A randomized feasibility trial of clonidine to reduce perioperative cardiac risk in patients on chronic beta-blockade: the EPIC study

Abstract

Purpose: Clonidine may help prevent cardiac complications in patients undergoing non-cardiac surgery and receiving chronic beta-blocker therapy. We conducted a multicentre pilot randomized trial to estimate recruitment rates for a full-scale trial and to assess the safety and tolerability of combining clonidine with chronic beta-blockade.

Methods: Patients who were at elevated perioperative cardiac risk, receiving chronic beta-blockade, and scheduled for major non-cardiac surgery were recruited in a blinded (participants, clinicians, outcome assessors) placebo-controlled randomized trial at three Canadian hospitals. Participants were randomized to clonidine (0.2 mg oral tablet one hour before surgery, plus 0.2 mg·day(-1) transdermal patch placed one hour before surgery and removed four days after surgery or hospital discharge, whichever came first) or matching placebo. Feasibility was evaluated based on recruitment rates, with each centre being required to recruit 50 participants within 12-18 months. Additionally, we reviewed study drug withdrawals and safety outcomes, including clinically significant hypotension or bradycardia.

Results: Eighty-two of the 168 participants were randomized to receive clonidine and 86 to receive placebo. The average time to recruit 50 participants at each centre was 14.3 months. Six patients (7%) withdrew from clonidine, while four (5%) withdrew from placebo. Based on qualitative review, there were no major safety concerns related to clonidine. There was a moderate overall rate of cardiac morbidity, with 18 participants (11%) suffering postoperative myocardial infarction.

Conclusion: This pilot randomized trial confirmed the feasibility, safety, and tolerability of a full-scale trial of oral and transdermal clonidine for reducing the risk of cardiac complications during non-cardiac surgery. This trial was registered at www.clinicaltrials.gov: NCT00335582.

Fig. 1

Flow of study participants through the trial

Fig. 2

Trends in postoperative heart rate over time in the clonidine and placebo arms. Heart rate was measured at the time of study recruitment (i.e., baseline measurement in the preoperative assessment clinic) and over the first 72 hr after surgery. Each participant’s heart rate was measured at least every eight hours postoperatively (i.e., three measurements per day as denoted on the x-axis). The lowest measured values within each interval are presented in this figure. Boxplots are used to represent the distribution of heart rate at each time point. The box extends from the 25^th to 75^th percentile, while the thick horizontal line within each box represents the median value. The whisker bars denote the minimum and maximum values

Fig. 3

Trends in postoperative systolic blood pressure over time in the clonidine and placebo arms. Blood pressure was measured at the time of study recruitment (i.e., baseline measurement in the preoperative assessment clinic) and over the first 72 hr after surgery. Each participant’s blood pressures was measured at least every eight hours postoperatively (i.e., three measurements per day as denoted on the x-axis). The lowest measured values within each interval are presented in this figure. Boxplots are used to represent the distribution of blood pressure at each time point. The box extends from the 25^th to 75^th percentile, while the thick horizontal line within each box represents the median value. The whisker bars denote the minimum and maximum values