Inflammation Clinical Trial
Official title:
An Observational Trial of Perioperative Atorvastatin on Inflammatory and Endothelial Function in Patients Undergoing Vascular Surgery (STAR-VaS 2)
Despite improvements in perioperative care, non-cardiac surgery remains associated with
significant and costly complications. Analysis of perioperative deaths in the United Kingdom
suggests that roughly 80% are directly attributable to infectious and cardiovascular
complications. The best available evidence suggests that medical optimization is the
preferred strategy to reduce cardiac risks but there has been no novel strategy to reduce
nosocomial infection rates in over 20 years.
Emerging evidence in both the non-operative and operative setting suggest that statin drugs
may prevent both infectious and cardiac events. The mechanism(s) of action are not entirely
clear but appear to independent of lipid lowering effects and are often referred to as
pleiotropic effects. Two key elements of the pleiotropic effects of statins appear to be
their anti-inflammatory properties and improved endothelial vascular reactivity. The statin
dose required to maximize these effects is unknown. A large observational trial suggests a
contradictory dose effect with higher doses associated with reduced infectious complications
and lower doses associated with fewer cardiac complications. Doctors therefore still have
many unanswered questions about the use of statins in the perioperative setting. Should they
be routinely started on all or only certain surgical patients? What dose of statin should be
used? If a patient is already on a statin, should their dose be altered perioperatively? The
latter question is particularly relevant in light of the marked increase in statin use.
Recruitment logs for an ongoing trial demonstrate that over 70% of patients undergoing
high-risk surgery were taking a statin but at markedly variable doses. This population
presents an ideal opportunity to determine if there is a dose response relationship between
statins and pleiotropic effects. We therefore propose an observational study that will
determine anti-inflammatory and endothelial effects in high-risk surgical patients on
varying doses of a perioperative statin drug.
Atorvastatin diminishes the rise in C-reactive protein (CRP), measured 48 hours after
elective vascular surgery, in a dose dependent fashion.
Secondary Hypotheses:
Atorvastatin reduces endothelial dysfunction after elective vascular surgery, as measured by
brachial artery ultrasound, in a dose dependent fashion.
It is estimated that approximately 1.7 million surgical procedures are performed each year
in Canada. Unfortunately, perioperative complications are not an uncommon occurrence and
have substantial morbidity, mortality and costs associated with them. To date, the best
strategies to reduce nosocomial infections are aseptic practices, timely prophylactic
antibiotics and good surgical technique. Despite these strategies, it is estimated that at
least 1 in 5 major vascular surgical patients will have some type of nosocomial infection
within 30 days of their procedure. The direct and indirect mortality of infections in this
population is difficult to estimate but nosocomial infections are estimated to contribute to
at least 15% of the mortality in hospitalized patients.
The primary manner in which infections contribute to patient mortality is by progression to
sepsis. Sepsis is the tenth leading cause of death in Canadians and worldwide is increasing
in incidence and severity. The associated mortality of sepsis varies by population and
infection source but is usually between 30-60%. Despite significant improvements in the
management of sepsis in the last 5 years, there is still no generally effective preventive
medication or strategy. Although cardiovascular complications, including myocardial
infarction and heart failure, are less common at 15% of major vascular patients, they have a
staggering mortality of around 30-50%. Clearly, strategies or therapies to reduce these
complications could have profound benefits. The questions are therefore whether statin drugs
reduce sepsis, cardiovascular complications, or both and, if they do, how might they do so.
Understanding of the pathophysiology of sepsis and acute coronary syndromes in the
non-operative setting has led to tremendous advancements in the management. In sepsis, an
excessive, inappropriate and misguided response in the host defense response is likely
responsible. Massive cytokine release exacerbates endothelium dysfunction that then impacts
coagulation, thrombolysis, inflammation, tissue repair and tissue growth. If not corrected,
the endothelial cells either die directly or through the triggering of apoptosis. This then
leads to multiorgan dysfunction and ultimately death. How sepsis ultimately impairs and
damages endothelial cell function is likely multifactoral. Impairment of endothelial nitric
oxide synthetase occurs that causes impaired perfusion and inappropriate microvasculature
coagulation.
In a strikingly similar manner to sepsis, key elements to acute coronary syndromes again
appear to be inflammation and endothelial dysfunction. Rupture of coronary plaques and
thrombosis are central. Although perioperative myocardial events are traditionally said to
be supply-demand problems, this theory is in dispute and evidence suggests that
perioperative problems are very similar to non-operative events. Elevated levels of various
inflammatory markers, particularly C-Reactive Protein, are associated with adverse
cardiovascular events. Similarly, the vascular endothelium is responsible for regulating
vasomotor tone, thrombosis, platelet and leukocyte interactions. Dysfunction of the
endothelium is also believed to be a central component of the development of coronary
complications. Although endothelial dysfunction has not been extensively investigated in the
perioperative setting, pathophysiologic similarities make it probable that perioperative
endothelial dysfunction contributes to the occurrence of perioperative myocardial events.
Thus, strategies designed to control perioperative inflammation, as well as to improve
endothelial function and stabilize coronary plaque have the potential to reduce both
perioperative coronary and infectious events.
Although studies in both animals and humans strongly suggest that statins may both prevent
and treat sepsis, no prospective randomized trials in humans have been conducted to
demonstrate these effects. Although some statins have been demonstrated to directly
attenuate replication and infectivity of microorganisms, the evidence primarily suggests
that if statins are indeed protective it will likely be due to their anti-inflammatory and
favorable endothelial effects. Improvement of endothelial function by statins has been
suggested to prevent cardiac events by stabilizing coronary plaques and may even contribute
to plaque regression. Statins restore endothelial production of endogenous nitric oxide
synthetase thus improving organ perfusion and microvasculature thrombosis that is impaired
in the setting of sepsis.
The goals of the proposed trial, STAR VaS II are therefore twofold: First, it will help
determine if statin blunts the adverse perioperative changes in inflammation and endothelial
function in a dose-dependent fashion. Second, it will determine if patients chronically on
lower than maximal statin dose should have their dose increased in the perioperative period.
We will evaluate the influence of varying doses of statins on perioperative inflammation, as
assessed by C-reactive protein, and endothelial function as assessed by brachial artery
ultrasound. If atorvastatin, chronically administered before surgery, improves inflammatory
changes or endothelial function in a dose dependent fashion, then it is plausible that
patients chronically on lower statin doses should have their dose increased in the
perioperative period. If however patients on lower doses experienced similar benefit, as
those on higher doses, then conceivably the recommended perioperative dose could be lower
thereby theoretically further improving the risk-benefit ratio for a statin drug. All
patients will be assessed for infections as defined by the CDC.
;
Observational Model: Case-Only, Time Perspective: Prospective
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT03995979 -
Inflammation and Protein Restriction
|
N/A | |
Completed |
NCT03255187 -
Effect of Dietary Supplemental Fish Oil in Alleviating Health Hazards Associated With Air Pollution
|
N/A | |
Completed |
NCT04507867 -
Effect of a NSS to Reduce Complications in Patients With Covid-19 and Comorbidities in Stage III
|
N/A | |
Completed |
NCT03577223 -
Egg Effects on the Immunomodulatory Properties of HDL
|
N/A | |
Completed |
NCT04383561 -
Relationship Between LRG and Periodontal Disease
|
N/A | |
Active, not recruiting |
NCT03622632 -
Pilot Study to Measure Uric Acid in Traumatized Patients: Determinants and Prognostic Association
|
||
Completed |
NCT06216015 -
Exercise Training and Kidney Transplantation
|
N/A | |
Completed |
NCT04856748 -
Nomogram to Diagnose Prostatic Inflammation (PIN) in Men With Lower Urinary Tract Symptoms
|
||
Completed |
NCT05529693 -
Efficacy of a Probiotic Strain on Level of Markers of Inflammation in an Elderly Population
|
N/A | |
Recruiting |
NCT05415397 -
Treating Immuno-metabolic Depression With Anti-inflammatory Drugs
|
Phase 3 | |
Recruiting |
NCT05670301 -
Flemish Joint Effort for Biomarker pRofiling in Inflammatory Systemic Diseases
|
N/A | |
Recruiting |
NCT05775731 -
Markers of Inflammation and of the Pro-thrombotic State in Hospital Shift and Day Workers
|
||
Recruiting |
NCT04543877 -
WHNRC (Western Human Nutrition Research Center) Fiber Intervention Study
|
Early Phase 1 | |
Completed |
NCT03859934 -
Metabolic Effects of Melatonin Treatment
|
Phase 1 | |
Completed |
NCT03429920 -
Effect of Fermented Soy Based Product on Cardiometabolic Risk Factors
|
N/A | |
Completed |
NCT06065241 -
Quantifiably Determine if the Botanical Formulation, LLP-01, Has a Significant Clinical Effect on Proteomic Inflammatory Biomarkers and Epigenetic Changes in Healthy, Older Individuals.
|
N/A | |
Completed |
NCT05864352 -
The Role of Dietary Titanium Dioxide on the Human Gut Microbiome and Health
|
||
Completed |
NCT03318731 -
Efficacy and Safety of Fenugreek Extract on Markers of Muscle Damage and Inflammation in Untrained Males
|
N/A | |
Not yet recruiting |
NCT06134076 -
Comparing Effects of Fermented and Unfermented Pulses and Gut Microbiota
|
N/A | |
Not yet recruiting |
NCT06422494 -
The Role of the Adrenergic System in Hypoglycaemia Induced Inflammatory Response in People With Type 1 Diabetes and People Without Type 1 Diabetes-RAID-II
|
N/A |