Vaughan`s expert statement

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IN THE FEDERAL COURT OF AUSTRALIA
MELBOURNE DISTRICT REGISTRY
No. VID 451 of 2006
GRAEME ROBERT PETERSON
Applicant
MERCK SHARP & DOHME (AUSTRALIA)
PTYLTD
First Respondent
MERCK & CO., INC..
Second Respondent
STATEMENT OF DOUGLAS E. VAUGHAN MD
On 17 February 2009, I, DOUGLAS E. VAUGHAN MD of 454 West Deming Place, 3E,
Chicago, Illinois 60614, USA, cardiologist, say as follows:
Section
Details
Para(s)
Page(s)
Assignment
1
1
I.
Background and Qualifications
2-3
2
II.
Pathogenesis of Cardiovascular Disease
4-5
3-4
III.
Thrombosis and Cardiovascular Events
6
4-5
IV.
Biology of COX-1 and COX-2
7-8
5-6
IVa.
COX-2 and Atherosclerosis
9-10
6-7
Filed on behalf of the respondents
Clayton Utz
Lawyers
Level 18
333 Collins Street
Melbourne VIC 3000
Tel:
(03) 9286 6000
Fax:
(03) 9629 8488
Contact: A Morrison
Email: amorrison@claytonutz.com
637/80019440
Ref:
DX 38451 333 Collins VIC
2
1.
IVb.
COX-2 and Vascular Function
11
7-8
V.
VIOXX and Cardiovascular Events
12-23
8-15
Summary
24
15
Mr. Graeme R. Peterson
25-36
15-21
Declarations
37
21
App.1
Charts pertaining to Mr. Graeme R. Peterson
App.2
References Cited in Text
App.3
Curriculum Vitae of Douglas E. Vaughan
App.4
List of Materials Considered and Reviewed
I have been asked to provide my medical and scientific opinion as to: 1) whether there
is a relationship between VioJO( and ischemic heart disease; and 2) whether VioJO(
played any role in Mr. Peterson's acute myocardial infarction. Below is my review of
medical and scientific issues that are relevant to a consideration of these questions.
have reviewed the literature on the subject, paying particular attention to evidence
dealing with the biological plausibility of this potential relationship and the level of
certainty with which one might conclude that such a relationship exists based on the
evidence gathered from controlled clinical trials.
Section I " Background and Qualifications
2.
I graduated from the University of Oklahoma in 1976 with a BA in Psychology and
earned my Medical Degree from the University of Texas Southwestern Medical
School in 1980. I trained in Internal Medicine at Parkland Memorial Hospital in Dallas,
where I was a Chief Medical Resident. I did my fellowship training in Cardiology at
Brigham and Women's Hospital, Harvard Medical School, and during this time I began
my research in the area of thrombosis. I completed additional post-doctoral training at
the Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
3.
After completing my training, I was appointed as an Instructor at Harvard Medical
School and was promoted to Assistant Professor of Medicine in 1990. Until 1993, I
served as Co-Director for the Center for Research in Thrombolysis at Brigham and
3
Women's Hospital in Boston. I was recruited to Vanderbilt Medical School and
appointed as an Associate Professor of Medicine and Pharmacology at Vanderbilt
University Medical Center in 1993. I am Board Certified in Internal Medicine and Adult
Cardiovascular Disease, and have been a licensed cardiologist since 1987 focusing
on the care of patients with, or at risk for, coronary artery disease. I have received
several research awards in my career, including a Clinician-Scientist Award from the
American Heart Association and a Clinical Investigator Award from the Department of
Veterans Affairs Research Administration. I have been awarded fellowship status in
the American College of Cardiology, and by the Councils for High Blood Pressure
Research and Atherosclerosis, Thrombosis and Vascular Biology of the American
Heart Association. I was elected to the American Society of Clinical Investigation in
1997 and to the Association of American Physicians in 2000. I was named the C.
Sidney Burwell Professor of Medicine and Chief of the Division of Cardiovascular
Medicine at Vanderbilt in 1999, a position I held for nearly 10 years. In June of 2008, I
was appointed the Irving S. Cutter Professor and Chairman of the Department of
Medicine at the Northwestern University Feinberg School of Medicine in Chicago,
where I also serve as Physician-in-Chief of Northwestern Memorial Hospital. I have
co-authored more than 100 original publications in the area of thrombosis and
fibrinolysis. Prior to taking my new position, I directed a Specialized Center of
Clinically Oriented Research (SCCOR) in Thrombosis and Hemostasis,one of three
such centers supported by the National Heart, Lung and Blood Institute in the United
States. My investigative activity is focused on the mechanisms of thrombosis in
cardiovascular disease. I practice and teach cardiovascular medicine and focus on
the evaluation and management of patients with premature coronary artery disease
and arterial thrombosis. Additional information pertaining to my background can be
found in my Curriculum Vitae (Appendix 3).
Section II - Pathogenesis of Cardiovascular Disease
4.
Ischemic cardiovascular events predominantly occur in individuals with underlying
atherosclerosis, which is a common disease affecting arterial blood vessels.
Atherosclerosis is widely viewed as an inflammatory disease. Because high plasma
concentrations of cholesterol, in particular those of low-density lipoprotein (LDL)
cholesterol, are one of the principal risk factors for atherosclerosis, the process of
atherogenesis has been considered by many to consist largely of the accumulation of
lipids within the artery wall; however, it is much more than that. Despite changes in
lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol
concentrations, cardiovascular disease continues to be the principal cause of death in
4
the United States, Europe, Australia, and much of Asia. In fact, the lesions of
atherosclerosis represent a series of highly specific cellular and molecular responses
that can best be described, in aggregate, as an inflammatory disease.
5.
The lesions of atherosclerosis occur principally in large and medium-sized elastic and
muscular arteries and can lead to ischemia of the heart, brain, or extremities, resulting
in infarction, although the processes are not identical. They may be present
throughout a person's lifetime. In fact, the earliest type of lesion, the so-called fatty
streak, which is common in infants and young children, is a pure inflammatory lesion,
consisting only of monocyte-derived macrophages and T lymphocytes. In persons with
hypercholesterolemia, the influx of these cells is accompanied by the extracellular
deposition of amorphous and membranous lipids.
Figure 1. Stages of Atherosclerosis. From Ross, R. NEJM 340:115-126, 1999.
Section III - Thrombosis and Cardiovascular Events
6.
Thrombosis plays an important role in the pathogenesis of ischemic cardiovascular
events, including acute myocardial infarction (MI) and stroke. In most instances,
events are triggered by the rupture of thin, fibrous caps covering atherosclerotic, Iipidenriched lesions in the arterial wall (Ross 1993). The exposure of the lipid-rich
contents to the blood is pivotal in this process, as these materials promote the
5
activation of procoagulant factors that in turn lead to local thrombosis. In some
situations, the clot formed completely occludes the flow of blood down an artery and
infarction occurs. Humans and mammals generally possess a complex and balanced
array of procoagulant and anticoagulant factors that are present in the blood. There
are 3 complementary mechanisms that protect against intravascular clotting, including
the following: 1) endogenous anticoagulants, including endogenous heparin-like
substances, thrombomodulin, activated Protein C, heparin co-factor II and
antithrombin III; 2) a system of short-lived endothelial-derived platelet inhibitors,
including nitric oxide (NO), prostacyclin andADPase; and 3) an endogenous clot
dissolving system activated by plasminogen activators and mediated by plasmin
(Rosenberg and Aird 1999). It has been suggested that the 3 most important
anticoagulants against clotting in the mammalian coronary circulation are tissue-type
plasminogen activator (t-PA), thrombomodulin (which facilitates the activation of
Protein C), and the urokinase-type plasminogen activator (u-PA). The presence of
these multiple complementary mechanisms to prevent intravascular thrombosis
speaks to the redundancy of these systems. It is widely held that failure of more than
one system is required to promote coronary thrombosis, such as a combined
deficiency of tissue-type plasminogen activator and activated Protein C (Christie,
Edelberg et al. 1999; Rosenberg and Aird 1999). Experiments performed in my
laboratory support this hypothesis, as we observed spontaneous coronary arterial
thrombosis in transgenic mice that over express PAI-1, the natural inhibitor of t-PA, uPA and activated Protein C (Eren 2003).
Section IV - Biology of COX-1 and COX-2
7.
Any discussion of the role of Vioxx and COX-2 in arterial thrombotic events requires a
review of prostaglandin (PG) biology and function. Prostacyclin is derived from
arachidonic acid (AA), which is an unsaturated fatty acid that serves as the biological
precursor of a wide array of biologically active mediators commonly termed
eicosanoids. AA is metabolized by enzymes, including the cyclooxygenases (COX-1
and COX-2), lipoxygenases, and epoxygenases to generate biologically active
products that are important in cardiovascular homeostasis as well as other important
biological processes, including inflammation. The COX enzymes catalyze the
conversion of AA into the PG endoperoxide intermediates PGG 2 and PGH 2. These
are, in turn, acted on by other enzymes to form the PGs and thromboxane A z (TxA2)'
Prostacyclin exhibits both antithrombotic and vasodilating properties.
6
8.
Until the early 1990s, the existence of only one form of COX was recognized.
However, several groups made observations that led to the discovery of a second
COX enzyme (Rosen, Birkenmeier et al. 1989; Sebaldt, Sheller et al. 1990). Unlike
COX-1, which was expressed constitutively in many tissues, including the arterial wall,
COX-2 was an "inducible" form of COX whose formation was triggered by
inflammatory signals. This important discovery was rapidly embraced by the medical
scientific community to explain the mechanism for PG formation in inflammation and
cancer. COX-2 was hypothesized to be an important mediator of pain associated with
inflammation and with cellular processes linked with the development of colon cancer.
Drug screening in cellular and biological systems identified compounds that selectively
blocked the activity of COX-2. The attraction in developing such compounds was
based on the hypothesis that COX-2 selective inhibitors might be effective as
analgesic and anti-inflammatory drugs without inducing the gastrointestinal sideeffects linked with the administration of non-steroidal anti-inflammatory drugs
(NSAIDs). According to this hypothesis, inhibition of the production of COX-1-derived
protective PGE 2 and PGI 2 by NSAIDs in epithelial cells in the stomach and small
bowel was responsible for the common gastrointestinal side effects associated with
NSAID administration. Enthusiasm around this concept stimulated pharmaceutical
companies to develop and test three COX-2 inhibitors that eventually eamed US FDA
approval - celecoxib, rofecoxib, and valdecoxib. The initial approval of these drugs
was based on clinical studies demonstrating that these drugs were safe while effective
in reducing pain. Subsequently, the drugs received further US FDA approval for
additional indications.
Section IVa - COX-2 and Atherosclerosis
9.
Based on the link between COX-2 and inflammation, the potential role this enzyme
played in the pathogenesis of atherosclerotic cardiovascular disease began to be
investigated. Interest in this potential relationship was accelerated by the increasing
awareness in the cardiovascular community of the link between inflammation and
cardiovascular events. A series of prospective, large epidemiological studies
identified high sensitivity c-reactive protein (hs-CRP), a non-specific marker of
activation of the innate immune system and inflammation, as a predictor of increased
risk of cardiovascular disease in a variety of low, intermediate, and high risk
populations (Ridker, Buring et al. 1998; Ridker 2003; Ridker, Cannon et al. 2005).
Indeed, an enormous body of literature has convincingly identified inflammation as a
central factor in the initiation and progression of atherosclerotic lesions. Not
surprisingly, it was shown that COX-2 expression was increased in models of
7
experimental atherosclerosis and in human atherosclerotic lesions (Koki, Khan et al.
2002). This led to a series of experimental studies designed to explore the role of
COX-2 in the development and progression of atherosclerosis. While these
experimental studies were rigorous and well-contrOlled, the results were inconsistent.
For example, complete genetic deficiency of prostacyclin (IP) receptors in female (but
not male) mice promoted (Egan, Lawson et al. 2004) the development of
atherosclerotic lesions in a murine model of hypercholesterolemia. Others reported
an increase in atherosclerotic lesions in mice using the COX-2 inhibitor MF-Tricyclic
(Rott, Zhu et al. 2003). In contrast, others found that COX-2 inhibition with rofecoxib
protected against the development of atheroscleroSis (Burleigh, Babaev et al. 2002;
Burleigh, Babaev et al. 2005). No experimental studies have shown a relationship
between rofecoxib and initiation or progression of atherosclerosis.
10.
Independent of effects of COX-2 on the development of atherosclerosis, there was
other published data indicating that COX-2 activity actually increased in heart tissue
after an acute myocardial infarction, and that COX-2 inhibition might be helpful in the
prevention of cardiac dysfunction (Saito, Rodger et al. 2000). Furthermore, there is
experimental evidence that COX-2 activity in an atherosclerotic lesion can increase
the production of PGs that may induce the expression of matrix metalloproteinases
(MMPs) that might directly destabilize a plaque. Therefore, one might hypothesize
that COX-2 inhibition would actually stabilize atherosclerotic lesions. Based on these
studies and others, there was moderate to high enthusiasm in the cardiovascular
community for the potential benefits of COX-2 inhibitors in the prevention and
treatment of cardiac disease. In fact, there were clinical trials to suggest that COX-2
inhibition would be of benefit in the treatment of patients with cardiovascular disease,
reducing markers of systemic inflammation such as hs-CRP, while simultaneously
having no deleterious effects on endothelial function (Bogaty, Brophy et al. 2004).
Other investigators have found similar results in humans both with and without
coronary disease.
Section IVb - COX-2 and Vascular Function
11.
As noted above, prostacyclin is recognized as one of several biological mediators of
vasodilatation and platelet inhibition. Traditionally, it had been widely held that COX-1
was the exclusive source of vascular prostacyclin production. Relatively recently,
Fitzgerald and colleagues reported a series of studies measuring urinary metabolites
of prostacyclin suggesting that COX-2 might also contribute to vascular prostacyclin
production in healthy human beings (McAdam, Catella-Lawson et al. 1999). These
8
findings prompted the speculation that COX-2 inhibitors might produce some
undesirable cardiovascular effects by reducing the production of the antithrombotic
prostaglandin prostacyclin while simultaneously failing to inhibit COX-1-dependent
thromboxane production. This imbalance has been proposed to explain how COX-2
inhibitors might promote platelet aggregation and thrombosis in individuals that might
be predisposed to clot based on genetic or acquired factors. While this perspective
has some theoretical merit, there are numerous unresolved questions that limit the
interpretation of these findings. For example, prostacyclin is generally viewed as an
autocoid, meaning that it is generated and acts locally. At this time, I am not aware of
any studies that have ever been done to define the relevance or magnitude, if any, of
COX-2 dependent prostacyclin production in the human coronary circulation.
Importantly, there is no evidence to suggest that COX-2 is in fact present in normal
human arterial vasculature. Indeed, numerous studies indicate that human arteries
exclusively generate COX-1. Furthermore, the studies that suggested that COX-2
inhibition reduced systemic prostacyclin production were based on reductions in the
measurement of a stable prostacyclin metabolite in the urine. The precise location of
the tissue responsible for this effect and altered prostacyclin synthesis has not been
determined. Studies in humans suggest that COX-2 inhibitors do not, however, affect
prostacyclin production in the human vasculature (Chenevard, Hurlimann et al. 2003;
Tuleja, Mejza et 81. 2003; Kuklinska, Musial et al. 2005). Furthermore, it has been
shown that COX-2 inhibition has no effect on endothelial vasodilator function in adults
(Verma, Raj et al. 2001), a pararneter that is at least partially dependent upon
vascular prostacyclin production and has been shown in numerous studies to reflect
overall vascular health and prognosis (Schachinger, Britten et al. 2000). Taken
together, the data from experimental and preclinical studies have thus far failed to
generate a consistent picture or understanding of the potential impact that COX-2
inhibitors might or might not have on the progression of human cardiovascular
disease.
Section V - VIOXX and Cardiovascular Events
12.
With respect to Vioxx specifically, early pre-approval Phase lib/III studies did not show
evidence of increased cardiovascular risk. Reicin and colleagues assessed the risk
for thrombotic cardiovascular events among patients receiving rofecoxib, nonselective
NSAIDs, and placebo, in 5,435 partiCipants in 8 phase IIBIllI osteoarthritis trials
(Reicin 2002). The median treatment exposure was 3112 months. The primary end
point assessed was the risk of any arterial or venous thrombotic cardiovascular
9
adverse event (AE). A second analysis assessed differences in the Anti-Platelet
Trialists' Collaboration (APTC) events, a cluster end point that consists of the
combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2)
myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic
cardiovascular AEs were reported with rofecoxib, placebo, and comparator
nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared
rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100
patient-years in the rofecoxib treatment group compared with 2.27/100 patient-years
in the combined nonselective NSAID group. In trials that compared rofecoxib with
placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years
in the rofecoxib group compared with 2.57/100 patient years in the placebo group (see
Table below). Consistent with the risks of cardiovascular AEs, similar rates of APTC
events were reported with rofecoxib, placebb, and comparator nonselective NSAIDs.
TABlE.4 Incidence and Relative Risk of Investigator-Repo~d Cordiovascular
Thrombctic Events
Potientr.
No.
Treatment
Rebtivo& RitJc*
With
Evanis
9~CI
PatientYflj'" Rote&t EUimate
A Comporl!,on of Rofe<:oxIb With Nomo&lectrve. NSAIDS
Ovaroll fX?pulafion
3,357 32
1,657
1.93 1.15
Nonselective NSAlD 1,564
16
706
2.27
SubgroopAooraT$· Based on History of SymptomatiC Afhe.ro&clerofic
Rofeooxib
10.63, 2.09)
COrdlOV06oCU or DiMlosel
AspIrin indioated
Ro!.coxlb
235
127
10
6
121
49
9.27
12.47
1.45
[0.53,4.00]
Aspirin nct indiooted
Rofecoxlb
3,072
NonMlective NSAID 1,437
22
10
1,536
659
1.43
1.52
1.04
[0.49,2.21]
14
2,253
516
2.71 0.94
4
711
156
2.57
Subgroop Aoorai& Based on History of Sympbmatic A'lhe.ro$Clarotic
Cordrovasc::u or Dhe05&I
Aspirin indicated
Ro!.coxlb
190
3
39
7.99 1.24
Placebo
55
1
10
9.92
Aspirin not indiooted
Ro!.coxlb
2,063
11
479
2.3
0.99
Placebo
656
3
146
2.06
[0.31,2.92}
NonsekKtiv& NSAID
B. Complfi50n of
Rof",,,.;b wilh Placebo
Ovaron IX?pulation
Rofeooxib
PIo""bo
[0.02,15.47]
[0.24, 3.26]
·Pd~n~ at risk.
tper 100 po6em~~.
tReiatiw risk ofc:oenpcnrtor (nOn5ebdiw NSA.ID or ploc::ebo) with ~~ctb robxib.
iJhs "A,prin .,diw.,d" cohort ~n" pcrtienll witb 0 post medicol hl~ of Cerebtova.:CUIOT
occident, fronsicot ilchsnic
mto:ordiol .,Fcrdion, umlabb oneino, stobie a'lgino, COI'alOI)'
orfllry bypasl grolt 51.1'tF1)'. or ~ncOU5 col'Cll'lC7Y i~n.'etltion.
a = conQdcncc im:llvol.
otbdc.
(from Reicin et al. AJC 2002)
10
13.
The first large post-approval study was the Vioxx Gastrointestinal Outcome Research
(VIGOR) study, reported in the NEJM in 2000 (Bombardier, Laine et al. 2000). This
prospective, randomized trial enrolled over 8,000 patients with rheumatoid arthritis
and compared the effects of rofecoxib (50 mg daily) versus naproxen (500 mg twice
daily) on the incidence of upper gastrointestinal bleeding. The VIGOR study reported
a 2-fold difference in the incidence of serious GI adverse events favoring rofecoxib
versus naproxen. However, for the purposes of this discussion, the administration of
rofecoxib was associated with a 5-fold increase in the incidence of myocardial
infarction (20 versus 4 events). These results generated considerable interest, with
some researchers suggesting that rofecoxib was neutral and that the results reflected
a cardioprotective effect of naproxen, based on its extended duration of action,
permitting this mixed inhibitor of COX-1 and COX-2 to behave like aspirin. This data
was reviewed by the FDA and Vioxx approval was continued with a labeling change in
the United States in April of 2002. It is important to note that the VIGOR study
randomized participants to a dose of Vioxx that was 2x higher than the highest
recommended dose for osteoarthritis and rheumatoid arthritis, and it involved longer
term administration of the 50mg dose (average 9 months), which had not been
previously studied or recommended.
14.
Further investigation into a potential cardiovascular risk associated with the
administration of COX-2 inhibitors was prompted by a comparison of trial data for both
Vioxx and Celebrex, including the VIGOR and CLASS studies, with a control group,
based on data drawn from the placebo groups of 4 primary prevention trials of lowdose aspirin
(Mukhe~ee,
Nissen et al. 2001). Figure 3 of this analysis compared the
rate of MI for Vioxx and Celebrex and compared them to the placebo group of the
combined aspirin trials.
11
Comparison of MI RatesAmong Subjects Receiving Placebo vs Rofecoxib or Celecoxib
1.4
P=.04
I
(Placebo)
(Rofecoxib)
(Celecoxib)
4047
3987
No. of Patients 23407
Mukhe~,e~ D. et aL JAMA 2001~G:954-%9.
15.
This indirect analysis was subjected to considerable methodological criticism, partly
because the groups being compared were quite different in terms of disease burden
and apparent cardiovascular risk. However, the controversy around VIGOR and this
paper triggered a series of observational studies.
While these studies created a
great deal of discussion, in practice, observational studies are generally viewed as
hypothesis-generating and incapable of speaking to causation. The first of these
observational studies utilized a retrospective cohort study performed using the
Tennessee Medicaid database. Ray et al. reported that the use of rofecoxib was
associated with no apparent increase in risk at recommended chronic doses, while
doses greater than 25 mg daily were associated with increased risk of coronary heart
disease (Ray, Stein et al. 2002). Next, a retrospective cohort population-based study
of over 66,000 elderly patients and 100,000 controls (Mamdani, Rochon et al. 2003)
did not identify any differences in rates of myocardial infarction in patients taking
COX-2 inhibitors, naproxen, and NSAIDs. In 2004, Solomon and colleagues
published a retrospective case-control study involving nearly 55,000 elderly Medicare
reCipients (Solomon, Schneeweiss etal. 2004). These investigators found no
significant differences in CV risk when comparing rofecoxib to no current use,
ibuprofen, naproxen, or other NSAIDs. However, rofecoxib was associated with
increased risk (OR 1.24) of acute MI compared to celecoxib for 90 days but not
thereafter. An abstract of this study found no increased risk for Vioxx
S;
25 mg
compared to no use (OR 1.11 [0.96-1.28]) (Solomon). Interestingly, this study failed
to identify a CV benefit with statin administration, while hormone replacement therapy
12
provided a benefit. Kimmel et al. also published a case-control study to investigate
the effect of COX-2 inhibitors on risk of nonfatal myocardial infarction (Kimmel, Berlin
et al. 2005). This study examined over 1,700 cases and 6,800 controls and found no
evidence of increased risk of CV events comparing rofecoxib to nonusers of NSAIDs.
There are numerous recent examples of failures of observational studies to predict the
results of appropriately designed, randomized clinical trials, including the failure of
hormone replacement therapy to reduce cardiovascular risk in women (Hulley, Grady
et al. 1998), even though observational studies had. previously suggested a benefit
and had even motivated (inappropriate) practice guidelines. Many additional
observational studies have attempted to analyze the relationship between traditional
NSAIDs and Vioxx 25 mg daily and cardiovascular outcomes such as myocardial
infarction, with both positive (Levesque RR 1.21 (2006), Valentgas RR 1.54 (2005),
Andersohn RR 1.58 (2006)) and negative results reported.
16.
After the report of Mukherjee et al. in October of 2001, Konstam and colleagues
(Konstam, Weir et al. 2001) published a combined analysis of individual patient data
to determine whether there was an excess of CV thrombotic events in patients treated
with rofecoxib compared with those treated with placebo or nonselective NSAIDs. CV
thrombotic events were assessed across 23 phase lib to V rofecoxib studies.
Comparisons were made between patients taking rofecoxib and those taking either
placebo, naproxen, or another nonselective NSAID used in the development program
(diclofenac, ibuprofen, and nabumetone). The major outcome measure was the
combined APTC end point. More than 28 000 patients, representing >14000 patientyears at risk, were analyzed. The relative risk for the APTC end point was 0.84 (95%
CI: 0.51, 1.38) when comparing rofecoxib with placebo; 0.79 (95% CI: 0.40, 1.55)
when comparing rofecoxib with non-naproxen NSAIDs; and 1.69 (95% CI: 1.07, 2.69)
when comparing rofecoxib with naproxen. This analysis did not provide evidence for
an excess of CV events for rofecoxib relative to either placebo or the non-naproxen
NSAIDs that were studied. The investigators concluded that differences observed
between rofecoxib and naproxen were likely the result of the anti platelet effects of the
latter agent.
17.
This relationship was reviewed further in an analysis performed by Weir and
colleagues (Weir, Sperling et al. 2003). Reviewing the data from numerous sources,
including 5435 osteoarthritis trial partiCipants, the VIGOR gastrointestinal outcomes
trial, and the pooled analysis described in the previous paragraph (including some
additional data) from 23 studies (including VIGOR) encompassing multiple disease
states and including more than 14,000 patient-years at risk, they concluded that
13
rofecoxib was not associated with excess CV thrombotic events compared with either
placebo or non-naproxen NSAI Ds. Again, naproxen appeared to be the outlier,
suggesting a cardioprotective benefit of naproxen.
18.
After the withdrawal of Vioxx, Juni and colleagues (Juni, Nartey et al. 2004) used
standard and cumulative random-effects meta-analyses of randomised controlled
trials and observational studies to search for evidence that potential adverse effects of
rofecoxib was available before September, 2004. They searched bibliographic
databases and relevant files ofthe US Food and Drug Administration, and included all
randomized controlled trials in patients with chronic musculoskeletal disorders that
compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or
placebo, and cohort and case-control studies of cardiovascular risk and naproxen.
Myocardial infarction was the primary endpoint. They identified 18 randomized
controlled trials and 11 observational studies. The authors concluded that by the end
of 2000, based on identification of 52 myocardial infarctions in 20742 patients, the
relative risk of Vioxx versus all comparators from the randomized controlled trials was
2.30 (95% CI1.22-4.33, p=0.010), and 1 year later (64 events, 21432 patients) it was
2.24 (1.24-4.02, p=0.007). When limited to placebo-controlled studies, the authors
reported a non-significant relative risk of rofecoxib of 1.04 [95% CI 0.32-3.12]; and
Similarly found non-significant risks when compared to non-naproxen NSAIDs and for
doses of Vioxx of 25mg and lower. In the observational studies reviewed by Juni and
colleagues, they found that the cardioprotective effect of naproxen was small
(combined estimate 0.86 [95% CI 0.75-0.99]) and suggested that such an effect could
not have explained the findings of the VIGOR trial. It should be noted that Juni and
colleagues did not include the long-term placebo-controlled trials in patients with
cognitive impairment in their analysis.
19.
The relationship between COX-2 inhibitors and CV risk was investigated further in at
least 8 separate placebo-controlled trials. Two placebo-controlled studies of
valdecoxib were performed in high-risk patients undergoing CABG (Ott, Nussmeier et
al. 2003; Nussmeier, Whelton et al. 2005). Despite their small study sizes (462 and
1636 patients, respectively) and short duration (10 and 14 days of treatment,
respectively), pooled analysis ofthese 2 similar studies suggested that valdecoxib
increased the incidence of myocardial infarction and stroke by 3-fold in this high-risk
population. These studies have been interpreted by some experts as indicative of a
rapid emergence of increased cardiovascular risk based on suppression of COX-2derived PGI 2 in a population with preexisting, intense hemostatic activation. However,
this hypothesis has never actually been tested. Interestingly, a similar randomized,
14
double-blind placebo controlled trial of rofecoxib in patients undergoing CABG failed
to identify evidence of increased risk of Vioxx in this setting (Wong, Asmat et al.
2006).
20.
Additional studies have generated data concerning a potential link between the
administration of a COX-2 inhibitor and cardiovascular events. The Adenomatous
Polyp Prevention on Vioxx (APPROVe) and Adenoma Prevention with Celecoxib .
(APC) (Solomon, McMurray et al. 2005) studies both enrolled patients with colonic
adenomata. These 2 studies revealed the delayed emergence of an increased
incidence of cardiovascular events associated with the administration of rofecoxib and
celecoxib. It is interesting to note that aspirin, which has been shown to reduce the
risk of MI, failed to provide cardiovascular benefit when tested in a large, randomized
trial of patients with colonic adenomata (Baron, Cole et al. 2003). This reinforces the
challenges inherent in performing and interpreting clinical trials, and that outcomes
can be influenced by many factors, including sample size, the population tested, and
the play of chance.
21.
Finally, the effects of rofecoxib on the prevention of Alzheimer's disease was studied
in two, separate randomized, placebo-controlled trials involving over 1,400 patients
(Protocol 078) and 682 patients (Protocol 091). While the patients enrolled in these
studies were relatively elderly and statistically at greater risk for CV events, there was
no evidence of increased risk of a CV event associated with randomization to
rofecoxib (Reines, Block et al. 2004; Thai, Ferris et al. 2005). Interirn data from these
studies were included in the previously published meta-analysis of Konstam atal. and
Weir et al. described above.
22.
Two additional placebo-controlled trials with rofecoxib have recently been published
(the ViP Trial (Total N = 4741) and the VICTOR trial (Total N = 2327». Both of these
trials compared Vioxx 25mg and placebo, and were terminated early when rofecoxib
was withdrawn from the market in September of 2004. The ViP trial was designed to
examine the effects of Vioxx in the prevention prostate cancer. In terms of
cardiovascular thrombotic events, there was no significant difference between Vioxx
and placebo (RR 0.94 [95% CI 0.45-1.94]) (van Adelsberg, Gann et al. 2007).
The
VICTOR trial was designed to examine the effects of Vioxx in the recurrence of rates
of colorectal cancer. In terms of cardiovascular thrombotic events, after adjustment
for baseline cardiovascular risk factors, there was no significant difference between
Vioxx and placebo (RR 2.41 [95% CI 0.93-6.26]) (Kerr, Dunn et al. 2007).
15
23.
There have also been recent publications presenting meta-analyses of the numerous
randomized trials involving COX-2 inhibitors. One consistent finding in these large
meta-analyses is that COX-2 inhibitors do not differ in terms of risk for cardiovascular
thrombotic events from that associated with the administration of traditional NSAIDs
(Keamey, Baigent et al. 2006; Chen and Ashcroft 2007). The question that requires
consideration at this point can be framed as follows: how strong is the evidence
linking the administration of rofecoxib with an increased risk of cardiovascular events?
Using evidence-based standards as conventionally and widely applied, in order for a
finding to be accepted into practice, it needs to be validated by conceptual biological
plausibility and exhibit consistent effects across populations tested. While some
relationship between Vioxx and cardiovascular events may be theoretically plausible,
as discussed above, it is equally plausible that COX-2 inhibitors may be cardio- or
atheroprotective in selected populations, and in any event, causality has not been
established. One could easily argue, based on experimental evidence, that the drug
might protect against the progression of cardiovascular disease, either by reducing
inflammation or by reducing the progression of atherosclerotic lesions. To the
practictioner of evidence-based medicine, the data do not meet currently applied
standards to prove the relationship between Vioxx and cardiovascular events.
Summary
24.
Prostacyclin is one of many factors that playa role in the prevention of intravascular
thrombosis. While this factor was traditionally thought to be generated exclusively by
the action of COX-1, there is evidence to suggest that COX-2 may also contribute to
the production of prostacyclin in humans under certain circumstances and in some
specific organs. Preclinical data provided the basis for some cautious enthusiasm
that COX-2 inhibitors might have novel protective effects in preventing the progression
of atherosclerosis and ischemic heart disease, particularly in view of the link between
COX-2 and inflammation. Taken together, clinical trials are inconsistent as to whether
the administration of COX-2 inhibitors alters the risk of cardiovascular events when
administered long-term. There is little evidence of apparent increased risk when
COX-2 inhibitors are taken for short duration at the recommended doses (as is the
current opinion of the U.S. FDA as reflected in their April 6, 2005, memorandum). It is
my opinion that a knowledgeable practitioner of the art would view the totality of
evidence with equipoise, and conclude that the cumulative data fail to establish such a
relationship. The factors that contribute to the development of an acute MI or stroke
in a given patient are exceedingly complex and involve multiple known and unknown
16
factors, unrelated to the administration of a COX-2 inhibitor. Accordingly, I would
respectfully submit that, based on my expertise and my review of the evidence, the
data linkirig Vioxx with increased cardiovascular risk fail to meet currently accepted,
evidence-based standards of practice. Furthermore, the totality of the data fails to
establish causality.
Mr. Graeme R. Peterson
25.
I would now like to address the patient, Graeme R. Peterson. I have reviewed Mr.
Peterson's medical records in detail, as well as the witness statements provided to
me. Mr. Peterson suffered a ST segment elevation myocardial infarction on
December 8,2003. (PET.001.0131-134) Prior to June of 2000, Mr. Peterson had no
documented history of coronary artery disease; however, an exercise stress test
performed on June 23,2000, revealed horizontal ST depression in 1, aVL, V34; to ,,;
2.0 mm and using accepted AHA criteria (1 mm of horizontal or downsloping ST
segment depression), this test would be considered positive for exercise-induced
ischemia. (PET.001.0011-0028) Based on my review of the tracings, knowledge of
his medical history and applying the Bayes' Theorem of probability, it is my opinion
that the ECG changes during the exercise portion of this test are consistent with and
suggestive of flow limiting disease in the same territory in which his subsequent MI
occurred. An echocardiogram performed in January 2001 for the indication of
systemic hypertension found borderline left ventricular hypertrophy (LVH) with normal
left ventricular systolic function and a mildly dilated aortic root. (PET.001.0043) As of
the time of his myocardial infarction on December 8, 2003, Mr. Peterson had multiple
important risk factors for coronary artery disease, including his age (53), gender,
hypertension with LVH, hyperlipidemia, elevated BMI, and family history (Mr.
Peterson's mother was noted to have suffered from angina). (PET.001.0131-134; see
also Appendix 1) He was also noted to have impaired glucose tolerance (based on a
glucose tolerance test performed two years prior) that was improved with diet,
although I could not locate records of this glucose tolerance test. (PET.001.0132) Mr.
Peterson suffered from a long history of chronic migraines with typical symptoms
conSisting of a visual disturbance, a constricted feeling in his chest sometimes
involving his arms, and a rise in blood pressure followed by the onset of a headache.
(PET.001.0097) Mr. Peterson used to smoke heavily, but quit over 20 years ago.
(PET.001.0116)
26.
In early December 2003 and prior to his myocardial infarction, Mr. Peterson began
experiencing substernal resting chest pain. (PET.001.0131-134) These episodes of
17
chest pain lasted approximately 10 to 15 minutes each. (PET.001.0131-134) On
Monday, December 1, 2003, Mr. Peterson reportedly suffered 16 episodes of chest
pain. (PET.001.0131-134) On Tuesday, December 2,2003, Mr. Peterson sought
treatment from Dr. John Dickman, his primary care physician, for chest pain.
(PET.001.0054) During the visit, Dr. Dickman noted that Mr. Peterson's chest pain
was localized centrally and radiated down both arms. (PET.001.0054) Further, his
blood pressure was elevated at 155/90mmHg. (PET.001.0054) Dr. Dickman
diagnosed reflux and hypertension and started Mr. Peterson on antihypertensive
medication. (PET.001.0054) Dr. Dickman referred Mr. Peterson for an
electrocardiogram on the following day. (PET.001.0054) The ECG of December 3,
2003, was interpreted as showing T wave inversion in V2-V5 suggesting the
possibility of subendocardial ischemia (although the tracings were not available for my
review). (PET.003.001.0196) These ECG changes would be considered primary in
nature, and thus indicative of acute ischemia as opposed to chronic T wave inversion,
which is indicative of LV structural abnormalities. Furthermore, these ECG changes
are similar to the ECG changes noted during the exercise stress test in June of 2000
in that they correspond to the same territory of the myocardium at risk. Over the next
several days, Mr. Peterson traveled to Canberra to work and continued to experience
approximately one episode of resting chest pain per day, lasting 10 to 15 minutes in
length. (PET.001.0133; Peterson Stm!., p. 8) Mr. Peterson returned home from his
travels on Sunday, December 7,2003, at which point his episodes of angina
increased in frequency. (PET.001.0133; Peterson Stm!., p. 8) In the early hours of
Monday morning, December 8, 2003, Mr. Peterson awoke with severe chest pain
radiating down both arms. (PET.001.0133; Peterson Stm!., p. 8) The pain was more
severe than his prior episodes. (PET.001.0133; Peterson Stm!., p. 8) After taking two
aspirin at approximately 1:00 am. and taking a warm shower (which did not relieve his
symptoms), Mr. Peterson's wife drove him to the hospital, where he arrived at
approximately 3:00 a.m. (PET.001.0132-133; Peterson Stm!., p. 8-9) Upon
presentation to Frankston Hospital, Mr. Peterson was found to have acute
electrocardiographic changes including ST elevation in multiple contiguous leads and
was diagnosed with an anterior myocardial infarction. (PET.001.0131-134) He was
admitted and treated with nitroglycerine and thrombolytic therapy. (PET.001.0131134) His initial cardiac enzymes drawn at 3:47 am were not elevated; however, by
7:00 am, he had elevated markers of myocardial injury, including elevated troponin
and CK-MB. (PET.001.0161)
18
27.
Mr. Peterson underwent cardiac catheterization on December 11, 2003.
(pET.001.0130) At the time of coronary angiography, Mr. Peterson was found to have
significant coronary artery disease, including a 90% stenosis in his proximal left
anterior descending artery (LAD), a tight ostial stenosis in his LADD1 (first diagonal
artery off of the LAD), and minor disease in his right coronary artery (RCA).
(PET.001.0130) His left main and left circumflex arteries were noted to be free of
disease. (PET.001.0130) His ejection fraction was calculated at 40%.
(PET.001.0130) Mr. Peterson underwent successful PTCA and stenting to his
proximal LAD without complication. (PET.001.0130) Final angiographic result was
noted to be excellent with 0% residual stenosis. (PET.001.0130) I reserve the right to
view the angiogram and provide additional commentary.
28.
Mr. Peterson was discharged in stable condition on December 13, 2003, and enrolled
in cardiac rehabilitation therapy. (pET.001.0129; Peterson Stmt., p. 9) He was
affirmatively diagnosed with hyperlipidemia and started on statin therapy
(Pravastatin). (PET.001.0127) He remained on Vioxx 25mg daily, his Atenolol was
increased to 50mg daily, and he also began taking Coversyl 2mg daily, Clopidogrel
75mg daily, and aspirin 150 mg daily (PET. 001.0127).
29.
Since the time of his myocardial infarction in December 2003, Mr. Peterson has been
monitored by his primary care physician, Dr. Dickman, and cardiologists, Drs.
Bhupendra Pathik and Brian Wood. An echocardiogram on February 3, 2004,
revealed mildly impaired left ventricular function with apical aneurysm and no valvular
pathology, and Mr. Peterson was started on Warfarin in March 2004.
(PET.002.001.004-5) Multiple progress notes in the years following his event indicate
that Mr. Peterson has been feeling well, is generally active without recurrent chest
pain or shortness of breath , and is at least attempting to better control his diet and
exercise, although he admits this is difficult during periods when he travels for work.
(pET.001.0113-0116; PET.003.001.0056-57; 061) His lipids have been checked
regularly, and, with the exception of only a couple of elevated readings, have
remained better-controlled since his myocardial infarction in December 2003. (See
Appendix 1) His blood pressure has also been better controlled. (See Appendix 1)
Recent echocardiograms in February 2007 and October 2008 reveal an anteroapical
wall motion abnormality consistent with his previous myocardial infarction, but only
mild to moderate overall left ventricular dysfunction, with an estimated ejection fraction
of 40-45 percent. (PET.003.001.0067-68) A recent stress test in October 2008 was
stopped after Mr. Peterson achieved a maximal age predicted heart rate, was
negative for chest pain, and negatilie for ischemia. (PET.003.003.0020) Mr. Peterson
19
also had an adequate blood pressure response to exercise. (PET.003.003.0020) Mr.
Peterson reports that he ceased using Warfarin in 2007 due to "side effects," and his
current medications include aspirin 100mg/day, atenolol 50mg/day, coversyl 2mg/day,
ezetrol10mg/day, lipitor 80mg/day, and parlet 10mg/day, as well as fish oil and
glucosamine sulfate for joint pain. (Peterson Stm!., pp. 9-10)
30.
Mr. Peterson has a long history of debilitating lower back and hip pain apparently
related to his reported diagnosis of ankylosing spondylitis, which he reports was
diagnosed at the age of 25. (Peterson Stm!., p. 5) Over approximately the next three
decades', he tried a number of different products and medications to treat this
condition, including fish oil, glucosamine sulfate, extract-type medications (i.e. shark
cartilage and mussel extract), and multiple non-steroidal anti-inflammatory drugs, from
which he reportedly suffered serious gastrointestinal side effects, including peptic
ulcer disease. (Peterson Stm!., p. 5)
31.
I have been asked to render an opinion as to whether Mr. Peterson's use of Vioxx
25mg caused or contributed to his myocardial infarction on December 8, 2003. Dr.
Dickman first prescribed Vioxx (25mg once daily) to Mr. Peterson in May 2001 to treat
the pain of his osteoarthritis (Dickman Stm!., p.2). I could not locate any pharmacy
records noting that this prescription was filled. Based upon the available medical and
pharmacy records, it appears Mr. Peterson filled his Vioxx prescriptions fairly regularly
from June 2002 until the time of his event in December 2003, with an apparent gap in
usage in October and November 2003. (PET.001.0004-07; 003.003.0039-40) After
his event, Mr. Peterson continued to use Vioxx 25mg until the drug was voluntarily
withdrawn from the market in September 2004. (PET.001.0004-07; 003.003.0039-40)
Before his use of Vioxx, Mr .Peterson tried a number of other non-steroidal antiinflammatory medications for the treatment of his severe, chronic pain, which he
generally noted to be associated with unwanted gastrointestinal side effects (Peterson
Stm!. pp. 5 and 6). Mr. Peterson was prescribed meloxicam (Mobic) following his
discontinuation of Vioxx until mid-2006. (PET.003.003.0040-43)
32.
Based on all subsequent cardiac assessments and diagnostic studies, Mr. Peterson is
doing well from a cardiac standpoint and remains active and asymptomatic. In my
opinion, the myocardial infarction itself that Mr. Peterson suffered on December 8,
2003 should have little effect on his long-term cardiovascular prognosis and his
functional status. The major determinants of prognosis after an acute MI include the
size of the left ventricular chamber, the extent of coronary artery disease, and the
extent of LV wall motion abnormalities. Based on the medical records and using
20
these clinical criteria, it would appear that Mr. Peterson's overall prognosis is good. In
my opinion, Mr. Peterson's long term prognosis will primarily be driven by his ability to
control his risk factors and thus control the progression of atherosclerosis. Mr.
Peterson does have established coronary artery disease and is by definition at risk for
a future event.
33.
In my opinion, Vioxx did not cause or contribute to Mr. Peterson's myocardial
infarction. Mr. Peterson's clinical course is quite typical for patients with
atherosclerotic coronary artery disease. His clinical history and event were common
before and after Vioxx was on the market. It is crucial to note that Mr. Peterson had
numerous pre-existing risk factors for the development of atherosclerotic heart
disease which placed him at increased risk for the development of an acute
myocardial infarction. Further, the exercise stress test conducted in June of 2000 was
indicative of flow-limiting coronary artery disease prior to him ever being exposed to
Vioxx. It is my opinion that Mr. Peterson likely experienced the rupture of an
atherosclerotic plaque in his left anterior descending coronary artery and this
preCipitated multiple episodes of unstable angina. This is a very typical scenario for
progression to acute MI, which Mr. Peterson subsequently experienced. Knowing the
natural history of this common disorder and that Mr. Peterson had evidence of
coronary disease as early as 3 years before his event, in reasonable medical
probability, he was at high risk for a cardiovascular event prior to and regardless of
taking Vioxx.
34.
Given the clinical characteristics of Mr. Peterson and the circumstances of his
myocardial infarction, there is no need or reason to implicate other factors as
causative in his event. Nevertheless, as described in detail above, the totality of the
scientific evidence does not support that Vioxx contributes to the pathogenesis of
acute myocardial infarction: Vioxx does not contribute to the initiation or progression
of atherosclerosis in humans, does not weaken or destabilize the atherosclerotic
plaque, does not induce plaque rupture, nor does it alter a "theoretical balance"
between prostacyclin and thromboxane in the human vasculature. Importantly, the
clotting and anticoagulant mechanisms in humans are remarkably redundant and
complex, and there is nothing unusual about this case to suggest that primary or
secondary abnormalities in any of these systems contributed directly or indirectly to
Mr. Peterson's event.
35.
Finally, as detailed above, the totality of the clinical data does not establish an
increased risk of cardiovascular thrombotic events associated with use of Vioxx 25mg.
21
Even if one were to assume a small, but statistically significant risk associated with
the use of Vio)()( across populations olthe magnitude suggested by extensive metaanalysis (Kearney, Baigent 2006), this would not suggest a causal relationship
between Vlo)()( and Mr. Peterson's acute MI. Moreover, there is no evidence to
suggest that Vio)()( usage generates any greater risk for thrombotic events than the
other NSAIDs Mr. Peterson used; rather, the weight of the evidence to date suggests
that Vioxx does not pose any greater risk than traditional NSAIDs (other than
naproxen).
36.
I reserve the right to supplement my opinions should additional info rmation become
available to me. Further, I have attached several charts with respect to Mr. Peterson
that detail portions of his medical history (Appendix 1).
Declarations
37.
I declare that:
(a)
I have provided written expert reports to Merck & Co., Inc. in the Vioxx
products liability litigation in the United States. I have also given an
educational lecture series that was supported by Merck regarding my
research pertaining to cardiovascular disease and obesity. This was
unrelated to any Merck product or to Vio)()( specifically. I also advise and
consult for pharmaceutical companies, including Novartis and SanofiAventis.
(b)
I have made all the inquiries that I believe are desirable and appropriate
and no matters of significance that I regard as relevant have, to my
knowledge, been withheld from the Court.
.
.~£t!~
l'~~~~;~s E. Vaughan, MD
. ./l...I?-cI~. . . ."f!!~i
Date
22
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Appendix 2
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28
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Saito, T., I. W. Rodger, et al. (2000). "Inhibition of cyclooxygenase-2 improves cardiac function
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Schachinger, V., M. B. Britten, et al. (2000). "Prognostic impact of coronary vasodilator
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Sebaldt, R. J., J. R. Sheller, et al. (1990). "Inhibition of eicosanoid biosynthesis by
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Solomon, D. H., S. Schneeweiss, et al. (2004). "Relationship between selective
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29
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Appendix 3
CURRICULUM VITAE
NAME:
DATE OF BIRTH:
BIRTHPLACE:
Douglas Eugene Vaughan
March 19, 1954
Oklahoma City, Oklahoma
MARITAL STATUS:
Married:
Children:
ADDRESS:
Department of Medicine
Northwestern University Feinberg School of Medicine
251 East Huron Street
Gaiter Pavillion 3-150
Phone (312)-926-9436
Fax (312)-926-7260
e-mail: d-vaughan@northwestern.edu
Susannah (Sukie) Hawks Vaughan
Emily Allerton Vaughan (DOB 11/5/90)
James Clifford Vaughan (DOB 2/19/92)
454 W Deming Place, 3E
Chicago, IL 60614
(773)-253-5331 .
EDUCATION:
05/72
05/76 B.A.
06/80 M.D.
Tascosa High School, Amarillo, Texas
University of Oklahoma, Norman, OK
University ofTexas Southwestern Medical School, Dallas, TX
POSTDOCTORAL TRAINING:
Internships and Residencies:
1980-1981
1981-1983
1983-1984
Intern in Internal Medicine, Parkland Memorial Hospital/Veterans Affairs
Medical Center (VAMC), Dallas, TX
Assistant Resident in Internal Medicine, Parkland Memorial Hospital/VAMC,
Dallas, TX
Chief Resident in Internal Medicine, Parklancl Memorial Hospital/VAMC,
Dallas, TX
Douglas E. Vaughan, M.D.
Fellowships:
1984-1986
1984-1987
1987-1988
1988-1989
Clinical Fellow in Medicine (Cardiology), Brigham and Women's Hospital,
Boston, MA
Research Fellow in Medicine, Harvard Medical School (Preceptor: J Loscalzo,
MD, PhD)
Clinical Fellow in Interventional Cardiology, Brigham and Women's Hospital,
Boston, MA
Center for Thrombosis and Vascular Research, Katholieke University,
Leuven, Belgium (Pr7ceptor: Desire Collen, MD,PhD)
Postgraduate Courses:
1991
Licensure
Medical and Experimental Mammalian Genetics, Jackson Laboratory,
Bar Harbor, ME
and Certification:
1980
1980
1984
1984
1987
1993
2008
Federal Licensing Examination (FLEX)
Texas #F7528
Massachusetts #52589
Diplomate, American Board of Internal Medicine, Certificate #91431
Diplomate in Subspecialty of Cardiovascular Disease
Tennessee #MD 024579
Illinois #336.083530
Academic Appointments:
1983-1984
1987-1990
1990-1993 .
1993-1997
1994-1997
19972008-
Instructor in Internal Medicine, University of Texas Southwestern Medical
School, Dallas, TX
Instructor in Medicine, Harvard Medical School, Boston, MA
Assistant Professor of Medicine, Harvard Medical School, Boston, MA
Associate Professor of Medicine (with tenure), Vanderbilt University School
of Medicine, Nashville, TN
Associate Professor of Pharmacology, Vanderbilt University School of
Medicine
Professor of Medicine and Pharmacology, Vanderbilt University School of
Medicine
Irving S. Cutter Professor and Chairman, Department of Medicine,
Northwestern University Feinberg School of Medicine, Chicago, IL
Hospital Appointments:
1986-93
Associate PhYSician, Brigham and Women's Hospital, Boston, MA
Page
2
Douglas E. Vaughan, M.D.
1989-93
19931993-2001
Staff Physician, West Roxbury VAMC, Boston, MA
Staff Physician, Vanderbilt University Medical Center, Nashville, TN
Staff Physician, Nashville VAMC, Nashville, TN
Administrative Appointments:
1989-91
1991-93
1993-99
1993-97
1995-1999
1999-2008
2006-2008
200820082008-
Assistant Director, Center for Research in Thrombolysis, Brigham and
Women's Hospital, Boston, MA
Co-Director, Center for Research in Thrombolysis, Brigham and Women's
Hospital, Boston, MA
Director of Thrombosis Research, Cardiology Division, Vanderbilt University
Medical Center, Nashville, TN
Chairman, Cardiovascular Research Committee, Nashville Veterans
Administration Hospital
Director, Fellowship Training Program, Cardiovascular Division, Vanderbilt
University Medical Center, Nashville, TN
Chief, Division of Cardiovascular Medicine, Vanderbilt University Medical
Center
Physician-in-Chief, Vanderbilt Heart and Vascular Institute
Irving C. Cutter Professor and Chair of the Department of Medicine,
Northwestern University Feinberg School of Medicine, Chicago, IL
Chairman of Medicine, Northwestern University Faculty Foundation
Physician-in-Chief, Northwestern Memorial Hospital, Chicago, IL
Visiting Appointments:
1982
Fellow in Hematology/Oncology, Duke University Medical Center, Durham,
NC
Awards and Honors:
1972
1986
1989-94
1989
1992
1994
1994-98
1995
1996
University Scholar, University of Oklahoma
Fellowship Award, American Heart Association, Massachusetts Affiliate.
Clinician-Scientist Award, American Heart Association
Young Investigator Award, International Society on Thrombosis and
Hemostasis, Tokyo, Japan
International Academic Exchange Program, American College of
Cardiology/European Society of Cardiology
Co-Chairman, Gordon Research Conference of Thrombolysis, Ventura,CA
Clinical Investigator Award, Department of Veterans Affairs Research
Administration
Fellow, AHA Co~ncil for High Blood Pressure Research
Chairman, Gordon Research Conference on Thrombolysis, Ventura, CA
Page.3
Douglas E. Vaughan, M.D.
1997
1997
1999
2000
2001
2008
American Society of Clinical Investigation
Fellow, AHA Council on Arteriosclerosis, Thrombosis, and Vascular Biology
C. Sidney Burwell Professor of Medicine, Vanderbilt University School of
Medicine, Nashville, TN
. Association of American Physicians
Association of University Cardiologists
Alpha Omega Alpha, Northwestern University Feinberg School of Medicine
Professional Societies:
International Society on Thrombosis and Hemostasis.
Fellow, American College of Cardiology (FACe)
International Society for Fibrinolysis and Thrombolysis
AHA Council for High Blood Pressure Research
AHA Council on Arteriosclerosis, Thrombosis, and Vascular Biology
Invited Lectures: (Selected)
1990
1990
1992
1993
1993
1994
1994
1994
1995
1995
1996
1996
1996
1996
1996
1996
1996
1997
1997
1997
Session Moderator, Gordon Research Conference on Thrombolysis, Ventura, CA
Cardiovascular Grand Rounds, Brigham and Women's Hospital, Boston, MA
Plenary Lecture, "Pharmacologic Advances in Thrombolytic Therapy", American
Society of Cardiovascular and Interventional Radiology, Washington, D.C.
Cardiovascular Grand Rounds, Brigham and Women's Hospital, Boston, MA
Internal Medicine Grand Rounds, Vanderbilt University Medical Center, Nashville,
TN
Session Moderator, Gordon Research Conference on ThrombolYSis, Ventura, CA
Invited Speaker, European Society of Cardiology, Berlin, Germany
Invited Speaker; EuroTransMed Television Program, London, UK
International Symposium on Endothelium-Derived Factors and Vasculoprotection,
San Francisco,CA
Internal Medicine Grand Rounds, University of Kentucky Medical Center, Lexington,
KY
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, PA
Gordon Research Conference on ThrombolYSiS, Ventura, CA
Cardiology Research Conference, Hospital Lava Quebec City, Quebec,Canada
Cardiology Research Conference, Emory University Medical Center, Atlanta, GA
Cardiology Grand Rounds, Boston University Medical Center, Boston, MA
State of the. Art Talk, "The renin-angiotensin system and fibrinolysis", Council on
. High Blood Pressure Research, Chicago, IL
American Society of Nephrology, New Orleans, LA
American Society of Hypertension, San Francisco, CA
International Symposium on Angiotensin Converting Enzyme Inhibition, Hong Kong
Cardiology Research Seminar, Washington University, St. Louis, MO
Page
4
Douglas E. Vaughan, M.D.
1997
1997
1997
1997
1997
1998
1998
1998
1998
Joseph A. Nicholson Annual Lecture, Tufts University School of Medicine, Boston,
MA
Internal Medicine Grand Rounds, Cornell University Medical Center, New York, NY
International Society of Hypertension, Milan, Italy
Cardiology Grand Rounds, University of Pennsylvania, Philadelphia, PA
International Symposium on Thrombosis and Atherosclerosis, Galveston, TX
Gordon Conference on Thrombolysis, Ventura, CA .
Gordon Conference on Angiotensin, Ventura, CA
International Society of Hypertension, Amsterdam, The Netherlands
.
th
State of the Art Speaker, 24 International Aldosterone Conference, New Orleans,
LA
1998
1998
1998
1998
1998
1998
1998
1999
1999
1999
1999
1999
1999
1999
1999
2000
2000
2000
2000
2000
2000
2000
2000
2001
2001
2001
2001
2002
2002
2002
2002
2002
2002
Xth International Vascular Biology Meeting, Cairns, Australia
th
18 World Congress of the International Union of Angiology, Tokyo, Japan
Grand Rounds, Krannert Cardiovascular Institute, University of Indiana
Cardiology Grand Rounds, Brigham and Women's Hospital, Boston, MA
Update in Thrombolysis, Berlin, Germany
Cardiology Grand Rounds, Northwestern University, Chicago, IL
Cardiology Grand Rounds, University of Chicago, Chicago, IL
Medicine Grand Rounds, St. Louis University, St. Louis, MO
Cardiology Grand Rounds, Yale University, New Haven, CT
Medicine Grand Rounds, UTMB, Galveston, TX
Medicine and Endocrinology Grand Rounds, Wayne State University, Detroit, MI
Medicine Grand Rounds, University of Tennessee Medical Center, Knoxville, TN
Merck Sharp & Dohme ASEANZ Cardiovascular & Lipid Forum, Melbourne, Australia
rd
3 Annual Meeting, Heart Failure Society of America, San Francisco, CA
St. Thomas Hypertension Symposium, Nashville, TN
Vascular Biology and Hypertension Seminar, University of Alabama, Birmingham, AL
Gordon Conference on Thrombolysis, Ventura, CA
Medicine Grand Rounds, Meharry Medical College, Nashville, TN·
Internal Medicine Grand Rounds, Emory University, Atlanta, GA .
Medicine Grand Rounds, University of Rochester, Rochester, NY
Cardiology Grand Rounds, University of Michigan, Ann Arbor, MI
Cardiology Grand Rounds, Cedar Sinai Medical Center, Los Angeles, CA
Neuton Stern Visiting Professor, University of Tennessee, MemphiS, TN
Grollman Visiting Professor, University of Virginia, Charlottesville, VA
Cardiology Grand Rounds, University of Texas, Southwestern, Dallas, TX.
Cardiology Grand Rounds, University of New Mexico, Albuquerque, NM
Rose Weiss Visiting Professor, Lahey Clinic, Burlington, MA
Cardiology Grand Rounds, University of Washington, Seattle,WA
Cardiology Grand Rounds, University of Wisconsin, Madison, WI
Gordon Conference on Thrombolysis, Ventura, CA
Cardiology Grand Rounds, University of Rochester, Rochester, NY
Cardiology Grand Rounds, University of Arkansas, Little Rock, AR
Cardiology Fellows Research Symposium, Emory University, Atlanta, GA
Page
5
Douglas E. Vaughan, M.D.
2003
2003
2003
2003
2003
2003
2004
2004
2004
2004
2005
2005
2005
2005
2005
2005
2006
2006
2006
2006
.2006
2006
2006
2007
2007
2007
2007
2007
2008
2008
2008
2008
2008
2008
2009
Vascular Biology Seminar, University of Michigan, Ann Arbor, MI
Vascular Biology Seminar and Medicine Grand Rounds, University of North Carolina,
Chapel Hill, NC
Plenary Lecture, XIX Congress of the International Society of Thrombosis and
Haemostasis, Birmingham, England
Cardiology Grand Rounds, Dartmouth University, Lebanon, NH
Cardiology Grand Rounds, Yale University Medical Center, New Haven, CT
Cardiology Grand Rounds, Medical College of Virginia, Richmond, VA
Gordon Conference on Plasminogen Activation and Extracellular Proteolysis,
Ventura CA
Internal Medicine Grand Rounds, University of Chicago, Chicago, IL
Murray Visiting Professor, University of Washington, Seattle, WA
Medicine Grand Rounds, Vanderbilt University Medical Center, Nashville, TN
Cardiology Grand Rounds, Brigham and Women's Hospital, Boston, MA
Invited speaker and session moderator, Gordon Conference on Atherosclerosis,
Biddeford, ME
Pia Glas-Greenwalt Memorial Lecturer, XXth Congress of the International Society
of Thrombosis and Haemostasis, Sydney, Australia
Cardiology Grand Rounds, Harper University Hospital, Detroit, MI
Cardiology Grand Rounds, Beth Israel Medical Center, Newark, NJ
Cardiology Grand Rounds, University Hospitals of Cleveland, OH
Department of Medicine Grand Rounds, Drexel University College of MediCine,
Philadelphia, PA
Cardiology 2006: Advances in Science and P~actice, Nashville, TN
Gordon Conference on Plasminogen Activation and Extracellular Proteolysis,
Ventura CA
th
Plenary lecture, 8 Annual Symposium on Thrombosis and Hemostasis,
Indianapolis, IN
Invited speaker, Keystone Conference on Atherothrombosis, Keystone, CO
Cardiology Grand Rounds, University of Virginia, Charlottesville, VA
Invited speaker, Transcatheter Cardiovascular Therapeutics, Washington, DC
Invited speaker, Cardiology at the Limits, Cape Town, South Africa
Keystone Conference on Atherothrombosis, Keystone, CO
Plenary Lecture, ATVB Annual Meeting, Chicago, IL
Cardiology Grand Rounds, University of North Carolina, Chapel Hill, NC
Cardiology Grand Rounds, Case Western University Medical Center, Cleveland, OH
Cardiology Grand Rounds, New York University, New York, NY
Cardiology Grand Rounds, Tufts University Medical Center, Boston, MA
Gordon Conference on Plasminogen Activation and Extracellular Proteolysis,
Ventura, CA
Invited Speaker, SERPINS 2008, Leuven, Belgium
Cardiology Grand Rounds, Beaumont Hospital, Royal Oak, MI
Cardiology Grand Rounds, University of Oregon HSC, Portland, OR
Invited Speaker, Society for Thrombosis and Hemostasis, Vienna, Austria
Page
6
Douglas E. Vaughan, M.D.
Principal Clinical and Hospital Service Responsibilities:
1986-88
1987-88
1989-93
1989-93
1989-93
1993-95
1993-2003
1993-2008
2006-2008
2008-
. Attending Physician, Cardiac Transplant Service, Brigham and Women's Hospital,
Boston, MA
Attending Physician, Cardiac Catheterization laboratory, Brigham and Women's
Hospital
Attending Physician, Cardiology Service, Brigham and Women's Hospital, Boston,
MA
Attending Physician, Cardiology Service, West Roxbury VA Medical Center, Boston,
MA
Attending Physician, Brigham lipid Group, Brigham and Women's Hospital, Boston,
MA
Attending Physician, Adult Cardiac Catheterization laboratory, Vanderbilt
University Medical Center, Nashville, TN
Attending Physician, Medical Service, Veterans Affairs Medical Center, Nashville, TN
Attending Physician, Vanderbilt University Medical Center, Nashville, TN
Physician-in-Chief, Vanderbilt Heart and Vascular Institute, Nashville, TN
Physician-in-Chief, Northwestern Memorial Hospital, Chicago, Il
Committee Assignments
Fellowship Curriculum Committee, Cardiology Division, Vanderbilt University Medical Center,
Nashville, TN (1993-1994)
Scientific Advisory Committee, International Congress on Fibrinolysis, leuven, Belgium, 1994
Committee for the Protection of Human Subjects, Vanderbilt University Medical Center, Nashville, TN
(1994-1998)
Executive Committee, Vanderbilt Page-Campbell Heart Institute (1999-present)
Committee on Appointments and Promotions for the Department of Medicine, Vanderbilt University
Medical Center, Nashville, TN (2000-2002)
Medical Center Medical Board, Vanderbilt University Medical Center, Nashville, TN (2001-2003)
Data Safety Monitoring Board, PREVENT Study 1999-2003
Awards Committee, Council of Arteriosclerosis, Thrombosis and Vascular Biology (2003-2005)
Compensation Committee, Department of Medicine, Vanderbilt University (2000-present)
Awards Committee, Department of Medicine, Vanderbilt University (2000-present)
Publications Committee, American College of Cardiology (2003-2006)
Data Safety Moritoring Committee, JUPITER Study (2003-present)
Anesthesiology Chair Search Committee, Vanderbilt University Medical Center
Community Service
Board of Directors, American Heart Association, Davidson County Division (1995-99)
President, American Heart Association, Davidson County (1997-98)
Page
7
Douglas E. Vaughan, M.D.
Peer Review Committees
W.W. Smith Charitable Trust, Heart Research Advisor, 1993-96
Veterans Affairs Research Service, Cardiovascular Study Section (External Reviewer), 1993American Heart Association, Abstract Reviewer, 1996-present
American College of Cardiology, Abstract Reviewer, 1995-present
Judge, Young Investigators Competition (Vascular Biology), ACC National Meeting, 1998
American Heart Association, Clinical and Integrative CV Physiology & Pathophys II, 1999-2001
ACCjMerck Fellowship/International Academic Exchange Committee, 1999-2002
Scientific Advisory Board, S.l Sarnoff Foundation, 1999-2000
Permanent Member, Experimental Cardiovascular Science Study Section, NHlB11999-2003
International Society of Thrombosis and Haemostasis, Abstract Reviewer 2002Chairman, Vascular Cell and Molecular Biology (VCMB) Study Section, NHlBI 2003-2004
Protocol Review Committee, NHlBI Heart Failure Research Network 2007German National Genome Research Network, Berlin, Germany 2007
Editorial Boards:
Atherosclerosis, Thrombosis and Vascular Biology
Cardiology Today
Circulation
Journal of Thrombosis and Haemostasis
Editorial Consultant:
American Journal of Cardiology
American Journal of Hypertension
American Journal of Medicine
Arteriosclerosis. Thrombosis. and Vascular Biology
Blood
Blood Coagulation and Fibrinolysis
Chest
Circulation
Circulation Research
Coronary Artery Disease
Fibrinolysis and Proteolysis
Hypertension .
Journal of Biological Chemistry
Journal of Cardiovascular Pharmacology
Journal of Clinical Investigation
Journal of Vascular Medicine and Biology
Page
8
Douglas E. Vaughan, M.D.
Lancet
Nature Medicine
New England Journal of Medicine
Proceedings of the National Academy of Science
Thrombosis and Haemostasis
Research Grants
Previous
1986
1989
1989-94
1990-92
1992-97
1996
1994-99
1995-99
1997-02
1998-03
Fellowship Award, American Heart Association, Massachusetts Affiliate. (Title:
Membrane fluidity and cholesterol metabolism. Principal Investigator: D.E. Vaughan;
Preceptor: J Loscalzo)
Research Advisory Group Award, Department of Veterans Affairs Research Service.
(Title: Characterization of the platelet urokinase receptor. P.I.: D.E. Vaughan)
Clinician-Scientist Award, American Heart Association (Title: Platelets and
plasminogen activators. P.I.: D.E.Vaughan; Preceptor: Desire Collen)
Merit Award, Department of Veterans Affairs Research Service. (Title:
Characterization ofthe platelet urokinase receptor. P.I.: D.E. Vaughan)
Merit Award, Department of Veterans Affairs Research Service. (Title: Regulatory
mechanisms in mammalian fibrinolysis. P.I.: D.E. Vaughan)
R13 HL56219, NHLBI (Title: Gordon Conference on Thrombolysis. P.I.: D.E. Vaughan)
Clinical Investigator Award, Department of Veterans Affairs Research Service. (Title:
PAI-1: Structure, function, and regulation. P.I.: D.E. Vaughan)
R01 HL50878, NHLBI. (Title: Role of estrogen in the regulation of fibrinolysis. P.I.: D.E.
Vaughan)
Merit Award, Department of Veterans Affairs Research Service. (Title: Role of
plasminogen activator inhibitor-1 in diabetic vasculopathy. P.I.: D.E. Vaughan)
R01 HL59424 NHLBI. (Title: Vascular disease in HPB: Ang II, PAI-1, insulin and genes.
P.I.: Gordon Williams; Co-PI: D.E. Vaughan)
Current
1994-2011
1998-2007
1999-2010
2000-2009
2001-2006
R01 HL51387, NHLBI. (Title: Angiotensin, the vascular endothelium and fibrinolysis.
P.1.: D.E. Vaughan.)
R01 HL60906, NHLBI. (Title: The renin-angiotensin system and fibrinolysis in
humans. P.I.: N.J. Brown; Co. I.: D.E. Vaughan)
T32 HL07411 NHLBI (Title: Cardiovascular Mechanisms: Training and Investigation. P.I.:
D.E. Vaughan)
R01 HL65192. NHLBI (Title: PAI-1 and Arterial Thrombosis: Models and Mechanisms.
P.1.: D.E. Vaughan) .
U24 DK59637 NIDDK (Title: Vanderbilt Mouse Metabolic Physiology Center. P.I.: D.
. Wasserman. D.E;Vaughan-Director of Murine Cardiovascular Physiology Core)
Page
9
Douglas E. Vaughan, M.D.
2006-2011
2007-2012
P50 HL 081009-01 (Title: SCCOR in Hemostatic and Thrombotic Diseases. P.I.:
D.E.Vaughan)
U01 HL087043 NHLBI (Cell Therapy for Improving Cardiac Function. P.I.: D. E.
Vaughan)
,Research Interests:
The plasminogen activator system in cardiovascular disease and tissue remodeling
Biochemistry/molecular biology of mammalian fibrinolysis
Regulation of vascular gene expression
Celi therapy for cardiovascular disease
Patents Awarded
U.S. 5,599,663
April 1996
Applicant: Douglas E. Vaughan
Title: ANGIOTENSIN IV AND ANALOGS AS REGULATORS OF FIBRINOlYSIS
U.S. 7,057,086
June 2006
Applicant: Douglas E. Vaughan
Title: THERAPEUTIC METHODS EMPLOYING PAI-1 INHIBITORS AND TRANSGENIC NON-HUMAN
ANIMALS FOR SCREENING CANDIDATE PAI-1 INHIBITORS
Consulting Relationships
Wyeth (PAI-1 antagonists)
Novartis'{Cardiovascular Pipeline)
BIBLIOGRAPHY
A. Original Reports:
1.
Goldhaber SZ, Vaughan DE, Markis JE, Selwyn AP, Meyerovitz ME, Loscalzo J, Kim DS, Kessler
CM, Dawley DL, Sharma GVRK, Sasahara A, Grossbard EB, Braunwald E. Acute pulmonary
embolism treated with tissue plasminogen activator. Lancet 1986;2:886-889.
2.
Vaughan DE, Goldhaber SZ, Kim J, Loscalzo J. Recombinant tissue plasminogen activator in
pulmonary embolism: Correlation of fibrinolytic specificity and efficacy. Circulation 1987;
75:1200-1204.
3.
Loscalzo J, Vaughan DE. Human tissue-type plasminogen activator facilitates platelet
disaggregation. J Clin Invest 1987;79:1749-1755.
Page 10
Douglas E. Vaughan, M.D.
4.
Brasier AR, Macklis JD, Vaughan DE, Warner L, Kirshenbaum JM. Myopericarditis as initial
presentation of meningococcemia. Am J Med 1987;82:641-644.
5.
Loscalzo J, Freedman J, Rudd MA, Vaughan DE. Unsaturated fatty acids enhance low-density
lipoprotein uptake and degradation by peripheral blood mononuclear cells." Arteriosclerosis
1987;7:450-455.
6.
Vaughan DE, Kirshenbaum JM, Loscalzo J. Streptokinase-induced, antibody-mediated platelet
aggregation: a potential cause of clot propagation in vivo. J Am Coli Cardiol1988; 11:13431348.
7.
Lamas GA, Vaughan DE, Pfeffer MA. Left ventricular thrombus formation following first
anterior wall acute myocardial infarction. Am J CardioI1988;62:31-35.
8.
Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effects of captopril on
progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988;
319:80-86.
9.
Goldhaber SZ, Vaughan DE, Tumeh S, Loscalzo J. Utility of cross-linked fibrin degradation
products in the diagnosis of pulmonary embolism. Am Heart J 1988;116:505-508.
10.
Stamler JS, Vaughan DE, Rudd MA, Mudge GH, Kirshenbaum J, Young P, Alexander RW,
Loscalzo J. Frequency of hypercholesterolemia after cardiac transplantation. Am J Cardiol
1988;62:1268-72.
11.
Goldhaber SZ, Kessler CM, Heit J, Markis JE, Sharma GVRK, Dawley D, Nagel JS,
Meyerovitz M, Kim D, Vaughan DE, Parker JA, Tumeh SS, Drum D, Loscalzo J, Reagan K,
Selwyn AP, Anderson J, Braunwald E. A randomized controlled trial of recombinant tissue
plasminogen activator versus urokinase in the treatment of acute pulmonary embolism.
Lancet 1988;2:293-298.
12.
Vaughan DE, Plavin SR, Schafer AI, Loscalzo J. Prostaglandin El accelerates thrombolysis
by tissue plasminogen activator. Blood 1989;73:1213-1217.
13.
Stamler JS, Vaughan DE, Loscalzo J. Synergistic disaggregation of platelets by tissue
plasminogen activator, prostaglandin El and nitroglycerin. Cire Res 1989;65:796-804.
14.
Vaughan DE, Loscalzo J. Comparative effects of plasminogen activators on platelet
disaggregation. J Vase Med Bioi 1989;1:27-31.
15.
Lamas GA, Vaughan DE, Parisi AF, Pfeffer MA. Effects of left ventricular shape and
captopril therapy on exercise capacity following anterior wall acute myocardial infarction.
Am J CardioI1989;63:1167-1173.
Page 11
Douglas E. Vaughan, M.D.
16.
Vaughan DE, Declerck PJ, De Mol M, Collen D. Recombinant plasminogen activator
inhibitor-l (PAI-l) reverses the bleeding tendency associated with combined administration
of tissue-type plasminogen activator and aspirin in rabbits. J Clin Invest 1989;84:586-591.
17.
Kuo PC, Kirshenbaum JM, Gordon J, Laffel G, Young P, DiSesa VJ, Mudge GH, Vaughan
DE. Lovastatin therapy of hypercholesterolemia in cardiac transplant recipients. Am J
CardioI1989;69:631-635.
18.
Vaughan DE, Mendelsohn ME, Declerck PJ, Van Houtte E, Collen D, Loscalzo J.
Characterization of the binding of human tissue-type plasminogen activator to platelets. J
Bioi Chem 1989;264:15869-15874.
19.
Lamas GA, Vaughan DE, Pfeffer M. Significance of a lateral Q wave following first
anterior wall acute myocardial infarction. Am J CardioI1990;65:674-675.
20.
Vaughan DE, Van Houtte E, Collen D. Urokinase binds to platelets through a specific,
saturable low affinity mechanism. Fibrinolysis 1990;4:141-46.
21.
Vaughan DE, Lamas G, Pfeffer MA. Role of left ventricular dysfunction in neurohumoral
activation .during the recovery phase of anterior wall acute myocardial infarction. Am J
CardioI1990;66:529-532.
22.
Vaughan DE, Declerck PJ, Van Houtte E, De Mol M, Collen D. Studies of recombinant
plasminogen activator inhibitor (rPAI-l) in rabbits: Evidence for reactivation of latent PAI-l in
vivo. Circ Res 1990;67:1281-1286.
23.
Rudd MA, George D, Amaranti P, Vaughan DE, Loscalzo J. The temporal effects of ti~sue
plasminogen activator infusion on platelet aggregation ex vivo and their modulation by
prostaglandin E, . Cire Res 1990;67:1175-1181.
24.
Vaughan DE, Van Houtte E, Declerck PJ, Collen D. Streptokinase-induced platelet
aggregation: prevalence and mechanism. Circulation 1991;84:84-91.
25.
Mitchell GF, Lamas GA, Vaughan DE, Pfeffer MA. Left ventricular remodeling in the year
following first anterior myocardial infarction: a quantitative analysis of alterations in
contractile segment lengths and ventricular shape. J Am Coli CardioI1992;19:1136-1144.
26.
Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Shen C, Newcomer L, Goldhaber SZ,
Hennekens CH. Baseline fibrinolytic state and the risk of future venous thrombosis.
Circulation 1992;85:1822-1827.
27.
Vaughan DE, Declerck PJ, Van Houtte E, De Mol M, Collen D. Reactivated recombinant
plasminogen activator inhibitor (rPAI-l) effectively prevents thrombolysis in vivo.
Thrombosis and Haemostasis 1992;68:60-63.
Page 12
Douglas E. Vaughan, M.D.
28.
Declerck PJ, DeMol M, Vaughan DE, Collen D. Identification of a conformationally
distinct form of plasminogen activator inhibitor-l, which is a non-inhibitory substrate for
tissue plasminogen activator. J Bioi Chem 1992;267:11693-11696.
29.
Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissuetype plasminogen activator and the risk of future myocardial infarction. Lancet
1993;341:1165-68.
30.
Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation
of plasminogen activator inhibitor (PAI-l) in vivo by infusion of angiotensin II. Circulation
1993;87:1969-73.
31.
Vaughan DE, Declerck PJ, ReillyTM, Park K, Collen D, Fasman GD. Dynamic structural
and functional relationships in recombinant plasminogen activator inhibitor-l (rPAI-l).
Biochimica et Biophysica Acta 1993;1202:221-229.
32.
Ridker PM, Vaughan DE, Stampfer MJ, Hennekens CH. A cross-sectional study of
endogenous tissue plasminogen activator, total cholesterol, HDL cholesterol, and
apolipoproteins A-I, A-II, and B-I00. Arteriosclerosis and Thrombosis 1993;13:1587-92.
33.
Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. A prospective study
of endogenous tissue-type plasminogen activator and the risk of stroke. Lancet
1994;343:940-943.
34.
Ridker PM, Vaughan DE, Stampfer MJ, Hennekens CH. Association of moderate alcohol
consumption and plasma concentration of endogenous tissue plasminogen activator. JAMA
1994;272:929-33.
35.
Vaughan DE, Lazos SA, Tong K. Angiotensin II induces the synthesis of PAI-l in cultured
endothelial cells: Evidence that the renin-angiotensin system participates in the regulation of
fibrinolysis. J Clin Invest 1995;95:95-1001.
36.
Simon DI, Hui X, Vaughan DE. Cathepsin D mediates the degradation of tissue-type
plasminogen activator/plasminogen activator inhibitor complexes in human monocytes.
Biochimica et Biophysica Acta 1995;1268:143-151.
37.
Kerins D, Hao Q, Vaughan DE. Angiotensin induction of PAI-l expression in endothelial
cells is mediated by the hexapeptide angiotensin IV. J Clin Invest 1995;96:2515-2520.
38.
Lee E, Vaughan DE, Parikh SH, Grodzinsky AJ, Lark MW, Lee RT. Matrix
metalloproteinase production and activation by human vascular smooth muscle cells is
regulated by plasminogen. Circ Research 1996;78:44-49.
Page 13
Douglas E. Vaughan, M.D.
39.
Venkov C, Rankin A, Vaughan DE. Identification of authentic estrogen receptors in
cultured endothelial cells. Circulation 1996;94:727-733.
40.
Vaughan DE, Rouleau J-l, Ridker PM, Arnold JMO, Menapace FJ, Pfeffer MA. Effects of
ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction.
Circulation 1997;96:442-447.
41.
Oikawa T, Freeman M, lo W, Vaughan DE, Fogo A. Modulation of plasminogen
activator inhibitor-1 (PAI-1):a new mechanism for the anti-fibrotic effect of reninangiotensin inhibition. Kidney International 1997;51:164-172.
42.
Brown NJ, Nadeau J, Vaughan DE. Stimulation of tissue-type plasminogen activator in vivo by
infusion of bradykinin. Evidence of a second complementary interaction between the reninangiotensin system and fibrinolysis. Thrombosis and Haemostasis 97;77:522-525.·
43.
McConnell MV, Vavouranakis I, Vaughan DE, Ridker PM. Effects of a single, daily
alcoholic beverage on lipid and hemostatic markers of cardiovascular risk. Am J Card
1997;80:1226-28.
44.
Perkins WR, Vaughan DE, Plavin SR, Daley Wl, Rauch J, lee l, Janoff AS. Streptokinase
entrapment in interdigitation-fusion liposomes improves its thrombolytic activity in an
experimental rabbit model. Thrombosis and Haemostasis 1997;77:1174-1178.
45.
Venkov CD, Su M, Shyr V, Vaughan DE. Ethanol-induced alterations in the expression of
endothelial-derived fibrinolytic components. Fibrinolysis and Proteolysis 1997;11:11-118.
46.
Ridker PM, Baker MJ, Stampfer MJ, Hennekens CH, Vaughan DE. Alu-repeat
polymorphism in the gene coding for tissue-type plasminogen activator (t-PA) and risks
of myocardial infarction among middle-aged men. Arteriosclerosis, Thrombosis, and
Vascular Biology 1997;17:1687-1690.
47.
lang RM, Elkayam U, Vellen lG, Krauss D, McKelvie RS, Vaughan DE, Ney DE,
Makris l, Chang PI. Comparative effects of losartan and enalapril on exercise capacity
and clinical status in patients with heart failure. J Am Coli Card 1997;30:983-91.
48.
Chen V-C, Walia RP, Su M, Hao Q, Vaughan DE. Sp1 mediates glucose activation of the
. plasminogen activator inhibitor-1 promoter in vascular smooth muscle cells. Journal of
Biological Chemistry 1998;273:8225-8231.
49.
Tang H, Kerins DM, Hao Q, Inagami T, Vaughan DE. The urokinase-type plasminogen
activator receptor mediates tyrosine phosphorylation of focal adhesion kinase and
. activation of mitogen activated protein kinase in cultured endothelial cells. Journal of
Biological Chemistry 1998;273:18268-18272.
Page 14
Douglas E. Vaughan, M.D.
50.
Stein CM, Brown NJ, Vaughan DE, lang CC, Wood A1J. Regulation of local tissue-type
plasminogen activator release by endothelial-dependent and endothelium-independent
agonists in human vasculature. J Am Coli Card 1998;32:117-122.
51.
Brown NJ, Agirbasli M, Kerins DM, Vaughan DE. Effect of activation and inhibition of
the renin-angiotensin system on plasma PAl-i. Hypertension 1998;32:965-971.
52.
Roselli H, Su M, Kerins DM, Vaughan DE, Russell WE. liver regeneration is impaired
in urokinase-type plasminogen activator deficient mice. American Journal of Physiology
1998;275:G1472-G1479.
53.
Venkov CD, Tanner MA, Su M, Myers PR, Vaughan DE. Ethanol increases endothelial
nitric oxide production through modulation of nitric oxide synthase expression.
Thrombosis and Haemostasis 1999;81:638-642.
54.
Brown NJ, Gainer JV, Stein CM, Vaughan DE. Bradykinin stimulates t-PA release in
human vasculature. Hypertension 1999;33:1431-1435.
55.
Brown NJ, Agirbasli M, Kerins DM, Vaughan DE. Comparative effect of ACE inhibition
and angiotensin 11 type 1 receptor antagonism on plasma fibrinolytic balance in humans.
Hypertension 1999;34:285-290.
56.
Brown NJ, Chen Y-Q, Blevins LS, Nadeau JH, Meranze SG, Vaughan DE. Synergistic
effect of adrenal steroids and angiotensin 11 on PAI-l synthesis .. J Clin Endocrin and
Metabolism 2000;85:336-344.
57.
Nakamura S, Nakamura I, Vaughan DE, Fogo AB. Plasminogen activator inhibitor-l
(PAl-i) expression is regulated by the angiotensin type 1 receptor in vivo. Kidney
International 2000;58:251-259.
58.
Murphey U, Gainer JV, Vaughan DE, Brown NJ. Angiotensin-converting enzyme
insertion/deletion polymorphism modulates the human in vivo metabolism of bradykinin.
Circulation 2000;102:829-832.
59.
Brown NJ, Gainer JV, Murphy U, Vaughan DE. Bradykinin stimulates t-PA release
from human forearm vasculature through a B2- receptor dependent, NOS- and COXindependent pathway. Circulation 2000;102:2190-2196.
60.
Brown NJ, Nakamura S, Ma l, Nakamura I, Donnert E, Freeman M, Vaughan DE, Fogo
AB. Aldosterone modulates plasminogen activator inhibitor-l and glomerulosclerosis in
vivo. Kidney International 2000;58:1219-1227.
Page 15
Douglas E. Vaughan, M.D.
61.
Coats SR, Covington JW, Su M, Pabon-Pena LM, Eren M, Hao Q, Vaughan DE. SSeCKS
gene expression in vascular smooth muscle cells: Regulation by angiotensin II and
potential role in the regulation of PAI-l expression. J Mol Cell Card 2000;32:2207-2219.
62.
Gainer JV, Stein CM, Neal T, Vaughan DE, Brown NJ. Interactive effect of ethnicity and
ACE I/D polymorphism on vascular reactivity. Hypertension 2001;37:46-51.
63.
Kaikita K, Fogo AB, Ma L, Schoenhard JA, Brown, NJ, Vaughan DE. Plasminogen
activator inhibitor-l deficiency prevents hypertension and vascular fibrosis in response to
chronic nitric oxide synthase inhibition. Circulation 2001;104:839-844.
64.
Brown NJ, Murphey U, Srikumar N, Koschachuhanan N, Williams GH, Vaughan DE.
Interactive effect of PAI-14G/5G genotype and salt intake on PAI-l antigen. Arterioscler
Thromb Vasc BioI. 2001;22:1071-1077.
65.
WilsdorfT, Gainer JV, Murphey U, Vaughan DE, Brown NJ. Angiotensin-(1-7) does not
affect vasodilator or tPA responses to bradykinin in human forearm. Hypertension. 2001;
37:1136-1140.
66.
Sawathiparnich P, Kumar S, Vaughan DE, Brown NJ. Spironolactone abolishes the
relationship between aldosterone and plasminogen activator inhibitor-l in humans. J Clin
Endocrin & Metabolism. 2002;87:448-52.
67.
Brown NJ, Abbas Am, Schoenhard JA, Vaughan DE. Comparative effects of estrogen
and angiotensin-converting enzyme inhibitor on plasma plasminogen activator inhibitor-l
in healthy post-menopausal women. Circulation 2002;105:304-309.
68.
Pretorius M, Rosenbaum DA, LeFebvre J, Vaughan DE, Brown NJ. Smoking impairs
bradykinin-stimulated t-PA release. Hypertension. 2002;39:767-771.
69.
Moore JH, Smoken ME, Lamb JM, Brown NJ, Vaughan DE. The relationship
between plasma t-PA and PAI-llevels is dependent on epistatic effects of the ACE I/D
and PAI-l 4G/5G polymorphisms. Clinical Genetics 2002;62:53-59.
70.
Moore JH, Lamb JM, Brown NJ, Vaughan DE. A comparison of combinatorial portioning and
linear regression for the detection of epistatic effects ofthe ACE I/D and PAI-14G/5G
polymorphisms on plasma PAI-llevels. Clinical Genetics 2002;62:74-79.
71.
Schoen hard JA, Eren M, Johnson CH, Vaughan DE. Alternative splicing yields novel
BMAL2 variants: tissue distribution and functional characterization. Am J Physiol (Cell
Physiol) 2002;283:CI03-C114.
Page 16
Douglas E. Vaughan, M.D.
72.
Eren M, Atkinson JB, Declerck PJ, Vaughan DE. Age-dependent spontaneous
coronary thrombosis in transgenic mice that express a stable form of human
plasminogen activator inhibitor-!. Circulation 2002;106:491-491.
73.
Kakita K, Schoenhard JA, Painter CA, Ripley RT, Brown NJ, Fogo AB, Vaughan DE.
Potential roles of plasminogen activator system in coronary vascular remodeling induced by
long-term nitric oxide synthase inhibition. J Mol Cell CardioI2002;34:617-627.
74.
Rosenbaum DA, Pretorius M, Gainer JV, Byrne D, Murphey U, Painter CA, Vaughan DE,
Brown NJ. Ethnicity affects vasodilation, but not endothelial tissue plasminogen activator
release, in response to bradykinin. Arterioscler Throm Vase Bioi 2002;22:1023-28.
75.
Smith LH, Boutaud 0, Breyer M, Morrow JD, Oates JA, Vaughan DE. Cyclooxygenase-2dependent prostacyclin formation is regulated by low-density lipoprotein cholesterol in vitro.
Arterioscler Thromb Vasc Bioi 2002;22:983-988.
76.
Srikumar N, Brown NJ, Hopkins PN, Jeunemaitre X, Hunt 5C, Vaughan, DE, Williams
GH. PAI-1 in human hypertension: relation to activity of renin angiotensin system. Am
J Hypertension 2002;26:683-690.
77.
Brown NJ, Kumar S, Painter CA, Vaughan DE. ACE inhibition versus angiotensin type 1
receptor antagonism: differential effects on PAl-lover time. Hypertension 2002;40:859865.
78.
Coats SR, Pabon-Pena L, Covington JW, Vaughan DE. Ligand-specific control ofsrcsuppressed C kinase substrate gene expression. Biochem Biophys Res Commun. 2002;
297:1112-20.
79.
Pretoriu5 M, Rosenbaum DA, Vaughan DE, Brown NJ Angiotensin-converting enzyme
inhibition increases human vascular tissue-type plasminogen activator release through
endogenous bradykinin. Circulation 2003;107:579-85.
80.
5choenhard JA, Painter CA, Johnson CH, Vaughan, DE. Regulation of the PAI-1 promoter
by circadian clock components. Differential activation by BMAL1 and BMAL2. J Mol Cell
Card 2003;35:473-81.
81.
Eren M, Painter CA, Gleaves LA, Schoen hard JA, Atkinson JB, Vaughan DE. Tissue-and
agonist-specific regulation of human and murine plasminogen activator inhibitor-1
promoters in transgenic mice. Journal of Thrombosis and Haemostasis. 2003;11:2389-96 ..
82.
Murphy U, Morrow JD, Sawathiparnich P, Williams GH, Vaughan DE, Brown NJ.
Acute angiotensin II increases plasma F2-isoprostanes, an index of oxidative stress in
human hypertension. Free Radical Bioi Med 2003;35:711-718.
Page 17
Douglas E. Vaughan, M.D.
83.
Sawathiparnich P, Murphey U, Kumar S, Vaughan DE, Brown NJ. Effect of combined AT,
receptor and aldosterone receptor antagonism on plasminogen activator inhibitor-1. J Clin
Endocrinol Metab 2003;88:3867-3873.
84.
Pretorius M, Murphey U, McFarlane JA, Vaughan DE, Brown NJ. Angiotensin-converting
enzyme inhibition alters the fibrinolytic response to cardiopulmonary bypass.
Circulation. 2003;108:3079-83.
8S.
Hou B, Eren M, Painter CA, Covington JW, Dixon JD, Schoen hard JA, Vaughan DE. Tumor
necrosis factor alpha activates the human plasminogen activator inhibitor-1 gene through
a distal nuclear factor kappaB site. J Bioi Chem. 2004;279:18127-36.
86.
Ma U, Mao SL, Taylor KL, Kanjanabuch T, Guan Y, Zhang Y, Brown NJ, Swift LL, McGuinness
OP, Wasserman DH, Vaughan DE, Fogo AB. Prevention of obesity and insulin resistance in
mice lacking plasminogen activator inhibitor 1. Diabetes. 2004;53:336-46.
87.
Coffey CS, Hebert PR, Ritchie MD, Krumholz HM, Gaziano JM, Ridker PM, Brown NJ,
Vaughan DE, Moore JH. An application of conditional logistic regression and multifactor
dimensionality reduction for detecting gene-gene interactions on risk of myocardial
infarction: The importance of model validation. BMC Bioinformatics. 2004;5:49-59.
88.
Summar ML, Gainer JV, Pretorius M, Malave H, Harris S, Hall LD, Weisberg A, Vaughan DE,
Christman BW, Brown NJ. Relationship between carbamoyl-phosphate synthetase
genotype and systemic vascular function. Hypertension. 2004;43:186-91.
89.
Smith LH, Coats SR, Qin H, .Petrie MS, Covington JW, Su M, Eren M, Vaughan DE.
Differential and opposing regulation of PAI-1 promoter activity by estrogen receptors a
and (3. Circ Research 2004;95:269-75.
90.
Muldowney JA 3 , Davis SN, Vaughan DE, Brown NJ. NO synthase inhibition increases
aldosterone in humans. Hypertension 2004;44:739-45.
91.
Pretorius M, MCFarlane JA, Vaughan DE, Brown NJ, Murphey U. Angiotensin-converting
enzyme inhibition and smoking potentiate the kinin response to cardiopulmonary bypass.
Clin Pharmacol Ther 2004;76:379-87.
92.
Weisberg AD, Albornoz F, Griffin JP, Crandall DL, Elokdah H, Fogo AB, Vaughan DE, Brown
NJ. Pharmacological inhibition and genetic deficiency of PAI-1 attenuates angiotensin
II/salt-induced aortic remodeling. Arterioscler Thromb Vase Bioi 2004;25:365-71.
93.
Smith LH, Petrie MS, MorrowJD, Oates JA, Vaughan DE. The sterol response element
binding protein (SREBP) regulates human COX-2 gene expression in vascular endothelial
cells. J Lipid Res. 2005;46:862-71.
rd
Page 18
Douglas E. Vaughan, M.D.
94.
Lin Z, Kumar A, Sen Banerjee S, Staniszewski K, Parmar K, Vaughan DE, Gimbrone MA Jr,
Balasubramanian V, Garcia-Cardena G, Jain MK. Kruppel-like factor 2 (KLF2) regulates
endothelial thrombotic function. Cire Res. 2005;96:48-57.
95.
McLaughlin IN, Mazzoni MR, Cleator JH, Earls L, Perdigoto AL, Brooks JD, Muldowney JA
3rd, Vaughan DE, Hamm HE. Thrombin modulates the expression of a set of genes
including thrombospondin-1 in human microvascular endothelial cells. J Bioi Chem.
2005;280:22172-22180
96.
Ma J, Albornoz F, Yu C, Byrne DW, Vaughan DE, Brown NJ. Differing effects of
mineralocorticoid receptor-dependent and -independent potassium-sparing diuretics on
fibrinolytic balance. Hypertension. 2005;46:313-20.
97.
Pretorius M, Luther JM, Murphey U, Vaughan DE, Brown NJ. Angiotensin-converting
enzyme inhibition increases basal vascular tissue plasminogen activator release in women
but not in men. Arterioscler Thromb Vase Bioi 2005;25:2435-40.
98.
Cleator JH, Zhu Wo, Vaughan DE, Hamm HE. Differential regulation of endothelial
exocytosis of P-selectin and von Willebrand Factor by protease-activated receptors and
cAMP. Blood 2006; 107:2736-44.
99.
Smith LH, Dixon JD, Stringham JR, Eren M, Elokdah H, Crandall DL, Washington K, Vaughan
DE. Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis. Blood
2006;107:132-134.
100.
Brown NJ, Muldowney III JA, Vaughan DE. Endogenous NO regulates plasminogen
activator inhibitor-1 during angiotensin-converting enzyme inhibition. Hypertension 2006;
47:441-8.
101.
Fujita H, Kang M, Eren M, Gleaves LA, Vaughan DE, Kume T. Foxc2 is a common mediator
of insulin and transforming growth factor (beta) signaling to regulate plasminogen
activator inhibitor type I gene expression. Cire Res 2006; 98:626-34.
102.
Ma J, Weisberg A, Griffin JP, Vaughan DE, Fogo AB, Brown NJ. Plasminogen activator
inhibitor-1 deficiency protects against aldosterone-induced glomerular injury.
Kidney International 2006;69:1064-72.
103.
De Taeye B, Novitskaya T, Gleaves L, Covington J, Vaughan DE. Bone marrow derived
plasminogen activator inhibitor-1 influences the development of obesity. J Bioi Chem
2006; 281(43):32796-805
104.
Muldowney, JAS III, Stringham JR, Levy SE, Painter CA, Piana RN, Vaughan DE.
Antiproliferative agents stimulate endothelial PAI-1 expression: a potential prothrombotic
mechanism of drug-eluting stents. Arterioscler Thrombosis Vase Bioi 2007; 27:400-6.
Page 19
Douglas E. Vaughan, M.D.
105.
Luther JM, Gainer JV, Murphey U, Yu C, Vaughan DE, Morrow JD, Brown NJ._Angiotensin II
induces interleukin-6 in humans through a mineralocorticoid receptor-dependent
mechanism. Hypertension. 200648:1050-7.
106.
Asselbergs fW, Williams SM, Hebert PR, Coffey CS, Hillege HL, Navis G, Vaughan DE, van
Gilst WH, Moore JH. The gender-specific role of polymorphisms from the fibrinolytic,
renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1Ievels.
Thromb Haemost. 2006; 96(4}:471-7.
107.
Muldowney, JAS III, Painter CA, Falck JR, Brown NJ, Vaughan DE. Role of
epoxyeicosatrienoic acids in mediating endothelial tissue-type plasminogen activator
secretion in response to G-protein-coupled receptor activation. Thromb Haemost 2007;
97:263-71.
108.
Asselbergs FW, Williams SM, Hebert PR, Coffey CS, Hillege HL, Navis G, Vaughan DE, van
Gilst WH, Moore JH. Epistatic effects of polymorph isms from the rennin-angiotensin,
bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1Ievels. Genomics 2007 (in
press)
109. Devin JK, Johnson JE, Eren M, Gleaves L, Bloodworth J, Vaughan DE. Transgenic overression
of PAI-1 promotes polycystic ovaries in mice. J Mol Endocrinology 2007: 39:9-16.
110.
Eren M, Gleaves LA, Atkinson JB, Declerck PJ, King LE, Vaughan DE. Reactive-site
dependent phenotypic alterations in PAI-1 transgenic mice. J Thromb Haemost 2007;
5:1500-8.
111.
Schoen hard JA, Muldowney, JAS, Emens, JS, Lewy, AJ, Vaughan DE. Plasminogen activator
inhibitor-1 has a circadian rhythm in blind individuals. Thrombosis and Haemostasis
2007; 98:479-81.
112.
DeTaeye BM, Novitskaya T, McGuinness, Gleaves L, Covington JW, Vaughan DE. Bone
marrow-derived tumor necrosis factor-Cl influences insulin resistance. Am J Phys 2007;
293:E713-25.
113.
Devin JK, Blevins Jr LS, Verity DK, Chen Q, Bloodworth Jr. JR, Covington J, Vaughan DE.
Markedly impaired fibrinolytic balance contributes to cardiovascular risk in adults with
growth hormone deficiel1cy. J Clin Endo Met 2007; 92:3622-39.
114.
Nordstrom SM, Carleton SM, Carleton WL, Eren M, Phillips CL, Vaughan DE. Transgenic
over-expression of plasminogen activator inhibitor-1 results in age-dependent and genderspecific increases in bone strength and mineralization. Bone 2007;41:995-1004.
Page 20
Douglas E. Vaughan, M.D.
115.
Ryzhov S, Solenkova NV, Goldstein AE, Lamparter M, Fleenor T, Young PP, Greelish JP,
Byrne JG, Vaughan DE, Biaggioni I, Hatzopoulos AK, Feoktistov I. Adenosine receptormeidated adhesion of endothelial progenitors to cardiac microvascular endothelial cells.
Circ Res 2008; 102:356-63.
116.
Williams SM, Stocki S, Jiang L, Brew K, Gordon S, Vaughan DE, Brown NJ, Poku KA, Moore
JH. A population-based study in Ghana to investigate inter-individual variation in plasma tPA and PAI-1. Ethnic Disease 2007; 17:492-7.
117.
Khoo MS, Grueter CE, Eren M, Yang J, Zhang R, Bass MA, Lwin ST, Mendes LA, Vaughan DE,
Colbran RJ, Anderson ME. Calmodulin kinase II inhibition disrupts cardiomyopathic effects
of enhanced green fluorescent protein. J Mol Cell Cardiol 2008; 44:40S-10.
118.
Devin JK, Vaughan DE, Blevins LS Jr, Chen Q, Covington J, Verity DK, Young PP. Low-dose
growth hormone administration mobilizes endothelial progenitor cells in healthy adults.
Growth Horm IGF Res 2008; 18:253-63.
119.
Agirbasli M, Baykan OA, Tekin A, Sengor F, Cincin AA, Demir M, Vaughan DE. Short term
effects of GnRH agonists on plasma fibrinolytic balance in patients with advanced prostate
cancer. J Thromb Thrombolysis 2008; {in press)
120.
Mathew RP, Byrne DW, Linton MF, Vaughan DE, Fazio S, Russell WE. Evidence of
metabolic syndrome in lean children with premature pubarche at diagnosis. Metabolism
2008; 57:733-40.
B. Manuscripts Submitted/In Preparation
1.
Smith LH, De Taeye B, Novitskaya T, Painter C, Eren M, Gleaves L, Morrow JD, Washington
K, Vaughan DE. Plasminogen activator inhibitor-1 (PAI-1) deficiency reduces the extent of
fibrosis but not steatosis in a murine model of nonalcoholic steatohepatitis (NASH).
(Submitted)
2.
Kaneko T, Eren M, Vaughan DE. Plasminogen activator inhibitor-1 protects against
angiotensin II-induced cardiac fibrOSis. (in preparation)
C. Book Chapters
1.
Verstraete M, Vaughan DE. Latest update in thrombolysis. In: Jl.llian D. Kubler W, Norris·
RM, Swan HJC, Collen D, Verstraete M, eds. Thrombolysis in Cardiovascular Disease.
Marcel Dekker Inc., 1989.
2.
Vaughan DE. Pathogenetic mechanisms of unstable angina. In: Rutherford JD
Unstable Angina. Marcel Dekker, Inc., 1991.
Page 21
Douglas E. Vaughan, M.D.
3.
Vaughan DE, Schafer AI, Loscalzo J. Normal mechanisms of hemostasis and fibrinolysis. In:
Loscalzo J, Dzau VJ, Creager M, eds. Textbook of Vascular Medicine. Little, Brown and Co.
1992.
4.
Vaughan DE, Lamas GA, Pfeffer MA. Left ventricular remodeling. In: Barnett DB,
Pouleur H, Francis GS, eds. Congestive Heart Failure: Pathophysiology and Treatment.
Marcel Dekker, Inc., 1993.
5.
Declerck PJ, Vaughan DE. Regulation of fibrinolysis. In: Loscalzo J, Schafer A., eds.
Thrombosis and Hemorrhage. Blackwell Scientific Publications, Inc. 1993.
6.
Vaughan DE, Gold HK, Collen D. Animal models of thrombolysis. In: Loscalzo J,
Schafer A., eds. Thrombosis and Hemorrhage. Blackwell Scientific, Inc. 1993.
7.
Vaughan DE, Passamani E, Loscalzo J. Tissue-type plasminogen activator
in acute myocardial infarction. In: Alpert JS, Francis GS, eds. Coronary Care. Second
Edition. W.B.Saunders Company 1995.
8.
Vaughan DE, Pfeffer MA. Ventricular remodeling following myocardial infarction and
angiotensin converting enzyme inhibitors. In: Fuster V, Ross R, Topol EJ, eds.
Atherosclerosis and Coronary Artery Disease. Lippincott-Raven Publishers 1995.
9.
Vaughan DE, Declerck PJ. Fibrinolysis and its regulation. In: Loscalzo J, Schafer A.,eds.
Thrombosis and Hemorrhage. Second Edition. Williams and Wilkins 1998.
10.
Brown NJ, Vaughan DE. Prothrombotic effects of angiotensin. Advances in Internal
Medicine. Mosby 2000.
11.
Vaughan DE. Endothelial dysfunction and vascular thrombosis in diabetes. In: Porte Jr.D,
SherWin RS, Baron A, eds. Ellenberg & Rifkin's Diabetes Mellitus. McGraw Hill 2003.
12.
Vaughan DE, Declerck PJ. Regulation offibrinolysis. In: Loscalzo J, Schafer A.,eds.
Thrombosis and Hemorrhage. Third Edition. Lippincott Williams and Wilkins 2003.
13.
Vaughan DE. Plasminogen activation and the renin-angiotensin system. In: Izzo JL Jr
Black HR, Goodfriend TL, Sowers JR, eds. Hypertension Primer. Third Edition .. Lippincott
Williams and Wilkins 2003.
D. Reviews/Editorials
1.
Vaughan DE, Loscalzo J. New directions in thrombolytic therapy: molecular mutants and
biochemical conjugates. Trends in Cardiovascular Medicine 1991;1:36-39.
.Page 22
Douglas E. Vaughan, M.D.
2.
lamas GA, Vaughan DE, Pfeffer MA. Predictors of the development of heart failure in
asymptomatic patients with left ventricular dysfunction following anterior myocardial
infarction. Cardiovasc Risk Factors 1991;8:522-526.
3.
Vaughan DE, Braunwald E. Accelerated dosage regimens oftissue plasminogen activator:
Putting a better foot forward. J Am Coli CardioI1992;19:1076-1078.
4.
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Page 25
Appendix 4
Douglas Vaughan, MD
Graeme Peterson v. Merck & Co., Inc., et aL; Materials Reviewed
Medical Records and Reports
BHP Health & Medical Services Melbourne
Cavenagh Medical CentrelD. Horsten MD
Records provided by B.W. Chung
Records provided by L. K. Cleeve
Dorevitch Pathology
Frankston Hospital
Gribbles Pathology
Medical One FrankstonIM. Grosman MD
Medicare Australia's Pharmaceutical Benefits Scheme
Melville Medical Family Doctors/G. Hartill MDlDr. Dalitz
Mornington Medical GrouplM. Cross MD
Bhupendra Pathik MD
Peninsula Health
Pulse Pharmacy
R. Rollinson MD
TenixiTransfield Defence Systems
Towerhill Medical Centre/J. Dickman MDIP. Anderson MD
Brian Wood MD
W. Young MD and Dr. Rope
Records provided by R.P. Zent
• 1•
Testimony
Witness Statement of Dr. Paul D. Anderson, dated October 3, 2008
Witness Statement of Dr. John W. Dickman, dated October 6, 2008
Witness Statement of Graeme Peterson, dated October 1, 2008
Witness Statement of Dr. Brian Wood, dated October 7, 2008
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Merck Report dated 02-08-2001 presented to Arthritis Advisory Committee regarding. FDA
Advisory Committee Background Information on NDA 21-042 VIOXX™ Tablets, NDA 21052: VIOXX™ Oral Suspension (Rofecoxib) VIOXX™ Gastrointestinal Outcomes Research
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