institute, Montreal, Québec, Canada
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19
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Capodanno D, Bhatt DL, Gibson CM, James S, Kimura T, Mehran R, Rao SV, Steg PG, Urban P, Valgimigli M, Windecker S, Angiolillo DJ. Bleeding avoidance strategies in percutaneous coronary intervention. Nat Rev Cardiol 2022; 19:117-132. [PMID: 34426673 DOI: 10.1038/s41569-021-00598-1] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/05/2021] [Indexed: 02/08/2023]
Abstract
For many years, bleeding has been perceived as an unavoidable consequence of strategies aimed at reducing thrombotic complications in patients undergoing percutaneous coronary intervention (PCI). However, the paradigm has now shifted towards bleeding being recognized as a prognostically unfavourable event to the same extent as having a new or recurrent ischaemic or thrombotic complication. As such, in parallel with progress in device and drug development for PCI, there is clinical interest in developing strategies that maximize not only the efficacy but also the safety (for example, by minimizing bleeding) of any antithrombotic treatment or procedural aspect before, during or after PCI. In this Review, we discuss contemporary data and aspects of bleeding avoidance strategies in PCI, including risk stratification, timing of revascularization, pretreatment with antiplatelet agents, selection of vascular access, choice of coronary stents and antithrombotic treatment regimens.
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Affiliation(s)
- Davide Capodanno
- Division of Cardiology, Azienda Ospedaliero-Universitaria Policlinico "G. Rodolico-San Marco", University of Catania, Catania, Italy
| | - Deepak L Bhatt
- Department of Medicine, Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, MA, USA
| | - C Michael Gibson
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Stefan James
- Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden
| | - Takeshi Kimura
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Roxana Mehran
- Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sunil V Rao
- The Duke Clinical Research Institute, Durham, NC, USA
| | | | | | - Marco Valgimigli
- Cardiocentro Ticino Institute and Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Stephan Windecker
- Department of Cardiology, Bern University Hospital, Bern, Switzerland
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20
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Komarov AL, Shahmatova OO, Korobkova VV, Kurilina EV, Shuleshova AG, Panchenko EP. Gastric mucosa condition in patients with coronary artery disease and high risk of gastrointestinal bleeding (register REGATTA-1). TERAPEVT ARKH 2022; 93:1457-1462. [DOI: 10.26442/00403660.2021.12.201224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 01/14/2022] [Indexed: 11/22/2022]
Abstract
The key side effects of antiplatelet therapy are associated with the damage of the upper gastrointestinal tract (GIT) mucous that can lead to erosions or ulcers and specifically complicated by bleeding.
Aim. To assess the upper gastrointestinal mucosal condition by endoscopic and histological methods in patients with stable coronary arteries disease receiving long-term antiplatelet therapy with gastrointestinal bleeding (GIB) history or with high risk of this complication.
Materials and methods.The study included patients from the single-center prospective registry of long-term antithrombotic therapy REGATTA-1.
The gastric mucosa endoscopic examination with biopsy was performed in 20 patients with gastrointestinal bleeding history less than 1 year ago and in 24 patients without GIB, which have concomitant risk factors such as erosions and ulcers history and/or persistent dyspepsia clinical signs. The mucosal condition (erosions and ulcers) was estimated using a modified Lanz scale. The presence of Helicobacter pylori was determined by Histological verification. The inflammatory process characteristics were evaluated according to the modified Sydney classification. All participants received antithrombotic therapy at the time of esophagogastroduodenoscopy; 81.8% of patients received proton pump inhibitors.
Results. Chronic inflammation (93.2%), atrophy (59.1%), multiple erosions (45.5%) or ulcers (18.2%) were the most frequent endoscopic finding. H. pylori infection, found in mucosal samples in 90.9% of patients was one of the most important pathogenesis mechanism, which support the gastrointestinal mucosa damage.
Conclusion. Mucosal damage endoscopic signs remains despite long-term proton pump inhibitors therapy in patients with coronary arteries disease and concomitant GIB risk factors, receiving antithrombotic therapy. H. pylori contamination may be the cause of these changes. Тtherefore, its active screening and eradication is necessary in such patients.
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21
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Ozaki Y, Hara H, Onuma Y, Katagiri Y, Amano T, Kobayashi Y, Muramatsu T, Ishii H, Kozuma K, Tanaka N, Matsuo H, Uemura S, Kadota K, Hikichi Y, Tsujita K, Ako J, Nakagawa Y, Morino Y, Hamanaka I, Shiode N, Shite J, Honye J, Matsubara T, Kawai K, Igarashi Y, Okamura A, Ogawa T, Shibata Y, Tsuji T, Yajima J, Iwabuchi K, Komatsu N, Sugano T, Yamaki M, Yamada S, Hirase H, Miyashita Y, Yoshimachi F, Kobayashi M, Aoki J, Oda H, Katahira Y, Ueda K, Nishino M, Nakao K, Michishita I, Ueno T, Inohara T, Kohsaka S, Ismail TF, Serruys PW, Nakamura M, Yokoi H, Ikari Y. CVIT expert consensus document on primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) update 2022. Cardiovasc Interv Ther 2022; 37:1-34. [PMID: 35018605 PMCID: PMC8789715 DOI: 10.1007/s12928-021-00829-9] [Citation(s) in RCA: 101] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 11/15/2021] [Indexed: 12/14/2022]
Abstract
Primary Percutaneous Coronary Intervention (PCI) has significantly contributed to reducing the mortality of patients with ST-segment elevation myocardial infarction (STEMI) even in cardiogenic shock and is now the standard of care in most of Japanese institutions. The Task Force on Primary PCI of the Japanese Association of Cardiovascular Interventional and Therapeutics (CVIT) society proposed an expert consensus document for the management of acute myocardial infarction (AMI) focusing on procedural aspects of primary PCI in 2018. Updated guidelines for the management of AMI were published by the European Society of Cardiology (ESC) in 2017 and 2020. Major changes in the guidelines for STEMI patients included: (1) radial access and drug-eluting stents (DES) over bare-metal stents (BMS) were recommended as a Class I indication, (2) complete revascularization before hospital discharge (either immediate or staged) is now considered as Class IIa recommendation. In 2020, updated guidelines for Non-ST-Elevation Myocardial Infarction (NSTEMI) patients, the followings were changed: (1) an early invasive strategy within 24 h is recommended in patients with NSTEMI as a Class I indication, (2) complete revascularization in NSTEMI patients without cardiogenic shock is considered as Class IIa recommendation, and (3) in patients with atrial fibrillation following a short period of triple antithrombotic therapy, dual antithrombotic therapy (e.g., DOAC and single oral antiplatelet agent preferably clopidogrel) is recommended, with discontinuation of the antiplatelet agent after 6 to 12 months. Furthermore, an aspirin-free strategy after PCI has been investigated in several trials those have started to show the safety and efficacy. The Task Force on Primary PCI of the CVIT group has now proposed the updated expert consensus document for the management of AMI focusing on procedural aspects of primary PCI in 2022 version.
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Affiliation(s)
- Yukio Ozaki
- Department of Cardiology, Fujita Health University School of Medicine, Aichi, Japan.
| | - Hironori Hara
- Department of Cardiology, National University of Ireland, Galway (NUIG), Galway, Ireland
- Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Yoshinobu Onuma
- Department of Cardiology, National University of Ireland, Galway (NUIG), Galway, Ireland
| | - Yuki Katagiri
- Department of Cardiology, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Tetsuya Amano
- Department of Cardiology, Aichi Medical University, Aichi, Japan
| | - Yoshio Kobayashi
- Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Takashi Muramatsu
- Department of Cardiology, Fujita Health University School of Medicine, Aichi, Japan
| | - Hideki Ishii
- Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Ken Kozuma
- Department of Cardiology, Teikyo University Hospital, Tokyo, Japan
| | - Nobuhiro Tanaka
- Division of Cardiology, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan
| | | | - Shiro Uemura
- Cardiovascular Medicine, Kawasaki Medical School, Kurashiki, Japan
| | | | | | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Junya Ako
- Department of Cardiology, Kitasato University Hospital, Sagamihara, Japan
| | - Yoshihisa Nakagawa
- Division of Cardiovascular Medicine, Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Yoshihiro Morino
- Department of Cardiology, Iwate Medical University Hospital, Morioka, Japan
| | - Ichiro Hamanaka
- Cardiovascular Intervention Center, Rakuwakai Marutamachi Hospital, Kyoto, Japan
| | - Nobuo Shiode
- Division of Cardiology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Junya Shite
- Cardiology Division, Osaka Saiseikai Nakatsu Hospital, Osaka, Japan
| | | | | | | | | | | | - Takayuki Ogawa
- Division of Cardiology, The Jikei University School of Medicine, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | | | | - Masakazu Kobayashi
- Department of Cardiology, Fujita Health University School of Medicine, Aichi, Japan
| | - Jiro Aoki
- Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan
| | | | | | | | - Masami Nishino
- Division of Cardiology, Osaka Rosai Hospital, Osaka, Japan
| | - Koichi Nakao
- Division of Cardiology, Saiseikai Kumamoto Hospital, Cardiovascular Center, Kumamoto, Japan
| | | | | | - Taku Inohara
- Keio University School of Medicine, Tokyo, Japan
| | - Shun Kohsaka
- Keio University School of Medicine, Tokyo, Japan
| | - Tevfik F Ismail
- Department of Cardiology, Fujita Health University School of Medicine, Aichi, Japan
- King's College London & Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Patrick W Serruys
- Department of Cardiology, National University of Ireland, Galway (NUIG), Galway, Ireland
- NHLI, Imperial College London, London, UK
| | - Masato Nakamura
- Division of Cardiovascular Medicine, Ohashi Medical Center, Toho University School of Medicine, Tokyo, Japan
| | - Hiroyoshi Yokoi
- Cardiovascular Center, Fukuoka Sanno Hospital, Fukuoka, Japan
| | - Yuji Ikari
- Department of Cardiology, Tokai University School of Medicine, Isehara, Japan
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22
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Pickett SJ, Levine GN, Jneid H, Bhatt DL, Nambi V. Is There an Optimal Antiplatelet Strategy after Gastrointestinal Bleeding in Patients with Coronary Artery Disease? Cardiology 2021; 146:668-677. [PMID: 34521081 DOI: 10.1159/000517051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 05/04/2021] [Indexed: 11/19/2022]
Abstract
Gastrointestinal bleeding after percutaneous coronary intervention (PCI) is a not too uncommon clinical situation and is associated with high morbidity and mortality. After initial treatment, a number of clinical decisions must be made weighing the risks of ischemic events and future bleeding. In particular, healthcare providers must carefully balance the effectiveness of antiplatelet therapy in the secondary prevention of coronary events, primarily future spontaneous myocardial infarction and stent thrombosis, against the risk of major, most commonly gastrointestinal bleeding. The first question is whether a dual antiplatelet therapy strategy is required or if a single antiplatelet agent will suffice. Then, if a single antiplatelet agent is adequate, which agent should be continued. Although there is some guidance to answer some of these questions, there are inadequate evidence-based data for others. Below, we review the various considerations and summarize our approach and rationale to manage patients who had gastrointestinal bleeding after PCI.
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Affiliation(s)
- Stephen J Pickett
- Michael E DeBakey Veterans Affairs Hospital, Baylor College of Medicine, Houston, Texas, USA,
| | - Glenn N Levine
- Michael E DeBakey Veterans Affairs Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Hani Jneid
- Michael E DeBakey Veterans Affairs Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Deepak L Bhatt
- Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Vijay Nambi
- Michael E DeBakey Veterans Affairs Hospital, Baylor College of Medicine, Houston, Texas, USA
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23
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Zhang WT, Wang MR, Hua GD, Li QY, Wang XJ, Lang R, Weng WL, Xue CM, Zhu BC. Inhibition of Aspirin-Induced Gastrointestinal Injury: Systematic Review and Network Meta-Analysis. Front Pharmacol 2021; 12:730681. [PMID: 34475825 PMCID: PMC8406693 DOI: 10.3389/fphar.2021.730681] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 07/12/2021] [Indexed: 11/23/2022] Open
Abstract
Background: Administration of aspirin has the potential for significant side effects of gastrointestinal (GI) injury mainly caused by gastric acid stimulation, especially in long-term users or users with original gastrointestinal diseases. The debate on the optimal treatment of aspirin-induced gastrointestinal injury is ongoing. We aimed to compare and rank the different treatments for aspirin-induced gastrointestinal injury based on current evidence. Methods: We searched PubMed, EMBASE, Cochrane Library (Cochrane Central Register of Controlled Trials), and Chinese databases for published randomized controlled trials (RCTs) of different treatments for aspirin-induced gastrointestinal injury from inception to 1 May 2021. All of the direct and indirect evidence included was rated by network meta-analysis under a Bayesian framework. Results: A total of 10 RCTs, which comprised 503 participants, were included in the analysis. The overall quality of evidence was rated as moderate to high. Eleven different treatments, including omeprazole, lansoprazole, rabeprazole, famotidine, geranylgeranylacetone, misoprostol, ranitidine bismuth citrate, chili, phosphatidylcholine complex, omeprazole plus rebamipide, and placebo, were evaluated in terms of preventing gastrointestinal injury. It was suggested that omeprazole plus rebamipide outperformed other treatments, whereas geranylgeranylacetone and placebo were among the least treatments. Conclusion: This is the first systematic review and network meta-analysis of different treatments for aspirin-induced gastrointestinal injury. Our study suggested that omeprazole plus rebamipide might be considered the best option to treat aspirin-induced gastrointestinal injury. More multicenter, high quality, large sample size randomized controlled trials will confirm the advantages of these medicines in the treatment of aspirin-induced gastrointestinal injury in the future.
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Affiliation(s)
- Wan-Tong Zhang
- Institute of Clinical Pharmacology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Miao-Ran Wang
- Department of Endocrinology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Guo-Dong Hua
- Department of Pharmacy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Qiu-Yan Li
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Xu-Jie Wang
- Institute of Clinical Pharmacology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Rui Lang
- Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wei-Liang Weng
- Institute of Clinical Pharmacology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Chun-Miao Xue
- Department of Pharmacy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Bao-Chen Zhu
- Department of Pharmacy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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24
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Tran PHL, Lee BJ, Tran TTD. Current Studies of Aspirin as an Anticancer Agent and Strategies to Strengthen its Therapeutic Application in Cancer. Curr Pharm Des 2021; 27:2209-2220. [PMID: 33138752 DOI: 10.2174/1381612826666201102101758] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 09/22/2020] [Indexed: 11/22/2022]
Abstract
Aspirin has emerged as a promising intervention in cancer in the past decade. However, there are existing controversies regarding the anticancer properties of aspirin as its mechanism of action has not been clearly defined. In addition, the risk of bleeding in the gastrointestinal tract from aspirin is another consideration that requires medical and pharmaceutical scientists to work together to develop more potent and safe aspirin therapy in cancer. This review presents the most recent studies of aspirin with regard to its role in cancer prevention and treatment demonstrated by highlighted clinical trials, mechanisms of action as well as approaches to develop aspirin therapy best beneficial to cancer patients. Hence, this review provides readers with an overview of aspirin research in cancer that covers not only the unique features of aspirin, which differentiate aspirin from other non-steroidal anti-inflammatory drugs (NSAIDs), but also strategies that can be used in the development of drug delivery systems carrying aspirin for cancer management. These studies convey optimistic messages on the continuing efforts of the scientist on the way of developing an effective therapy for patients with a low response to current cancer treatments.
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Affiliation(s)
- Phuong H L Tran
- Deakin University, School of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Geelong, Australia
| | - Beom-Jin Lee
- College of Pharmacy, Ajou University, Suwon, Korea
| | - Thao T D Tran
- Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam
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25
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Christiansen M, Grove EL, Hvas AM. Contemporary Clinical Use of Aspirin: Mechanisms of Action, Current Concepts, Unresolved Questions, and Future Perspectives. Semin Thromb Hemost 2021; 47:800-814. [PMID: 34130339 DOI: 10.1055/s-0041-1726096] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The ability of aspirin to inhibit platelet aggregation has positioned this agent within the most frequently used drugs worldwide. The aim of this article is to review the contemporary clinical use of aspirin and also to discuss unresolved issues not yet translated into clinical practice. Results from several clinical trials have led to strong guideline recommendations for aspirin use in the acute management and secondary prevention of cardiovascular disease. On the contrary, guidelines regarding aspirin use as primary prevention of cardiovascular disease are almost conservative, supported by recent trials reporting that the bleeding risk outweighs the potential benefits in most patients. In pregnancy, aspirin has proved efficient in preventing preeclampsia and small-for-gestational-age births in women at high risk, and is hence widely recommended in clinical guidelines. Despite the vast amount of clinical data on aspirin, several unresolved questions remain. Randomized trials have reported that aspirin reduces the risk of recurrent venous thromboembolism, but the clinical relevance remains limited, because direct oral anticoagulants are more effective. Laboratory studies suggest that a twice-daily dosing regimen or evening intake may lead to more efficient platelet inhibition, and the potential clinical benefit of such strategies is currently being explored in ongoing clinical trials. Enteric-coated formulations of aspirin are frequently used, but it remains unclear if they are safer and as efficient as plain aspirin. In the future, aspirin use after percutaneous coronary interventions might not be mandatory in patients who also need anticoagulant therapy, as several trials support shorter aspirin duration strategies. On the other hand, new treatment indications for aspirin will likely arise, as there is growing evidence that aspirin may reduce the risk of colorectal cancer and other types of cancer.
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Affiliation(s)
- Mikael Christiansen
- Department of Clinical Biochemistry, Regional Hospital in Horsens, Horsens, Denmark
| | - Erik Lerkevang Grove
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Anne-Mette Hvas
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.,Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
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Bhatt DL, Pollack CV. The Future of Aspirin Therapy in Cardiovascular Disease. Am J Cardiol 2021; 144 Suppl 1:S40-S47. [PMID: 33706989 DOI: 10.1016/j.amjcard.2020.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 12/11/2020] [Indexed: 10/22/2022]
Abstract
Much has been written about the demise of aspirin (ASA) but reports of its death are premature. The drug remains one of the most widely prescribed by physicians worldwide. It is cheap, familiar, and effective for a variety of uses, including in patients with acute or prior myocardial infarction, ischemic stroke, peripheral artery disease, and percutaneous or surgical revascularization procedures, as well as for use for pain and fever relief. Beyond physician prescription or recommendation, over the counter use of ASA is common, including for primary cardiovascular prevention, though this decision really should involve a discussion of risks and benefits with a physician. ASA is an essential member of the duo that makes up dual antiplatelet therapy (a P2Y12 inhibitor plus ASA) and also dual pathway inhibition (vascular dose rivaroxaban plus ASA), and data for both approaches are growing. Furthermore, research is ongoing as to the optimal dosing frequency (once vs twice daily), potentially safer gastrointestinal delivery, and possibly more effective formulations in terms of platelet inhibition. One goal of ASA research is to try to reduce bleeding complications that are a risk with all anti-thrombotic therapies. Although its exact roles will continue to evolve, the future for ASA remains bright.
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Hoogevest P, Tiemessen H, Metselaar JM, Drescher S, Fahr A. The Use of Phospholipids to Make Pharmaceutical Form Line Extensions. EUR J LIPID SCI TECH 2021. [DOI: 10.1002/ejlt.202000297] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Peter Hoogevest
- Phospholipid Research Center Im Neuenheimer Feld 515 Heidelberg 69120D‐69120 Germany
| | - Harry Tiemessen
- Technical & Research Development PHAD PDU Specialty Novartis Campus Physical Garden (WSJ 177) 2.14 Basel CH‐4002 Switzerland
| | - Josbert M. Metselaar
- Institute for Experimental Molecular Imaging, RWTH Aachen University Clinic Aachen D‐52074 Germany
- Institute for Biomedical Engineering, Faculty of Medicine RWTH Aachen University Aachen D‐52074 Germany
| | - Simon Drescher
- Phospholipid Research Center Im Neuenheimer Feld 515 Heidelberg D‐69120 Germany
| | - Alfred Fahr
- Professor Emeritus, Pharmaceutical Technology Friedrich‐Schiller‐University Jena Jena Germany
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Xie S, Wang Y, Huang Y, Yang B. Mechanisms of the antiangiogenic effects of aspirin in cancer. Eur J Pharmacol 2021; 898:173989. [PMID: 33657423 DOI: 10.1016/j.ejphar.2021.173989] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 02/14/2021] [Accepted: 02/22/2021] [Indexed: 01/04/2023]
Abstract
Aspirin is an old drug extracted from willow bark and is widely used for the prevention and treatment of cardiovascular diseases. Accumulating evidence has shown that aspirin use may significantly reduce the angiogenesis of cancer; however, the mechanism of the association between angiogenesis and aspirin is complex. Although COX-1 is widely known as a target of aspirin, several studies reveal other antiangiogenic targets of aspirin, such as angiotensin II, glucose transporter 1, heparanase, and matrix metalloproteinase. In addition, some data indicates that aspirin may produce antiangiogenic effects after acting in different cell types, such as endothelial cells, platelets, pericytes, and macrophages. In this review, we concentrate on research regarding the antiangiogenic effects of aspirin in cancer, and we discuss the molecular mechanisms of aspirin and its metabolites. Moreover, we discuss some mechanisms through which aspirin treatment may normalize existing blood vessels, including preventing the disintegration of endothelial adheres junctions and the recruitment of pericytes. We also address the antiangiogenic effects and the underlying mechanisms of aspirin derivatives, which are aimed at improving safety and efficacy.
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Affiliation(s)
- Shiyuan Xie
- College of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, PR China
| | - Youqiong Wang
- College of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, PR China
| | - Yixuan Huang
- College of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, PR China
| | - Bin Yang
- College of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, PR China.
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Angiolillo DJ, Bhatt DL, Lanza F, Deliargyris EN, Prats J, Fan W, Marathi U. Bioavailability of aspirin in fasted and fed states of a novel pharmaceutical lipid aspirin complex formulation. J Thromb Thrombolysis 2021; 49:337-343. [PMID: 32080811 PMCID: PMC7145786 DOI: 10.1007/s11239-020-02051-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Dyspeptic symptoms are common with aspirin and clinicians frequently recommend that it be taken with food to reduce these side effects. However, food can interfere with absorption, especially with enteric-coated aspirin formulations. We evaluated whether food interferes with the bioavailability of a new, pharmaceutical lipid-aspirin complex (PL-ASA) liquid-filled capsule formulation. In this randomized, open label, crossover study, 20 healthy volunteers fasted for ≥ 10 h and then randomized as either "fasted", receiving 650 mg of PL-ASA, or as "fed", with a standard high-fat meal and 650 mg of PL-ASA 30 min later. After a washout of 7 days, participants crossed over to the other arm. The primary outcome was comparison of PK parameters of the stable aspirin metabolite salicylic acid (SA) between fasted and fed states. Mean age of participants was 36.8 years and 55% were male. The ratios for the fed to fasted states of the primary SA PK parameters of AUC0-t and AUC0-∞ were 88.7% and 88.8% respectively, with 90% confidence intervals between 80 and 125%, which is consistent with FDA bioequivalence guidance. Mean peak SA concentration was about 22% lower and occurred about 1.5 h later in the fed state. Food had a modest effect on peak SA levels and the time required to reach them after PL-ASA administration, but did not impact the extent of exposure (AUC) compared with intake in a fasted state. These data demonstrate that PL-ASA may be co-administered with food without significant impact on aspirin bioavailability.Clinical Trial Registration:http://www.clinicaltrials.gov Unique Identifier: NCT01244100.
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Affiliation(s)
- Dominick J Angiolillo
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, 655 West 8th Street, Jacksonville, FL, 32209, USA.
| | - Deepak L Bhatt
- Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, MA, USA
| | - Frank Lanza
- Houston Institute for Clinical Research, Houston, TX, USA
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Capodanno D, Angiolillo DJ. Antithrombotic Therapy for Atherosclerotic Cardiovascular Disease Risk Mitigation in Patients With Coronary Artery Disease and Diabetes Mellitus. Circulation 2020; 142:2172-2188. [PMID: 33253005 DOI: 10.1161/circulationaha.120.045465] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Patients with diabetes mellitus (DM) are characterized by enhanced thrombotic risk attributed to multiple mechanisms including hyperreactive platelets, hypercoagulable status, and endothelial dysfunction. As such, they are more prone to atherosclerotic cardiovascular events than patients without DM, both before and after coronary artery disease (CAD) is established. In patients with DM without established CAD, primary prevention with aspirin is not routinely advocated because of its increased risk of major bleeding that largely offsets its ischemic benefit. In patients with DM with established CAD, secondary prevention with antiplatelet drugs is an asset of pharmacological strategies aimed at reducing the risk of atherosclerotic cardiovascular events and their adverse prognostic consequences. Such antithrombotic strategies include single antiplatelet therapy (eg, with aspirin or a P2Y12 inhibitor), dual antiplatelet therapy (eg, aspirin combined with a P2Y12 inhibitor), and dual-pathway inhibition (eg, aspirin combined with the vascular dose of the direct oral anticoagulant rivaroxaban) for patients with chronic ischemic heart disease, acute coronary syndromes, and those undergoing percutaneous coronary intervention. Because of their increased risk of thrombotic complications, patients with DM commonly achieve enhanced absolute benefit from more potent antithrombotic approaches compared with those without DM, which most often occurs at the expense of increased bleeding. Nevertheless, studies have shown that when excluding individuals at high risk for bleeding, the net clinical benefit favors the use of intensified long-term antithrombotic therapy in patients with DM and CAD. Several studies are ongoing to establish the role of novel antithrombotic strategies and drug formulations in maximizing the net benefit of antithrombotic therapy for patients with DM. The scope of this review article is to provide an overview of current and evolving antithrombotic strategies for primary and secondary prevention of atherosclerotic cardiovascular events in patients with CAD and DM.
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Affiliation(s)
- Davide Capodanno
- Division of Cardiology, A.O.U. Policlinico "G. Rodolico-San Marco," University of Catania, Italy (D.C.)
| | - Dominick J Angiolillo
- Division of Cardiology, University of Florida College of Medicine, Jacksonville (D.J.A.)
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31
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Davis JS, Kanikarla-Marie P, Gagea M, Yu PL, Fang D, Sebastian M, Yang P, Hawk E, Dashwood R, Lichtenberger LM, Menter D, Kopetz S. Sulindac plus a phospholipid is effective for polyp reduction and safer than sulindac alone in a mouse model of colorectal cancer development. BMC Cancer 2020; 20:871. [PMID: 32912193 PMCID: PMC7488444 DOI: 10.1186/s12885-020-07311-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023] Open
Abstract
Background Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time. Since prolonged, regular use is needed for chemopreventive benefit, it is important to know whether GI safety is maintained over longer use periods and whether cancer prevention efficacy is preserved when an NSAID is combined with a phospholipid. Methods As a first step to answering these questions, we treated seven to eight-week-old, male and female C57B/6 Apcmin/+ mice with the NSAID sulindac, with and without phosphatidylcholine (PC) for 3-weeks. At the end of the treatment period, we evaluated polyp burden, gastric toxicity, urinary prostaglandins (as a marker of sulindac target engagement), and blood chemistries. Results Both sulindac and sulindac-PC treatments resulted in significantly reduced polyp burden, and decreased urinary prostaglandins, but sulindac-PC treatment also resulted in the reduction of gastric lesions compared to sulindac alone. Conclusions Together these data provide pre-clinical support for combining NSAIDs with a phospholipid, such as phosphatidylcholine to reduce GI toxicity while maintaining chemopreventive efficacy.
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Affiliation(s)
- Jennifer S Davis
- Departments of Epidemiology, The University of Texas, MD Anderson Cancer Center, PO Box 301439, Houston, TX, 77230-1439, USA.
| | - Preeti Kanikarla-Marie
- Departments of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Mihai Gagea
- Departments of Veterinary Medicine and Surgery, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Patrick L Yu
- McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Dexing Fang
- McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Manu Sebastian
- Departments of Epigenetics & Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Peiying Yang
- Departments of Palliative, Rehabilitation and Integrative Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Ernest Hawk
- Division of Cancer Prevention and Population Sciences, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Roderick Dashwood
- Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA
| | | | - David Menter
- Departments of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Scott Kopetz
- Departments of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
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Scheidl E, Benz C, Loeff P, Groneck V, König A, Schulte-Fischedick A, Lück H, Fuhr U. Frequency and Types of Pathological Upper Gastrointestinal Endoscopy Findings in Clinically Healthy Individuals. Drugs R D 2020; 20:115-124. [PMID: 32335854 PMCID: PMC7221033 DOI: 10.1007/s40268-020-00303-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Beyond its application for diagnostics in patients, esophagogastroduodenoscopy (EGD) is used to assess gastrointestinal drug effects in clinical trials, where the interpretation of any pathological findings depends on the respective background variability. The objective of this analysis was to characterize the occurrence of pathological findings in the upper gastrointestinal tract in symptom-free healthy individuals. METHODS A baseline EGD was performed in clinically healthy individuals in three clinical trials aimed to assess gastrointestinal tolerability of drugs. Pathological findings were described by type (redness, erosion, ulcer or other), number, size and location, and by clinical relevance as assessed by the endoscopist. Characteristics of volunteers were tested as potential covariates. RESULTS A total of 294 EGDs were assessed. Characteristics of individuals were as follows: 257 (87.4%) males, age (mean ± SD) 32.0 ± 8.1 years, body weight 76.0 ± 10.6 kg, body mass index (BMI) 24.0 ± 2.5 kg/m2, 200 consumed alcohol, 250 (of 290 where this information was available) consumed caffeine and 39 (of 152) were smokers, 30 (of 151) tested positive for H. pylori. Any pathological finding was present in 79.6%. Clinically relevant findings occurred in 44.2%, mainly erosions (39.1%). Nine stomach ulcers were observed. Only age and BMI had a statistically significant relationship to overall pathological findings [age 3.4 years higher (p = 0.027), and BMI 1.6 kg/m2 higher (p < 0.001); for clinically relevant vs no findings]. CONCLUSION Upper gastrointestinal tract mucosal lesions, including those assessed as clinically relevant, are frequent in clinically healthy individuals, impeding the assessment of causality for both disease and drug effects on gastrointestinal health.
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Affiliation(s)
- Elisabeth Scheidl
- Clinical Pharmacology Unit, Department I of Pharmacology, Center for Pharmacology, University Hospital Cologne (AöR), Gleueler Straße 24, 50931, Köln, Germany
- ITECRA GmbH & Co. KG, Köln, Germany
| | - Claus Benz
- Department of Gastroenterology, Ev. Krankenhaus Köln-Weyertal, Köln, Germany
| | - Peter Loeff
- Department of Gastroenterology, Ev. Krankenhaus Köln-Weyertal, Köln, Germany
| | - Volker Groneck
- Department of Gastroenterology, Ev. Krankenhaus Köln-Weyertal, Köln, Germany
| | - Andreas König
- Department of Gastroenterology, Ev. Krankenhaus Köln-Weyertal, Köln, Germany
| | | | | | - Uwe Fuhr
- Clinical Pharmacology Unit, Department I of Pharmacology, Center for Pharmacology, University Hospital Cologne (AöR), Gleueler Straße 24, 50931, Köln, Germany.
- ITECRA GmbH & Co. KG, Köln, Germany.
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33
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Hoogevest P. Non‐Aqueous Phospholipid Concentrates for Increasing the Bioavailability of Poorly Soluble Compounds. EUR J LIPID SCI TECH 2020. [DOI: 10.1002/ejlt.201900411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Peter Hoogevest
- Phospholipid Research Center Im Neuenheimer Feld 515 Heidelberg D‐69120 Germany
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34
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Angiolillo DJ, Bhatt DL, Lanza F, Cryer B, Dong JF, Jeske W, Zimmerman RR, von Chong E, Prats J, Deliargyris EN, Marathi U. Pharmacokinetic/pharmacodynamic assessment of a novel, pharmaceutical lipid-aspirin complex: results of a randomized, crossover, bioequivalence study. J Thromb Thrombolysis 2020; 48:554-562. [PMID: 31420787 PMCID: PMC6800884 DOI: 10.1007/s11239-019-01933-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Aspirin (acetylsalicylic acid, ASA) can lead to gastrointestinal mucosal injury through disruption of its protective phospholipid bilayer. A liquid formulation of a novel pharmaceutical lipid-aspirin complex (PL-ASA) was designed to prevent this disruption. We sought to determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of PL-ASA compared with immediate release aspirin (IR-ASA). In this active-control crossover study, 32 healthy volunteers were randomized to receive 1 of 2 dose levels (a single dose of 325 mg or 650 mg) of either PL-ASA or IR-ASA. After a 2-week washout period between treatment assignments, subjects received a single dose of the alternative treatment, at the same dose level. The primary objectives of the study were to assess, for PL-ASA and IR-ASA at 325 mg and 650 mg dose levels, PK and PD bioequivalence, and safety, over a 24-h period after administration of both drugs. PK parameters were similar for PL-ASA and IR-ASA, and met FDA-criteria for bioequivalence. Regarding PD, both drugs also showed Cmin TxB2 values below 3.1 ng/mL (cut-off associated with decreased cardiovascular events) and > 99% inhibition of serum TxB2 ( ≥ 95% inhibition represents the cut-off for aspirin responders) along with similar results in several secondary PK/PD parameters. There were no serious adverse events or changes from baseline in vital signs or laboratory values in either of the 2 treatment groups. PL-ASA's novel liquid formulation has similar PK and PD performance compared with IR-ASA, supporting functional and clinical equivalence. These data coupled with the improved gastric safety of PL-ASA suggest that this novel formulation may exhibit an improved benefit-risk profile, warranting evaluation in future trials.Clinical trial registration: http://www.clinicaltrials.gov . Unique Identifier: NCT04008979.
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Affiliation(s)
- Dominick J Angiolillo
- Division of Cardiology, University of Florida College of Medicine, 655 West 8th street, Jacksonville, FL, 32209, USA.
| | - Deepak L Bhatt
- Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, MA, USA
| | - Frank Lanza
- Houston Institute for Clinical Research, Houston, TX, USA
| | - Byron Cryer
- University of Texas Southwestern Medical School, Dallas, TX, USA
| | - Jin-Fei Dong
- Division of Hematology, Department of Medicine, University of Washington, Member, BloodWorks NW Research Institute, Seattle, WA, USA
| | - Walter Jeske
- Cardiovascular Research Institute, Loyola University Chicago Health Sciences Division, Maywood, IL, USA
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Burge S, Lichtenberger LM. Growth inhibitory effects of PC-NSAIDs on human breast cancer subtypes in cell culture. Oncol Lett 2019; 18:6243-6248. [PMID: 31788101 PMCID: PMC6864988 DOI: 10.3892/ol.2019.10951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 08/07/2019] [Indexed: 11/05/2022] Open
Abstract
The potential role of non-steroidal anti-inflammatory drug (NSAID) therapy in the prevention and treatment of cancer has generated considerable research interest. Phosphatidylcholine (PC)-associated NSAIDs decrease the gastrointestinal side effects of NSAID therapy, and may be more effective than traditional NSAIDs in limiting tumor growth. In the present study, human cells representing three major breast cancer subtypes were cultured with aspirin, indomethacin and PC-associated forms of each drug, with PC alone as a control. All tested drugs decreased the tumor cell number after 8 days of culture, with PC-NSAIDs having the greatest inhibitory effect, and NSAIDs alone, particularly aspirin, having the least effect. PC alone was effective in limiting the proliferation of all cell lines, suggesting that the two components of PC-NSAIDs have an additive effect. The ELISA results did not support a strong role for inhibition of cyclooxygenase enzymes in the decrease in cancer cell proliferation, which may account for the limited effectiveness of aspirin alone. PC-NSAIDs, particularly indomethacin-PC, are attractive candidate drugs in the prevention and treatment of different types of breast cancer, including triple negative breast cancer.
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Affiliation(s)
- Shelley Burge
- Department of Integrative Biology and Pharmacology, McGovern Medical School at UTHealth, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA
| | - Lenard M. Lichtenberger
- Department of Integrative Biology and Pharmacology, McGovern Medical School at UTHealth, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA
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Buccheri S, Capodanno D, James S, Angiolillo DJ. Bleeding after antiplatelet therapy for the treatment of acute coronary syndromes: a review of the evidence and evolving paradigms. Expert Opin Drug Saf 2019; 18:1171-1189. [DOI: 10.1080/14740338.2019.1680637] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Sergio Buccheri
- Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
| | - Davide Capodanno
- Division of Cardiology, C.A.S.T., P.O. “G. Rodolico”, Azienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, University of Catania, Catania, Italy
| | - Stefan James
- Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
| | - Dominick J. Angiolillo
- Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA
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Raber I, McCarthy CP, Vaduganathan M, Bhatt DL, Wood DA, Cleland JGF, Blumenthal RS, McEvoy JW. The rise and fall of aspirin in the primary prevention of cardiovascular disease. Lancet 2019; 393:2155-2167. [PMID: 31226053 DOI: 10.1016/s0140-6736(19)30541-0] [Citation(s) in RCA: 129] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 03/04/2019] [Accepted: 03/05/2019] [Indexed: 12/21/2022]
Abstract
Aspirin is one of the most frequently used drugs worldwide and is generally considered effective for the secondary prevention of cardiovascular disease. By contrast, the role of aspirin in primary prevention of cardiovascular disease is controversial. Early trials evaluating aspirin for primary prevention, done before the turn of the millennium, suggested reductions in myocardial infarction and stroke (although not mortality), and an increased risk of bleeding. In an effort to balance the risks and benefits of aspirin, international guidelines on primary prevention of cardiovascular disease have typically recommended aspirin only when a substantial 10-year risk of cardiovascular events exists. However, in 2018, three large randomised clinical trials of aspirin for the primary prevention of cardiovascular disease showed little or no benefit and have even suggested net harm. In this narrative Review, we reappraise the role of aspirin in primary prevention of cardiovascular disease, contextualising data from historical and contemporary trials.
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Affiliation(s)
- Inbar Raber
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Cian P McCarthy
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Muthiah Vaduganathan
- Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, USA
| | - Deepak L Bhatt
- Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, USA
| | - David A Wood
- National Institute for Prevention and Cardiovascular Health, National University of Ireland, Galway, Ireland; National Heart and Lung Institute, Imperial College, London, UK
| | - John G F Cleland
- National Heart and Lung Institute, Imperial College, London, UK; Robertson Centre for Biostatistics and Clinical Trials, University of Glasgow, Glasgow, UK
| | - Roger S Blumenthal
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - John W McEvoy
- National Institute for Prevention and Cardiovascular Health, National University of Ireland, Galway, Ireland; Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Division of Cardiology, Department of Medicine, Saolta University Healthcare Group, University College Hospital Galway, Galway, Ireland.
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38
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Wang L, Pei D, Ouyang YQ, Nie X. Meta-analysis of risk and protective factors for gastrointestinal bleeding after percutaneous coronary intervention. Int J Nurs Pract 2018; 25:e12707. [PMID: 30456863 DOI: 10.1111/ijn.12707] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 09/30/2018] [Accepted: 10/05/2018] [Indexed: 01/22/2023]
Abstract
AIM To quantitatively analyse factors related to gastrointestinal bleeding after percutaneous coronary intervention and provide evidence for the prevention of gastrointestinal bleeding. DATA SOURCES AND REVIEW METHODS Cochrane Library, Pubmed, Embase, and Ovid databases were searched from inception to 31 May 2018; case-control and cohort studies published in English were included. The methodological quality of each study was assessed by two independent reviewers using the Newcastle-Ottawa Scale. Meta-analysis was performed using Revman version 5.3. RESULTS A total of 16 publications yielded data about risk factors. It was found that age older than 70 years, age (per 10-year increase), female sex, baseline anaemia, history of smoking, history of using alcohol, history of peptic ulcer disease, chronic renal failure, previous bleeding, shock, congestive heart failure, acute myocardial infarction, prior use of inotropic medications, and prior use of antithrombotic medications were positively associated with gastrointestinal bleeding. Four articles yielded data about protective factors. It was found that proton-pump inhibitor and bivalirudin therapy were negatively associated with gastrointestinal bleeding after percutaneous coronary intervention. CONCLUSION This research found risk and protective factors which can assist in effective management of this potentially fatal complication.
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Affiliation(s)
- Lan Wang
- School of Health Sciences of Wuhan University, Wuhan, China.,Department of Nursing, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dajun Pei
- Department of Nursing, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Xiaofei Nie
- School of Health Sciences of Wuhan University, Wuhan, China
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Tarnawski AS, Ahluwalia A. Increased susceptibility of aging gastric mucosa to injury and delayed healing: Clinical implications. World J Gastroenterol 2018; 24:4721-4727. [PMID: 30479459 PMCID: PMC6235800 DOI: 10.3748/wjg.v24.i42.4721] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 10/12/2018] [Accepted: 10/21/2018] [Indexed: 02/06/2023] Open
Abstract
In this editorial we comment on the article by Fukushi K et al published in the recent issue of the World Journal of Gastroenterology 2018; 24(34): 3908-3918. We focus specifically on the mechanisms of the anti-thrombotic action of aspirin, gastric mucosal injury and aging-related increased susceptibility of gastric mucosa to injury. Aspirin is widely used not only for the management of acute and chronic pain and arthritis, but also importantly for the primary and secondary prevention of cardiovascular events such as myocardial infarcts and strokes. Clinical trials have consistently shown that antiplatelet therapy with long term, low dose aspirin (LDA) - 75 to 325 mg daily, dramatically reduces the risk of non-fatal myocardial infarcts, stroke and mortality in patients with established arterial diseases. However, such treatment considerably increases the risk of gastrointestinal (GI) ulcerations and serious bleeding by > 2-4 fold, especially in aging individuals. This risk is further increased in patients using LDA together with other antiplatelet agents, other nonsteroidal anti-inflammatory agents (NSAIDs) and/or alcohol, or in patients with Helicobacter pylori (H. pylori) infection. Previous studies by our group and others have demonstrated prominent structural and functional abnormalities in gastric mucosa of aging individuals (which we refer to as aging gastric mucosa or “aging gastropathy”) compared to the gastric mucosa of younger individuals. Aging gastric mucosa has impaired mucosal defense, increased susceptibility to injury by a variety of noxious agents such as aspirin, other NSAIDs and ethanol, and delayed and impaired healing of injury. The mechanism underlying these abnormalities of aging gastric mucosa include reduced mucosal blood flow causing hypoxia, upregulation of PTEN, activation of pro-apoptotic caspase-3 and caspase-9, and reduced survivin (anti-apoptosis protein), importin-α (nuclear transport protein), vascular endothelial growth factor, and nerve growth factor. The decision regarding initiation of a long-term LDA therapy should be made after a careful consideration of both cardiovascular and GI risk factors. The latter include a previous history of GI bleeding and/or ulcers, age ≥ 70, male gender, concurrent use of other NSAIDs, alcohol consumption and H. pylori infection. Furthermore, the incidence of GI ulcers and bleeding can be reduced in patients on long term LDA treatment by several measures. Clinicians treating such patients should test for and eradicate H. pylori, instruct patients to avoid alcohol and non-aspirin NSAIDs, including cyclooxygenase-2-selective NSAIDs, and prescribe proton pump inhibitors in patients on LDA therapy. In the future, clinicians may be able to prescribe one of several potential new drugs, which include aspirin associated with phosphatidylcholine (PL2200), which retains all property of aspirin but reduces by approximately 50% LDA-induced GI ulcerations.
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Affiliation(s)
- Andrzej S Tarnawski
- Department of Gastroenterology Research, University of California Irvine and the Veterans Administration Long Beach Healthcare System, Long Beach, CA 90822, United States
| | - Amrita Ahluwalia
- Department of Gastroenterology Research, University of California Irvine and the Veterans Administration Long Beach Healthcare System, Long Beach, CA 90822, United States
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García-Rayado G, Navarro M, Lanas A. NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs. Expert Rev Clin Pharmacol 2018; 11:1031-1043. [DOI: 10.1080/17512433.2018.1516143] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Guillermo García-Rayado
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
- IIS Aragón, Zaragoza, Spain
| | - Mercedes Navarro
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
- IIS Aragón, Zaragoza, Spain
| | - Angel Lanas
- Service of Digestive Diseases, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
- IIS Aragón, Zaragoza, Spain
- CIBERehd, Madrid, Spain
- University of Zaragoza, Zaragoza, Spain
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Bjarnason I, Scarpignato C, Holmgren E, Olszewski M, Rainsford KD, Lanas A. Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs. Gastroenterology 2018; 154:500-514. [PMID: 29221664 DOI: 10.1053/j.gastro.2017.10.049] [Citation(s) in RCA: 286] [Impact Index Per Article: 40.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 10/28/2017] [Accepted: 10/31/2017] [Indexed: 12/13/2022]
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing widespread morbidity and mortality. Although mechanisms of damage involve the activities of prostaglandin-endoperoxide synthase 1 (PTGS1 or cyclooxygenase [COX] 1) and PTGS1 (COX2), other factors are involved. We review the mechanisms of gastrointestinal damage induction by NSAIDs via COX-mediated and COX-independent processes. NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the gastrointestinal barrier. The resulting increase in intestinal permeability leads to low-grade inflammation. NSAID inhibition of COX enzymes, along with luminal aggressors, results in erosions and ulcers, with potential complications of bleeding, protein loss, stricture formation, and perforation. We propose a model for NSAID-induced damage to the gastrointestinal tract that includes these complex, interacting, and inter-dependent factors. This model highlights the obstacles for the development of safer NSAIDs.
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Affiliation(s)
- Ingvar Bjarnason
- Department of Gastroenterology, King's College Hospital, London, United Kingdom.
| | - Carmelo Scarpignato
- Department of Clinical and Experimental Medicine, University of Parma, Italy
| | - Erik Holmgren
- Department of Gastroenterology, King's College Hospital, London, United Kingdom
| | - Michael Olszewski
- Department of Gastroenterology, King's College Hospital, London, United Kingdom
| | - Kim D Rainsford
- Biomedical Sciences, Biomedical Research Centre, Sheffield Hallam University, Sheffield, United Kingdom
| | - Angel Lanas
- Department of Gastroenterology, University of Zaragoza School of Medicine, IIS Aragón, CIBERehd, Zaragoza, Spain
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van Hoogevest P. Review - An update on the use of oral phospholipid excipients. Eur J Pharm Sci 2017; 108:1-12. [PMID: 28711714 DOI: 10.1016/j.ejps.2017.07.008] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 06/30/2017] [Accepted: 07/07/2017] [Indexed: 12/24/2022]
Abstract
The knowledge and experiences obtained with oral phospholipid excipients is increasing continuously. Nevertheless the present number of oral products using these excipients as essential excipient is very limited. This is remarkable to note, since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies. In addition, phospholipid excipients are multifunctional biodegradable, non-toxic excipients, which can be used in oral dosage forms as wetting agents, emulsifier, solubilizer and matrix forming excipients. Especially natural phospholipid excipients, made from renewable sources, may be considered as environmentally friendly excipients and as a viable alternative to synthetic phospholipid and non-phospholipid analogues. This review describes 1) essential physico-chemical properties of oral phospholipid excipients 2) the fate of orally administered phospholipids with respect to absorption and metabolism in the GI tract 3) the main dosage forms used for oral administration containing phospholipids. These elements are critically assessed and areas of future research of interest for the use of oral phospholipid excipients are summarized.
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Affiliation(s)
- Peter van Hoogevest
- Phospholipid Research Center, Im Neuenheimer Feld 515, D-69120 Heidelberg, Germany.
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Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus. J Am Coll Cardiol 2017; 69:603-612. [DOI: 10.1016/j.jacc.2016.11.050] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 10/24/2016] [Accepted: 11/07/2016] [Indexed: 12/11/2022]
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Pereira-Leite C, Nunes C, Jamal SK, Cuccovia IM, Reis S. Nonsteroidal Anti-Inflammatory Therapy: A Journey Toward Safety. Med Res Rev 2016; 37:802-859. [PMID: 28005273 DOI: 10.1002/med.21424] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 09/27/2016] [Accepted: 10/05/2016] [Indexed: 01/01/2023]
Abstract
The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.
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Affiliation(s)
- Catarina Pereira-Leite
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.,Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Cláudia Nunes
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Sarah K Jamal
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Iolanda M Cuccovia
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Salette Reis
- UCIBIO, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
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Lichtenberger LM, Fang D, Bick RJ, Poindexter BJ, Phan T, Bergeron AL, Pradhan S, Dial EJ, Vijayan KV. Unlocking Aspirin's Chemopreventive Activity: Role of Irreversibly Inhibiting Platelet Cyclooxygenase-1. Cancer Prev Res (Phila) 2016; 10:142-152. [PMID: 27998883 DOI: 10.1158/1940-6207.capr-16-0241] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 11/29/2016] [Accepted: 11/30/2016] [Indexed: 12/21/2022]
Abstract
The mechanism by which aspirin consumption is linked to significant reductions in the incidence of multiple forms of cancer and metastatic spread to distant tissues, resulting in increased cancer patient survival is not well understood. In this study, using colon cancer as an example, we provide both in vitro (cell culture) and in vivo (chemically induced mouse model of colon cancer) evidence that this profound antineoplastic action may be associated with aspirin's ability to irreversibly inhibit COX-1-mediated platelet activation, thereby blocking platelet-cancer cell interactions, which promote cancer cell number and invasive potential. This process may be driven by platelet-induced epithelial-mesenchymal transition (EMT), as assessed using confocal microscopy, based upon changes in cell morphology, growth characteristics and fibronectin expression, and biochemical/molecular analysis by measuring changes in the expression of the EMT markers; vimentin, β-catenin, and SNAIL. We also provide evidence that a novel, gastrointestinal-safe phosphatidylcholine (PC)-associated aspirin, PL2200 Aspirin, possesses the same or more pronounced actions versus unmodified aspirin with regard to antiplatelet effects (in vitro: reducing platelet activation as determined by measuring the release of thromboxane and VEGF in culture medium; in vivo: inhibiting platelet number/activation and extravasation into tumor tissue) and chemoprevention (in vitro: inhibiting colonic cell growth and invasive activity; in vivo: inhibiting colonic dysplasia, inflammation, and tumor mass). These results suggest that aspirin's chemopreventive effects may be due, in part, to the drug blocking the proneoplastic action of platelets, and the potential use of Aspirin-PC/PL2200 as an effective and safer chemopreventive agent for colorectal cancer and possibly other cancers. Cancer Prev Res; 10(2); 142-52. ©2016 AACR.
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Affiliation(s)
- Lenard M Lichtenberger
- Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas.
| | - Dexing Fang
- Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas
| | - Roger J Bick
- Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas
| | - Brian J Poindexter
- Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas
| | - Tri Phan
- Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas
| | - Angela L Bergeron
- Department of Medicine, Baylor College of Medicine and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Subhashree Pradhan
- Department of Medicine, Baylor College of Medicine and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Elizabeth J Dial
- Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston-McGovern Medical School, Houston, Texas
| | - K Vinod Vijayan
- Department of Medicine, Baylor College of Medicine and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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Huang Y, Lichtenberger LM, Taylor M, Bottsford-Miller JN, Haemmerle M, Wagner MJ, Lyons Y, Pradeep S, Hu W, Previs RA, Hansen JM, Fang D, Dorniak PL, Filant J, Dial EJ, Shen F, Hatakeyama H, Sood AK. Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer. Mol Cancer Ther 2016; 15:2894-2904. [PMID: 27638860 PMCID: PMC5136300 DOI: 10.1158/1535-7163.mct-16-0074] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 08/08/2016] [Accepted: 08/21/2016] [Indexed: 02/07/2023]
Abstract
To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose-response studies were performed to compare the growth-inhibitory effect of aspirin-PC versus aspirin on three human (A2780, SKOV3ip1, and HeyA8) and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following antiangiogenic therapy, and we examined their underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in blocking the growth of both human and mouse ovarian cancer cells in monolayer culture. Using in vivo model systems of ovarian cancer, we found that aspirin-PC significantly reduced ovarian cancer growth by 50% to 90% (depending on the ovarian cell line). The efficacy was further enhanced in combination with Bevacizumab or B20. The growth-inhibitory effect on ovarian tumor mass and number of tumor nodules was evident, but less pronounced for aspirin and the VEGF inhibitors alone. There was no detectable gastrointestinal toxicity. Both aspirin and aspirin-PC also inhibited cell proliferation, angiogenesis, and increased apoptosis of ovarian cancer cells. In conclusion, PC-associated aspirin markedly inhibits the growth of ovarian cancer cells, which exceeds that of the parent drug, in both cell culture and in mouse model systems. We also found that both aspirin-PC and aspirin have robust antineoplastic action in the presence of VEGF-blocking drugs. Mol Cancer Ther; 15(12); 2894-904. ©2016 AACR.
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Affiliation(s)
- Yan Huang
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Lenard M Lichtenberger
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas
| | - Morgan Taylor
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Justin N Bottsford-Miller
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Monika Haemmerle
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael J Wagner
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yasmin Lyons
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sunila Pradeep
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wei Hu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rebecca A Previs
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jean M Hansen
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Dexing Fang
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas
| | - Piotr L Dorniak
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Justyna Filant
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Elizabeth J Dial
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas
| | - Fangrong Shen
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hiroto Hatakeyama
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Bhatt DL, Hunt RH. Concurrent Lower Gastrointestinal Bleeding Risk and Myocardial Ischemic Risk: Resume Aspirin or Not? Gastroenterology 2016; 151:222-5. [PMID: 27374367 DOI: 10.1053/j.gastro.2016.06.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Deepak L Bhatt
- Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts.
| | - Richard H Hunt
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University Health Science Centre, Hamilton, Ontario, Canada
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Vaduganathan M, Bhatt DL, Cryer BL, Liu Y, Hsieh WH, Doros G, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Cannon CP. Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy. J Am Coll Cardiol 2016; 67:1661-71. [PMID: 27012778 DOI: 10.1016/j.jacc.2015.12.068] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 12/13/2015] [Accepted: 12/22/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin. OBJECTIVES The authors investigated the safety and efficacy of PPI therapy in patients receiving DAPT in low- and high-dose aspirin subsets. METHODS Randomized patients with available aspirin dosing information in COGENT (N = 3,752) were divided into "low-dose" (≤ 100 mg) and "high-dose" (>100 mg) aspirin groups. The primary GI and cardiovascular endpoints were composite upper GI events and major adverse cardiac events, respectively. All events were adjudicated by independent, blinded gastroenterologists and cardiologists. RESULTS Median duration of follow-up was 110 days. Low-dose aspirin users (n = 2,480; 66.1%) were more likely to be older, female, and have higher rates of peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users (n = 1,272; 33.9%) had higher rates of hyperlipidemia, smoking, a history of percutaneous coronary intervention, and were more than twice as likely to be enrolled from sites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-day Kaplan-Meier estimates of adjudicated composite GI events (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95% confidence interval: 0.46 to 1.66) and major adverse cardiac events (4.8% vs. 5.5%; adjusted hazard ratio: 0.73; 95% confidence interval: 0.48 to 1.11) compared with low-dose aspirin. Randomization to PPI therapy reduced 180-day Kaplan-Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group. CONCLUSIONS Gastroprotection with PPI therapy should be utilized in appropriately selected patients with coronary artery disease requiring DAPT, even if the patients are on low-dose aspirin. (Clopidogrel and the Optimization of Gastrointestinal Events Trial [COGENT]; NCT00557921).
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Affiliation(s)
- Muthiah Vaduganathan
- Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts
| | - Deepak L Bhatt
- Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts.
| | - Byron L Cryer
- University of Texas Southwestern and Veterans Affairs North Texas Health Care System, Dallas, Texas
| | - Yuyin Liu
- Harvard Clinical Research Institute, Boston, Massachusetts; Department of Biostatistics, Boston University, Boston, Massachusetts
| | - Wen-Hua Hsieh
- Harvard Clinical Research Institute, Boston, Massachusetts
| | - Gheorghe Doros
- Harvard Clinical Research Institute, Boston, Massachusetts; Department of Biostatistics, Boston University, Boston, Massachusetts
| | - Marc Cohen
- Newark Beth Israel Medical Center, Newark, New Jersey
| | - Angel Lanas
- University of Zaragoza, Instituto de Investigación Sanitaria Aragón, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Zaragoza, Spain
| | - Thomas J Schnitzer
- Departments of Physical Medicine and Rehabilitation and Internal Medicine-Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | | | | | | | - Loren Laine
- Yale School of Medicine, New Haven, Connecticut; VA Connecticut Healthcare System, West Haven, Connecticut
| | - Christopher P Cannon
- Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts; Harvard Clinical Research Institute, Boston, Massachusetts
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Vaduganathan M, Bhatt DL. Aspirin and proton-pump inhibitors: interpreting the interplay. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2015; 2:20-2. [DOI: 10.1093/ehjcvp/pvv038] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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50
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Distrutti E, Santucci L, Cipriani S, Renga B, Schiaroli E, Ricci P, Donini A, Fiorucci S. Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa. J Gastroenterol 2015; 50:707-19. [PMID: 25708288 DOI: 10.1007/s00535-015-1041-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 01/09/2015] [Indexed: 02/04/2023]
Abstract
Bile acids are the end product of cholesterol metabolism. Synthesized in the liver, primary bile acids are secreted by hepatocytes and are transformed by intestinal microbiota into secondary bile acids. In addition to their role in cholesterol and lipid absorption, bile acids act as signaling molecules activating a family of nuclear and G-protein-coupled receptors collectively known as bile acid activated receptors (BARs). These receptors are expressed at high density in enterohepatic tissues, but their expression occurs throughout the body and their activation mediates regulatory functions of bile acids on lipids and glucose metabolism and immunity. In the gastrointestinal tract, BARs maintain intestinal integrity, and their deletion makes the intestine more susceptible to the damage caused by acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs). Deficiency in farnesoid X receptor and G-protein-coupled bile acid receptor 1 genes alters the expression/activity of cystathione γ-lyase and endothelial nitric oxide synthase, two genes involved in the synthesis of hydrogen sulfide and nitric oxide, i.e., two gaseous mediators that have been shown to be essential in maintaining the intestinal homeostasis. In addition, farnesoid X receptor regulates the expression of transporters required for secretion of phospholipid by hepatocytes. Because phospholids attenuate intestinal injury caused by acetylsalicylic acid and NSAIDs, BAR agonism could be exploited to protect the intestinal mucosa against injury caused by anti-inflammatory medications. This approach might be useful in the prevention of so-called NSAID enteropathy, a common clinical condition occurring in long-term users of NSAIDs, which is not effectively prevented either by cotreatment with proton pump inhibitors or by the use of coxibs.
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