A global view of atherothrombosis: Baseline characteristics in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial
Article Outline
Background
The manifestations of atherothrombosis such as myocardial infarction, ischemic stroke, limb ischemia, or cardiovascular death pose a global health care burden. Additional therapies to decrease ischemic events in patients with established vascular disease or at risk for developing vascular disease are necessary. We sought to characterize the risk factors and treatments of a diverse contemporary population of patients with atherothrombosis.
Methods
The CHARISMA trial has enrolled 15
603 patients from around the world. Patients with established coronary, cerebrovascular, or peripheral arterial disease, or those at high risk of developing atherothrombosis due to multiple risk factors, have been randomized to receive either the adenosine diphosphate receptor antagonist clopidogrel or placebo, in addition to background therapy with low- to moderate-dose aspirin.
Results
A high percentage of enrolled patients are being treated with statins and angiotensin-converting enzyme inhibitors. In the CHARISMA population, a total of 75.6% of the population had an abnormal body mass index: 42.2% were overweight and 33.4% were obese, with particularly high rates in the United States, especially of morbid obesity. Correspondingly, the prevalence of diabetes was 42%.
Conclusion
The CHARISMA trial will further characterize atherothrombosis and provide insight into the role of dual antiplatelet therapy in improving outcomes in patients with multiple risk factors or established vascular disease. Of note, the rates of obesity and diabetes in patients with atherothrombosis throughout the world are particularly alarming.
Atherothrombosis results largely from the interaction between genetic predisposition and an unhealthful lifestyle. Symptomatic atherothrombosis typically occurs when risk factors and genetic substrate coexist; typically, a perturbation in one or the other, unless extreme, does not result in symptomatic disease. Patients with a history of prior ischemic events are at particular risk for recurrence.1 Although the recurrent event may be in the same arterial territory as the initial event, there is also substantial risk for an event in another artery. For example, patients with a history of ischemic stroke are at risk for not only recurrent stroke, but also myocardial infarction. Similarly, asymptomatic patients with diabetes mellitus or with a multiplicity of risk factors for atherosclerosis (eg, hypertension, hyperlipidemia, or tobacco abuse) are all at high risk for ischemic events.2
Antiplatelet therapy with either aspirin or clopidogrel reduces ischemic events.3, 4 However, the incremental value of long-term dual antiplatelet therapy, validated in the settings of coronary stenting and acute coronary syndromes, is unknown in the broader population of patients with symptomatic or asymptomatic atherothrombosis.5, 6, 7, 8 These observations led to the genesis of the CHARISMA trial. The design of CHARISMA has previously been published.9 The baseline characteristics of the CHARISMA patient population are herein described.
Methods
The specific inclusion and exclusion criteria for CHARISMA have been previously published.9 Briefly, CHARISMA randomized patients either with risk factors for development of atherothrombosis or with established coronary, cerebrovascular, or peripheral arterial disease (PAD) to either clopidogrel or placebo, on top of background therapy with aspirin. Adherence to practice guidelines and evidence-based medicine was emphasized. Specifically, appropriate use of statins and angiotensin-converting enzyme (ACE) inhibitors was encouraged. Baseline characteristics were examined. Overweight was defined as a body mass index (BMI) of 25 to <30 kg/m2. Obese was defined as a BMI of ≥30 kg/m2. Morbidly obese was defined as a BMI ≥40 kg/m2.
Results
A total of 15603 patients were enrolled from 768 sites in 32 countries in 6 continents. Figure 1 describes the geographic distribution of the patients by region. Most patients were from North America and Western Europe, although Northern/Central Europe, Latin America, Asia, South Africa, and Australia were also represented. Table I describes the demographic characteristics and Table II describes the medical history of the entire patient population. The median age of the patients in CHARISMA at baseline is 64.9 years (mean age 64.8 years); the very elderly patients (≥75 years) comprise 16.2% of the population. A total of 29.8% are female. Table III lists the medications administered within 10 days before randomization. There was a high prevalence of use of statins and ACE inhibitors. In fact, most patients were already on multiple evidence-based medical therapies. Most patients were on low- or moderate-dose aspirin before enrollment (Table IV). Even in asymptomatic patients, most were already on aspirin therapy. Table V describes the breakdown of patients by inclusion criteria. Of the total of 15603 patients, 21.0% were asymptomatic. Table VI shows the time since the qualifying ischemic event until randomization in the symptomatic patients. Qualifying strokes and transient ischemic attacks were mostly recent due to inclusion criteria. Table VII describes the percentage of risk factors in the enrolled asymptomatic patients.
Figure 1.
Geographic distribution by region of patients in CHARISMA.
Table I. Demographic characteristics of patients in CHARISMA
| Characteristic | n (%) |
|---|---|
| Age (y), median (range) | 64.9 (39-96) |
| Age (y) | |
| <65 | 7873 (50.5) |
| ≥65 to <75 | 5207 (33.4) |
| ≥75 | 2523 (16.2) |
| Female | 4644 (29.8) |
| Race | |
| White | 12495 (80.1) |
| Hispanic | 1614 (10.3) |
| Asian | 776 (5.0) |
| Black | 486 (3.1) |
| Other | 229 (1.5) |
| BMI (kg/m2) | |
| Normal (<25) | 3792 (24.4) |
| Overweight (25 to <30) | 6560 (42.2) |
| Obese (≥30) | 5180 (33.4) |
Table II. Patient history
| Characteristic | n (%) |
|---|---|
| Smoking status | |
| Current | 3154 (20.2) |
| Former | 7612 (48.8) |
| Hypertension | 11470 (73.5) |
| Hypercholesterolemia | 11526 (73.9) |
| Congestive heart failure | 925 (5.9) |
| Prior myocardial infarction | 5396 (34.6) |
| Atrial fibrillation | 583 (3.7) |
| Prior stroke | 3837 (24.6) |
| TIA | 1864 (11.9) |
| Diabetes | 6552 (42.0) |
| PAD | 3528 (22.6) |
| PCI | 3554 (22.8) |
| CABG | 3079 (19.7) |
| Carotid endarterectomy | 823 (5.3) |
| Peripheral angioplasty or bypass | 1736 (11.1) |
| Diabetic nephropathy | 2006 (12.9) |
Table III. Number (percentage) of patients on selected medications within 10 days of study entry
| Medication | Total N = 15603 |
|---|---|
| Antiplatelets | 14609 (93.6) |
| Aspirin | 14457 (92.7) |
| Ticlopidine | 92 (0.6) |
| Clopidogrel | 544 (3.5) |
| Dipyridamole | 127 (0.8) |
| Diuretics | 5145 (33.0) |
| Nitrates | 2559 (16.4) |
| Calcium antagonists | 4227 (27.1) |
| β-Blockers | 7217 (46.3) |
| Angiotensin II receptor blockers | 2610 (16.7) |
| Ramipril | 1996 (12.8) |
| Other ACE inhibitors | 5847 (37.5) |
| Other antihypertensives | 1205 (7.7) |
| Statins | 10108 (64.8) |
| Atorvastatin | 4140 (26.5) |
| Simvastatin | 3866 (24.8) |
| Pravastatin | 1460 (9.4) |
| Fluvastatin | 319 (2.0) |
| Lovastatin | 305 (2.0) |
| Other statins | 104 (0.7) |
| Other lipid-lowering agents | 1246 (8.0) |
| Fibrates | 887 (5.7) |
| Binding resins | 122 (0.8) |
| Nicotinic acid | 282 (1.8) |
| Antidiabetic medications | 5977 (38.3) |
| Insulin | 2096 (13.4) |
| Thiazolidinediones | 790 (5.1) |
| Other oral hypoglycemics | 4688 (30.0) |
Table IV. Aspirin doses before randomization
| Prior aspirin daily dosage (mg/d) | n (%) |
|---|---|
| Total population (N = 15603) | |
| Any | 14457 (92.7) |
| ≤162 | 10832 (69.4) |
| >162 | 3625 (23.2) |
| Asymptomatic patients (n = 3284) | |
| Any | 2705 (82.4) |
| ≤162 | 2198 (66.9) |
| >162 | 507 (15.4) |
Table V. Breakdown of patients in CHARISMA (N = 15603) by primary inclusion criteria
| Primary inclusion criteria | n (%) |
|---|---|
| Symptomatic | 12152 (77.9) |
| Documented coronary disease | 5835 (37.4) |
| Angina with documented multivessel coronary disease | 1774 (11.4) |
| History of multivessel PCI | 835 (5.4) |
| History of multivessel CABG | 1469 (9.4) |
| Previous myocardial infarction | 3846 (24.7) |
| Documented cerebrovascular disease | 4319 (27.7) |
| Previous TIA | 1233 (7.9) |
| Previous ischemic stroke | 3245 (20.8) |
| Documented symptomatic PAD | 2837 (18.2) |
| Current intermittent claudication + ABI ≤0.85 | 1778 (11.4) |
| History of intermittent claudication + prior intervention | 1634 (10.5) |
| Asymptomatic | 3284 (21.0) |
Table VI. Time since qualifying event
| Symptomatic condition | Median duration (m) |
|---|---|
| Myocardial infarction | 23.3 |
| Stroke | 3.5 |
| TIA | 2.7 |
| PAD | 23.3 |
Table VII. Distribution of risk factors for asymptomatic patients (n = 3284)
| Inclusion risk factors for asymptomatic patients | n (%) |
|---|---|
| Major | |
| Type 1 or 2 diabetes | 2654 (80.8) |
| Diabetic nephropathy | 1402 (42.7) |
| ABI <0.9 | 187 (5.7) |
| Presence of at least 1 carotid plaque | 412 (12.5) |
| Asymptomatic carotid stenosis ≥70% | 256 (7.8) |
| Minor | |
| Systolic blood pressure ≥150 mm Hg | 1551 (47.2) |
| Primary hypercholesterolemia | 2021 (61.6) |
| Current smoking >15 cigarettes per day | 556 (16.6) |
| Male ≥65 y or female ≥70 y | 1696 (51.6) |
Figure 2 shows the distribution of BMI and the prevalence of overweight, obese, and morbidly obese patients in the overall population (A), the United States (B), and outside the United States (C). Median BMI values at baseline are 27.9 (25th and 75th percentiles: 25.1 and 31.3) for the overall CHARISMA population and 29.5 (25th and 75th percentiles 26.2 and 33.6) for the United States. The prevalence of obesity was significantly higher in the United States versus the rest of the world (P < .0001).
Figure 2.
The prevalence of overweight, obese, and morbidly obese patients in the overall CHARISMA population is quite high (A). The difference between US patients (B) and non-US patients (C) is quite striking.
Discussion
The triumvirate of obesity, metabolic syndrome, and diabetes mellitus is fueling a global atherothrombosis epidemic.10 In CHARISMA, 75.6% of patients had an elevated BMI: 42.2% were overweight, 33.4% were obese, and 3.4% were morbidly obese. In the United States in particular, obesity and morbid obesity were highly prevalent. Thus, labeling of obesity as an epidemic is not premature; in fact, it is somewhat late. Distressingly, parts of the world that were felt to have a low prevalence of obesity are catching up to the Western world.11 As lifestyle modification does not appear to be embraced by patients as a means to combat obesity, in the future, pharmacologic adjuncts may increasingly need to be explored.12
In keeping with the high prevalence of obesity, a high rate of diabetes mellitus was also observed in CHARISMA. In the patients with symptomatic atherothrombosis, 31.0% were diabetic. In the asymptomatic cohort, 82.6% were diabetic patients largely because this diagnosis was a criterion for entry into the trial. Although aspirin is recommended for primary prevention in diabetic patients, there are data to suggest that aspirin monotherapy may not be the optimal antiplatelet regimen for diabetic patients, with potentially less efficacy seen than in other populations in the Primary Prevention Project.13 Data from the CAPRIE trial demonstrated that clopidogrel is more effective than aspirin in secondary prevention, particularly in high-risk patients.14 Therefore, the combination of clopidogrel and aspirin may provide the optimal antiplatelet therapy across the range of indications. Beyond the question of optimal antiplatelet therapy in diabetic patients, other important data will be obtained because the overall CHARISMA population has 6552 diabetic patients, making it one of the largest current trials of diabetes mellitus.
The prevalence of symptomatic polyvascular disease in CHARISMA is further evidence that atherothrombosis is best viewed as a systemic disorder that may have various local manifestations. Although coronary artery disease and cerebrovascular disease each get a fair amount of attention, they are often viewed as disconnected. Indeed, a patient who survives an ischemic stroke is most likely to die of myocardial infarction.15 Similarly, patients with PAD are also likely to ultimately succumb to a cardiac death.16 As a whole, PAD is underrecognized and undertreated.17 Patients with PAD are at markedly increased risk of coronary and cerebral ischemia. With 2837 patients enrolled with symptomatic PAD, CHARISMA contains within it one of the largest trials of patients with PAD ever performed. A North American substudy currently underway will contribute to evaluating the ankle-brachial index in patients without symptomatic PAD. Thus, CHARISMA will provide valuable information about the prognosis of patients with symptomatic as well as asymptomatic PAD.
The specific value of long-term dual antiplatelet therapy in a broad range of patients will be evaluated in the CHARISMA trial. It appears that a high percentage of patients with symptomatic atherothrombosis are already receiving therapy with aspirin. Perhaps because of concerns with a possible association with higher doses of aspirin and bleeding, it appears that physicians have shifted to prescribing lower doses of aspirin.18, 19 Despite recent controversy regarding the interpretation of the data, in actual clinical practice, most asymptomatic patients at high risk of developing atherothrombosis are also receiving therapy with aspirin.20, 21
Beyond the question of optimal antiplatelet therapy, CHARISMA will enable detailed study of patients with coronary, cerebral, and PAD, as well as those at risk for developing these maladies. The incremental value of genetic markers in this population will also be assessed. Thus, across the spectrum of atherothrombosis, both symptomatic and asymptomatic, CHARISMA will provide data regarding risk factors and outcomes in a geographically diverse population. At this early stage, in the context of a randomized clinical trial with specific inclusion and exclusion criteria, CHARISMA has already provided a glimpse into contemporary medical management of atherothrombosis and has substantiated concerns about a global obesity epidemic.
The executive committee would like to acknowledge the efforts of Drs Bernard Job and Christophe Gaudin from Sanofi-Aventis and Drs Mel Blumenthal and Ravi Saini from Bristol-Myers Squibb on behalf of the CHARISMA trial.
Appendix A.
Independent Data and Safety Monitoring Board
Robert L. Frye, MD, Chairman
Pierre Amarenco, MD
Lawrence M. Brass, MD
Marc Buyse
Lawrence S. Cohen, MD
David L. DeMets, PhD
Valentin Fuster, MD, PhD
Robert G. Hart, MD
John R Marler, MD
Charles McCarthy, PhD
Albert Schömig, MD
Clinical Events Committee
A. Michael Lincoff, MD, Chairman
Sorin J. Brener, MD (cardiology)
Cathy A. Sila, MD (neurology)
Aladar Ronaszeki, Androniki Plomaritoglou, Angel Chamorro Sanchez, Anibal Albuquerque, Anna Cavallini, Anna Kaminska, Antonio Bastos Lima, Armando L. Bordalo e Sá, Barbara Hesse, Barbara Srichai, Benjamin Atkeson, Christian Jones, Claes Held, D.C.G. Basart, David Tschopp, Dmitri Artemiev, Elmar W.A. Busch, Erik Danielsson, France Woimant, Frank Zidar, Gaietà Permanyer-Miralda, Gregory Aroutiounov, Grzegorz Opala, Gudrun Boysen, Guido Belli, Gundars Rasmanis, Helge J. Nordal, Iana A. Orlova, Jan Sitar, Jan Stam, Jean Phillipe Neau, Joan Marti-Fàbregas, John Chiu, John Hostetter, Julie Huang, Kaj Groundstroem, Karel Urbanek, Katalin Sas, Kristof Karlocai, Laszlo Vecsei, Manolis Vavuranakis, Martial Hamon, Michael Haude, Miguel Viana Baptista, Mikko Syvanne, Patrick Sweeney, Peer Grande, Petr Vojtisek, Piotr Pruszczyk, Risto O. Roine, Robert Mikulik, Robert Shields, Simona Marcheselli, Thomas Bartel, Tomasz Pasierski, Trond Dahl, Tugrul Okay, Vladimir Parfenov, Xavier Bosch, Yilmaz Nisanci, Marco L. Rossi.
National Coordinators
Argentina
Sebastian F. Ameriso
Fernando A. Cura
Australia
Phillip Aylward
Graeme J. Hankey
Belgium
Benoît J. Boland
Brazil
Angelo Amato
Vicenzo De Paola
Canada
Eric A. Cohen
André Roussin
Phillip Teal
Czech Republic
Edvard Ehler
Denmark
Henrik Sillesen
Finland
Markku Nieminen
France
P. Gabriel Steg
Germany and Austria
Ulrich Hoffmann
Franz-Josef Neumann
Greece
Alexios P. Dimas
Hungary
Tamàs Forster
Italy
Diego Ardissino
Mexico
Ricardo Alvarado
The Netherlands
Harry Roger Büller
Norway
Bent Indredavik
Poland
Zbigniew A. Gaciong
Portugal
Joao Morais
Russia
Viacheslav Mareev
Spain
Amadeo Betriu
Luis M. Ruilope
South Africa
Anthony J. Dalby
Sweden
Jan B. Östergren
Switzerland
Thomas F. Luscher
Turkey
Hakan Kultursay
United Kingdom
Marcus D. Flather
Keith A.A. Fox
United States
William E. Boden
J. Donald Easton
Steven M. Haffner
Thomas A. Pearson
Steven R. Steinhubl
Investigators
Nathan Abenhaim, György Acsády, Jennifer Adgey, Benaissa Agraou, José M. Aguilera, Bashir Ahmad, James R. Allison, III, Irfan Altafullah, Jose Alvarez-Sabin, Ângelo Amato Vicenzo De Paola, Sebastian Ameriso, Jerome Anderson, Richard Arakaki, Gordon Arnold, Carlos-Gabriel Ascanio, Pierre Auger, Alexander Axelrod, Carolyn Baer, Peter Bailey, Dorothy Banish, Garry G. Banks, Michal Bar, Noe-Saul Barroso, Philip Bath, Murat Bayazit, Michel Beaudry, Louise Becnel, Hans-Juerg Beer, Jill Belch, Jury Belousov, Joseph Berlingieri, Joerg Berrouschot, H.S. Bhatia, Nor Azmi Bin Kamaruddin, Jon Bittrick, Serge Blecic, Henri Boccalon, Julien Bogousslavsky, Benoît Boland, Kristine K. Bordenave, Michel Bourgoin, Terry Bowers, Michael Brack, Jeffrey R. Brady, Franciszek Brakowiecki, D.P.M. Brandjes, Andrei Brateanu, David Brill, Robert E. Broker, Christopher Brown, Timothy E. Bruya, J. Kern Buckner, Leslie Burgess, Dennis Buth, Alberto Caccavo, Marc Cairols, Mark Cameron, Robert Capodilupo, Patrick Carpentier, Ignacio Casas Parera, Björn Cederin, Andreas Cerny, Jeff Chambers, Siew Pheng Chan, Harish Chandna, Hui-Meng Chang, Sergio Chekherdemian, Wai-Hong Chen, Raymond Cheung, Derek Chew, Thomas Chippendale, Marian Cholewa, Isabelle Cibois-Honnorat, Antonio Coca, Michael Collins, Stuart Connolly, Christian Constance, James R. Cook, John Corbelli, Robert Cote, Dennis Crimmins, Karoly Cseh, Márta Csornai, Domenico Cucinotta, Luis Cunha, Richard Curless, Bernard D. Hautefeuille, Pierre Dambrine, Antoni Davalos, Michel David, Tim Davis, P. De Deyn, Guy E. Degent, Michele Degregorio, Joshua Deleon, Hiren Desai, Thomas Devlin, Bernard Devulder, Hans-Christoph Diener, D.W.J. Dippel, Ronald Dlin, Richard Donnelly, Margaret Drehobl, Maciej Dryjski, J. Duchateau, Douglas Dulli, Paul Durrington, Bernd Eber, Edvard Ehler, Moesses Elissaf, Simon Ellis, Steve Erlemeier, MR Essop, William Felten, Paul E. Fenster, Emile Ferrari, Daniel Ferreira, Hugo Fideleff, Bohumil Filipensky, Tim Fischel, Marcus Flather, Luis-Fernando Flota, Sandro Forconi, Christian Fortin, Aloísio Francischetti, David Freilich, Fernando Antônio Frota Bezerra, Anthony Furlan, Rubens Gagliardi, Augusto Gallino, Raul Gaona, Luis Gardete Correia, Joseph Gelormini, John George, Harry Gibbs, Alberto Gil-Peralta, Anthony Glanz, Nicola Glorioso, Mark C. Goldberg, Jerome Goldstein, Mark A. Goodman, Denis Gossard, Bradley P. Grayum, Paolo Gresele, Bernd Griewing, Robert Griffin, Jr, Donata Guidetti, Dinesh Gupta, Sushil Gupta, Piotr Gutowski, Bret Haake, Vladimir Hachinski, David Hambly, Christian Hamm, Jonathan Harris, Mark V. Hart, Jasper Hein, Barbara Hejdankova, Michael Hennerici, Magdalena Heras, Sergio Hernandez, Rodolfo Herrera, James Hii, John Hoch, Joshua Hollander, Thomas Horacek, Victor N. Howard, Thomas Huber, William Hughes, Richard Hull, Robert J. Hye, Bent Indredavik, Bruce Iteld, Bradley Jacobs, Krzysztof Janik, Arkadiusz Jawien, Damian Jenkinson, Dean Johnston, Cam Joyner, Kerry Kaplan, Sadettin Karacagil, Jeff Karrasch, Clifford J. Kavinsky, Csaba Kerekes, J. King, Dariusz Kleczkowski, W. Peter Klinke, Gregory Koshkarian, Simon Kouz, Hans Kraemmer Nielsen, Wlodzimierz Krasowski, Vic Krisciunas, Marek Kruk, Hakan Kultursay, Kursad Kutluk, Hubert Kwiecinski, Ricardo La Mura, Nasser Lakkis, Daniel Landry, Matthew Lasala, Zoltan Laszlo, Pablo Lavados, Bernard Lawlor, Ken Lees, Dana Leifer, Dan Lender, Jacques Lenis, Marc Levine, Jose-Luis Leyva, Richard Libman, Thomas Little, George Locke, Jerzy Lopatynski, Theodore J. Lowenkopf, Mark Lurie, Patrick Ma, Ariane Mackey, Frank Maggiacomo, Gerhard Mahla, Elmo Mannarino, Pedro Marques Da Silva, John D. Martin, Jean-Louis Mas, Ayrton Massaro, Edward K. Massin, Thomas G. Mattio, D. Mceneaney, Eduardo Meaney, Antoine Medvedowsky, Gabriel Meinhardt, Ian Meredith, James H. Mersey, Giuseppe Micieli, Jerry Miller, John Milton, Alberto Miranda, Paul Misch, Garry Moddel, T. ĂMonchesky, Arshag D. Mooradian, João Morais, Joseph T. Morelli, Robert Moses, Luis Mota Capitão, K. Muir, Thomas Münzel, Conrad Murphy, Anne Nafziger, Kenji Nakiri, Patrice Nault, Franz-Josef Neumann, Alan Niederman, Markku Nieminen, Herwig Niessner, Joseph P. O. Bryan, Hermann Ochs, J. Miller Oppy, Jan Östergren, Paul Overlie, Theodore Pacheco, Alberto Pagnamenta, Renato Pasquali, Andrew Penn, Patrice Perron, Paddy Phillips, Marek Piepiorka, Krystyna Pilarska, Irina Pines, Julio Pita, Terry Poling, Stewart Pollock, Gary L. Post, Rakesh Prashad, Jacques Puel, J. Purvis, George Raad, Manu Rajachandran, Baldomero Ramirez, Alejandra Ranero, Salvador Rassi, David Rees, Marc Rendell, Ricardo Rey, Joseph Ricci, Tadarro Richardson, Michael E. Ring, Roberto Rivas, Thompson Robinson, Josep Rodés, Simon Roger, Ramon Romero, Thierry Rosolacci, Eli M. Roth, Janusz Rudzinski, Jose Luis Ruiz, Andrzej Rynkiewicz, Luigi Saccà, Demetrios Sahlas, Vasco Salgado, Holger Samer, Carlos-Jerjes Sanchez, Francisco Sanchez-Ruiz, EACM Sanders, André Scheen, Kenneth C.J. Scherbarth, Reinhold Schmidt, Ulrich Schubart, Adam Schussheim, John Seaworth, Paul Seigel, Mátyás Sereg, Shaukat Shah, Mukul Sharma, Leonard Shelhamer, Hamsaraj Shetty, Thomas L. Shook, Ashfaq Shuaib, Sigmund Silber, Brian Silver, Alexander Sinopalnikov, Juhani Sivenius, Veronika Skvortsova, Greg Sloan, Jan Smid, James Smith, III, João Soares Felício, R. Sommers, Anthony Spaedy, David Spence, Andrea Spissu, David Sprigings, Karl Stangl, E Stark, Susan Steen, Gabriel Steg, Scott Stenstrom, Larry Dee Stonesifer, Leonid Stratchounsky, Donald Studney, John Sullivan, D.P. Suresh, Bruce A. Sussex, Michal Szpajer, Juan-Antonio Tamez, Kay-Sin Tan, Jam Chin Tay, Girma Tefera, Jeanne Teitelbaum, Udho Thadani, Raymond Tidman, Hugh Tildesley, Steven Tishler, Christophe Tribouilloy, Anthony Turel, Hasan Tuzun, Walter Van Mieghem, B. Van Vlies, Konstantinos Vemmos, Eddy Verjans, Nicolás Vila, Francesco Violi, Jean-Yves Vogel, Peter Von Bilderling, Jorge Waitman, Phillip Walker, Michael Warren, Gerald Watts, Kenneth Weeks, Michael Weisbach, Robert J. Weiss, Robert Whitbourn, Johann Willeit, Michael Winger, David Wolinsky, Kam-Sang Woo, Peter Wozniak, Joachim Wunderlich, Jay Yadav, Louis Yao, Jorge Yovanovich, Patricio Zaefferer, Barbara Zalska, George Ziakas, George Zimakas.
References
- Benefit of clopidogrel over aspirin is amplified in patients with a history of ischemic events. Stroke. 2004;35:528–532
- Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–234
- . Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71–86
- . A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329–1339
- Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411–2420
- Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502
- Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527–533
- . Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov. 2003;2:15–28
- . Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Am Heart J. 2004;148:263–268
- Lifetime risk for diabetes mellitus in the United States. JAMA. 2003;290:1884–1890
- . Filling the world's belly. Economist. 2003;369:3–7
- . Cannabinoid receptor antagonists and obesity. Curr Opin Investig Drugs. 2004;5:389–394
- Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care. 2003;26:3264–3272
- Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol. 2002;90:625–628
- Mortality and causes of death after first ischemic stroke: the Northern Manhattan Stroke Study. Neurology. 2001;57:2000–2005
- . Peripheral arterial disease—epidemiological aspects. Vasc Med. 2001;6(3 Suppl.):3–7
- . Peripheral arterial disease in the catheterization laboratory: an underdetected and undertreated risk factor. Mayo Clin Proc. 2004;79:1107–1109
- Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease. Circulation. 2003;108:399–406
- Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108:1682–1687
- . Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med. 2002;136:157–160
- Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart. 2001;85:265–271
The CHARISMA trial is sponsored by Sanofi-Aventis and Bristol-Myers Squibb.
PII: S0002-8703(05)00284-X
doi:10.1016/j.ahj.2005.03.017
© 2005 Mosby, Inc. All rights reserved.
Refers to erratum:
- Correction
