Pollack CV, Varon J, Garrison NA, et al. Clevidipine, an Intravenous Dihydropyridine Calcium Channel Blocker, Is Safe and Effective for Treatment of Patients With Acute Severe Hypertension
Refers to article:
Clevidipine, an Intravenous Dihydropyridine Calcium Channel Blocker, Is Safe and Effective for the Treatment of Patients With Acute Severe Hypertension
, 06 June 2008
Charles V. Pollack, Joseph Varon, Norman A. Garrison, Ramin Ebrahimi, Lala Dunbar, W. Frank Peacock
Annals of Emergency Medicine
March 2009 (Vol. 53, Issue 3, Pages 329-338) Abstract |
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1.In this uncontrolled, single-treatment arm study, the inclusion criteria were patients, greater than or equal to 18 years old, with systolic blood pressure greater than or equal to 180 and/or diastolic blood pressure greater than or equal to 115 mm Hg. Evidence of end-organ injury was not a requirement for inclusion in this study. The investigators included left ventricular hypertrophy on ECG as a criterion for end-organ injury.
Editor's Capsule Summary
What is already known on this topic
Most intravenous agents used to acutely lower blood pressure have problems with safety characteristics, and some require continuous direct arterial monitoring during use.
What question this study addressed
This study examined the safety and efficacy of intravenous clevidipine, an investigational drug, in an open-label convenience sample of 126 patients with severe hypertension.
What this study adds to our knowledge
Blood pressure was quickly decreased in most patients to target range using a non–weight-based dosing of intravenous clevidipine. Further titration of blood pressure by continuous infusion was safely achieved with simple blood pressure cuff monitoring.
How this might change clinical practice
Further experience will be required before this investigational agent is considered for routine clinical practice.
A. Find this study's trial registration information at clinicaltrials.gov. Does the planned study differ in any way from that specified in the registry? Consider the inclusion criteria, exclusion criteria, outcome measures, and sample size. If any of these differ, discuss the importance of the differences.B. Based on this study's inclusion criteria, an asymptomatic 23-year-old man with a blood pressure of 185/100 mm Hg would be eligible for enrollment. The authors state that clevidipine is “effective for controlling blood pressure in patients with severe hypertension requiring urgent treatment.” Are patients without evidence of end-organ injury a representative sample of patients requiring urgent treatment? Include in your answer the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7 Report) and American College of Emergency Physicians treatment recommendations for patients with elevated blood pressure without evidence of end-organ damage.
2.The authors conducted an unmasked, uncontrolled, single-treatment-arm phase 3 clinical trial to evaluate the safety and efficacy of intravenous clevidipine.A. Why might these investigators have chosen this study design rather than comparing clevidipine to placebo or a standard treatment for hypertensive emergencies? Are randomized, placebo-controlled trials always considered the optimal study design to test new treatments? Would the inclusion of a placebo arm in this study be considered ethical research?B. Compare this study's design to a double-blind randomized trial of this agent against a standard therapy for hypertensive emergency. What additional concerns must one have about this study design compared to the randomized controlled trial?C. The authors chose to use the intention-to-treat (ITT) principle to evaluate clevidipine's safety and a modified-ITT analysis for measuring drug efficacy. Define the ITT principle and the rationale for ITT in clinical trials. Imagine a randomized trial of a standard drug that cures 40% of subjects who complete standard therapy and 95% complete therapy, versus a new drug which cures 60% of subjects who complete therapy and 60% complete therapy. The 40% who are unable to tolerate the new drug revert to the standard drug. Calculate the absolute risk difference using completer and intent-to-treat methods. What are the potential advantages and disadvantages of ITT analysis?
3.A primary study outcome was the evaluation of clevidipine's safety profile by measuring the percentage of patients whose systolic blood pressure decreased below the target range within the first 3 minutes of therapy. The investigators also recorded adverse events up to 1 week after clevidipine treatment.A. This study did not have a formal data and safety monitoring board, although a future clevidipine trial in heart failure patients (PRONTO, NCT00803634) intends to have periodic data and safety monitoring board review. What is the data and safety monitoring board's role, and ideally who should and should not preside on the committee?B. Serious adverse events were reported in 11 of the 126 (8.7%) patients who comprised the safety population. How does this adverse event rate compare with that of other commonly used agents such as β-blockers and nitrates? According to this single-treatment-arm study design, can these authors be certain that only one of the serious adverse events was possibly related to clevidipine?
4.A. What is the relationship between the investigators and the trial's sponsor? What is the relationship between the trial's sponsor and the investigational agent? What conflicts of interest could be at play? How might these conflicts of interest affect the choice of study design? How is the trial's sponsor using this study to market the drug? (Hint: see company Web site.)B. A journal's editor must weigh the pros and cons of publishing each submitted article. Consider the list of pros and cons that might be at play here. What do you think of the article's title?C. The Editor's Capsule Summary published with this article states: “Comparative randomized trials will be required before this investigational agent is considered for routine clinical practice.” This drug was approved by the Food and Drug Administration in August 2008. Attempt to reconcile these facts. Would you use this drug at this time? If not, what additional information would you desire before using this drug?
aVanderbilt University Medical Center, Nashville, TN
bUniversity of California, Los Angeles, Los Angeles, CA
SEE RELATED ARTICLE, P. 329.
Editor's Note: You are reading the eighth installment of Annals of Emergency Medicine Journal Club. This bimonthly feature seeks to improve the critical appraisal skills of emergency physicians and other interested readers through a guided critique of actual Annals of Emergency Medicine articles. Each Journal Club will pose questions that encourage readers—be they clinicians, academics, residents, or medical students—to critically appraise the literature.
During a 2- to 3-year cycle, we plan to ask questions that cover the main topics in research methodology and critical appraisal of the literature. To do this, we will select articles that use a variety of study designs and analytic techniques. These may or may not be the most clinically important articles in a specific issue, but they are articles that serve the mission of covering the clinical epidemiology curriculum. Journal Club entries are published in 2 phases. In the first phase, a list of questions about the article is published in the issue in which the article appears. Questions are rated “novice,” () “intermediate,” () and “advanced” () so that individuals planning a journal club can assign the right question to the right student. The answers to this journal club will be published in the August 2009 issue. US residency directors will have immediate access to the answers through the Council of Emergency Medicine Residency Directors Share Point Web site. International residency directors can gain access to the questions by going to http://www.emergencymedicine.ucla.edu/annalsjc/and following the directions. Thus, if a program conducts its journal club within 5 months of the publication of the questions, no one will have access to the published answers except the residency director. The purpose of delaying the publication of the answers is to promote discussion and critical review of the literature by residents and medical students and discourage regurgitation of the published answers.
It is our hope that the Journal Club will broaden Annals of Emergency Medicine's appeal to residents and medical students. We are interested in receiving feedback about this feature. Please e-mail journalclub@acep.org with your comments.
FULL TEXT
Clevidipine, an Intravenous Dihydropyridine Calcium Channel Blocker, Is Safe and Effective for the Treatment of Patients With Acute Severe Hypertension
A. Find this study's trial registration information at 
B. Based on this study's inclusion criteria, an asymptomatic 23-year-old man with a blood pressure of 185/100 mm Hg would be eligible for enrollment. The authors state that clevidipine is “effective for controlling blood pressure in patients with severe hypertension requiring urgent treatment.” Are patients without evidence of end-organ injury a representative sample of patients requiring urgent treatment? Include in your answer the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7 Report) and American College of Emergency Physicians treatment recommendations for patients with elevated blood pressure without evidence of end-organ damage.
B. Compare this study's design to a double-blind randomized trial of this agent against a standard therapy for hypertensive emergency. What additional concerns must one have about this study design compared to the randomized controlled trial?