Published in the June 2018 issue of Today’s Hospitalist
WHEN IT COMES to patients’ perioperative use of chronic medications, Paul Grant, MD, the director of perioperative and consultative medicine at the University of Michigan Medical Center in Ann Arbor, maintains this general rule: “Most meds are tolerated just fine, and it actually wouldn’t matter in most cases if you continued them or not on the day of surgery.”
But some medications have known periop benefits (think statins) or could have rebound or withdrawal effects if stopped, including clonidine, benzodiazepines and opioids. There are also medications that patients should avoid taking the morning of surgery, if not days or even weeks ahead.
At a discussion of perioperative medications at this year’s Society of Hospital Medicine annual meeting, Dr. Grant highlighted his recommendations for what to stop, continue or at least think about.
While statins’ lipid-lowering benefits may not take effect for weeks, the drugs’ other advantages—preventing plaque rupture, reducing inflammation, optimizing endothelial function—”happen within hours of initiating someone on a statin,” Dr. Grant explained. Those can help lower patients’ perioperative cardiovascular risk.
“Most meds are tolerated just fine, and it actually wouldn’t matter in most cases if you continued them or not on the day of surgery.”
~ Paul Grant, MD University of Michigan Medical Center
Results from the VISION trial, published in the Jan. 7, 2016, European Heart Journal, found an association between preop statin use and a host of better 30-day outcomes, including lower all-cause and cardiovascular mortality. And a study in the February 2017 issue of JAMA Internal Medicine looked at 30-day mortality for more than 180,000 patients undergoing major noncardiac surgery who took a statin either the day of or the day after surgery.
“This had quite a high number needed to treat—244—in terms of mortality, but a very strong endpoint,” said Dr. Grant. “Secondary outcomes were also significantly reduced.”
The latest (2014) ACC/AHA guidelines recommend that patients already taking a statin should continue to do so during surgery. Other recommendations include initiating statins in patients undergoing vascular surgery and in those with risk factors, including a history of stroke, MI, diabetes or heart failure.
As for Dr. Grant, he starts patients on a moderate or high statin dose, a strategy endorsed in trials. And “I tell them to take it for at least a month and then talk to their primary care doctor. Clearly, there are many indications for long-term statins in patients beyond perioperative protection.”
HERBALS, VITAMINS, SUPPLEMENTS
More than half of all Americans take some kind of herbal therapy, vitamin or supplement, if not a combination of all three. “Patients seldom mention them unless you specifically ask,” Dr. Grant said. “We tell patients to stop taking them a week or two before surgery.”
What he called the “3Gs”—garlic, ginkgo and ginseng—have some antiplatelet function and could cause bleeding. “I lump these in when I’m talking about what to do with NSAIDs, multivitamins and other drugs that need to be stopped in advance of surgery.”
Metformin is certainly one drug you want to hold the day of surgery, even though the risk of lactic acidosis is rare.
“We used to hold it for two days before, but that’s not necessary—except for someone with renal dysfunction,” said Dr. Grant. While patients shouldn’t be on metformin if their creatinine is more than 1.5, “you often see it, so you might hold it an extra day.” You might also hold metformin an extra day for patients getting IV contrast with a procedure.
As for other oral diabetes medications, “we stop them the day of surgery”—a pretty straightforward recommendation, given that patients won’t be eating. And because these medications can’t be titrated and patients’ food intake is unpredictable, “we typically hold all oral diabetes medications throughout the entire hospital stay.”
Dr. Grant lumps all psychiatric medications—SSRIs as well as dementia, antipsychotic and antiseizure medications—together with this recommendation: Continue them, including the morning of surgery with water, and throughout the hospitalization.
There is some concern that SSRIs increase bleeding risk. A small retrospective review in the March 2010 issue of Anesthesiology looked at 66 patients on SSRIs getting a hip replaced. Patients taking SSRIs had slightly greater blood loss but no additional need for transfusions.
But a study in the July 2016 issue of Anesthesia & Analgesia looked at patients undergoing what Dr. Grant called “big bleeding-risk surgery”: vascular, spinal, intracranial or cardiac. “Exposure to an SSRI increased patients’ risk of needing a transfusion twofold, up to postop day 2, so there may be something there.” He has patients take SSRIs the day of surgery, given that those who’ve taken the drug for many months or years could experience withdrawal by stopping abruptly.
As for carbidopa-levodopa to treat Parkinson’s: “That one you really have to make sure you’re not skipping,” Dr. Grant said. “That’s often dosed three, four, five times a day, and patients should be taking it right up until surgery.” Stopping these drugs abruptly may cause a Parkinson’s disease flare or neuroleptic malignant syndrome, “and patients can become extremely sick on postop day 1.” While IV levodopa would help ensure that patients get all their doses even if they’re NPO, it’s not available in the U.S. An oral dissolving formulation is available, however, and can be helpful.
ACE INHIBITORS, ARBs
Clinicians have a “fair amount of data” on the perioperative use of ACE inhibitors. Unfortunately, those data are conflicting.
A meta-analysis in the July 2008 Journal of Hospital Medicine looked at the relative risk of hypotension requiring vasopressors and of MI in patients with or without an immediate preop dose of an ACE inhibitor or an angiotensin II receptor antagonist.
“Hypotension requiring pressors was significant,” Dr. Grant pointed out, “but a trend toward postop MI was not.”
Research in the May 2014 Journal of Hospital Medicine looked specifically at orthopedic patients. “Those who received their ACE inhibitor or ARB up to and including the day of surgery had almost double the incidence of hypotension,” he noted. Acute kidney injury (AKI) was also significantly higher, “probably because of hypotension”—and AKI drove considerably longer length of stay.
But another study in the May 2014 Journal of Hospital Medicine issue looked at patients who had their ACE inhibitor stopped for surgery. Researchers compared 30-day mortality for patients who weren’t restarted within 14 days to those who were.
They found an association between not restarting within 14 days and higher 30-day mortality. “I think it’s reasonable to hold the ACE inhibitor or ARB on the day of surgery,” he said, “but make sure you restart it by the time patients go home.”
A subgroup analysis of the VISION trial published in the January 2017 issue of Anesthesiology found that patients who withheld their ACE inhibitors/ARBs within 24 hours of surgery had an 18% relative risk reduction in 30-day all-cause mortality compared to those who did not, and a 20% relative risk reduction in intraoperative hypotension.
“That seems to be driving the problems with ACE inhibitors and ARBs before surgery,” said Dr. Grant.
Muddying the waters even further, the 2014 ACC/ AHA guidelines say it’s reasonable to continue ACE inhibitors/ARBs. “I’m not really in favor of that,” he countered. “The guidelines do say that if you hold them, restart as soon as possible after surgery.” He holds ACE inhibitors and ARBs the morning of surgery, which is his medical center’s policy.
Having a standardized approach throughout the hospital helps anesthesia. At the same time, “you have to individualize that recommendation.” Patients with systolic blood pressures in the 160s or 170s, for instance, who could have their surgeries cancelled if their systolic hits 180 might be good candidates for continuing an ACE inhibitor or ARB the day of surgery.
A randomized trial published in the November 2010 issue of the American Journal of Medicine looked at 212 patients taking loop diuretics and undergoing noncardiac surgery.
“Researchers randomized patients into taking vs. holding the loop diuretic the morning of surgery, with no difference in any outcomes,” said Dr. Grant. At his center, loop diuretics are held the day of surgery, “but I don’t think it really matters which you choose.”
With this class of medications, “we always struggle a bit,” Dr. Grant said. That’s in part because periop data aren’t really clear. It’s also because “they’re fairly complicated, potentially dangerous medications, so you’re really weighing the risks and benefits.”
On one hand, continuing the drugs could increase patients’ risk of infection or problems with postop wound healing. But by stopping them, you risk causing the patient’s lupus or inflammatory bowel disease to flare, which “will really impair their recovery. So this is a challenge.”
Clinicians have the most data for methotrexate, although most of those data pertain to orthopedic patients. The largest trial, published in the March 2001 Annals of the Rheumatic Diseases, included fewer than 400 patients with rheumatoid arthritis. Patients were randomized into three groups: those on methotrexate who continued it during surgery, those who had the drug held for two weeks before and after surgery, and those who weren’t taking methotrexate. Patients were then followed for a year.
Those who continued taking the drug had significantly fewer flares than the other two groups. Further, they had no more infections than the group holding methotrexate two weeks before and after surgery. An update in the September-October 2010 issue of Clinical and Experimental Rheumatology concluded that data don’t suggest a need to stop methotrexate for surgery.
Dr. Grant said he believes it’s safe to continue methotrexate for most surgeries. “But our hospital is guilty of not doing this,” he admitted. “Our orthopods are very concerned about infections, even though the data are fairly clear.” Cases in which it makes sense to hold methotrexate include patients with bad kidney or liver disease or if the surgery is for an infection.
As for TNF-alpha antagonists, “we’re seeing these medications—etanercept, infliximab and adalimumab— used for all kinds of things,” he said, “but the risk of infection is real.” A meta-analysis in the May 17, 2006, Journal of the American Medical Association found that the use of these medications doubled patients’ overall risk of infections, not just perioperatively.
“It’s opportunistic infections, TB reactivation, as well as bacterial infections,” Dr. Grant pointed out. “It’s things we don’t want to see.”
The perioperative data are both limited and conflicting. One retrospective paper in Arthritis Care & Research in January 2017 looked at the timing of infliximab for patients undergoing knee or hip replacement. It found no association between stopping infliximab less than four weeks before surgery—vs. eight to 12 weeks before—and increased infection risk at 30 days.
“Factors that increased the infection risk were older patients, multiple comorbidities, patients with revision surgery and patients previously hospitalized for infection,” said Dr. Grant. “Those were the high-risk patients.” (The study also found an association between steroid doses of more than 10 mg per day and 30-day infection risk.)
Further, Dr. Grant pointed out, “the risk of infection is highest when these medications are newly started. And patients with established rheumatoid arthritis are the ones likely to flare if you stop one abruptly.” If you do decide to hold, “restart it as soon as possible after surgery.
Dr. Grant takes a very individualized approach when deciding whether to continue a TNF-alpha antagonist. “I get a feel for how bad their disease is, what the surgeon thinks, whether patients have stopped the medication before without complications, and whether patients have an even higher infection risk because of diabetes or being on steroids.” While he doesn’t stop these medications for smaller surgeries, he will if the surgery is for an infection.
“And it never hurts,” he added, “to consult the prescribing rheumatologist on whether it should be continued or held.”
Guidelines from both the American College of Rheumatology and the British Society of Rheumatology recommend holding TNF alpha antagonists for one dosing cycle before surgery. That’s one week for etanercept, between six and eight weeks for infliximab, and two weeks for adalimumab.
“Typically, we hold it one dosing cycle after surgery as well,” Dr. Grant added. “The surgeon at the two-week follow-up will decide if the wound looks good and patients can restart.”
LESS COMMON DMARDs
Then there’s rituximab, a monoclonal antibody used for vasculitis and lymphomas. “Its half life is 76 hours,” Dr. Grant pointed out, “but its effect lasts longer than six months.” It also has been shown to have a lower risk of bacterial infection compared to the TNF alphas.
Hydroxychloroquine is considered safe, based on two small trials. But there are conflicting data for other disease-modifying antirheumatic drugs such as leflunomide. It has a long half-life (two weeks), and it seems reasonable to stop it between two to four weeks before surgery for a high-risk patient or if you anticipate large surgical wounds. But “you might not have the time to deal with this medication before surgery.”
As for tofacitinib, a janus kinase inhibitor: “This is a very powerful medication with a much shorter half-life that’s dosed twice daily,” Dr. Grant said. “This one should be stopped before surgery, if possible.” Meanwhile, sulfasalazine “could be held the day of surgery. It really doesn’t need to be stopped much in advance.” Another immunosuppressive, azathioprine, can be continued perioperatively, as can cyclosporine.
Edward Doyle is Editor of Today’s Hospitalist.