Tackling sepsis — How innovative therapies and treatment protocol can save lives

Approximately 1.5 million people in the U.S. get sepsis each year, and 250,000 Americans die from sepsis annually.1 Patients with severe sepsis can develop septic shock, which is a significantly dangerous drop in blood pressure (hypotension) causing compromised blood flow to critical organs and can kill patients within hours. Deaths associated with sepsis and septic shock could be drastically reduced if healthcare providers appropriately detect the complication and intervene early on.

Despite implementation of quality measures associated with sepsis and septic shock, sepsis remains a significant problem for the healthcare system today. Many patients with septic shock are unable to achieve or maintain the recommended blood pressure target of mean arterial pressure (MAP) > 65 mmHg per the Surviving Sepsis Campaign.2 Rapid innovation may improve treatment methods and survival in the future. La Jolla Pharmaceutical Company (La Jolla) received FDA approval for GIAPREZATM (angiotensin II), a vasoconstrictor indicated to increase blood pressure in adults with septic shock or other disruptive shock, in December 2017 and launched the drug in March.

"What we consider to be innovative is that we take naturally occurring peptides that have evolved with us over millennia and we are just using those in purified forms to give back to patients what they are deficient in," said George Tidmarsh M.D., Ph.D., President and Chief Executiveof La Jolla, during a workshop presentation at the Becker's Hospital Review 9th Annual Meeting in Chicago. "That applies to GIAPREZA, and it's true as well for our product candidate, LJPC-401, which is in a pivotal trial."

La Jolla's LJPC-401, a synthetic human hepcidin, is designed to treat iron overload caused by diseases like hereditary hemochromatosis, thalassemia, sickle cell disease and Myelodysplastic syndromes. Iron overload affects criticalbodyorgans such as the heart, liver and endocrine organs. La Jolla aims to deliver solutions for patients that mimic natural physiology.

"That's our focus — putting the patient first. We do that by really developing natural peptides we already know serve a function in the body, and in that way, we think it's a safer and better way to treat disease, and we think that was validated in the approval of GIAPREZA," Dr. Tidmarsh said.

Clinical evidence for sepsis protocol and treatment
La Jolla researchers mined detailed single-institution ICU data from the Medical Information Mart for Intensive Care, which logged patient data from a single institution over an 11-year span between 2001 and 2012. The researchers identified and examined data for 5,725 septic patients who experienced more than six hours of hypotension, among other criteria.3

The data showed that at resuscitation, providers did a good job of maintaining blood pressure, but almost all patients reported MAP that dipped below 65 mmHG at some point during treatment and 62.3 percent spent two hours or more with below-target blood pressure. Almost 7.7 percent of the patients spent more than 12 hours below the target blood pressure, and 68.6 percent of patients reported MAP lower than 55 mmHG at one point during treatment.

"This was surprising and at the same time troubling," Dr. Tidmarsh said. "The data is clear that the longer time you are below the thresholds, the greater the likelihood that you are going to die. The conclusion is that MAP does matter."

A separate article published in the New England Journal of Medicine provides further evidence to support GIAPREZA. The article, titled "Angiotensin II for the Treatment of Vasodilatory Shock," examined the benefit of GIAPREZA on mean arterial pressure and survival for patients in the ATHOS-3 trial.4 The international, multi-center, double-blind study included 344 patients randomly assigned to the GIAPREZA or placebo group.

All the patients received standard care vasopressors and one-third reported MAP below 65 mmHg despite high dose vasopressors. The study found:

• Better blood pressure management in the GIAPREZA group: 70 percent of patients on GIAPREZA achieved the target blood pressure, compared to 23 percent in the placebo group.
• Improved organ function in the GIAPREZA group: around 28 percent of the patients in the GIAPREZA group discontinued dialysis compared to 15 percent in the placebo group.
• Higher survival rates at 28 days: all-cause mortality at 28 days was 46 percent in the GIAPREZA group and 54 percent in the placebo group
• Percent of patients with AEs were similar between the two treatment arms5
• There is a potential for venous and arterial thromboembolic events (AEs 12.9 percent v 5.1 percent, DVT SAEs 1.8 percent v 0 percent)6

"We believe that GIAPREZA represents a new tool to manage blood pressure and improve outcomes for these patients," said Dr. Tidmarsh.

Sepsis protocol standardization
In conjunction with pharmacological solutions to sepsis, efforts such as the Surviving Sepsis Campaign aim to create sepsis protocol and promote treatment standardization to decrease mortality rates across the country.

The Surviving Sepsis Campaign is a collaboration, which the Society of Critical Care Medicine and European Society of Intensive Care Medicine founded in 2002 with the goal of reducing mortality and morbidity from sepsis and septic shock worldwide. The organization updates their best practices in sepsis treatment guidelines every four years, with the most recent update being in 2016.

"These guidelines create bundles and, as you may know in your hospitals, you have a focus on these bundles. They are a quality measure, and CMS is looking at to determine how you as an organization are doing in identifying and intervening early in the septic shock," said Dr. Tidmarsh.

CMS' sepsis management bundle evaluates hospitals heavily in the three- and six-hour timeframes, which are critical in controlling the outcome. The bundle requires providers to reverse low blood pressure associated with septic shock, which is essential to resuscitating patients. Low blood pressure leads to low profusion, lack of blood flow and oxygenation, which also drives critical organ failure.

Patients treated for septic shock should maintain a MAP of at least 65 mmHg to avoid further organ damage. However, clinicians don't always monitor or maintain the appropriate blood pressure levels as closely as they track other metrics. "Many people lose sight of that, because those metrics aren't as closely followed for your quality assessments," said Dr. Tidmarsh. "But it's clear that maintaining blood pressure is essential to saving these people."

There is now a national movement for states to update sepsis protocol guidelines, which began with a 12-year-old boy in New York. The boy was rushed to the hospital in 2012 after collapsing on the basketball court from septic shock. He wasn't treated appropriately and died within five days. The boy's family began advocating for change. As a result, New York Governor Andrew Cuomo spearheaded legislative efforts to implement "Rory's Regulations" in 2013 mandating all New York hospitals use evidence-based clinical practice protocols for timely sepsis identification and management. Hospitals are required to submit protocols to the New York Department of Health for approval as well as collect and report data to the Department of Health, which monitors compliance and updates best practices.

Data gathered on patients treated at New York hospitals between 2014 and 2016 shows the sepsis protocol utilization increased from 73.7 percent to 84.7 percent; timely management increased 41.5 percent to 55.2 percent; and mortality decreased 30.2 percent to 25.4 percent.7 "The boy's family is now working across the country to get legislation in every state to mandate hospitals have a protocol and follow that protocol based on these results," Dr. Tidmarsh said.

References

1. CDC. "Making Health Care Safer: Think Sepsis. Time Matters."
2. Rhodes A, et al. Intensive Care Medicine. 2018 ;Cecconi M, et al. Intensive Care Medicine, 2014.
3. Nielsen et al, 2018, Blood pressure control and clinical outcomes in patients with distributive shock in an Academic Setting, 4. ISICEM 2018, Brussel, Belgium
5. Khanna A et al. "Angiotensin II for the Treatment of Vasodilatory Shock." New Engl J Med. 2017; 377: 419-430.
6. GIAPREZA™ (angiotensin II) [package insert]. San Diego, CA: La Jolla Pharmaceutical Company; 2017.

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