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Neither perioperative aspirin therapy nor perioperative clonidine prevented death or MI in patients undergoing noncardiac surgery who were at risk for major vascular complications, according to data reported at the annual meeting of the American College of Cardiology.
Far from being protective, both preventive strategies exerted harmful effects: Aspirin raised the risk of major bleeding, and clonidine increased the risks of clinically important hypotension, bradycardia, and nonfatal MI, said Dr. P. J. Devereaux of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton (Ont.) General Hospital, and his associates in the POISE-2 (Perioperative Ischemic Evaluation 2) clinical trial.
The POISE-2 findings were simultaneously reported online in the New England Journal of Medicine 2014 March 31 [doi:10/1056.
NEJMoa1401105] and [doi:10/1056.
NEJMoa1401106]).
MI is the most common major vascular complication related to noncardiac surgery, and perioperative aspirin is thought to prevent it by inhibiting thrombus formation. At present, one-third of patients at risk for vascular complications receive perioperative aspirin even though the risks and benefits of this preventive strategy are uncertain.
Similarly, small trials have indicated that the antihypertensive agent clonidine, an alpha2 adrenergic agonist, reduces the risk of myocardial ischemia without inducing hemodynamic instability when given to at-risk patients undergoing noncardiac surgery, which in turn may prevent MI and death. Clonidine has additional analgesic, anxiolytic, antishivering, and anti-inflammatory effects that may be helpful.
The POISE-2 trial was designed to determine whether either of these approaches was more effective than placebo at preventing the composite endpoint of MI or death within 30 days of surgery.
A total of 10,010 patients were enrolled at 135 hospitals in 23 countries, stratified by whether they were already taking daily aspirin prophylaxis, and randomly assigned in a double-blind fashion to receive either perioperative aspirin (4,998 subjects) or placebo (5,012 subjects), and to receive either perioperative clonidine (5,009 subjects) or placebo (5,001 subjects). The mean age of these participants was 68.6 years, and 52.8% were men. Most were at risk because of their history of vascular disease; advanced age; need for dialysis; smoking status; or comorbid diabetes, heart failure, transient ischemic attack, or hypertension.
The types of surgery they underwent included general, orthopedic, urologic, gynecologic, vascular, and thoracic procedures.
The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference. The risks of other adverse outcomes, including stroke, cardiac revascularization, pulmonary embolism, acute kidney injury, and deep vein thrombosis, also were not significantly different between the two groups.
Median length of hospital stay and length of ICU and CCU stays also were not significantly different between patients who received aspirin and those who received placebo. However, aspirin raised the risk of major bleeding (4.6%), compared with placebo (3.8%), for a hazard ratio of 1.23. The most common sites of bleeding were the surgical site and the GI tract.
These effects were consistent across all subgroups of patients. In particular, they were the same whether the patients were already taking daily prophylactic aspirin therapy.
Clonidine also did not prevent death or MI within 30 days, compared with placebo; the rates were 7.3% and 6.8%, respectively. The risks of other adverse outcomes also were not significantly different between the two groups, nor were lengths of hospital, ICU, or CCU stays. However, clonidine raised the risk of clinically important hypotension (47.6% vs. 37.1%), clinically important bradycardia (12% vs. 8.1%), and nonfatal cardiac arrest (0.3% vs. 0.1%).
These effects were consistent across all subgroups of patients. In particular, clonidine was no more beneficial than was placebo in patients who underwent vascular surgery, a subgroup in whom previous, smaller studies found the drug to protect against both MI and mortality.
POISE-2 was not designed to determine why aspirin wasn’t effective at preventing perioperative MI, but Dr. Devereaux and his associates offered three possible explanations. First, MI was associated with major bleeding, and aspirin raises the risk of this complication. "It is possible that aspirin prevented some perioperative MI through thrombus inhibition [but] caused some MIs through bleeding and the subsequent mismatch between the supply of and the demand for myocardial oxygen, thus resulting in the overall neutral effect in our study," they said.
Second, the heart rate findings couldn’t statistically rule out a possible moderate beneficial effect of aspirin therapy. And third, it is possible that coronary-artery thrombus isn’t the dominant mechanism of perioperative MI, and aspirin’s antithrombotic effect didn’t address this unknown dominant mechanism.
Similarly, it is not known why clonidine failed to be protective, but the investigators offered two possible reasons. First, the drug induced hypotension, which raises the risk of perioperative MI. And second, it also induced bradycardia, which may be a proxy for an overall adverse effect on heart rate control; this also can increase the risk of perioperative MI, they said.
The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study, and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.
Myriad, and sometimes opposing, mechanisms contribute to perioperative MI, including excess bleeding, dramatic fluid shifts, unrelenting tachycardia, myocardial stress with fixed coronary obstruction, profound hypo- or hypertension, coronary plaque rupture, and coronary spasm, said Dr. Prashant Vaishnava and Dr. Kim A. Eagle.
So it shouldn’t be surprising that a medical therapy aimed at one of these mechanisms may actually augment a different mechanism, and end up raising MI risk. "Aspirin may reduce coronary thrombosis at the expense of excess bleeding; clonidine may reduce hypertensive swings only to be countered by clinically important hypotension," they noted.
On balance, the POISE-2 results provide cogent evidence against the use of either perioperative aspirin or clonidine.
Dr. Vaishnava and Dr. Eagle are at the Samuel and Jean A. Frankel Cardiovascular Center at the University of Michigan Health System, Ann Arbor. They reported no potential conflicts of interest. These remarks were taken from their editorial accompanying the POISE-2 trial reports (New Engl. J. Med. 2014 March 31 [doi:10.1056/NEJMe1402976]).
Myriad, and sometimes opposing, mechanisms contribute to perioperative MI, including excess bleeding, dramatic fluid shifts, unrelenting tachycardia, myocardial stress with fixed coronary obstruction, profound hypo- or hypertension, coronary plaque rupture, and coronary spasm, said Dr. Prashant Vaishnava and Dr. Kim A. Eagle.
So it shouldn’t be surprising that a medical therapy aimed at one of these mechanisms may actually augment a different mechanism, and end up raising MI risk. "Aspirin may reduce coronary thrombosis at the expense of excess bleeding; clonidine may reduce hypertensive swings only to be countered by clinically important hypotension," they noted.
On balance, the POISE-2 results provide cogent evidence against the use of either perioperative aspirin or clonidine.
Dr. Vaishnava and Dr. Eagle are at the Samuel and Jean A. Frankel Cardiovascular Center at the University of Michigan Health System, Ann Arbor. They reported no potential conflicts of interest. These remarks were taken from their editorial accompanying the POISE-2 trial reports (New Engl. J. Med. 2014 March 31 [doi:10.1056/NEJMe1402976]).
Myriad, and sometimes opposing, mechanisms contribute to perioperative MI, including excess bleeding, dramatic fluid shifts, unrelenting tachycardia, myocardial stress with fixed coronary obstruction, profound hypo- or hypertension, coronary plaque rupture, and coronary spasm, said Dr. Prashant Vaishnava and Dr. Kim A. Eagle.
So it shouldn’t be surprising that a medical therapy aimed at one of these mechanisms may actually augment a different mechanism, and end up raising MI risk. "Aspirin may reduce coronary thrombosis at the expense of excess bleeding; clonidine may reduce hypertensive swings only to be countered by clinically important hypotension," they noted.
On balance, the POISE-2 results provide cogent evidence against the use of either perioperative aspirin or clonidine.
Dr. Vaishnava and Dr. Eagle are at the Samuel and Jean A. Frankel Cardiovascular Center at the University of Michigan Health System, Ann Arbor. They reported no potential conflicts of interest. These remarks were taken from their editorial accompanying the POISE-2 trial reports (New Engl. J. Med. 2014 March 31 [doi:10.1056/NEJMe1402976]).
Neither perioperative aspirin therapy nor perioperative clonidine prevented death or MI in patients undergoing noncardiac surgery who were at risk for major vascular complications, according to data reported at the annual meeting of the American College of Cardiology.
Far from being protective, both preventive strategies exerted harmful effects: Aspirin raised the risk of major bleeding, and clonidine increased the risks of clinically important hypotension, bradycardia, and nonfatal MI, said Dr. P. J. Devereaux of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton (Ont.) General Hospital, and his associates in the POISE-2 (Perioperative Ischemic Evaluation 2) clinical trial.
The POISE-2 findings were simultaneously reported online in the New England Journal of Medicine 2014 March 31 [doi:10/1056.
NEJMoa1401105] and [doi:10/1056.
NEJMoa1401106]).
MI is the most common major vascular complication related to noncardiac surgery, and perioperative aspirin is thought to prevent it by inhibiting thrombus formation. At present, one-third of patients at risk for vascular complications receive perioperative aspirin even though the risks and benefits of this preventive strategy are uncertain.
Similarly, small trials have indicated that the antihypertensive agent clonidine, an alpha2 adrenergic agonist, reduces the risk of myocardial ischemia without inducing hemodynamic instability when given to at-risk patients undergoing noncardiac surgery, which in turn may prevent MI and death. Clonidine has additional analgesic, anxiolytic, antishivering, and anti-inflammatory effects that may be helpful.
The POISE-2 trial was designed to determine whether either of these approaches was more effective than placebo at preventing the composite endpoint of MI or death within 30 days of surgery.
A total of 10,010 patients were enrolled at 135 hospitals in 23 countries, stratified by whether they were already taking daily aspirin prophylaxis, and randomly assigned in a double-blind fashion to receive either perioperative aspirin (4,998 subjects) or placebo (5,012 subjects), and to receive either perioperative clonidine (5,009 subjects) or placebo (5,001 subjects). The mean age of these participants was 68.6 years, and 52.8% were men. Most were at risk because of their history of vascular disease; advanced age; need for dialysis; smoking status; or comorbid diabetes, heart failure, transient ischemic attack, or hypertension.
The types of surgery they underwent included general, orthopedic, urologic, gynecologic, vascular, and thoracic procedures.
The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference. The risks of other adverse outcomes, including stroke, cardiac revascularization, pulmonary embolism, acute kidney injury, and deep vein thrombosis, also were not significantly different between the two groups.
Median length of hospital stay and length of ICU and CCU stays also were not significantly different between patients who received aspirin and those who received placebo. However, aspirin raised the risk of major bleeding (4.6%), compared with placebo (3.8%), for a hazard ratio of 1.23. The most common sites of bleeding were the surgical site and the GI tract.
These effects were consistent across all subgroups of patients. In particular, they were the same whether the patients were already taking daily prophylactic aspirin therapy.
Clonidine also did not prevent death or MI within 30 days, compared with placebo; the rates were 7.3% and 6.8%, respectively. The risks of other adverse outcomes also were not significantly different between the two groups, nor were lengths of hospital, ICU, or CCU stays. However, clonidine raised the risk of clinically important hypotension (47.6% vs. 37.1%), clinically important bradycardia (12% vs. 8.1%), and nonfatal cardiac arrest (0.3% vs. 0.1%).
These effects were consistent across all subgroups of patients. In particular, clonidine was no more beneficial than was placebo in patients who underwent vascular surgery, a subgroup in whom previous, smaller studies found the drug to protect against both MI and mortality.
POISE-2 was not designed to determine why aspirin wasn’t effective at preventing perioperative MI, but Dr. Devereaux and his associates offered three possible explanations. First, MI was associated with major bleeding, and aspirin raises the risk of this complication. "It is possible that aspirin prevented some perioperative MI through thrombus inhibition [but] caused some MIs through bleeding and the subsequent mismatch between the supply of and the demand for myocardial oxygen, thus resulting in the overall neutral effect in our study," they said.
Second, the heart rate findings couldn’t statistically rule out a possible moderate beneficial effect of aspirin therapy. And third, it is possible that coronary-artery thrombus isn’t the dominant mechanism of perioperative MI, and aspirin’s antithrombotic effect didn’t address this unknown dominant mechanism.
Similarly, it is not known why clonidine failed to be protective, but the investigators offered two possible reasons. First, the drug induced hypotension, which raises the risk of perioperative MI. And second, it also induced bradycardia, which may be a proxy for an overall adverse effect on heart rate control; this also can increase the risk of perioperative MI, they said.
The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study, and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.
Neither perioperative aspirin therapy nor perioperative clonidine prevented death or MI in patients undergoing noncardiac surgery who were at risk for major vascular complications, according to data reported at the annual meeting of the American College of Cardiology.
Far from being protective, both preventive strategies exerted harmful effects: Aspirin raised the risk of major bleeding, and clonidine increased the risks of clinically important hypotension, bradycardia, and nonfatal MI, said Dr. P. J. Devereaux of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton (Ont.) General Hospital, and his associates in the POISE-2 (Perioperative Ischemic Evaluation 2) clinical trial.
The POISE-2 findings were simultaneously reported online in the New England Journal of Medicine 2014 March 31 [doi:10/1056.
NEJMoa1401105] and [doi:10/1056.
NEJMoa1401106]).
MI is the most common major vascular complication related to noncardiac surgery, and perioperative aspirin is thought to prevent it by inhibiting thrombus formation. At present, one-third of patients at risk for vascular complications receive perioperative aspirin even though the risks and benefits of this preventive strategy are uncertain.
Similarly, small trials have indicated that the antihypertensive agent clonidine, an alpha2 adrenergic agonist, reduces the risk of myocardial ischemia without inducing hemodynamic instability when given to at-risk patients undergoing noncardiac surgery, which in turn may prevent MI and death. Clonidine has additional analgesic, anxiolytic, antishivering, and anti-inflammatory effects that may be helpful.
The POISE-2 trial was designed to determine whether either of these approaches was more effective than placebo at preventing the composite endpoint of MI or death within 30 days of surgery.
A total of 10,010 patients were enrolled at 135 hospitals in 23 countries, stratified by whether they were already taking daily aspirin prophylaxis, and randomly assigned in a double-blind fashion to receive either perioperative aspirin (4,998 subjects) or placebo (5,012 subjects), and to receive either perioperative clonidine (5,009 subjects) or placebo (5,001 subjects). The mean age of these participants was 68.6 years, and 52.8% were men. Most were at risk because of their history of vascular disease; advanced age; need for dialysis; smoking status; or comorbid diabetes, heart failure, transient ischemic attack, or hypertension.
The types of surgery they underwent included general, orthopedic, urologic, gynecologic, vascular, and thoracic procedures.
The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference. The risks of other adverse outcomes, including stroke, cardiac revascularization, pulmonary embolism, acute kidney injury, and deep vein thrombosis, also were not significantly different between the two groups.
Median length of hospital stay and length of ICU and CCU stays also were not significantly different between patients who received aspirin and those who received placebo. However, aspirin raised the risk of major bleeding (4.6%), compared with placebo (3.8%), for a hazard ratio of 1.23. The most common sites of bleeding were the surgical site and the GI tract.
These effects were consistent across all subgroups of patients. In particular, they were the same whether the patients were already taking daily prophylactic aspirin therapy.
Clonidine also did not prevent death or MI within 30 days, compared with placebo; the rates were 7.3% and 6.8%, respectively. The risks of other adverse outcomes also were not significantly different between the two groups, nor were lengths of hospital, ICU, or CCU stays. However, clonidine raised the risk of clinically important hypotension (47.6% vs. 37.1%), clinically important bradycardia (12% vs. 8.1%), and nonfatal cardiac arrest (0.3% vs. 0.1%).
These effects were consistent across all subgroups of patients. In particular, clonidine was no more beneficial than was placebo in patients who underwent vascular surgery, a subgroup in whom previous, smaller studies found the drug to protect against both MI and mortality.
POISE-2 was not designed to determine why aspirin wasn’t effective at preventing perioperative MI, but Dr. Devereaux and his associates offered three possible explanations. First, MI was associated with major bleeding, and aspirin raises the risk of this complication. "It is possible that aspirin prevented some perioperative MI through thrombus inhibition [but] caused some MIs through bleeding and the subsequent mismatch between the supply of and the demand for myocardial oxygen, thus resulting in the overall neutral effect in our study," they said.
Second, the heart rate findings couldn’t statistically rule out a possible moderate beneficial effect of aspirin therapy. And third, it is possible that coronary-artery thrombus isn’t the dominant mechanism of perioperative MI, and aspirin’s antithrombotic effect didn’t address this unknown dominant mechanism.
Similarly, it is not known why clonidine failed to be protective, but the investigators offered two possible reasons. First, the drug induced hypotension, which raises the risk of perioperative MI. And second, it also induced bradycardia, which may be a proxy for an overall adverse effect on heart rate control; this also can increase the risk of perioperative MI, they said.
The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study, and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.
FROM ACC 14
Major finding: The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference; it also occurred in 7.3% of the clonidine group and 6.8% of the placebo group, also a nonsignificant difference.
Data source: A randomized, blinded clinical trial evaluating perioperative aspirin vs. placebo and perioperative clonidine vs. placebo in 10,010 patients undergoing noncardiac surgery who were at risk for major vascular complications.
Disclosures: The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.
