Increasing Stroke Tied to Injectable Opioids, Infective Endocarditis

Deborah Brauser

January 31, 2019

HONOLULU — The dramatic increase over the last decade in US hospitalizations for stroke associated with injectable drug-related infective endocarditis (IE) dovetails with the surge in opioid misuse in the country, new research suggests.

Using data from the National Inpatient Sample (NIS), investigators found that more than 5200 individuals had this type of hospitalization between 1993 and 2015. This translated into 2.4 per 10 million people in 1993 vs 18.8 per 10 million people in 2015.

Although the rate of stroke hospitalizations from opioid-related IE did not increase significantly between 1993 and 2008, it increased by 20% each year between 2008 and 2015.

The greatest increases were in non-Hispanic white patients, those living in the southern part of the United States, women, and those younger than age 45.

Lead author Setareh Salehi Omran, MD, fellow in vascular neurology at the Weill Cornell Medical Center and Columbia University Medical Center, New York City, told Medscape Medical News that, to their group's knowledge, this is the first study to examine these trends with stroke.

"I'd say the biggest takeaway for clinicians is to keep in mind that this is a complication of opioid misuse that we need to be concerned about, especially for younger patients who are using opioids more now," Salehi Omran said.

Dr Setareh Salehi Omran

"In a hospital setting, if you see a patient coming in with intravenous opioid use and with infective endocarditis, you need to be concerned that they may be at risk for having a stroke," she added.

The study was published online January 30 in Stroke to coincide with its upcoming presentation at next week's International Stroke Conference (ISC) 2019 in Honolulu.

Paucity of Data

As reported by Medscape Medical News, past research has shown a "staggering increase" in the occurrence of drug use-associated IE that appears to be a consequence of the current opioid epidemic.

In 2016, about 11.8 million people in the United States reported having misused opioids, including almost 1 million who used heroin, the current investigators report, citing data from the 2016 National Survey on Drug Use and Health. Nonsterile intravenous opioid use can lead to IE.

"IE results from endothelial damage related to repetitive injections and introduction of bacteria into the bloodstream via unsterile needles and preparation techniques," the researchers write.

Although stroke affects around 20% of patients with IE, there are "few data on trends in the occurrence of stroke as a complication of opioid-related IE, particularly in relation to the increasing severity of the opioid epidemic," they add.

The investigators examined inpatient discharge data from 1993 to 2015 from the Healthcare Cost and Utilization Project's NIS to identify hospitalizations with codes for stroke, IE, and opioid use. The NIS includes about 8 million total inpatient hospitalizations per year, "representing a 20% stratified sample of all nonfederal US hospitals."

During the full study period, there were:

  • 14,429,338 stroke-related hospitalizations,

  • 12,169,131 opioid use-related hospitalizations, and

  • 815,482 IE-related hospitalizations.

In addition, there were 5283 stroke hospitalizations related to IE and opioid use (65.8% men; mean age, 41.2 years; 57.6% non-Hispanic white).

Increasing Trends

Hospitalizations for stroke associated with both IE and opioid use increased from 2.4 (95% confidence interval [CI], 0.5 – 4.3) per 10 million US residents per year in 1993 to 18.8 (95% CI, 14.4 – 23.3) per 10 million in 2015.

Between 1993 and 2008, the annual percentage change (APC) was a nonsignificant 1.9% (95% CI, -2.2% to 6.1%). However, the APC was a highly significant 20.3% (95% CI, 10.5% - 30.9%) from 2008 to 2015.

When examining specific demographics of the patients, the investigators found significantly increased APCs in this type of hospitalization for those under the age of 45 years, women, Non-Hispanic whites, those living in the South, and those experiencing either an ischemic or hemorrhagic stroke.

Table. Joinpoint Analysis of Hospitalization Rates Per 10 Million Population

Demographic Trend 1: Years APC (95% CI) Trend 2: Years APC (95% CI)
Age < 45 years 1993-2006 -1.4 (-7.2 to 4.8) 2006-2015 20.5 (12.1-29.5)
Women 1993-2008 0.6 (-4.6 to 6.1) 2008-2015 24.4 (12.1-38.1)
Non-Hispanic white 1993-2007 6.5 (1.6-11.7) 2007-2015 25.7 (17.7-34.1)
South 1993-2006 -1.7 (-9.1 to 6.4) 2006-2015 20.2 (10.7-30.4)
Ischemic Stroke 1993-2008 2.7 (-1.5 to 7.0) 2008-2015 17.7 (8.2-27.9)
Hemorrhagic Stroke 1993-2005 -3.1 (-9.5 to 3.8) 2005-2015 19.4 (12.9-26.4)

In addition, the rate of hospitalization jumped from 2.2 per 10 million population in 1993 to 28.4 per 10 million in 2015 for those who lived in the Northeast. Their APC was 6.6 for the entire study period (95% CI, 3.8 – 9.5).

"In a large, nationally representative sample, we found that US hospitalization rates for stroke associated with IE and opioid use were stable for about 2 decades before rising sharply in 2008, which coincides with known trends in opioid abuse in the United States," the investigators write.

"Our study provides new information on the neurological consequences of the opioid epidemic," they add.

They note that prevention strategies aimed at reducing the misuse of prescription opioids have led to some patients using intravenous heroin. In fact, there has been a significant increase since 2007 in the use of heroin and in overdose-related deaths.

"The rise in heroin use combined with…high-risk injection practices may explain why opioid-related IE is becoming more prevalent and leading to complications, such as stroke and death," the researchers write.

Salehi Omran noted that because this was a national study, it shows that this is a wide-reaching problem.

"I think clinicians just need to be aware of this complication, which has been shown to be increasing based on our study," she said.

"Staggering" Numbers

Asked to comment on the study, Alysse Wurcel, MD, Tufts Medical Center, Boston, Massachusetts, told Medscape Medical News that, as an infectious disease physician, the results aren't surprising to her — but they are important.

"Neurologists can understand and appreciate the changing epidemiology and increasing responsibility we all have as clinicians to address the opioid epidemic," she said.

Dr Alysse Wurcel

Wurcel, who was not involved with the current research, is a member of the Infectious Diseases Society of America/HIV Medicine Association Opioid Working Group. She also published a study in 2016 on the increasing number of hospital admissions related to IE for young people who inject drugs.

"I'm married to a neuro-intensive care doctor, so we have been traveling this journey together. We've been seeing this, but the numbers and increases that [the current investigators] found were quite impressive. The numbers of people affected by stroke are really staggering," Wurcel said.

"We've always known stroke is a complication of endocarditis, but they found quite shocking numbers of people with endocarditis related to drug use that are having strokes. It brings up interesting questions," she added.

These include, is there something about drug use-related IE that's different from endocarditis that occurs in individuals who don't use drugs? Is it that those with drug-related IE are more likely to have a stroke or is it more about the type of bacteria involved?

Drug-related IE is often caused by Staphylococcus aureus, "which is a really bad bacteria that can cause really severe infection," Wurcel said. "Also, are people with drug-use endocarditis delaying entry to care until they have these very severe complications?"

For anyone coming in with a stroke, especially a younger person, drug use disorder should be considered, she said. "Any clinician can then say, 'we can hook you into sustainable treatment early on,' " she said. It's important to conduct an investigation, "whether through questions or a toxicology screen, just figuring out what it is so that you can treat the underlying issue that caused the stroke."

Wurcel added that normal use of oral opioids should not put an individual at risk for IE — and the same holds true for those with diabetes who take insulin injections.

Epidemic Repercussions

In video comments posted to the AHA/ASA website, Ralph Sacco, MD, past AHA president and current president of the American Academy of Neurology, noted that it's important to realize that there are many repercussions from the current opioid epidemic.

"The use of prescription medications and opioids is causing a greater risk of mortality and it can have effects on cognition. It can also lead to other kinds of drug abuse, including using drugs intravenously," he said.

"It's an important epidemic for us to be focusing on, and I think this abstract takes it another step in bringing it into perspective regarding stroke," added Sacco, who is also professor and chair of neurology at the University of Miami Miller School of Medicine, Florida.   

He noted a concern, however, that the research didn't look into what specific agents were injected by the individuals. Also, reiterating Wurcel's comments, he noted that the study is not saying that oral opioids are associated with IE and stroke.

"In this abstract, I believe they're talking more about injectable drugs like heroin, fentanyl, and other kinds of street drugs that could be abused," he said.

"We don't know exactly what they were injecting in terms of what kind of opioid it was, but we did use codes that were frequently used in patients who come in with opioid abuse or any complications from opioid use," said Salehi Omran when asked about this. "It's hard to pin down what agents were being injected intravenously, but they were all under the umbrella of opioids."

Still, Sacco called the current research "intriguing" and important. "It's a good study that shows an alarming increase in the number of strokes due to infective endocarditis," he added.

The study was supported by the National Institutes of Health, NIH/National Institute of Neurological Disorders and Stroke, American Heart Association, Leon Levy Fellowship in Neuroscience, and the Michael Goldberg Research Fund. The study authors and Wurcel have disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2019: Abstract 8. To be presented February 6, 2019.

Stroke. Published online January 30, 2019. Abstract

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