A Manitoba clinician-scientist is investigating whether this well-known blood thinner could be used to help treat community-acquired pneumonia
By Brian Cole
June 6, 2023
A Manitoba clinician-scientist who played a key role in establishing the blood thinner heparin as a treatment for COVID-19 is now working to determine whether the drug can be used to help treat another deadly infection – community-acquired pneumonia (CAP).
Dr. Ryan Zarychanski, a hematologist and critical care physician with the University of Manitoba and CancerCare Manitoba, recently launched an international clinical trial to determine whether heparin could help prevent patients hospitalized with CAP from becoming critically ill or dying.
The trial, which is being supported by Research Manitoba, will involve as many as 4,000 patients at more than 60 sites throughout Canada, the United States and Brazil. Several local scientists, including co-principal investigator and junior faculty member Dr. Sylvain Lother, research personnel, and students from Winnipeg, will be involved in the trial, which is the second largest of its kind ever initiated and led from this province.
So far, Zarychanski and his team have received a five-year grant worth $500,000 from Research Manitoba and $4 million from the Canadian Institutes of Health Research to support the trial, which is officially known as the Anti-thrombotic Therapy to Ameliorate Clinical Complications in Community-Acquired Pneumonia trial, or ATTACC-CAP for short.
CAP is an acute viral or bacterial infection of the lungs acquired in the community (ie. outside of a hospital or institutional setting) and is one of the leading causes of hospitalization in the world.
Patients with CAP experience inflammation of the air sacs in the lungs, which become filled with fluid and unable to take in oxygen. CAP can also cause blood clots that may trigger a stroke or impair the function of various organs, such as the liver, heart and kidneys.
Dr. Ryan Zarychanski is leading the second largest international clinical trial ever initiated and led from Manitoba.
Dr. Sylvain Lother is part of the team investigating whether heparin can be used to treat patients with community-acquired pneumonia.
Currently, there is only one proven type of therapy for CAP: antibiotics.
But Zarychanski believes that heparin, which has proven useful in combatting inflammation and blood clots in COVID-19 patients, may also be helpful in treating CAP.
If so, the trial has the potential to change how CAP is treated around the globe.
“Should this inexpensive and widely available treatment improve CAP outcomes, the results will represent a paradigm shift in how pulmonary infections are treated beyond antimicrobials, and will directly impact practice throughout the world,” he says in an outline for the trial.
For Zarychanski, the trial marks another chapter in his ongoing study of heparin. As he explains, the drug has historically been the “workhorse” of blood thinners, which are commonly used to prevent or treat blood clots.
“It’s somewhat of an old, unexciting, blood-thinning drug,” he says with a chuckle.
But the drug also possesses some other interesting properties. For example, heparin is the most negatively charged molecule in medicine.
“Because of its strong negative charge, heparin binds to many molecules, such as the lining of blood vessels and immune cells. These interactions mediate the many anti-inflammatory actions of heparin – actions that are independent of its role as a blood thinner.”
Zarychanski started studying heparin about a decade ago to determine whether it could be used to treat patients with septic shock, a potentially fatal condition caused by an infection.
“People who die of (septic shock) often die of overwhelming inflammation associated with small blood clots in their organs causing organ dysfunction. The appeal of heparin is its ability to reduce inflammation and reduce blood clotting,” he says.
But his research took a sudden turn in March 2020 with the emergence of COVID-19, a respiratory infection caused by a novel coronavirus. At the time, scientists around the world were scrambling to identify potential treatments for the disease, which has killed an estimated 6.9 million people over the last three years, including more than 50,000 in Canada.
Heparin emerged as an early potential treatment for COVID-19 after health-care providers noticed that many patients with COVID-19 infection had evidence of lung inflammation and both small and large blood vessel blood clots. And, given his background in heparin research, Zarychanski was well prepared to develop and lead an international clinical trial to test the drug’s effectiveness in treating the disease.
Zarychanski didn’t waste any time getting to work. In short order, he secured $1.6 million from Research Manitoba and the Manitoba government to launch a randomized clinical trial, known as the Anti-thrombotic Therapy to Ameliorate Clinical Complications in COVID (ATTACC-COVID) trial. He then leveraged Manitoba’s investment to obtain a $3.6 million grant from the Canadian Institutes of Health Research and $1.8 million from an international foundation. Additional funding from local foundations and foreign governments were also secured.
By May 12, 2020, about two months after the virus had been declared a pandemic, the clinical trial for heparin was underway. In addition, Zarychanski and his team simultaneously helped lead or participated in trials that evaluated several other potential treatments, including steroids, hydroxychloroquine, anti-viral therapies, and other anti-inflammatory treatments.
Eventually, the ATTACC-COVID trial, carried out in record time, yielded some fascinating findings.
For example, Zarychanski discovered that a full dose of heparin is more helpful in reducing inflammation and blood clots than a low dose, which is commonly given to patients who are admitted to hospital for a variety of health issues to prevent blood clots. His trial also discovered that the drug is helpful in treating non-critically ill patients on the ward, but was not helpful to treat critically ill patients. All told, it was estimated that heparin could reduce the number of non-critically ill patients needing intensive care by approximately 25 percent.
The bottom line: therapeutic-dose heparin is now one of the treatments commonly used in hospital to treat COVID-19 patients, and is estimated to have save thousands of lives and ICU admissions around the world.
But the story doesn’t end there. As the pandemic showed signs of easing up through the end of 2022 and early 2023, Zarychanski started wondering whether heparin might have other applications. And it didn’t take him long to settle on CAP as a potential target.
As he explains in his project overview, both COVID-19 and CAP share converging pathways of inflammation and thrombosis (blood clots). It is only logical, then, to wonder if therapeutic-dose heparin will similarly work in patients with CAP caused by other viruses or bacteria. But that hypothesis has to be tested.
“Does therapeutic-dose heparin work in everyone with pneumonia? asks Zarychanski. “Does it work for all viruses (that cause pneumonia)? Does it work for pneumonia caused by bacteria as well? At this time we don’t know, but through the clinical trial now underway, we’re going to find out.”
But Zarychanski says the clinical trial is about more than determining the effectiveness of heparin in treating CAP. It’s also about demonstrating the value of building a learning health-care system in Manitoba.
As he explains, clinical trials are essential to creating the knowledge necessary to develop better treatments for a variety of diseases and conditions.
“Physicians have data for probably around 10 percent of the clinical decisions they make every day,” says Zarychanski. “For example, if you come to the hospital with pneumonia, we know we should probably give you antibiotics, but we don’t know which, of several, work best for pneumonia,” he says. “Likewise, we’re frequently not certain about what is the optimal strategy for controlling pain, treating nausea, or even helping a patient sleep. We have lots of decisions that need to be made every day, but we don’t have sufficiently robust data to confidently guide our decision-making. The ideal way to answer these questions is through clinical trials.”
The problem is that clinical trials are not generally embedded into the health-care system, here in Manitoba or elsewhere, for that matter.
“Right now, we (health-care providers and physician-scientists) either care for patients or conduct research. But what we should be doing is caring for patients while learning how best to care for these same patients. This is the core function of a learning health-care system and exactly what we demonstrated, with success, in COVID.”
The reference speaks to the fact that when COVID-19 emerged as a world-wide health threat, there were no known treatments. As a result, teams of health-care providers and researchers had to carry out clinical trials on the fly to test various treatments for the virus.
“Instead of guessing which treatment might work, in Manitoba, we didn’t permit the use of unproven treatments for COVID unless it was part of a clinical trial. That is a core component of a learning health-care system. We’ll give patients what we know works, and if unsure, we’re going to study it until we know the answer,” he says.
The end result was that after a year of study, the clinical trials carried out by Zarychanski’s team demonstrated that some treatments – such as steroids and anticoagulants like heparin – were beneficial in treating COVID-19 patients, while others – such as hydroxychloroquine and other anti-inflammatory treatments – were not.
Zarychanski says the COVID-19 experience underscores the need to build more capacity in Manitoba, not just to participate in international clinical trials, but to lead them as well – just as Manitoba led in COVID.
And, his hope is that the ATTACC-CAP trial now underway will help pave the way.
“For 50 years, research into treatments for pneumonia centred on antibiotics. With the ATTACC-CAP trial, health-care providers around the world will work together to explore a number of potential therapies over time,” he says.
The near-term goal, he says, is to “build an ecosystem of research around pneumonia… so we can take a deep dive into the challenge of CAP – the most common cause of hospitalization in the world,” he says.
But longer term, the objective must be to build the capacity necessary to fully integrate clinical trials into the health-care system.
“Our successes in COVID placed Manitoba squarely on the map as international clinical leaders,” he says. “With this has come an opportunity to spread, scale and cement clinical trials into processes of clinical care at Manitoba’s largest hospitals.
“The (ATTACC-CAP) trial will serve to recognize the University of Manitoba and create skilled jobs within our province. More importantly, still, the trial, and everything that orbits around such a venture, will leave Manitoba with profoundly more capacity to lead high-priority clinical trials through training, recruitment and retention,” says Zarychanski.
The first results from the clinical trial could be available as early as 2026.
Brian Cole is a Winnipeg writer.