Guest Editorial
Managinghemostatic imbalance inanimals: beyondequipoise
Clinical equipoise means a genuine uncertainty on the part ofthe expert medical community about the comparative therapeu-tic merits of each arm of a clinical trial. The tenet of clinicalequipoise provides a clear moral foundation to the requirementthat the health care of subjects not be disadvantaged by researchparticipation.1
This concept of equipoise was included in the first
Declaration of Helsinki, a set of ethical principles re-
garding clinical research on human subjects. The
World Medical Association originally adopted the
Declaration in 1964 as a statement of basic and oper-
ational guidelines addressing patient rights and re-
search integrity. The document has since undergone
several revisions, at first to incorporate greater over-sight and transparency in study design and publica-
tion, and more recently to address disparities in
standards of care between technically advanced and
developing countries. While medical ethics are in-
creasingly complex in this age of globalization, the
basic premise of equipoise remains unchanged and is
applicable to veterinary medicine. Equipoise is an
honest admission that clinicians often don’t know the‘‘best’’ treatment. It is also a commitment to improve
future patient outcomes through well-designed clinical
trials that do not jeopardize the health of active partic-
ipants. The variety and scope of articles in this special
issue of JVECC illustrate the complexity of managing
disease syndromes arising from hemostatic imbalance.
As clinician scientists, we must accept the fact that our
current treatment options reflect a state of equipoise,with inadequate evidence base to guide our selection for
specific patients and disease conditions.
Several articles in this issue synthesize current con-
cepts in the physiology and pathophysiology of hemo-
stasis and lay the groundwork for developing treatment
strategies. As described in these reviews, a cell-based
model provides the best conceptual framework for un-
derstanding in vivo hemostasis, in contrast to the fluidphase cascade reactions that generate fibrin in vitro.
The central roles that tissue factor and thrombin play in
promoting hemostasis are well established, but recent
studies emphasize their complex regulation and their
participation in the processes of inflammation and angio-
genesis. Additional articles illustrate the difficulties in
clinical diagnosis of pulmonary thromboembolism
and hypercoagulability syndromes, and the potentialpromise of global hemostasis analyzers, such as the
Sonoclot and TEG, to aid in the recognition of hyper-
coagulability in horses. The original studies in this
issue examine specific aspects of pretransfusion testing
for recipients of red cell transfusion, oxyglobin as a
substitute for red cell transfusion, and anticoagulant
therapy using unfractionated and low-molecular-weight heparins in dogs and horses.
A broad awareness and interest in hypercoagulability
syndromes among critical care clinicians is an impor-
tant first step; developing good clinical research ques-
tions to design methodologically sound studies is our
next task. Clinical research questions generally fall into
1 of 4 categories: therapy, harm, diagnosis, and prog-
nosis.2 The best study type varies among these catego-ries, with randomized controlled trials most likely
to yield useful information on therapy questions and
cohort studies best suited to answer questions of diag-
nosis and prognosis. The mnemonic device PICOT
helps frame the clinical question to define specifics of
the study Population, Intervention, Comparison, Out-
come, and Time. Selection of appropriate outcome mea-
sures bears special consideration in light of recentclinical trials to prevent vascular disease in humans.3
Four large multicenter treatment studies (ILLUMI-
NATE, ENHANCE, ACCORD, and ADVANCE) aimed
at lowering risk factors for vascular disease failed to
yield net patient benefit. ILLUMINATE and EN-
HANCE evaluated the cholesterol-lowering drugs tor-
cetrapib and ezetimibe, respectively. While both drugs
succeeded in reducing LDL cholesterol levels, neitherimproved the relevant clinical endpoint of arterial
disease progression. Patients in the active arm of the
ILLUMINATE trial actually had higher mortality rates
that prompted premature study closure. Similarly, AC-
CORD and ADVANCE involved the use of multiple
medications to achieve tight glucose control in patients
with type-2 diabetes. Unfortunately, neither approach
reduced the risk of macrovascular complications, inspite of better glucose regulation. The ACCORD study’s
most intense glucose regulation was associated with
higher risk of death and the ADVANCE strategy led to
an excess of hypoglycemic events. We should heed
these lessons as we design studies of hemostatic im-
balance in animals to ensure measurement of clinically
important patient outcomes. In fact, greater emphasis
on clinical outcomes makes a virtue of necessity, as in-clusion of too many surrogate markers and laboratory
& Veterinary Emergency and Critical Care Society 2009 1
Journal of Veterinary Emergency and Critical Care 19(1) 2009, pp 1–2
doi:10.1111/j.1476-4431.2009.00385.x
parameters becomes impractical and cost prohibitive in
veterinary trials.
Ultimately, progress in managing hypercoagulability
syndromes in animals will require cross-discipline
and international collaborations among specialists and
generalists in academic and private practice. Can we
muster sufficient statistical power in well-designedmulti-institution trials to move beyond the uncertain-
ties of clinical equipoise? If we can follow the lead of a
recent political campaign and use technology to facil-
itate our goals of communication, organization, and
wide participation, then the answer will be the affir-
mative – Yes We Can.
References
1. Rits IA. Declaration of Helsinki. Recommendations guiding doc-tors in clinical research. World Med J 1964; 11:281.
2. Heddle N. The research question. Transfusion 2007; 47:15–17.3. Krumholz HM, Lee TH. Redefining quality-implications of recent
clinical trials. N Engl J Med 2008; 358:2537–2510.
Marjory Brooks, DVM DACVIM
Department of Population and Diagnostic Sciences
College of Veterinary Medicine
Cornell University
Ithaca, NY
Email: [email protected]
& Veterinary Emergency and Critical Care Society 2009, doi: 10.1111/j.1476-4431.2009.00385.x2
Editorial