Volume 98, Number 11, September 15, 1998
`'SSN 0009-7322
`http://www.circulationaha.org
`Volume 98, Number 11, September 15, 1998
`ISSN 0009-7322
`http://www.circulationaha.org
`
`f*
`
`American Heart
`Association
`American Heart
`Fighting Heart Disease
`Association®
`and Stroke
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`Fighting Heart Disease
`and Stroke
`
`Circulation
`circulation
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`J O U R N A L O F T H E A M E R I C A N H E A R T A S S O C I A T I O N
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`Cells
`to Endothelial
`Antibodies
`* Editorial
`AHA J0
`Johan Frostegdrd, MD, PhD, et al
`urnals Online
`Antibodies to Endothelial Cells in Borderline Hypertension
`III Editorial
`Supraventricular Tachyarrhythmias
`1092
`Johan Frostegdrd, MD, PhD, et al (cid:9)
`Rapid Communication
`1099
`ANA Journals Online (cid:9)
`Kritvikrom Durongpisitkul,
`MD,
`1047
`Supraventricular Tachyarrhythmias
`CAD
`and M1DCAB
`in Patients With Multivessel
`p
`• (cid:9)
`Kritvikrorn Durongpisitkul, MD, et al (cid:9)
`1048 • Basic Science Reports
`Brief Rapid Communication
`Howard A. Coh
`en, MD, et al
`Tis!flin'Cal
`TCA and MIDCAB in Patients With Multivessel CAD
`Anti-fii GP 1 and Atherosclerosis
`n Basic Science Reports
`'nvest'9ation
`and Reports
`1048
`Howard A. Cohen, MD, et al (cid:9)
`Jacob George, MD,
`et al
`1108
`Anti-I32 GP I and Atherosclerosis
`A?K ' act01 Pathway Inhibitor
`in
`Human
`Electromechanical Mapping
`Myocardium
`Clinical Investigation and Reports
`1108
`lerosclerotic Plaques
`Jacob George, MD, et al
`Ran Kornowsld, MD, et al
`1116
`Tissue Factor Pathway Inhibitor in Human
`, °el M- CapUce, MD. PhD. el al
`Electromechanical Mapping in Infarcted Myocardium
`Atherosclerotic Plaques
`Ml
`Cardiac Hypertrophy, Electrical Remodeling, and Acquired
`1116
`Ran Kornowski, MD, et al (cid:9)
`and Use ol Low-Dose Oral Contraceptives
`1051
`Noel M. Caplice, MD, PhD, et a! (cid:9)
`Torsade dc Pointes
`1058
`
`^Phen Sid,
`Cardiac Hypertrophy, Electrical Remodeling, and Acquired
`^ MD'
`et al
`I
`()|
`M.A. Vos. PhD. et al
`MI and Use of Low-Dose Oral Contraceptives
`<^ra'
`
`Anticoagulant Therapy in
`Patients With
`U Clm
`Torsade de Pointes
`1058
`Stephen Sidney MD, MPH, et al (cid:9)
`Cellular Basis of Biventricular Hypertrophy
`s a le Angina or Suspected Non-Q-Wave
`Ml
`M.A. Vos, PhD, et al
`Long-Term Oral Anticoagulant Therapy in Patients With
`Arrhythmogenesis
`1064
`Car V10 S' Anand- MD. MSc, FRCP(C).
`et al
`Cellular Basis of Biventricular Hypertrophy and
`Unstable Angina or Suspected Non—Q-Wave MI
`Paul G.A. Volders, MD,
`et
`al
`avascular Variability
`in
`Sleep Apnea
`Arrhythmogenesis
`Ki
`1064
`Sonia S. Anand, MD, MSc, FRCP(C), et al
`1071
`ysztofNarkiewicz,
`MD,
`PhD,
`el al
`Pr
`Paul G.A. Volders, MD, et al
`• Images in Cardiovascular Medicine
`Cardiovascular Variability in Sleep Apnea
`nostic Value ot Myocardial
`After
`an
`Acute
`Viability
`1071
`Krzysztof Narkiewicz, MD, PhD, et al (cid:9)
`^"complicated Ml
`Aortic Valve Stenosis
`in
`Alkaptonuria
`• Images in Cardiovascular Medicine
`"Senio Picano MD phD etal
`Prognostic Value of Myocardial Viability After an Acute
`
`et
`Misako Hangaishi, MD. al
`IDJX
`Aortic Valve Stenosis in Alkaptonuria
`Uncomplicated MI
`^bcixi
`Pulmonary Arterial
`Obstruction
`mab Binding
`to and GP Mb/Ilia
`Misako Hangaishi, MD, et al
`Su
`1078
`Eugenio Picano, MD, PhD, et al (cid:9)
`•Sa" "• Tarn, MS, el al..
`
`Vibeke E. Hjortdal. MD. PhD, al
`1085
`Pulmonary Arterial Obstruction
`Abciximab Binding to (43 and GP Ilb/Illa
`Vibeke E. Hjortdal, MD, PhD, et a! (cid:9)
`Susan H. Tarn, MS, et al
`
`1047
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`1051
`
`1085
`
`in
`
`Borderline
`1092
`
`et al
`
`1099
`
`in
`
`Infarcted
`
`1125
`and
`1125
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`1136
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`1136
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`1148
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`1150
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`1148
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`1150
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`et
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`MYLAN - EXHIBIT 1036
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Circulation
`Circulation
`
`J O U R N A I . oi T Hi. A M E R I C A N H E A R T A S S O C I A T I O N
`
`JOURNAL OF THE AMERICAN HEART ASSOCIATION
`
`Volume 98 • Number 11
`September 15, 1998
`Volume 98 n Number 11
`September 15, 1998
`
`Editorial
`AHA Journals Lead With Definitive New Online Site
`Editorial
`AHA Journals Lead With Definitive New Online Site
`Brief Rapid Communication
`Feasibility of Combined Percutaneous Transluminal Angioplasty and Minimally Invasive Direct Coronary
`Artery Bypass in Patients With Multivessel Coronary Artery Disease
`Brief Rapid Communication
`Howard A. Cohen, MD; Marco Zenati, MD; A.J. Conrad Smith, MI); Joan S. Lee, MD: Simon Chough, MD;
`Feasibility of Combined Percutaneous Transluminal Angioplasty and Minimally Invasive Direct Coronary
`Zuhair J afar, MD: Peter Counihan, MD; Mark hzo, MD; J.E. Burchenal, MD; Arthur M. Feldman, MD, PhD;
`Artery Bypass in Patients With Multivessel Coronary Artery Disease
`Hartley Griffith, MD
`Howard A. Cohen, MD; Marco Zenati, MD; A.J. Conrad Smith, MD; Joon S. Lee, MD; Simon Chough, MD;
`Zubair Jafar, MD; Peter Counihan, MD; Mark Izzo, MD; J.E. Burchenal, MD; Arthur M. Feldman, MD, PhD;
`Bartley Griffith, MD (cid:9)
`Clinical Investigation and Reports*
`Presence of Tissue Factor Pathway Inhibitor in Human Atherosclerotic Plaques Is Associated With
`Reduced Tissue Factor Activity
`Clinical Investigation and Reports*
`Noel M. Caplice, MD. PhD; Cheryl S. Mueske; Laurel S. Kleppe, BS; Robert D. Simari, MD
`Presence of Tissue Factor Pathway Inhibitor in Human Atherosclerotic Plaques Is Associated With
`Myocardial Infarction and Use of Low-Dose Oral Contraceptives: A Pooled Analysis of 2 US Studies
`Reduced Tissue Factor Activity
`Stephen Sidney, MD, MPH; David S. Siscovick, MD, MPH; Diana B. Petitti, MD, MPIl;
`Noel M. Caplice, MD, PhD; Cheryl S. Mueske; Laurel S. Kleppe, BS; Robert D. Simari, MD (cid:9)
`Stephen M. Schwartz, PhD, MPH; Charles P. Quesenberry, PhD; Bruce M. Psaty, MD, PhD, MPH;
`Myocardial Infarction and Use of Low-Dose Oral Contraceptives: A Pooled Analysis of 2 US Studies
`Triveilore E. Raghunathan, PhD; Joseph Kelaghan, MD, MPH; Thomas D. Koepsell, MD, MPH
`Stephen Sidney, MD, MPH; David S. Siscovick, MD, MPH; Diana B. Petitti, MD, MPH;
`Long-Term Oral Anticoagulant Therapy in Patients With Unstable Angina or Suspected Non-Q-Wave
`Stephen M. Schwartz, PhD, MPH; Charles P. Quesenberry, PhD; Bruce M. Psaty, MD, PhD, MPH;
`Myocardial Infarction: Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot
`Trivellore E. Raghunathan, PhD; Joseph Kelaghan, MD, MPH; Thomas D. Koepsell, MD, MPH (cid:9)
`Study Results
`Long-Term Oral Anticoagulant Therapy in Patients With Unstable Angina or Suspected Non—Q-Wave
`Soma S. Anand, MD, MSc, FRCP; Salim Yusuf DP hi!, FRCP; Janice Pogue, MSc; Jeffrey I. Weitz, MD, FRCP;
`Myocardial Infarction: Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot
`Marcus Flather, MBBS, MRCP; for the OASIS Pilot Study Investigators
`Study Results
`Altered Cardiovascular Variability in Obstructive Sleep Apnea
`Sonia S. Anand, MD, MSc, FRCP; Salim. Yusuf, DPhil, FRCP; Janice Pogue, MSc; Jeffrey I. Weitz, MD, FRCP;
`Krzysztof Narkiewicz, MD, PhD; Nicola Montano, MD, PhD; Chiara Cogliati, MD;
` 1064
`Marcus Flather, MBBS, MRCP; for the OASIS Pilot Study Investigators
`Philippe J.H. van de Borne, MD, PhD; Mark E. Dyken, MD; Virend K. Somers, MD, PhD
`1071
`Altered Cardiovascular Variability in Obstructive Sleep Apnea
`Prognostic Value of Myocardial Viability in Medically Treated Patients With Global Left Ventricular
`Krzysztof Narkiewicz, MD, PhD; Nicola Montano, MD, PhD; Chiara Cogliati, MD;
`Dysfunction Early After an Acute Uncomplicated Myocardial Infarction: A Dobutamine Stress
`Philippe J.H. van de Borne, MD, PhD; Mark E. Dyken, MD; Virend K. Somers, MD, PhD (cid:9)
`Echocardiographic Study
`Prognostic Value of Myocardial Viability in Medically Treated Patients With Global Left Ventricular
`Eugenio Picano, MD, PhD; Rosa Sicari, MD, PhD; Patrizia Landi, BSc; Lauro Cortigiani, MD;
`Dysfunction Early After an Acute Uncomplicated Myocardial Infarction: A Dobutamine Stress
`Riccardo Bigi, MD; Claudio Coletta, MD; Alfonso Galati, MD; Joanna Hey man, MD; Roberto Mattioli, MD;
`Mario Previtali, MD; Wilson Mathias Jr, MD; Claudio Dodi, MD; Giovanni Minardi. MD;
`Echocardiographic Study
`Eugenio Picano, MD, PhD; Rosa Sicari, MD, PhD; Patrizia Landi, BSc; Lauro Cortigiani, MD;
`Jorge Lowenstein, MD; Giovanni Seveso, MD; Alessandro Pingitore, MD; Alessandro Salustri, MD;
`Riccardo Bigi, MD; Claudio Coletta, MD; Alfonso Galati, MD; Joanna Heyman, MD; Roberto Mattioli, MD;
`Mauro Raciti, BSc; for the EDIC Study Group
`Mario Previtali, MD; Wilson Mathias Jr, MD; Claudio Dodi, MD; Giovanni Minardi, MD;
`Abciximab (ReoPro, Chimeric 7E3 Fab) Demonstrates Equivalent Affinity and Functional Blockade of
`Jorge Lowenstein, MD; Giovanni Seveso, MD; Alessandro Pingitore, MD; Alessandro Salustri, MD;
`Glycoprotein lib/Ilia and <*,0, Integrins
`Mauro Raciti, BSc; for the EDIC Study Group (cid:9)
`Susan H. Tain, MS; Patricia M. Sassoli, BS; Robert E. Jordan, PhD; Marian T. Nakada, PhD
`Abciximab (ReoPro, Chimeric 7E3 Fab) Demonstrates Equivalent Affinity and Functional Blockade of
`Antibodies to Endothelial Cells in Borderline Hypertension
`Glycoprotein Hb/IIIa and 003 Integrins
`Johan Frostegard, MD, PhD; Ruihua Wu, MD, PhD; Caroline Giliis-Haegerstrand, MD, PhD;
`Susan H. Tam, MS; Patricia M. Sassoli, BS; Robert E. Jordan, PhD; Marian T. Nakada, PhD (cid:9)
`Carola Lemne, MD, PhD; Ulf de Faire, MD, PhD
`Antibodies to Endothelial Cells in Borderline Hypertension
`Johan Frostegdrd, MD, PhD; Ruihua Wu, MD, PhD; Caroline Gillis-Haegerstrand, MD, PhD;
`*Supported in concept by an unrestricted gift from Merck & Co. Pfizer provides an unrestricted gift for subscriptions to Circulation for Cardiology
` 1092
`Fellows in training.
`Carola Lemne, MD, PhD; Ulf de Faire, MD, PhD (cid:9)
`
`1047
`
` 1047
`
`1048
`
` 1048
`
`1051
`
` 1051
`
`1058
`
` 1058
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`1064
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` 1071
`
`1078
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` 1078
`1085
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` 1085
`1092
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`*Supported in concept by an unrestricted gift from Merck & Co. Pfizer provides an unrestricted gift for subscriptions to Circulation for Cardiology
`CIRCULATION (ISSN 0009-7322) is published weekly except combined the tirst two weeks in January and the last two weeks in December by Williams & Wilkins, 351 West Camden
`Fellows in training.
`Street, Baltimore, MD 21201-2436. Individuals may subscribe for their personal use at the following rates: $146 for members of an American Heart Association scientific council and
`$194 for nonmembers; international: $254 for members of an American Heart Association scientific council and $302 for nonmembers. Periodicals postage paid at Baltimore, MD,
`and additional mailing offices. POSTMASTER: Send address changes to CIRCULATION, American Heart Association, Williams & Wilkins, Subscription Fulfillment Dept, 351 West Camden
`CIRCULATION (ISSN 0009-7322) is published weekly except combined the first two weeks in January and the last two weeks In December by Williams & Wilkins, 351 West Camden
`Street, Baltimore, MD 21201-2436.
`Street, Baltimore, MD 21201-2436. Individuals may subscribe for their personal use at the following rates: $146 for members of an American Heart Association scientific council and
`$194 for nonmembers; international: $254 for members of an American Heart Association scientific council and $302 for nonmembers. Periodicals postage paid at Baltimore, MD,
`and additional mailing offices. POSTMASTER: Send address changes to CIRCULATION, American Heart Association, Williams & Wilkins, Subscription Fulfillment Dept, 351 West Camden
`Street, Baltimore, MD 21201-2436.
`
`(cid:9)
`(cid:9)
`

`
`Long-Term Oral Anticoagulant Therapy in Patients With
`Long-Term Oral Anticoagulant Therapy in Patients With
`Unstable Angina or Suspected Non-Q-Wave
`Unstable Angina or Suspected Non-Q-Wave
`Myocardial Infarction
`Myocardial Infarction
`Organization to Assess Strategies for Ischemic Syndromes
`Organization to Assess Strategies for Ischemic Syndromes
`(OASIS) Pilot Study Results
`(OASIS) Pilot Study Results
`Sonia S. Anand, MD, MSc, FRCP; Salim Yusuf, DPhil, FRCP; Janice Pogue, MSc;
`Sonia S. Anand, MD, MSc, FRCP; Salim Yusuf, DPhil, FRCP; Janice Pogue, MSc;
`Jeffrey I. Weitz, MD, FRCP; Marcus Flather, MBBS, MRCP; for the OASIS Pilot Study Investigators
`Jeffrey I. Weitz, MD, FRCP; Marcus Flather, MBBS, MRCP; for the OASIS Pilot Study Investigators
`
`Background—Patients with acute ischemic syndromes (AIS) suffer high rates of recurrent ischemic events despite aspirin
`Background—Patients with acute ischemic syndromes (AIS) suffer high rates of recurrent ischemic events despite aspirin
`treatment. Long-term therapy with oral anticoagulants in addition to aspirin may reduce this risk. We studied the effects
`treatment. Long-term therapy with oral anticoagulants in addition to aspirin may reduce this risk. We studied the effects
`of long-term warfarin at 2 intensities in patients with AIS without ST elevation in 2 consecutive randomized
`of long-term warfarin at 2 intensities in patients with AIS without ST elevation in 2 consecutive randomized
`controlled studies.
`controlled studies.
`In phase I, after the cessation of 3 days of intravenous antithrombotic therapy, 309 patients were
`Methods and Results
`Methods and Results—In phase 1, after the cessation of 3 days of intravenous antithrombotic therapy, 309 patients were
`randomized to receive fixed low-dose (3 mg/d) warfarin for 6 months that produced a mean international normalized
`randomized to receive fixed low-dose (3 mg/d) warfarin for 6 months that produced a mean international normalized
`ratio (INR) of 1.5±0.6 or to standard therapy. Eighty-seven percent of patients received aspirin in both groups. The rates
`ratio (INR) of 1.5±0.6 or to standard therapy. Eighty-seven percent of patients received aspirin in both groups. The rates
`of cardiovascular (CV) death, new myocardial infarction (Ml), and refractory angina at 6 months were 6.5% in the
`of cardiovascular (CV) death, new myocardial infarction (MI), and refractory angina at 6 months were 6.5% in the
`warfarin group and 3.9% in the standard therapy group (relative risk [RR), 1.66; 95% CI, 0.62 to 4.44; /J=().31). The
`warfarin group and 3.9% in the standard therapy group (relative risk [RR], 1.66; 95% CI, 0.62 to 4.44; P=0.31). The
`rates of death, new MI, and stroke were 6.5% in the warfarin group and 2.6% in the standard therapy group (RR, 2.48;
`rates of death, new MI, and stroke were 6.5% in the warfarin group and 2.6% in the standard therapy group (RR, 2.48;
`95% CI, 0.80 to 7.75; /,=0.10). The overall rate of rehospitalization for unstable angina was 21% and did not differ
`95% CI, 0.80 to 7.75; p=0.10). The overall rate of rehospitalization for unstable angina was 21% and did not differ
`significantly between the groups. Four patients in the warfarin group (2.6%) and none in the control group experienced
`significantly between the groups. Four patients in the warfarin group (2.6%) and none in the control group experienced
`a major bleed (RR, 2.48; 95% CI, 0.80 to 7.75), and there was a significant excess of minor bleeds in the warfarin group
`a major bleed (RR, 2.48; 95% CI, 0.80 to 7.75), and there was a significant excess of minor bleeds in the warfarin group
`(14.2% versus 2.6%; RR, 5.46; 95% CI, 1.93 to 15.5; P=0.00l). In phase 2, the protocol was modified, and 197 patients
`(14.2% versus 2.6%; RR, 5.46; 95% CI, 1.93 to 15.5; P=0.001). In phase 2, the protocol was modified, and 197 patients
`were randomized <48 hours from the onset of symptoms to receive warfarin at an adjusted dose that produced a mean
`were randomized <48 hours from the onset of symptoms to receive warfarin at an adjusted dose that produced a mean
`INR of 2.3±0.6 or standard therapy for 3 months. Eighty-five percent received aspirin in both groups. The rates of CV
`INR of 2.3±0.6 or standard therapy for 3 months. Eighty-five percent received aspirin in both groups. The rates of CV
`death, new Ml, and refractory angina at 3 months were 5.1 % in the warfarin group and 12.1% in the standard group (RR.
`death, new MI, and refractory angina at 3 months were 5.1% in the warfarin group and 12.1% in the standard group (RR,
`0.42; 95% CI, 0.15 to 1.15; P=0.()8). The rates of all death, new MI, and stroke were 5.1%J in the warfarin group and
`0.42; 95% CI, 0.15 to 1.15; P=0.08). The rates of all death, new MI, and stroke were 5.1% in the warfarin group and
`13.1% in the standard therapy group (RR, 0.39; 95% CI, 0.14 to 1.05; P=0.05). Significantly fewer patients were
`13.1% in the standard therapy group (RR, 0.39; 95% CI, 0.14 to 1.05; P=0.05). Significantly fewer patients were
`rehospitalized for unstable angina in the warfarin group than in the control group (7.1% and 17.2%, respectively; RR,
`rehospitalized for unstable angina in the warfarin group than in the control group (7.1% and 17.2%, respectively; RR,
`0.42; 95% CI, 0.18 to 0.96; f,=0.03). Two patients in the warfarin group and I in the control group experienced a major
`0.42; 95% CI, 0.18 to 0.96; P=0.03). Two patients in the warfarin group and 1 in the control group experienced a major
`bleed, and there was a significant excess of minor bleeds in the warfarin group (28.6% versus 12.1%; RR, 2.36; 95%
`bleed, and there was a significant excess of minor bleeds in the warfarin group (28.6% versus 12.1%; RR, 2.36; 95%
`CI, 1.37 to 4.36; P=0.004).
`CI, 1.37 to 4.36; P=0.004).
`Conclusions—Long-term treatment with moderate-intensity warfarin (INR, 2.0 to 2.5) plus aspirin but not low-intensity
`Conclusions—Long-term treatment with moderate-intensity warfarin (INR, 2.0 to 2.5) plus aspirin but not low-intensity
`warfarin (INR, 1.5) plus aspirin appears to reduce the rate of recurrent ischemic events in patients with AIS without ST
`warfarin (INR, 1.5) plus aspirin appears to reduce the rate of recurrent ischemic events in patients with AIS without ST
`elevation. {Circulation. 1998;98:1064-1070.)
`elevation. (Circulation. 1998;98:1064-1070.)
`Key Words: warfarin • ischemia • thrombosis • angina
`Key Words: warfarin n ischemia n thrombosis n angina
`
`Acute ischemic syndromes (AIS) represent a continuum
`
`A cute ischemic syndromes (AIS) represent a continuum
`xVof acute myocardial ischemia (MI), which includes
`of acute myocardial ischemia (MI), which includes
`acute transmural MI with ST elevation, MI without ST
`acute transmural MI with ST elevation, MI without ST
`elevation, and unstable angina. In patients with unstable
`elevation, and unstable angina. In patients with unstable
`angina, although short-term intravenous heparin and aspirin
`angina, although short-term intravenous heparin and aspirin
`are effective1 in reducing the incidence of cardiovascular
`are effective' in reducing the incidence of cardiovascular
`(CV) death and new Ml, patients continue to suffer recurrent
`(CV) death and new MI, patients continue to suffer recurrent
`
`ischemic events over the long term. It is believed that these
`ischemic events over the long term. It is believed that these
`recurrent ischemic events are a consequence of an ongoing
`recurrent ischemic events are a consequence of an ongoing
`thrombotic stimulus,2 a concept supported by the long-term
`thrombotic stimulus,' a concept supported by the long-term
`benefits of aspirin therapy.' Despite the use of aspirin,
`benefits of aspirin therapy.' Despite the use of aspirin,
`however, the rate of recurrent ischemic events remains high.
`however, the rate of recurrent ischemic events remains high.
`For example, in the OASIS registry, 9.5% of patients suffered
`For example, in the OASIS registry, 9.5% of patients suffered
`CV death, MI, or stroke in the 6 months after their initial
`CV death, MI, or stroke in the 6 months after their initial
`
`Received October 28, 1997; revision received March 13, 1998; accepted May 10, 1998.
`Received October 28, 1997; revision received March 13, 1998; accepted May 10, 1998.
`From the Preventive Cardiology and Therapeutics Program, Hamilton Civics Hospital Research Centre, and Division of Cardiology, McMaster
`From the Preventive Cardiology and Therapeutics Program, Hamilton Civics Hospital Research Centre, and Division of Cardiology, McMaster
`University, Hamilton, Canada.
`University, Hamilton, Canada.
`See the Appendix for a complete list of participants.
`See the Appendix for a complete list of participants.
`Correspondence to Sonia Anand, McMaster Clinic-2nd Floor, 237 Barton St E, Hamilton, Ontario, L8L 2X2, Canada. E-mail anands@flis.mcmaster.ca
`Correspondence to Sonia Anand, McMaster Clinic-2nd Floor, 237 Barton St E, Hamilton, Ontario, L8L 2X2, Canada. E-mail anands@fhs.mcmaster.ca
`© 1998 American Heart Association, Inc.
`0 1998 American Heart Association, Inc.
`
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`
`hospitalization for unstable angina,'1 and an additional 7.2%
`were rehospitali/ed for unstable angina. Furthermore, mark­
`hospitalization for unstable angina,' and an additional 7.2%
`ers of thrombin generation (F 1.2) remain elevated for months
`were rehospitalized for unstable angina. Furthermore, mark-
`in patients with unstable angina, indicating an ongoing
`ers of thrombin generation (F 1.2) remain elevated for months
`thrombotic stimulus.5,6 Therefore, the combination of oral
`in patients with unstable angina, indicating an ongoing
`anticoagulants to suppress activation of the coagulation sys­
`thrombotic stimulus.5•`' Therefore, the combination of oral
`tem and aspirin to block platelet activation may be better than
`anticoagulants to suppress activation of the coagulation sys-
`aspirin alone for long-term reduction of ischemic events in
`tem and aspirin to block platelet activation may be better than
`patients with A1S.
`aspirin alone for long-term reduction of ischemic events in
`Therefore, we tested first the efficacy, feasibility, and
`patients with AIS.
`safety of fixed-dose low-intensity warfarin and then, in a
`Therefore, we tested first the efficacy, feasibility, and
`second trial, the effects of moderate-intensity warfarin (inter­
`safety of fixed-dose low-intensity warfarin and then, in a
`national normalized ratio [INRJ, 2 to 2.5) in patients with AIS
`second trial, the effects of moderate-intensity warfarin (inter-
`without ST elevation.
`national normalized ratio [INR], 2 to 2.5) in patients with AIS
`without ST elevation.
`
`Methods
`The 2 OASIS pilot studies were randomized trials of hirudin (low
`Methods
`dose, 0.20-mg/kg bolus, 0.1-mg • kg 1 • h 1 infusion; medium dose,
`The 2 OASIS pilot studies were randomized trials of hirudin (low
`infusion) versus heparin
`().4-mg/kg bolus, 0.15-mg • kg^1 • h 1
`dose, 0.20-mg/kg bolus, 0.1-mg • kg" • h- ' infusion; medium dose,
`(5000-U bolus, 1200 U/h) and warfarin versus standard therapy in
`0.4-mg/kg bolus, 0.15-mg • kg' • h" infusion) versus heparin
`patients with AIS without ST elevation using a partial 2X2 factorial
`(5000-U bolus, 1200 U/h) and warfarin versus standard therapy in
`design. Results of the safety and efficacy for heparin and different
`patients with AIS without ST elevation using a partial 2><2 factorial
`doses of hirudin have previously been published.7 All eligible
`design. Results of the safety and efficacy for heparin and different
`patients who participated in the OASIS pilot study were approached
`doses of hirudin have previously been published.' All eligible
`for consent to participate in the warfarin substudy. Patients were
`patients who participated in the OASIS pilot study were approached
`eligible if they were admitted to hospital within 12 hours of an
`for consent to participate in the warfarin substudy. Patients were
`episode of chest pain suspected to be due to unstable angina or MI
`eligible if they were admitted to hospital within 12 hours of an
`without ST-segment elevation on their admission ECG. The diagno­
`episode of chest pain suspected to be due to unstable angina or MI
`sis of unstable angina was based on symptoms of angina that were
`without ST-segment elevation on their admission ECG. The diagno-
`worsening or occurring with minimal activity associated with either
`sis of unstable angina was based on symptoms of angina that were
`current ECG evidence of ischemia or previously documented objec­
`worsening or occurring with minimal activity associated with either
`tive evidence of coronary artery disease. Patients who suffered major
`current ECG evidence of ischemia or previously documented objec-
`bleeding on or within 48 hours of the initial intravenous infusion,
`tive evidence of coronary artery disease. Patients who suffered major
`those who had a clear clinical indication for warfarin treatment, and
`bleeding on or within 48 hours of the initial intravenous infusion,
`those in whom CABG surgery was planned before or within 1 week
`those who had a clear clinical indication for warfarin treatment, and
`of hospital discharge were excluded.
`those in whom CABG surgery was planned before or within 1 week
`In phase I of the study, consenting patients were randomized to a
`of hospital discharge were excluded.
`fixed dose of warfarin (3 mg), which was aimed to achieve a
`In phase 1 of the study, consenting patients were randomized to a
`low-intensity level of anticoagulation (target INR, 1.5) or standard
`fixed dose of warfarin (3 mg), which was aimed to achieve a
`therapy for 180 days. Warfarin therapy was started 5 to 7 days after
`low-intensity level of anticoagulation (target INR, 1.5) or standard
`randomization to the initial 72-hour intravenous infusion of heparin
`therapy for 180 days. Warfarin therapy was started 5 to 7 days after
`or hirudin because of concerns about potential hazards ol combining
`randomization to the initial 72-hour intravenous infusion of heparin
`hirudin with warfarin. The recommended loading dose for warfarin
`or hirudin because of concerns about potential hazards of combining
`was 10 mg on day 1, followed by a maintenance dose of 3 mg/d for
`hirudin with warfarin. The recommended loading dose for warfarin
`6 months. Aspirin treatment was advised for all participants. INR
`was 10 mg on day I, followed by a maintenance dose of 3 mg/d for
`monitoring was recommended at 3 to 6 days alter initiation ol
`6 months. Aspirin treatment was advised for all participants. INR
`warfarin and at 2 weeks and 1, 3, and 6 months or more frequently
`monitoring was recommended at 3 to 6 days after initiation of
`at the discretion of the responsible physician.
`warfarin and at 2 weeks and I, 3, and 6 months or more frequently
`In phase 2, consenting patients were randomized to moderate-
`at the discretion of the responsible physician.
`intensity anticoagulation (target INR, 2 to 2.5) by adjusting the INR
`In phase 2, consenting patients were randomized to moderate-
`or standard therapy for 3 months. Warfarin therapy was initiated 12
`intensity anticoagulation (target INR, 2 to 2.5) by adjusting the INR
`to 24 hours after the initiation of the intravenous infusion of heparin
`or standard therapy for 3 months. Warfarin therapy was initiated 12
`or hirudin. The recommended dose was 10 mg on day 1, 3 mg on day
`to 24 hours after the initiation of the intravenous infusion of heparin
`2, and 3 mg on day 3. Thereafter, dose adjustments of warfarin were
`or hirudin. The recommended dose was 10 mg on day 1, 3 mg on day
`left to the discretion of the treating physicians to target an INR value
`2, and 3 mg on day 3. Thereafter, dose adjustments of warfarin were
`of 2 to 2.5. The goal was to increase the INR into the therapeutic
`left to the discretion of the treating physicians to target an INR value
`range (INR, 2 to 2.5) by the lime of hospital discharge. However, the
`of 2 to 2.5. The goal was to increase the INR into the therapeutic
`intravenous infusion was not continued >72 hours if this target was
`range (INR, 2 to 2.5) by the time of hospital discharge. However, the
`not achieved. Aspirin treatment was advised for all patients. INR
`intravenous infusion was not continued >72 hours if this target was
`monitoring was done on days 2 and 3 after starting warfarin; on the
`not achieved. Aspirin treatment was advised for all patients. INR
`day of hospital discharge; and at 2 weeks, 35 days, and 2 and 3
`monitoring was done on days 2 and 3 after starting warfarin; on the
`months or as often as indicated for clinical reasons. Data on the
`day of hospital discharge; and at 2 weeks, 35 days, and 2 and 3
`following outcomes were documented; (1) CV death, (2) new MI as
`months or as often as indicated for clinical reasons. Data on the
`evidenced by recurrent symptoms with either new ECG changes or
`following outcomes were documented: (1) CV death, (2) new MI as
`new enzyme elevation, (3) refractory angina, (4)severe angina, and
`evidenced by recurrent symptoms with either new ECG changes or
`(5) rehospitalization with unstable angina. Refractory angina was
`new enzyme elevation, (3) refractory angina, (4)severe angina, and
`defined as a new episode of ischemic chest pain (with documented
`(5) rehospitalization with unstable angina. Refractory angina was
`characteristic ECG changes during pain) lasting >5 minutes occur-
`defined as a new episode of ischemic chest pain (with documented
`characteristic ECG changes during pain) lasting >5 minutes occur-
`
`1065
`
`Anand et al
`Anand et al (cid:9)
`
`September 15, 1998
`September 1S, 1998 (cid:9)
`1065
`ring despite "optimum" medical treatment and requiring an addi­
`tional intervention such as thrombolytic therapy for threatened Ml,
`ring despite "optimum" medical treatment and requiring an addi-
`insertion of an intra-aortie balloon pump, cardiac catheterization
`tional intervention such as thrombolytic therapy for threatened MI,
`within 24 hours, or transfer to a tertiary care center within 48 hours
`insertion of an intra-aortic balloon pump, cardiac catheterization
`of the onset of pain/symptoms. Optimum treatment was defined as at
`within 24 hours, or transfer to a tertiary care center within 48 hours
`least 2 antianginal treatments, I of which should be an intravenous
`of the onset of pain/symptoms. Optimum treatment was defined as at
`nitrate (unless contraindicated). After the initial hospitalization,
`least 2 antianginal treatments, I of which should be an intravenous
`refractory angina was defined as readmission to hospital with a
`nitrate (unless contraindicated). After the initial hospitalization,
`primary diagnosis of unstable angina leading to a cardiac procedure.
`refractory angina was defined as readmission to hospital with a
`Severe angina was defined as recurrent ischemic chest pain lasting
`primary diagnosis of unstable angina leading to a cardiac procedure.
`>5 minutes while the patient was on optimal therapy with documen­
`Severe angina was defined as recurrent ischemic chest pain lasting
`tation of new ECG changes associated with the episode of chest pain.
`>5 minutes while the patient was on optimal therapy with documen-
`Rehospitalization with unstable angina was defined as all readmis-
`tation of new ECG changes associated with the episode of chest pain.
`sions to the hospital (after initial hospitalization for study entry) with
`Rehospitalization with unstable angina was defined as all readmis-
`a diagnosis of unstable angina that was associated with typical ECG
`sions to the hospital (after initial hospitalization for study entry) with
`changes on the admission ECG or was confirmed as the primary
`a diagnosis of unstable angina that was associated with typical ECG
`diagnosis on the discharge summary by the most responsible
`changes on the admission ECG or was confirmed as the primary
`physician. The safety outcomes monitored included stroke and
`diagnosis on the discharge summary by the most responsible
`bleeding. Stroke was defined as the presence of a new focal
`physician. The safety outcomes monitored included stroke and
`neurological deficit thought to be vascular in origin with signs or
`bleeding. Stroke was defined as the presence of a new focal
`symptoms lasting >24 hours, and strokes were further classified as
`neurological deficit thought to be vascular in origin with signs or
`intracranial hemorrhage or ischemic infarction. Bleeding was clas­
`symptoms lasting >24 hours, and strokes were further classified as
`sified as major if the event was fatal or life threatening, was
`intracranial hemorrhage or ischemic infarction. Bleeding was clas-
`permanently or significantly disabling, or required transfusion of
`sified as major if the event was fatal or life threatenin