The objective of the proposed trial is therefore to determine the effect of continuation versus withdrawal of ACEi and ARB in the perioperative period on postoperative complications, expressed as acute kidney injury, myocardial injury, and quality…
ID
Source
Brief title
Condition
- Myocardial disorders
- Renal disorders (excl nephropathies)
- Therapeutic procedures and supportive care NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome for this study is acute kidney injury, defined according to
the Kidney Disease Improving Global Outcomes (KDIGO) guideline as any of the
following: - Increase in serum creatinin by >=0.3 mg/dl (>=26.5 µmol/l) within 48
hours; or - Increase in serum creatinin to >=1.5 times baseline, which is known
or presumed to have occurred within the prior 7 days; or - Urine volume <0.5
ml/kg/h for 6 hours.
Secondary outcome
- Postoperative myocardial injury, defined as an increased level of serum
troponin above the clinical cut-off value; - Intraoperative or postoperative
hypotension, defined as a mean arterial pressure <65 mmHg for at least 10
minutes from the start of anesthesia until the end of surgery; - Postoperative
hypotension, defined as a mean arterial pressure <65 mmHg from the end of
surgery up to and including the second postoperative day; - Postoperative
clinically diagnosed delirium. - Length of stay in hospital or nursing home; -
End-stage renal disease within three months after surgery, defined as renal
disease requiring dialysis or organ transplantation; - Major cardiovascular
complications (myocardial infarction, coronary revascularization, heart
failure, arrhythmia, stroke) within three months after surgery; - All-cause
mortality within three months after surgery; - Quality of life at 4-6 weeks and
three months after surgery. - Absenteeism during three months after surgery -
Protocol adherence regarding preoperative intake or withdrawal of ACEi/ARB.
Amendment due to early discontinuation: - Acute kidney function loss, defined
as the change between preoperative and postoperative creatinine and eGFR; -
Acute postoperative myocardial injury, defined as an absolute postoperative
increase in serum troponin of more than clinical cut-off value as compared to
the preoperative value; - Disability at three months after surgery based on the
World Health Organization Disability Activity Score (WHODAS)
Background summary
In The Netherlands alone each year over 1 million patients undergo a surgical
procedure under anesthesia. Many of these patients suffer from cardiovascular
diseases including hypertension. About one third of older surgical patients
chronically use angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin
receptor blockers (ARB) for the treatment of hypertension. These drugs lower
blood pressure by vasodilation and natriuresis through inhibition of the
renin-angiotensin-aldosterone system (RAAS), and have beneficial effects on
long-term outcome in patients with hypertension, heart failure and chronic
kidney disease. By their effect on blood pressure however, in the perioperative
period these drugs may have adverse effects. One of the most common effects of
anesthesia and surgery on the cardiovascular system is hypotension, which may
occur during anesthesia and in the first postoperative days, especially in
patients with cardiovascular disease. Importantly, concurrent use of ACEi or
ARB on top of anesthetic side effects blocks the physiologic response from the
RAAS to hypotension. As a result, hypotension may persist and contribute to
compromised tissue perfusion, leading to poor wound healing, organ failure and
death. On the other hand, withdrawal of ACEi and ARB around surgery may
increase RAAS activity, blood pressure and systemic vascular resistance, which
may in turn impair regional circulation. The kidney and heart are vulnerable to
injury resulting from poor tissue perfusion as provoked by perioperative
factors including hypotension. Both perioperative acute kidney injury and
myocardial injury occur frequently, and are associated with poor prognosis.
The available evidence on this topic suggests that perioperative continuation
of ACEi/ARB is associated with an increased incidence of intra- and
postoperative hypotension, but that perioperative withdrawal may be associated
with an increased incidence of perioperative hypertension. A recent
meta-analysis showed that hypotension occurs in 28% of patients who use
ACEi/ARB, and that patients who withheld their ACEi/ARB medication on the
morning of surgery had significantly lower risk of intraoperative hypotension
(23% versus 30%; OR 0.63; 95% CI, 0.47-0.85). Importantly, there is a strong
association between intraoperative hypotension and kidney injury, myocardial
injury, and death. Patients who suffer from perioperative hypotension have a
two- to five-fold higher risk of postoperative acute kidney injury, a two- to
four-fold higher risk of myocardial injury, and a two-fold higher risk of
death.
Hence, perioperative withdrawal of ACEi/ARB medication may prevent
postoperative complications and improve patient outcomes through the prevention
of perioperative hypotension. There is scarce evidence of a beneficial effect
of ACEi/ARB withdrawal on patient outcomes. However, these findings are from
cohort studies that likely were biased by residual confounding, and from
randomized studies that were too small to show any difference.
Therefore, it is still unknown whether these drugs should be continued or
withdrawn before and shortly after surgery. This is reflected in the fact that
current guidelines on this topic are discordant: the American guidelines advise
to continue ACEi and ARB in the perioperative period, while the European and
Canadian guidelines advise to withdraw these drugs before surgery. As a
consequence, policy varies between hospitals and even between
anesthesiologists.
Study objective
The objective of the proposed trial is therefore to determine the effect of
continuation versus withdrawal of ACEi and ARB in the perioperative period on
postoperative complications, expressed as acute kidney injury, myocardial
injury, and quality of life.
Study design
A pragmatic, multicenter randomized clinical trial.
Intervention
Withdrawal of ACEi/ARB in the perioperative period, i.e. from 24 hours before
surgery until 24-48 hours after surgery. The ACEi/ARB medication is resumed on
the second or third day after surgery as soon as the clinical condition allows
on judgment of the attending physician. In patients who use ACEi/ARB medication
in a combination pill together with a diuretic, this combination pill will be
withdrawn, hence including the diuretic.
This intervention will be compared to perioperative continuation of ACEi/ARB.
Study burden and risks
The burden of participating in this study, consisting of filling out some short
questionnaires and a medication diary, and some blood draws, is considered low.
Also the risks of participating is considered low. At this moment it is not
clear which strategy should be applied, and both strategies are used in current
clinical practice, depending on the hospital and/or anesthesiologist.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
- Chronic angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers use for the treatment of hypertension. Patients who use a com-bination
pill with a diuretic are eligible as well;
- Scheduled for elective intermediate to high risk noncardiac surgery, defined
according to the European Society of Cardiology / European Society of
Anesthesiology guidelines on noncardiac surgery under general or regional
(spinal, epidural) anesthesia,
- Expected postoperative length of stay of at least one postoperative night
Exclusion criteria
- Severe chronic kidney disease, defined as eGFR<30 ml/min/1.73 m2 -
Angiotensin converting enzyme-inhibitors (ACEi)/Agiotensin receptor blockers
(ARB) use for the treatment of chronic systolic heart failure, defined as left
ventricular ejection fraction <=40%. Patients in whom the ejection fraction
currently has improved to >40% as a result of heart failure treatment (e.g.
ACEi/ARB use or chronic resynchronization therapy (CRT)) are also excluded -
ACEi/ARB use within one year after ST-elevated myocardial infarction, according
to the fourth universal definition of myocardial infarction (20,21) -
Transplant surgery - ACEi/ARB use in a combination pill together with a drug
other than a diuretic, including calcium channel blockers, beta-blockers and
neprilysin inhibitorsUse of drugs acting on the renin-angiotensin-aldosterone
system other than ACEi/ARB, e.g. aliskiren. - Patients who are not able to
manage their medication themselves, e.g. patients who use a medication box or
pill dispenser including the *Baxterrol*. - Urgent (<48 hours of diagnosis) or
emergency surgery - Nephrectomy (partial or complete, no matter the cause) -
Pheochromocytoma surgery - Carotid surgery, including endarterectomy and
carotid bypass surgery
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT04506372 |
| CCMO | NL72045.041.20 |