POISE-2: Aspirin, clonidine not beneficial in noncardiac surgery

WASHINGTON — Patients treated with low-dose aspirin or clonidine to reduce the risk for CV-related events after noncardiac surgery did not experience benefit compared with placebo, according to new data from the POISE-2 trial reported at the American College of Cardiology Scientific Sessions.

Perspective from John A. Jarcho, MD

The trial was designed using a 2-by-2 factorial design to allow for separate evaluation of low-dose aspirin and low-dose clonidine vs. placebo. Researchers enrolled 10,010 adults (mean age, 68 years; 48% women) with or at risk for atherosclerotic disease who were undergoing noncardiac surgery at 135 centers in 23 countries.

Clonidine vs. placebo

For this comparison, patients were randomly assigned preoperative placebo (n=5,001) or 0.2 mg clonidine prior to surgery, with the same daily dose via skin patch for 72 hours after surgery (n=5,009). All patients had a systolic BP of at least 105 mm Hg and a heart rate of at least 55 beats per minute.

Compared with placebo, clonidine did not reduce the composite primary outcome of death or nonfatal MI at 30 days. There were 367 events reported in the clonidine group vs. 339 in the placebo group (HR with clonidine=1.08; 95% CI, 0.93-1.26). MI occurred in 6.6% of clonidine recipients vs. 5.9% of placebo recipients (HR=1.11; 95% CI, 0.95-1.3).

The researchers observed more clinically important hypotension in the clonidine group (47.6% vs. 37.1%; HR=1.32; 95% CI, 1.24-1.4). Rates of nonfatal cardiac arrest (0.3% vs. 0.1%; HR=3.2; 95% CI, 1.17-8.73) and clinically important bradycardia (12% vs. 8.1%; HR=1.49; 95% CI, 1.32-1.69) were also elevated after treatment with clonidine. Post-hoc multivariable analysis indicated that clinically important hypotension was predictive of subsequent MI (HR=1.37; 95% CI, 1.16-1.62).

Daniel I. Sessler

“We conclude that clonidine does not reduce death or MI after noncardiac surgery,” Daniel I. Sessler, MD, chair of the outcomes research department at Cleveland Clinic, said at a press conference. “It does, however, cause clinically important hypotension. Low-dose clonidine should therefore not be given to patients having noncardiac surgery in an effort to reduce the risk of death or MI. A safe, effective way of preventing MI after noncardiac surgery remains to be determined.”

Aspirin vs. placebo

For this comparison, patients were stratified based on pre-surgery aspirin use. A continuation stratum (n=4,382) included patients who were already on an aspirin regimen before surgery, and an initiation stratum (n=5,628) included patients who did not take any aspirin for 4 of the 6 weeks before surgery. For the continuation stratum, aspirin use was stopped at least 72 hours before surgery, according to a press release.

All patients were assigned placebo or 200 mg aspirin before surgery. The initiation stratum continued 100 mg aspirin or placebo daily for 30 days. The continuation stratum received 100 mg aspirin or placebo for 7 days and then resumed their previous aspirin regimen, according to the release.

The same primary outcome, a composite of death or nonfatal MI at 30 days, occurred in 7% of the aspirin group vs. 7.1% of the placebo group (HR=0.99; 95% CI, 0.86-1.15). MI was reported in 6.2% of the aspirin group vs. 6.3% of the placebo group (HR=0.98; 95% CI, 0.84-1.15).

Rates of major bleeding were more frequent in the aspirin group (4.6% vs. 3.8%; HR=1.23; 95% CI, 1.01-1.49). Post-hoc multivariable analysis indicated that major or life-threatening bleeding was independently predictive of MI (HR=1.82; 95% CI, 1.4-2.36).

Aspirin had a similar impact on the composite endpoint, and MI specifically, regardless of classification in the continuation or initiation stratum. Aspirin use was associated with significantly increased risk for bleeding and decreased risk for stroke in the initiation stratum (P=.03 for both), and with increased risk for acute kidney injury requiring dialysis in the continuation stratum (P=.04). However, researchers noted that strata interaction was only statistically significant for stroke (P=.01).

Receipt of clonidine did not impact the results of the aspirin analysis.

P.J. Devereaux

“Perioperative aspirin did not prevent death or MI, but increased the risk of major bleeding in both strata,” P.J. Devereaux, MD, PhD, associate professor of clinical epidemiology and biostatistics at McMaster University, Ontario, Canada, said here. “The primary and secondary outcome results are consistent in both of these strata. ... The optimal time to restart aspirin in patients who should be on it chronically may be about 8 to 10 days after surgery." Devereaux noted, however, that 65% of the study participants were also on a regimen of prophylactic anticoagulants. – by Adam Taliercio

For more information:

Devereaux PJ. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials. Abstract #9 and 11. Presented at: American College of Cardiology Scientific Sessions ; March 29-31, 2014; Washington, D.C.

Devereaux PJ. N Engl J Med. 2014;doi:10.1056/NEJMoa1401105.

Devereaux PJ. N Engl J Med. 2014;doi:10.1056/NEJMoa1401106.

Disclosure: Devereaux reports research/research grants from Abbott Diagnostics, Bayer, Boehringer Ingelheim, Covidien, Roche Diagnostis and Stryker. Sessler reports no relevant financial disclosures.

Perspective

John A. Jarcho, MD

How to protect people from having MI at the time of noncardiac surgery has been a big issue and there have been a number of interventions over the years to try to figure this out. There has been a lot of uncertainty about the use of medications. For a long time, it seemed fairly convincing that beta-blockers were something we ought to use, because we knew they were so beneficial in a lot of situations. But then POISE-1 came out and demonstrated that the situation was more complicated than that.

So people started to ask, ‘What can we do in this situation?’ This is really one of those ‘What can we do?’ trials, looking at a couple of hypotheses. In the case of aspirin, because it’s so clear that aspirin reduces the risk for MI in so many other situations, shouldn’t aspirin reduce the risk of MI after undertaking surgery? There’s some suspicion that, in fact, aspirin may have reduced some MIs, but then provoked others because of bleeding. That’s a hypothesis — we don’t know that that’s true for sure — but certainly overall it isn’t a good thing to be taking aspirin at the time of noncardiac surgery; this is clear now.

Clonidine was another hypothesis, and I think some thought of that as a slightly less-compelling hypothesis, but there actually had been a number of small trials and a meta-analysis that suggested this actually worked. And there’s a physiologic argument for it, which is the blocking of sympathetic stimulation. And again, a null result.

It’s disappointing, in a sense, because you can say, ‘All we know is some things not to do.’ But in this particular setting, where there aren’t very many things that we do know to do, it’s important to ‘clear the underbrush.’ Try some things that we think might be the obvious answers, and if they don’t work, move on to other ideas in the hopes of finding something that will work because it’s clearly an unmet need. You shouldn’t have to go into having your hip replacement or your gallbladder removed with the fear that you are going to have a heart attack.

John A. Jarcho, MD

Deputy Editor, The New England Journal of Medicine

Disclosures: Jarcho reports no relevant financial disclosures.