Optimal VAsopressor TitraTION in Patients 65 Years and Older

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

NA

Total Enrollment

159 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-02-16

Study Completion Date

2024-12-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Vasopressors Hypotension Mean Arterial Pressure Targets Usual Care

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

OTHER

Blinding Strategy

SINGLE

Outcome Assessors

Study Groups

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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.

Group Type EXPERIMENTAL

MAP target 60-65 mmHg

Intervention Type BEHAVIORAL

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).

Group Type ACTIVE_COMPARATOR

Usual care

Intervention Type BEHAVIORAL

Patients in the control arm will receive usual care (as per local practices).

Interventions

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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.

Intervention Type BEHAVIORAL

Usual care

Patients in the control arm will receive usual care (as per local practices).

Intervention Type BEHAVIORAL

Eligibility Criteria

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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.

Minimum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No