Optimal VAsopressor TitraTION in Patients 65 Years and Older

Hypotension Clinical Trial

— OVATION-65  

Official title:

Optimal VAsopressor TitraTION in Patients 65 Years and Older (OVATION-65)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03431181
• Other study ID #: MP-31-2018-1789
• Status: Active, not recruiting
• Phase: N/A
• Start date: February 16, 2018
• Est. completion date: December 31, 2024

Study information

• Verified date: May 2024
• Source: Université de Sherbrooke
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

We have designed OVATION-65 to evaluate the effects of permissive low blood pressure compared to usual care on markers of organ injury and survival in older patients.

Description:

Background:

When it is severe, hypotension compromises tissue perfusion and organ function, leading to multiple organ failure and death. Commonly in intensive care units (ICUs), excessive vasodilation causes hypotension. In response, clinicians administer vasopressors to induce vasoconstriction and thereby raise blood pressure. However, these medications may reduce blood flow to vital organs, including the heart, and therefore damage them. Titrating vasopressors therefore requires balancing the risks of organ dysfunction arising from vasopressors or hypotension. Current guidelines recommend titrating vasopressors to a mean arterial pressure (MAP) of 65 mmHg. By not specifying an upper limit, guidelines and clinicians put more emphasis on preventing hypotension than on minimizing vasopressor exposure. Permissive hypotension, defined as a MAP target below traditional levels, may reduce vasopressor-induced harm while avoiding organ dysfunction induced by severe hypotension.

Observational data show that the average MAP in Canadian patients on vasopressors is 75 mmHg, 10 mmHg above current guideline recommendations and self-reported practices.The recent CIHR-funded OVATION pilot RCT (n=118) of permissive hypotension met feasibility objectives of demonstrating a separation in mean MAP between arms (9 mmHg, p<0.0001) and enrolling patients efficiently (2.3 patients/site/month). Investigators have also completed an individual patient data meta-analysis with the French SEPSISPAM trial and found that a lower MAP target may be beneficial in patients 65 years old.

Objective:

The overarching goal of this randomized controlled trial (RCT) of permissive hypotension vs. usual blood pressure targets in hypotensive patients ≥65 years old is to determine whether permissive hypotension reduces the risk of harm associated with usual vasopressor therapy. The proposed RCT has specific objectives to ascertain the effect of permissive hypotension vs. usual care on: 1) markers of organ injury (primarily in the heart at day 3, secondarily (on day 3 and day 7) in the brain, liver, intestine, and skeletal muscle); 2) global tissue dysoxia (assessed by plasma lactate); 3) organ function (assessed by Sequential Organ Failure Assessment [SOFA] Score ); 4) resource utilization, 5) pre-specified adverse events, 6) mortality at 90 days and 6 months; 7) cognitive impairment in survivors at 6 months.

Methods:

Eligible patients will be randomized to target MAP 60-65 mmHg vs. usual care. By comparing permissive hypotension to usual care, we improve acceptance from clinicians and reduce the risk that the control group will diverge widely from usual care. Investigators will enroll patients in 7 Canadian ICUs. The deferred consent model will be adopted, successfully used in the pilot trial. Risk of bias will be minimized by allocation concealment, blinding of outcome assessors, complete hospital follow-up and intention-to-treat analysis.

Relevance:

This RCT proposal is embedded in the international OVATION-65 program of research, which includes the ongoing NIHR-funded UK65 Trial which measures 90-day mortality as the primary outcome. The Canadian OVATION-65 RCT is the only trial that measures organ injury biomarkers, providing crucial clinical information regardless of the effect on mortality. Results are expected to be incorporated into guidelines to inform practice worldwide.

Sample size:

The OVATION-65 Trial was designed to be complementary to the 65 Trial conducted in the United Kingdom. The original proposal, which consisted in a larger and simpler trial (n=800 participants, focused on biomarkers of organ injury) was abandoned because funding applications to the Canadian Institutes for Health Research and the Canadian Frailty Network were unsuccessful. The current trial was supported by a combination of multiple more modest operating grants awarded by the Université de Sherbrooke and the Centre de Recherche du CHU de Sherbrooke (see Funding sources). However, each grant required a distinct objective increasing the complexity of the analysis plan and sample size calculation. Certain analyses were incorporated into funding applications for local experiments on a small scale. By combining funds from multiple sources, we are able to enroll up to 200 participants, however we lack resources to measure every outcome on 200 participants. Outcomes that cannot be measured on every participant or as well as those that were planned originally but that remain unfunded are described briefly in the secondary outcomes section and specified as ancillary studies. They will be reported separately.

Attempts to obtain funding for a larger OVATION-65 Trial continued until the end of 2018. Sufficient funding was secured to enroll up to 200 patients, but trial enrollment was terminated on 21 February 2020 after 159 patients were enrolled, on the recommendation of the DSMC following publication of the 65 trial. Six-month follow-up will be complete in August 2020. The statistical analysis plan will be registered and published before analyzing the data.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 159
• Est. completion date: December 31, 2024
• Est. primary completion date: February 21, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

Inclusion Criteria:

1. Age 65 years or older

2. Working diagnosis of vasodilatory hypotension as assessed by treating team

3. Vasopressors started for 12 hours or less (window from ICU admission after/during adequate fluid resuscitation as assessed by treating physician)

4. Vasopressors expected for 6 additional hours as assessed by the treating team

Exclusion Criteria:

1. Actively treated for spinal cord injury or acute brain injury

2. Vasopressors being given solely for bleeding, acute ventricular failure or post-cardiopulmonary bypass vasoplegia

3. Lacking commitment to life-sustaining therapies (expected withdrawal of life-sustaining treatments within the next 48 hours

4. Death perceived as imminent

5. Previously enrolled in OVATION-65

6. Organ transplant within the last year

7. Extra corporeal life support at baseline

8. The treating physician(s) lacks equipoise regarding the overall effects of permissive hypotension versus usual care on patient important outcomes.

Related Conditions & MeSH terms

• Hypotension
• Mean Arterial Pressure Targets
• Usual Care
• Vasopressors

Intervention

Behavioral:
• MAP target 60-65 mmHg
Treating teams will adjust vasopressors to a target MAP range of 60 to 65 mmHg, avoiding vasopressor-induced MAP above this range.
• Usual care
Patients in the control arm will receive usual care (as per local practices).

Locations

Country	Name	City	State
Canada	CIUSSS de l'Estrie-CHUS	Sherbrooke	Quebec

Sponsors (1)

Lead Sponsor	Collaborator
Université de Sherbrooke

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma high-sensitivity cardiac troponin T at day 3 (primary mechanistic outcome)	Plasma high-sensitivity cardiac troponin T (hsTnT) at day 3 (corrected for baseline levels) (primary mechanistic outcome)	Day 3
Secondary	Concentration of biomarkers associated with tissue injury to the brain	Concentration of biomarkers associated with tissue injury to the brain (plasma GFAP, plasma Myelin Basic Protein and serum NSE)	Days 1 (baseline),3 and 7
Secondary	Concentration of biomarker associated with tissue injury to the liver	Concentration of biomarker associated with tissue injury to the liver (plasma ALT)	Days 1 (baseline),3 and 7
Secondary	Concentration of biomarker associated with tissue injury to the intestine	Concentration of biomarker associated with tissue injury to the intestine (plasma fatty acid binding protein (FABP))	Days 1 (baseline),3 and 7
Secondary	Concentration of biomarker associated with tissue injury to the skeletal muscle	Concentration of biomarker associated with tissue injury to the skeletal muscle (plasma creatinine kinase).	Days 1 (baseline),3 and 7
Secondary	Concentration of biomarker associated with cardiac wall stress	Concentration of biomarker associated with cardiac wall stress (plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP]).	Days 1 (baseline),3 and 7
Secondary	Global tissue dysoxia	Global tissue dysoxia will be assessed through plasma lactate	Days 1 (baseline),3 and 7
Secondary	Plasma high-sensitivity cardiac troponin T (hsTnT)	Plasma high-sensitivity cardiac troponin T (hsTnT) at day 7	Day 7
Secondary	Pre-specified adverse events	Pre-specified adverse events assessed by events of stroke, clinically detected supraventricular arrhythmia, acute kidney injury (KDIGO stage 3), limb or intestinal ischemia	28 days
Secondary	Organ function	Organ function using SOFA score (measured at baseline (day 1) and on days 2,3,4,7,10,14 and 28 while in the ICU)	Days 1 (baseline), 2, 3, 4, 7, 10, 14 and 28
Secondary	Mortality	Mortality at 90 days and at 6 months will be assessed during the phone call at 6 months	90 days and 6 months
Secondary	6-month cognitive impairment	6-month cognitive impairment assessed by Telephone Interview for Cognitive Status (TICS)	6 months
Secondary	Healthcare utilization	Healthcare utilization assessed by measuring duration of mechanical ventilation, renal replacement therapy, vasopressor therapy and ICU and hospital stay (through days of utilization)	28 days
Secondary	Plasma level of ascorbic acid (outcome for ancillary study)	Plasma level of ascorbic acid (measured at baseline (day 1))	Day 1 (baseline)
Secondary	Biomarkers of ascorbic acid deficiency-related organ injury (outcome for ancillary study)	Inflammation (IL-1ß; TNF-a; CRP) and endothelial injury (thrombomodulin, angiopoietin-2)	Days 1 (baseline), 3 and 7
Secondary	Discovery proteomic approach to identify peptides and proteins expressed in the urine (outcome for ancillary study)	Discovery proteomic approach through novel urine biomarkers	Days 1 (baseline), 3 and 7
Secondary	Validate the predictive value of five prespecified biomarkers of renal injury in urine using a proteomic approach (outcome for ancillary study): TIMP2, NGAL, FABPL, CYTC, IGFBP7	Proteomic discovery approach through validation of prespecified urine biomarkers: TIMP2, NGAL, FABPL, CYTC, IGFBP7	Days 1 (baseline), 3 and 7
Secondary	Impact of vasopressor regimen on the immune response, adrenergic receptor activity and related proteomic signature of peripheral blood mononuclear cell (PBMC) (outcome for ancillary study)	Immune response, adrenergic receptor activity and proteomic profile through Th1/Th2 profiling, PBMC adrenergic receptors AMPc activity and proteomic signature and associations with responses to catecholamines.	Day 1 (baseline) and 7