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

A Safety and Efficacy Study of Blood Pressure Control in Acute Heart Failure - A Pilot Study (PRONTO)

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Hypertension
• Intervention / Treatment: Drug: Clevidipine; Drug: Standard of Care IV antihypertensive

Detailed Description

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
• Enrollment (Actual): 117
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75004
    • Hopial AP-HP Hotel-Dieu
  • Paris, France, 75013
    • Hopital AP-HP La Pitie Sapetriere
  • Paris, France, 75475
    • Hopital AP-HP Lariboisiere Urgencies-SMUR
• Germany
  • Berlin, Germany, 13353
    • Charité - Universitätsmedizin Berlin
• United States
  • Alabama
    • Montgomery, Alabama, United States, 36106
      • Jackson Hospital
  • California
    • Inglewood, California, United States, 90301
      • Centinela Hospital
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70805
      • Louisiana State University Health Sciences Center
    • New Orleans, Louisiana, United States, 70112
      • Louisiana State University Health Sciences Center - Emergency Medicine
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Stony Brook, New York, United States, 11794
      • Stony Brook University and Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clevidipine; Clevidipine (0.5 mg/mL in 20% lipid emulsion) was administered intravenously via a single dedicated line to all patients randomized to the clevidipine arm. Clevidipine was infused at an initial rate of 2 mg/h for the first 3 minutes. If blood pressure was not in the target range at 3 minutes, clevidipine was titrated to effect thereafter by doubling the dose every 3 min, per physician discretion and as tolerated by the patient until the desired effect until the SBP target range was attained. Once target range was achieved, the infusion rate could be increased or decreased as needed to maintain blood pressure for minimum of 30 minutes and a maximum duration of 96 hours. The minimum infusion rate was 1 mg/h and maximum infusion rate was 32 mg/h.	Drug: Clevidipine; 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.; Other Names: clevidipine emulsion; Cleviprex; clevidipine injectible emulsion
Active Comparator: Standard of Care IV antihypertensive; For patients randomized to standard of care (SOC) IV antihypertensive treatment, a continuous infusion of an intravenous antihypertensive agent represented standard of care. The selection of treatment was at the discretion of the investigator. The infusion was to be administered according to the institution's treatment practice.	Drug: Standard of Care IV antihypertensive; 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.; Other Names: nicardipine; diltiazem; nitroglycerin; sodium nitroprusside; isosorbide dinitrate; hydralizine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	Initiation of study drug through the initial 30-minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	Initiation of study drug through end of monotherapy (up to 96 hours)
Percentage Falling Below Lower Limit of SBP Target Range Within First 30 Minutes	The percentage of patients in whom the SBP fell below the lower limit of the prespecified target range at any time during the first 30 minutes was calculated within each treatment group using the number of mITT patients achieving the endpoint divided by the number of mITT patients and multiplied by 100. Two-tailed 95% CIs were computed for these percentages.	Initiation of study drug through the initial 30-minutes
Percentage Falling Below Lower Limit of SBP Target Range at Any Time During Study	The percentage of patients in whom the SBP fell below the lower limit of the prespecified target range at any time during the entire study drug treatment period (up to 96 hours) was calculated within each treatment group using the number of mITT patients achieving the endpoint divided by the number of mITT patients and multiplied by 100. Two-tailed 95% CIs were computed for these percentages.	Initiation through termination of study drug (up to 96 hours)
Change From Baseline in Dyspnea (Measured By VAS) at Each Time Point	A validated visual analog scale (VAS) with a horizontal ruler showing increments from 0 to 100 mm with 0 = Best and 100 = Worst was used. The test was asked from the patient's perspective and had to be administered with patient sitting. Relative change in VAS from baseline is the value at each time point minus the baseline value. Relative change from baseline was summarized descriptively (with associated two-tailed 95% CIs of the mean values) at 15, 30 and 45 minutes and at 1, 2, 3 hours and 12 hours, and 1 hour post termination of study drug treatment.	Baseline (immediately prior to study drug administration) through 1 hour after study drug termination
Time to Use Other IV Antihypertensives During the Study Drug Administration	The length of time to use other IV antihypertensive agents was defined as the duration in hours from the initiation of study drug through the time when any other concomitant IV antihypertensive agent was administered, thus, representing the time period without use of any other concomitant IV antihypertensive agent. Median time to use other IV antihypertensive agents was obtained using Kaplan-Meier method. If a patient did not receive any concomitant IV antihypertensive during the 96-hour treatment period, this patient was considered censored at 96 hours. If study drug was stopped less than 96 hours and the patient has no concomitant IV antihypertensive agent, the patient was considered censored when study drug was stopped.	Initiation of study drug through any other concomitant IV antihypertensive agent administered, up to 96 hours
Percentage of Patients Who Received Any Alternative IV Antihypertensive Drug at Any Time During Study Drug Treatment	The percentage of patients who received any alternative IV antihypertensive drug at any time during the study drug treatment period (up to 96 hours) was calculated using mITT patients within each treatment group.	Initiation through termination of study drug (up to 96 hours)
Percentage of Patients With at Least One Episode of SBP < 90 mm Hg During Study Drug Administration (up to 96 Hours)	The percent of patients with at least one episode of SBP <90 mm Hg was calculated as the number of mITT patients who had at least one episode of SBP<90 mm Hg during study drug administration up to 96 hours divided by mITT patients, and multiplied by 100 for each treatment group.	Initiation through termination of study drug (up to 96 hours)
Number of Patients That Require Intubation During Study Drug Administration up to 96 Hours	The number of patients requiring intubation was calculated based on the total number of mITT patients.	Initiation through termination of study drug (up to 96 hours)

Collaborators and Investigators

• Sponsor: The Medicines Company
• Investigators: Principal Investigator: W. Frank Peacock, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: December 3, 2008
• First Submitted That Met QC Criteria: December 4, 2008
• First Posted (Estimate): December 5, 2008

Study Record Updates

• Last Update Posted (Estimate): August 29, 2014
• Last Update Submitted That Met QC Criteria: August 21, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Hypertension; Calcium Channel Blocker; Antihypertensive Agent
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Heart Failure; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics, Osmotic; Diuretics; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Nitric Oxide Donors; Antihypertensive Agents; Nitroglycerin; Isosorbide; Isosorbide Dinitrate; Diltiazem; Nicardipine; Clevidipine; Nitroprusside
• Other Study ID Numbers: TMC-CLV-08-01 (Other Identifier: Sponsor)