Clonidine reduces post-surgical risk of cardiovascular death in non-cardiac surgery

Patients with or at risk for heart disease who take the anti-hypertensive drug clonidine before non-cardiac surgery can significantly reduce the risk of complications and death due to inadequate blood flow to the heart, according to a study by UCSF researchers at the San Francisco Veterans Affairs Medical Center.

The findings add a second drug to the list of inexpensive preventive measures available to these patients before non-cardiac surgery. In 1998 the same UCSF/SFVAMC researchers identified the beta blocker atenolol as an effective preventive measure for this patient group. The clonidine research is reported in the August 2004 issue of the journal Anesthesiology.

“In the earlier study we found an inexpensive way to reduce the incidence of death due to surgery. Now we have found another drug to do the same thing,” said lead researcher Arthur Wallace, MD, PhD, UCSF associate professor of anesthesia and perioperative care and staff anesthesiologist at the SFVAMC.

The clonidine study focused on 190 male patients scheduled to undergo non-cardiac surgery who had been diagnosed with coronary artery disease or had at least two of five risk factors for cardiac disease: age 60 or older, hypertension, smoking within a year, cholesterol of 240 or greater or diabetes. Scheduled surgeries included orthopedic, head and neck, abdominal and others.

Of the patients, 125 received a .2 mg oral tablet of clonidine the night before surgery, a transdermal patch of clonidine the night before surgery and a .2 mg tablet one hour before surgery. A control group of 65 received placebos. After follow-ups of three days, 14 days, 30 days and two years, the clonidine group showed a death rate of 1 percent compared to 6 percent for the placebo group. After two years, the death rate of the clonidine group was 15 percent compared to 29 percent for the placebo group.

Patients were monitored for episodes of blocked blood flow using Holter electrocardiogram recorders—before, on the day of, and up to seven days after surgery. They also received electrocardiograms to measure the heartbeat every day for the first seven days after surgery and whenever necessary due to shortness of breath, chest pain or loss of consciousness. Blood pressure was recorded continuously from one hour before surgery to one hour following surgery, and blood samples were analyzed for presence of heart enzymes and clonidine concentrations.

Researchers found that patients who had received clonidine showed no evidence of myocardial ischemiac events (inadequate blood flow to the heart) before surgery compared to 5 percent for those who had received placebos.

On the day of surgery and up to three days after surgery only 14 percent of clonidine patients experienced such events, compared to 31 percent for placebo patients. After 30 days, one (.8 percent) of the clonidine patients had died compared to four (6.2 percent) of placebo patients. In a two-year follow up, 19 (15 percent) of the clonidine group had died compared to 19 (29 percent) of the placebo group.

“For these patients, myocardial ischemia is associated with a nine-fold increase in cardiac complications before hospital discharge and a two-fold greater two-year risk of death after surgery. Drug therapy to prevent blocked arteries prevents the start of a chain of events leading to heart attack and death,” said Wallace.

Researchers conclude that patients with or at risk for coronary artery disease who undergo non-cardiac surgery should be considered for pre-surgery treatment with either atenolol, which is a beta blocker, or clonidine, which is an alpha2-agonist, as these substances have been shown to prevent symptoms of cardiac disease and death. A beta blocker blocks stress hormones produced in the brain from stimulating the heart. An alpha2-agonist decreases the release of stress hormones produced in the brain.

Six million Americans with or at risk for cardiac disease undergo non-cardiac surgery each year. “The current study clearly demonstrates a significant difference in 30-day and two-year mortality using a prophylactic and anti-ischemic therapy,” the researchers wrote.

While the study does not indicate which treatment is superior, protocols for using both drugs are included in joint surgery guidelines of the American Heart Association and the American College of Cardiology.

The study was funded by the American Heart Association, Veterans Administration Merit Review Funding, Ischemia Research and Education Foundation and the Northern California Institute for Research and Education (NCIRE), a federal nonprofit foundation affiliated with the SFVAMC.

Study co-investigators are Daniel Galindez, MD, and Ali Salahieh, BS, research associates, Anesthesiology Service, SFVAMC; and Elizabeth L. Layug, MD, research associate; Eleanor A. Lazo, MD, research fellow; Kathy A. Haratonik, BA, research technician; and Dennis M. Boisvert, MS, and David Kardatzke, PhD, statisticians, all of the Ischemia Research and Education Foundation.