Aspin: Neurosurgical Aspirin Intervention Prognostic Study; perioperative continuation versus discontinuation of aspirin in spinal surgery, a randomized controlled, noninferiority trial.

Current guidelines regarding the safety of the perioperative (dis)continuation
of aspirin for surgical procedures fail to provide clear recommendations
regarding patients undergoing cranial and spinal surgery. Currently, aspirin is
discontinued in cranial and spinal surgery because of a potential increased
risk of hemorrhagic complications. However, this policy might delay surgical
procedures and carries the risk of resulting in an increase of cardiac and
neurologic thrombotic perioperative events. It is unclear if the possibility
for an increase of hemorrhage related complications outweighs the risk of an
increase of cardiac and neurologic thrombotic perioperative events. Therefore,
a randomized controlled trial is required.

Cardio vascular diseases (CVDs) are the primary cause of death in developed
countries, and are expected to be the leading cause of death worldwide.(1)
Cardio vascular diseases are a group of illnesses including myocardial
infarction, coronary heart disease, stroke and venous thromboembolism. In the
primary and secondary prevention of CVDs anticoagulant drugs play a key role,
with aspirin being the most commonly used.(1-3) Specifically for the
Netherlands, aspirin is prescribed for circa 230.000 patients annually.(4) With
the increasing incidence of CVDs, the usage of anticoagulant drugs will
increase forming a problem during surgical intervention.

Currently, there is no consensus whether aspirin should be discontinued before
neurosurgical intervention. One of the arguments leading the discussion is the
POISE-2 trial by Devereaux et al., in which the conclusion was that procedural
continuation of aspirin did not reduce the rates of all-cause mortality of
non-fatal myocardial infarction. But it does come together with increased risks
of major bleedings.(5)

These results are supported by two reviews that included mostly non-RCT studies.
A review and meta-analysis by Burger et al. in non-cardiac surgery showed a
significant increase of procedural bleeding complications, without a
significant reduction nor increase of death or nonfatal myocardial infarctions.
A low dose of aspirin did not significantly differ in bleeding risk or
complications or mortality related to it.(6) The same was concluded in the
review of Kiberd and Hall.(7)

Another interesting pharmacological phenomenon is the aspirin withdrawal
rebound effect, hyperactivity of platelets after interruption aspirin.(8) Even
though there is limited knowledge supporting this effect, it leads to clinical
caution to discontinue aspirin. Multiple cases in different surgical fields
describe fatal thrombo-embolic complication after discontinuing aspirin
perioperatively. Limited knowledge is available about the pharmacokinetic
availability of aspirin after interruption and the regaining of platelet
function thereafter. A small study of Alcock et al. showed, in healthy
participants, no evidence for a rebound phenomenon which leaves this argument
open for discussion. (9)

These results are contrasted by the study of Oscarsson et al..(10) This
randomized, double-blinded, placebo-controlled trial studied the effects of
discontinuing aspirin on the occurrence of major adverse cardiac events
together with hemorrhagic complications in a diversity of surgical
intervention. This study showed a significant reduction in cardiac events
perioperatively, a risk reduction of 7.2% and no difference in hemorrhagic
complications were found. Note bene, this difference is statistically not
significant because of an early termination of inclusion. Additionally, this
difference is based on mainly patients undergoing abdominal, urologic,
orhopaedic and gynaecologic surgery that are known as immobile patients
post-operatively leading to a higher thrombo-embolic risk and are not
completely comparable to neurosurgical patients undergoing spinal surgery which
is often improving mobility by pain reduction and motor control. Additional to
these results, the CLASP-study, a gynecological randomized trial studying the
effects of low-dose aspirin in the prevention and treatment of pre-eclampsia in
pregnant women, did not observe an increase in uterine, placental of fetal
hemorrhagic complications in the study group. Unfortunately, these studies
did not include any neurosurgical cases. This restricts the little evidence for
continuing aspirin in neurosurgical cases and leads to more interest and
concern in this matter.

A systematic review and meta-analysis regarding the safety of aspirin
continuation in spinal surgery was conducted by our research group.(11) Only
three non-randomized studies, including 370 patients undergoing cervical,
thoracic and lumbar spine surgery were identified. No significant differences
in mean perioperative blood loss were seen between the aspirin-continuing group
and the aspirin-discontinuing group. Similar non-significant differences
between the two groups were found for cardiac events, stroke, and surgical site
infections.(12-14)

In addition to spinal surgery, the evidence in cranial surgery is even more
limited. A comparative study by Rahman et al. in 83 patients undergoing
craniotomy for brain tumor demonstrated no increased risk of perioperative
hemorrhage related complications amongst patients continuing aspirin.(15)
Additionally, a observational study by Palmer at all, found no association
between aspirin and postoperative hemorrhage.(16) In case of cerebral
aneurysmatic pathology, aspirin is recommended for unruptured aneurysm and
prevents ruptures by its anti-inflammatory effects.(17) In ruptured aneurysm
with subarachnoidal hematomas continuation versus discontinuation of aspirin
did not lead to significant differences in bleeding risk, bleeding related
complications or prevention of secondary ischemia due to vasospasms.(18, 19)

In conclusion, there is a paucity of studies regarding the safety of
continuation of aspirin during cranial and spinal procedures, and the available
evidence is of low methodologic quality. The hypothesis is that potential
bleeding complications in cranial and spinal surgery might exceed the risks
reported in other surgical literature. Especially in cranial surgery, a
postoperative bleeding may be catastrophic due to the confined space and
vulnerability of the surrounding structures, but no studies exist to support
this hypothesis. The current clinical practice in patients on aspirin and due
to undergo a cranial of spinal is to discontinue aspirin 5-7 days prior to
surgery. There is no clinical evidence to support this policy. Therefore, we
propose a randomized controlled, non-inferiority study comparing the
perioperative (dis)continuation of aspirin in spinal surgery.

Co-primary objectives:
Hemorrhagic complications
Perioperative blood loss
Perioperative blood loss is determined by measuring blood recovered in the
suction device during surgery and weighting of blood saturated gauzes used
during surgery. In case a vacuum drainage system is applied to the surgical
wound the amount of blood loss is recorded at the time of removal. Blood loss
is registered in the hospital information system and recorded with a case
record form that is to be filled out at time of discharge from the hospital.

Hemorrhage related complications
Hemorrhage related complications include surgical site hemorrhages and
postoperative subcutaneous, epidural or subdural hematomas. Hemorrhage related
complications resulting in an increased length of hospital stay or that require
either invasive or non-invasive treatment are recorded in the hospital
information system and are recorded with a case record form that is to be
filled out at time of discharge from the hospital and during postoperative
outpatient clinic visits. Potentially, some complications of cranial and spinal
surgery can also be indirectly attributed to hemorrhage related complications.
For instance, surgical site hematomas are associated with an increased
incidence of postoperative infections. Therefore, the overall 30-day
complication rate is recorded and compared among both treatment groups.

Need for reoperation
The incidence of 30-day postoperative reoperation incidence is recorded in the
hospital information system and recorded with a case record form at discharge
from the hospital and during postoperative outpatient clinic visits. Of
particular interest are directly hemorrhage related reoperations. The afore
mentioned surgical site hemorrhages and postoperative subcutaneous, epidural or
subdural hematomas are infrequent complications spinal surgery. In case these
hemorrhages excerpt pressure on the surrounding neurologic structures (e.g.
spinal cord, cauda equine, nerve roots or peripheral nerves) a rapid evacuation
of the hematoma is required. Furthermore, perioperative hemorrhage related
complications can also result in an indirect need for reoperation. For
instance, suboptimal nervous tissue decompression or tumor removal due to
excessive bleeding during surgery might result in a need for reoperation.
Therefore, the overall 30-day reoperation rate is recorded and compared among
both treatment groups.

Autologous and allogeneic transfusion requirement
Excessive perioperative blood loss can require postoperative allogenic blood
transfusions. The postoperative need for allogenic blood transfusions is
registered in the hospital information system and is recorded with a case
record form at discharge from the hospital.
The use of autologous blood transfusion is restricted to patients undergoing
extensive surgical procedures with high expected blood loss. At the discretion
of the surgeon or the anesthesiologist a cell-saver autologous blood recovery
system can be used during surgery. Blood recovered by this system is considered
perioperative blood loss. In case a significant amount of blood is recovered
and the patient is likely to benefit from an autologous transfusion, autologous
blood will be transfused back to the patient.

Occurrence of cardio-vascular and cerebro-vascular thrombo-embolic
events
All 30-day complications perioperatively after spinal surgery are recorded.
During hospital stay and at regular postoperative outpatient clinical
appointment within 6-12 weeks after surgery all perioperative complications are
recorded and evaluated in a standardized manner using a case record form.
Complications are classified according to a hospital database thesaurus and the
severity of the complication is graded (see table 1). The occurrence of
postoperative myocardial infarction or cerebrovascular ischemia within 30 days
after surgery are of utmost relevance.

Table 1. Grading of complications according to Clavien-Dindo
Grade Description
1A Recovery after non-invasive treatment (e.g. medication, physical therapy)
1B Recovery after invasive treatment (except for operation in an OR) or
admission to intensive care
2 Recovery after (re-)operation in an OR
3A Complication still persists or treated at time of registration
3B Complication resulting in to permanent loss of function or disability
4 Death

The study is a randomized controlled, non-inferiority trial with two parallel
groups. Patients are randomly allocated to either perioperative continuation of
aspirin or discontinuation group prior to spinal surgery. Thrombotic cardiac
and neurologic events, perioperative blood loss, hemorrhage related
complications and need for reoperation events within 30 days after surgery are
evaluated in both treatment groups.

All patients referred to the outpatient clinic of the department of
neurosurgery that are scheduled for spinal surgery are eligible for inclusion.
The hospitals participating in this study are:
• Haaglanden Medical Center
• HAGA teaching hospital Den Haag
• Spaarne Gasthuis Haarlem
• Alrijne hospital Leiderdorp

The intervention group will be continuing asprin peri-operatively.

See study objectives.