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: mbb9@cornell.edu

& Veterinary Emergency and Critical Care Society 2009, doi: 10.1111/j.1476-4431.2009.00385.x2

Editorial