Clevidipine in the Treatment of Blood Pressure in Patients With Acute Heart Failure (PRONTO)

The Medicines Company117 enrolled

Overview

The purpose of this study was to evaluate the efficacy and safety of intravenous (IV) clevidipine as compared with standard of care IV antihypertensive agents for blood pressure (BP) lowering in patients with acute heart failure and elevated BP.

This study was an open-label randomized efficacy and safety pilot trial in patients with acute heart failure (AHF) and hypertension (systolic blood pressure \[SBP\] ≥160 mm Hg) requiring parenteral antihypertensive therapy. Eligible patients were randomized to receive clevidipine or standard of care (SOC) intravenous antihypertensive treatment in an open-label manner in a ratio of 1:1. At the time of randomization, a patient-specific, prespecified SBP target range was determined and be recorded, prior to study drug treatment. Information on the dosing regimen, use of additional or alternative agents and transition to oral therapy if needed is detailed in the study 'ARM' and 'INTERVENTION' sections. A Data Safety Monitoring Board was utilized periodically throughout the study to monitor the safety of patients. Adverse events were assessed for 7 days post-study randomization or hospital discharge, whichever occured first. Serious adverse events (SAEs) were assessed for 30 days following study randomization. Subjects were contacted by telephone or in person up to 5 days after their 30-day time point to determine if any SAEs occurred following study drug treatment and to follow up on the Heath Economic assessments.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

117

Conditions

Hypertension Heart Failure

Interventions

ClevidipineDRUG

Clevidipine was to be administered continuously as monotherapy during the first 30 minutes. Use of an alternative IV antihypertensive agent(s) was discouraged and was limited to where medically necessary to maintain patient safety. Patients who received an alternative antihypertensive agent along with the study drug were allowed to continue in the study. If transition to an oral antihypertensive agent was required, it was to be administered approximately 1 hour prior to the termination of clevidipine with study drug down-titrated or terminated in order to maintain the desired blood pressure level.

Standard of Care IV antihypertensiveDRUG

SOC IV antihypertensive agent will be administered for a minimum of 30 min and, if medically warranted, may continue beyond 96 hours at the investigator's discretion. As with clevidipine, the SOC agent was to be administered continuously as monotherapy during the first 30 minutes. Use of an alternative agent(s) was discouraged and was limited to where medically necessary to maintain patient safety. Higher dose titration rates were required to be attempted prior to making the decision to switch to or add on an alternative antihypertensive agent(s). Patients who received an alternative antihypertensive agent with SOC were allowed to continue in the study. If transition to an oral antihypertensive agent was required, it was to be administered per institutional practice.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age 18 years or older * Presentation consistent with acute heart failure and pulmonary congestion on physical examination as evidenced by rales * Baseline systolic blood pressure (immediately prior to initiation of study drug) of ≥160 mm Hg * Dyspnea score (sitting) of at least 5 on a 10 cm visual analog scale (VAS) * Required IV antihypertensive therapy to lower blood pressure * Written informed consent Exclusion Criteria: * Administration of an agent (IV or oral) for the treatment of elevated BP within the previous 2 hours of randomization. (Previous short-acting non-IV nitrates, continuous positive airway pressure (CPAP), and bi-level positive airway pressure (BiPAP) were permitted) * Chest pain and/or electrocardiogram with ST segment changes consistent with acute coronary syndrome * Known or suspected aortic dissection * Acute myocardial infarction within the prior 14 days * Dialysis-dependant renal failure * Requirement for immediate endotracheal intubation * Positive pregnancy test, known pregnancy or breast feeding female * Intolerance or allergy to calcium channel blockers * Allergy to soybean oil or egg lecithin * Known liver failure, cirrhosis or pancreatitis * Prior directives against advanced life support * Participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of enrollment

Locations (13)

Jackson Hospital

Montgomery, Alabama, United States

Centinela Hospital

Inglewood, California, United States

Louisiana State University Health Sciences Center

Baton Rouge, Louisiana, United States

Outcomes

Primary Outcomes

Time to First Achieve Initial Prespecified SBP Target Range and 15% Reduction From Baseline Within First 30 Minutes

Time to first achieve the initial pre-specified systolic blood pressure (SBP) target range and a 15% SBP reduction from baseline is the time in minutes between the initiation of study medication and the time the patient first achieved both components. Median time was estimated using Kaplan Meier method. 95% two-sided confidence interval of the median time is from 'Simon and Lee, 1982'. If patients did not reach both components within 30 minutes from the initial treatment with study medication, or another antihypertensive agent was administered, the patient was censored at 30 minutes or the time when another antihypertensive agent is given, whichever came first.

Time frame: Initiation of study drug through the initial 30-minutes

Percentage to First Achieve Initial Prespecified SBP Target Range [≥20 mm Hg and ≤40 mm Hg Apart] and 15% Reduction From Baseline Within First 30 Minutes

Analysis of the percentage of patients achieving both components of this composite endpoint (attainment of the initial prespecified SBP target range and a 15% reduction in SBP from baseline) was calculated within each treatment group using the number of mITT patients achieving the SBP reduction goal divided by the number of mITT patients, and multiplied by 100.

Time frame: Initiation of study drug through the initial 30-minutes

Secondary Outcomes

Percentage Reaching Prespecified Target Range Without Falling Below Lower Limit of Target Range Within First 30 Minutes

The percentage of patients reaching this endpoint was calculated within each treatment group using the number of mITT patients reaching the endpoint divided by the number of mITT patients, and multiplied by 100. Two-tailed 95% CIs were computed for these percentages.

Time frame: Initiation of study drug through the initial 30-minutes

SBP Area Under the Curve (AUC) Outside Prespecified Target Range

The magnitude and duration of SBP excursions was calculated as the area under the curve (AUC) for each patient, using the trapezoidal rule, related to time (in minutes) that each patient's SBP was outside the target range. AUC was determined based on data collected from the initiation of study medication through the end of monotherapy treatment up to 96 hours, normalized per hour, and expressed as mmHg × minute/hour.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.