More Deaths, Strokes Seen with Perioperative Beta Blocker One Year After Surgery

Be careful out there.
https://www.alphagalileo.org/ViewItem.aspx?ItemId=184440&CultureCode=en

12 March 2018 American College of Cardiology

During the 12 months after undergoing noncardiac surgery, patients with or at risk for heart disease who were treated with the beta blocker metoprolol for 30 days were less likely than patients who received a placebo to have a heart attack, but more likely to die or have a stroke, according to research presented at the American College of Cardiology’s 67th Annual Scientific Session.

These follow-up findings confirm that an increased risk for death or a stroke persists at one year post-surgery in patients treated with metoprolol, said P.J. Devereaux, MD, PhD, director of cardiology at McMaster University in Hamilton, Canada, and lead author of the study. Previously reported results from the same study at 30 days post-surgery showed a similar pattern, with a reduction in heart attacks but increases in deaths and strokes.

“Our results suggest at one year, for every 1,000 patients having noncardiac surgery, treatment with metoprolol would prevent heart attacks in 12 patients but would result in an excess of 13 deaths and six strokes,” Devereaux said. 

“While there is little doubt that some patients benefit from receiving beta blockers during the period immediately before and after noncardiac surgery, these data show that at least as many patients are seriously harmed,” he said. “These data tell us that we need to exercise caution when using beta blockers in this setting until we figure out how to mitigate the substantial risks and enable all patients to obtain the potential benefits of this intervention.”

Beta blockers work by slowing the heart rate and relaxing the blood vessels, which in turn reduces blood pressure. The problem, Devereaux said, is that during the period immediately after major noncardiac surgery (such as a hip or knee replacement, bowel resection or abdominal aortic aneurysm repair), patients are usually treated with opioid medications to relieve pain. The effects of those medications may mask drops in blood pressure or heart rate to dangerously low levels.

“Low blood pressure, or hypotension, is common in this setting and is a main contributor to the adverse effects resulting from perioperative beta blockers,” he said.

Patients who become hypotensive for whatever reason after surgery (e.g., sepsis, bleeding, heart failure) find their problem exacerbated when they are receiving a beta blocker, which further lowers blood pressure and makes treating hypotension more challenging. 

The PeriOperative Ischemic Evaluation (POISE) trial enrolled 8,351 patients in 23 countries. Eligible patients were 45 years or older and had a history of heart disease, blood-vessel disease, stroke, congestive heart failure or other health problems such as diabetes or impaired kidney function. Patients’ median age was 69 and 63 percent were men.

Patients were randomly assigned to receive metoprolol or a placebo, beginning a few hours before surgery and for 30 days afterward. Patients, health care providers and research staff, except those analyzing data, were blinded to which group received metoprolol and which received a placebo. The study’s primary endpoint was a composite of the combined rate of death from heart disease, nonfatal heart attack and nonfatal cardiac arrest after 30 days.

At one-year follow-up, fewer patients in the metoprolol group than in the placebo group had heart attacks (5 percent vs. 6.2 percent), but more patients in the metoprolol group had died (9.8 percent vs. 8.5 percent in the placebo group) or had a stroke (2 percent vs. 1.4 percent in the placebo group).

These results followed the same pattern that had previously been seen at the 30-day follow-up: statistically fewer heart attacks in the metoprolol group (4.2 percent vs. 5.7 percent in the placebo group), but statistically more deaths (3.1 percent vs. 2.3 percent in the placebo group) and strokes (1 percent vs. 0.5 percent in the placebo group).

According to Devereaux, some observers have suggested that the metoprolol dose received by patients in the POISE trial (200 mg per day) was too high and that a lower dose would have produced fewer adverse effects. However, a lower dose might also have decreased the drug’s effectiveness in reducing heart attacks, he said, noting that the metoprolol dose in POISE only resulted in a seven beats per minute lower heart rate compared with placebo.

“I believe the answer is more continuous patient monitoring during the immediate post-surgical period so that dangerous drops in heart rate or blood pressure are promptly identified and treated,” he said.

Devereaux and his colleagues are currently conducting a study to test the effectiveness of remote automated patient monitors in reducing post-surgical cardiac complications.

This study was funded by the Canadian Institutes of Health Research.

Scientists discover how a decades-old drug reduces the size of a heart attack

With just the tiniest bit of research we could followup this to see if using this would help after stroke.
Neutrophils were documented way back in Jan. 2013 as causing damage post TBI.

Neutrophil Extracellular Traps (Nets) Formation After Traumatic Brain Injury

Jan. 2013

Scientists discover how a decades-old drug reduces the size of a heart attack 

Scientists at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) have discovered a new mechanism of action of metoprolol, a drug that can reduce the damage produced during a heart attack if administered early. The team led by Dr. Borja Ibáñez, Clinical Research Director at the CNIC and cardiologist at the Fundación Jiménez Díaz University Hospital Health Research Institute (IIS-FJD), has identified the mechanism that explains why this drug is so beneficial: rapid administration of metoprolol during a heart attack directly inhibits the inflammatory action of neutrophils, a type of blood cell. The reduced inflammation translates into a smaller area of damaged tissue in the post-infarcted heart. The finding, published in Nature Communications, opens the way to new applications for this cheap, safe, and simple drug.

Acute myocardial infarction is a serious disease that affects more than 50 000 people a year in Spain. Treatment has advanced a great deal in recent years, especially in the extensive use of coronary angioplasty, in which a catheter is used to re-establish blood flow through the blocked coronary artery. Nevertheless, many heart attack survivors have seriously impaired heart function that limits their long-term health and generates major costs to the health system. The search for treatments to limit the irreversible damage caused by a heart attack is an extremely important research area in terms of both patient care and health policy.
Neutrophils
Neutrophils are white blood cells that target and fight infections. In noninfectious diseases, neutrophils mount an excessive response, and after a myocardial infarction these cells attack the heart, contributing to the long-term injury and impaired function. "In an infarction," explained Dr. Ibañez, "the most important thing is to re-establish blood flow as soon as possible. But unfortunately, the incoming blood sets off an inflammatory process, started by neutrophils, that causes additional, permanent damage to the heart." This additional damage due to blood flow restoration is known as reperfusion injury, and has been regarded as a necessary evil because it is essential to unblock the coronary artery as rapidly as possible.
Metoprolol is a beta-blocker that has been in clinical use for more than 30 years and costs less than €2 per dose, therefore of little commercial interest. In 2013, the METOCARD-CNIC clinical trial, led and coordinated by the same CNIC research team, showed that administration of metoprolol very early after an infarction reduces the size of the cardiac injury and improves long-term health. It has taken the team seven years to determine why this simple and cheap pharmacological strategy is so effective.
The study published today in Nature Communications shows that early administration of metoprolol protects the heart by acting directly on neutrophils. "Metoprolol stuns the blood neutrophils, altering their behavior and limiting their injurious inflammatory action on cardiac muscle," explained first author Jaime García-Prieto. When coronary blood flow is re-established, neutrophils launch a complex and organized inflammatory reaction, with negative consequences.
According to García-Prieto, "When neutrophils enter the infarcted heart tissue after the restoration of blood flow, they act disproportionately, inducing the death of cells that, while weakened, have survived the infarction." As Andrés Hidalgo, CNIC scientist and expert on neutrophils, explained, "Neutrophil tissue invasion is intimately related to their interactions with platelets. Metoprolol blocks these interactions, drastically limiting the number of neutrophils arriving in the infarcted tissue." Moreover, impeding neutrophil invasion also prevents the formation of blood-cell aggregates that block the microcirculation in the post-infarction heart.
Dr. Antonio Fernández-Ortiz, study co-author and a cardiologist at the Hospital Clínico San Carlos, clarified that "we knew that platelets were an important factor in the clotting that causes an infarct, but until now we could not be certain that they also act together with neutrophils to magnify injury after blood flow restoration." Dr. Ibañez concluded that "the priority after a heart attack remains the restoration of blood flow as soon as possible, but we need to prepare the heart for this by administering metoprolol."
Also an author on the study is Dr. Valentín Fuster, CNIC General Director and Physician in Chief at the Mount Sinai Hospital in New York. Commenting on the study, he said, "The imaging technology at the CNIC has allowed us to rapidly determine the status of a patient's heart after a heart attack, and this has enabled us to discover a new mechanism of action of this drug that we have been using for decades."

Explore further: Heart-resident macrophages call in neutrophils following ischemic injury

More information: Jaime García-Prieto et al. Neutrophil stunning by metoprolol reduces infarct size, Nature Communications (2017). DOI: 10.1038/ncomms14780

Journal reference: Nature Communications

Read more at: https://medicalxpress.com/news/2017-04-scientists-decades-old-drug-size-heart.html#jCp

Scientists at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) have discovered a new mechanism of action of metoprolol, a drug that can reduce the damage produced during a heart attack if administered early. The team led by Dr. Borja Ibáñez, Clinical Research Director at the CNIC and cardiologist at the Fundación Jiménez Díaz University Hospital Health Research Institute (IIS-FJD), has identified the mechanism that explains why this drug is so beneficial: rapid administration of metoprolol during a heart attack directly inhibits the inflammatory action of neutrophils, a type of blood cell. The reduced inflammation translates into a smaller area of damaged tissue in the post-infarcted heart. The finding, published in Nature Communications, opens the way to new applications for this cheap, safe, and simple drug.
Acute myocardial infarction is a serious disease that affects more than 50 000 people a year in Spain. Treatment has advanced a great deal in recent years, especially in the extensive use of coronary angioplasty, in which a catheter is used to re-establish blood flow through the blocked coronary artery. Nevertheless, many heart attack survivors have seriously impaired heart function that limits their long-term health and generates major costs to the health system. The search for treatments to limit the irreversible damage caused by a heart attack is an extremely important research area in terms of both patient care and health policy.
Neutrophils
Neutrophils are white blood cells that target and fight infections. In noninfectious diseases, neutrophils mount an excessive response, and after a myocardial infarction these cells attack the heart, contributing to the long-term injury and impaired function. "In an infarction," explained Dr. Ibañez, "the most important thing is to re-establish blood flow as soon as possible. But unfortunately, the incoming blood sets off an inflammatory process, started by neutrophils, that causes additional, permanent damage to the heart." This additional damage due to blood flow restoration is known as reperfusion injury, and has been regarded as a necessary evil because it is essential to unblock the coronary artery as rapidly as possible.
Metoprolol is a beta-blocker that has been in clinical use for more than 30 years and costs less than €2 per dose, therefore of little commercial interest. In 2013, the METOCARD-CNIC clinical trial, led and coordinated by the same CNIC research team, showed that administration of metoprolol very early after an infarction reduces the size of the cardiac injury and improves long-term health. It has taken the team seven years to determine why this simple and cheap pharmacological strategy is so effective.
The study published today in Nature Communications shows that early administration of metoprolol protects the heart by acting directly on neutrophils. "Metoprolol stuns the blood neutrophils, altering their behavior and limiting their injurious inflammatory action on cardiac muscle," explained first author Jaime García-Prieto. When coronary blood flow is re-established, neutrophils launch a complex and organized inflammatory reaction, with negative consequences.
According to García-Prieto, "When neutrophils enter the infarcted heart tissue after the restoration of blood flow, they act disproportionately, inducing the death of cells that, while weakened, have survived the infarction." As Andrés Hidalgo, CNIC scientist and expert on neutrophils, explained, "Neutrophil tissue invasion is intimately related to their interactions with platelets. Metoprolol blocks these interactions, drastically limiting the number of neutrophils arriving in the infarcted tissue." Moreover, impeding neutrophil invasion also prevents the formation of blood-cell aggregates that block the microcirculation in the post-infarction heart.
Dr. Antonio Fernández-Ortiz, study co-author and a cardiologist at the Hospital Clínico San Carlos, clarified that "we knew that platelets were an important factor in the clotting that causes an infarct, but until now we could not be certain that they also act together with neutrophils to magnify injury after blood flow restoration." Dr. Ibañez concluded that "the priority after a heart attack remains the restoration of blood flow as soon as possible, but we need to prepare the heart for this by administering metoprolol."
Also an author on the study is Dr. Valentín Fuster, CNIC General Director and Physician in Chief at the Mount Sinai Hospital in New York. Commenting on the study, he said, "The imaging technology at the CNIC has allowed us to rapidly determine the status of a patient's heart after a heart attack, and this has enabled us to discover a new mechanism of action of this drug that we have been using for decades."

Explore further: Heart-resident macrophages call in neutrophils following ischemic injury

More information: Jaime García-Prieto et al. Neutrophil stunning by metoprolol reduces infarct size, Nature Communications (2017). DOI: 10.1038/ncomms14780

Journal reference: Nature Communications