Surgery Clinical Trial
Official title:
A Prospective, Multi-centre, Randomised Trial of B-type Natriuretic Peptide Guided Therapy to Improve Clinical Outcomes for Patients Undergoing Non-cardiac Surgery: the BETTER Surgery Pilot Trial
The primary hypothesis of the BETTER pilot trial is that B-type natriuretic peptide (BNP) directed medical therapy prior to noncardiac surgery will be associated with improved cardiovascular outcomes, when compared to standard of care.
Study hypothesis and aim. The primary hypothesis of the BETTER Surgery Pilot Trial is that
BNP directed medical therapy prior to noncardiac surgery will be associated with improved
cardiovascular outcomes, when compared to standard of care. The aim of this pilot trial is
to test the feasibility of a preoperative BNP directed medical therapy trial, with the
intention of then going onto a large international multicentred RCT.
Primary outcome measure. A composite of 30 day mortality, nonfatal myocardial infarction,
nonfatal cardiac arrest, congestive cardiac failure and re-operation.
Secondary outcome measures.
Difference in BNP levels at the time of surgery An analysis of outcomes as a measure of
achieved value i.e. the value measured immediately prior to surgery.
Duration of hospital stay Admission to critical care Time to surgery Reoperation
Trial design. A prospective, multi-centre, randomised trial of BNP guided therapy to improve
clinical outcomes for patients undergoing non-cardiac surgery.
Inclusion criteria. High risk elective preoperative noncardiac surgical patients who are
referred to a preanaesthetic clinic for preoperative risk stratification.
Exclusion criteria.
Patient refusal to participate Where clinical opinion suggests that surgery cannot be
postponed for at least 3 to 4 weeks to allow for clinical response to a change in medical
therapy Randomisation. Patients will only be randomized during the outpatient clinic visit
once a decision has been taken that surgery is necessary. This will follow informed consent.
Patients would be randomized to standard of care or BNP directed care. Following
randomization, BNP will be measured in all patients.
1. Standard-of-care arm. These patients will be managed as per standard preoperative
stratification strategies at the participating units. All personnel will be blinded to
the BNP results. Optimisation of medical therapies will be encouraged.
2. BNP guided therapy patients. Based on an individual patient data meta-analysis of
noncardiac surgical patients, the thresholds associated with BNP and MACE are known.
Based on these BNP thresholds, the following recommendations are made;
High risk: Additional medical therapy and/or uptitration of current therapies is strongly
recommended. It is strongly recommended that surgery is deferred until the BNP falls below
the high risk threshold if possible to allow for therapy response.
Intemediate risk: Additional therapy and/or uptitration of current therapies is recommended.
It is recommended that surgery is deferred if possible to allow for therapy response.
Low risk: Surgery is recommended as soon as any other perioperative considerations have been
addressed. Ideally, surgery is recommended at the earliest convenience.
Additional visits may also be scheduled at the discretion of the investigator for further
BNP risk stratification prior to surgery at the discretion of the treating physician.
Neither the attending physicians, nor the patient will be blinded to the BNP result in the
BNP guided therapy arm.
BNP levels will be repeated in all patients before scheduled surgery. These preoperative BNP
results will be blinded.
Irrespective of the treatment group to which the noncardiac patient has been randomized, it
is recommended that all these surgical patients receive statin therapy during the
perioperative period and if on aspirin, that it is stopped 72 hours before surgery, and
re-instituted at 7 days postoperatively. Intraoperative and postoperative management will be
at the discretion of the local physicians.
Drug therapies. Drug therapies used in the BETTER trial will be compliant with practice
guidelines for heart failure therapy, up to the point of ensuring ACE-inhibition,
beta-blockade and mineralocorticoid receptor antagonism. Uptitration of drugs known to
decrease mortality associated with cardiac failure and secondary prevention for myocardial
infarction will be considered. The minimum and maximum doses advocated in the PROTECT study
have been adopted for the BETTER Surgery Pilot Trial. Uptitration will only considered where
uptitration of therapy has been associated with improved survival in heart failure studies.
End point adjudication. All end points will be adjudicated by physicians blinded to
treatment allocation.
Withdrawal rules. Subjects are free to voluntarily withdraw from the BETTER Surgery Trial at
any time. However, events experienced by any withdrawn patient will be analyzed at the end
of the trial as a function of treatment allocation under intent-to-treat considerations.
Ethics approval. Ethics approval will be obtained from each university centre. Steering
committee members will ensure ethics approval is obtained from their respective centres
prior to trial participation.
Data collection and collation. Access to the electronic data entry system will be protected
by username and password. Username and password will be delivered during the registration
process for individual local investigators. All electronic data transfer between
participating centres and the co-ordinating centre will be username and password protected.
Each centre will maintain a trial file including a protocol, local investigator delegation
log, ethics approval documentation etc. Pseudo-anonymised (coded) data may also be sent by
mail to the coordinating centre if necessary for event adjudication.
Statistical analysis. Categorical variables will be described as proportions and will be
compared using chi-square or Fisher's exact test. Continuous variable will be described as
mean and standard deviation if normally distributed or median and inter-quartile range if
not normally distributed. Comparisons of continuous variables will be performed using
one-way ANOVA or Mann-Whitney test as appropriate.
Primary clinical end point. Kaplan-Meier curves will be constructed to evaluate time to
first event and compared using the log-rank test. Lastly, univariable followed by
multivariable analyses will identify independent predictors of outcomes, with subsequent
regression analysis performed to compare event rates, adjusting for differences between
baseline variables.
It is expected that patients in the BNP guided therapy arm may end up with more repeat
visits compared to the standard of care arm of the trial. To understand whether such
increased contact itself is associated with better outcomes rather than a lowering of BNP, a
covariate analysis controlled for total visits versus visits triggered by BNP evaluation for
further therapeutic intervention, will be performed to determine the potential effect of
increased visits on patient outcomes.
Trial management. Participating centres need to routinely provide preoperative risk
stratification services for high risk noncardiac surgical patients. The pilot trial will be
led by Bruce Biccard. Site leaders, have been identified as co-participants in this
application.
Sample size calculation. For the proposed composite outcome we expect at least a 10% event
rate. In a large international multicentre trial, assuming a 25% relative risk reduction in
the primary outcome in the BNP directed therapy group with an event rate of 10%, we
estimated a sample size of 2075 patients per group would provide a 80% power (α =0.05).
For the pilot trial we will recruit 100 patients.
How this trial will lead to a larger study.
A review of all the literature on preoperative BNP risk stratification suggests that
integrating preoperative BNP into risk stratification models has reached the 4th stage
integrating a biomarker into clinical practice (clinical utility). This surpasses the
current Revised Cardiac Risk Index (RCRI) clinical standard in preoperative risk
stratification in the process. There is good individual patient data meta-analyses which
have been used to establish the BNP thresholds associated with adverse outcomes. This
stresses the importance (yet lack) of randomised controlled trials which address the utility
of biomarker risk stratification to improve patient outcomes through biomarker directed
therapy, management and monitoring in noncardiac surgical patients. The fifth stage of
integration of a biomarker into clinical practice demands demonstration that biomarker
directed therapy improves clinical outcomes. A single study has been conducted in the
non-surgical population, which showed a more aggressive heart failure therapy regimen driven
by targetting BNP was generally well tolerated in the elderly and associated with
significantly fewer cardiovascular events.
This pilot trial will assess the feasibility of such an important preoperative surgical
clinical RCT. These data will be used to plan and conduct a large, multicentre RCT to
address this question.
References.
1. Hlatky MA, et al. Criteria for evaluation of novel markers of cardiovascular risk: a
scientific statement from the American Heart Association. Circulation.
2009;119:2408-16.
2. Biccard BM, Devereaux PJ and Rodseth RN. Cardiac biomarkers in the prediction of risk
in the non-cardiac surgery setting. Anaesthesia. 2014;69:484-93.
3. Gaggin HK, et al. Heart failure outcomes and benefits of NT-proBNP-guided management in
the elderly: results from the prospective, randomized ProBNP outpatient tailored
chronic heart failure therapy (PROTECT) study. J Card Fail 2012;18(8):626-34.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Prevention
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