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The Department of Epidemiology and Biostatistics, Western University, London, Ont, CanadaSchool of Epidemiology and Public Health, University of Ottawa, Ottawa, Ont, CanadaInstitute for Mental Health Policy Research, Centre for Addiction and Mental Health (CAMH), London, Ont, CanadaDalla Lana School of Public Health, University of Toronto, London, Ont, Canada
Requests for reprints should be addressed to Michael Silverman, The Department of Epidemiology and Biostatistics, Western University, London, ON, Canada.
The Department of Epidemiology and Biostatistics, Western University, London, Ont, CanadaDivision of Infectious Diseases, Schulich School of Medicine and Dentistry, Western University, London, Ont, Canada
People who inject drugs and have infective endocarditis have a high risk of recurrent infective endocarditis and death. We aimed to characterize clinical factors associated with mortality and assess the probability of infective endocarditis recurrence in the presence of death as a competing risk.
Methods
A retrospective cohort study was conducted of people who inject drugs, identified between April 5, 2007 and March 15, 2018 with the Modified Duke Criteria for definite infective endocarditis. Fine-Gray sub-distribution and Cox proportional hazards modeling were conducted to determine variables associated with the rate of infective endocarditis recurrence and mortality, respectively.
Results
Of the 310 patients with infective endocarditis who inject drugs, 236 experienced a single episode and 74 experienced recurrent episodes. Peripherally inserted central catheter misuse was associated with an increased rate of infective endocarditis recurrence (sub-distribution hazard ratio 2.41; 95% confidence interval [CI], 1.17-4.98; P = .02) and mortality (hazard ratio [HR] 2.44; 95% CI, 1.15-5.17; P = .02). Non-right-sided infection, peripheral intravenous therapy, and intensive care unit admission were also associated with increased mortality. Oral therapy (HR 0.38; 95% CI, 0.16-0.91; P = .03), outpatient treatment (HR 0.39; 95% CI, 0.19-0.82; P = .01), and inpatient referral to addiction services (HR 0.39; 95% CI, 0.22-0.70; P = .002) were associated with a decrease in mortality.
Conclusions
Patients who misuse their peripherally inserted central catheter are at higher risk of recurrent infective endocarditis and death. Avoidance of peripherally inserted central catheter lines and use of intravenous peripheral therapy did not reduce mortality, but oral therapy was associated with reduced risk. Inpatient addiction services referral is important.
Peripherally inserted central catheter misuse was associated with increased rates of infective endocarditis recurrence and mortality, however, avoidance of peripherally inserted central catheters and use of intravenous peripheral therapy did not reduce mortality.
•
Identifying clinical factors associated with infective endocarditis recurrence and death will aid in developing effective harm reduction approaches, such as inpatient addiction counseling and linkage to outpatient ongoing services, for these patients.
Background
It is suggested that the incidence of infective endocarditis is stable among the general population;
Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
Despite the rising incidence of infective endocarditis among people who inject drugs, there is limited literature that assesses the relationship between clinical predictors and disease recurrence.
However, these studies failed to account for survival bias as patients who succumb to a first episode or to complications of addiction cannot have a recurrent episode. A survey by van Walraven and McAlister
observed 46% (46/100) of studies were biased by competing risks, of which 37.5% produced estimates that were overestimated by ≥10%.
Individuals who inject drugs have distinct risk factors that contribute to the recurrence of infective endocarditis. Previous studies observed significant associations between drug use and recurrent infective endocarditis.
In addition, surgical intervention has been suggested to increase the probability of recurrent infective endocarditis by fivefold among people who inject drugs.
Moreover, reinfection among people who inject drugs is significantly increased and results in an increased risk of mortality should operation on a prosthetic valve be necessary.
Peripherally inserted central catheters are commonly used during inpatient and outpatient treatment to administer medical drug treatments. However, misuse of peripherally inserted central catheters is an increasing concern, as these lines provide ease of access to a patient's vein. Using a smaller cohort, we previously identified peripherally inserted central catheter misuse as a leading risk factor for recurrent infective endocarditis among people who inject drugs;
however, we did not account for death as a competing risk. It has been postulated that referring people who inject drugs to addiction services may decrease the probability of recurrence of infective endocarditis. Current evidence has not observed this association; however, this may be the result of low statistical power.
We aimed to determine clinical factors that contribute to infective endocarditis recurrence, assess the probability of infective endocarditis recurrence in the presence of death as a competing risk, and evaluate the associations of clinical factors with mortality among people who inject drugs and have infective endocarditis. In particular, we aimed to clarify the potential association of peripherally inserted central catheter misuse (which has had limited study previously) with infective endocarditis recurrence and death.
Methods
Study Design and Patient Population
This study used a retrospective cohort analysis of patients aged ≥18 years admitted to 1 of the 3 acute care hospitals in London, Ontario, Canada, between April 5, 2007 and March 15, 2018. Cases were reported using electronic medical records and the Strengthening the Reporting of Observational Studies in Epidemiology guidelines for cohort studies.
The advanced electronic medical record system in London is an integrated database of clinical data (bloodwork, clinical notes, radiological studies, pharmacy dispensing) from any health care point of contact in the city. This allowed comprehensive long-term follow-up information to be obtained.
Ethics approval was granted from the Lawson Research Institute's Review Board. This study cohort was previously reported in a study of bloodstream infections in patients while on treatment for infective endocarditis.
The focus of the present study was on factors associated with recurrent infective endocarditis within the cohort. Informed consent from participants was not required due to the de-identified and retrospective nature of the study.
Demographic variables of interest included age at time of admission and patient sex. Age at time of admission was a continuous variable derived from subtracting the date of admission from date of birth. Patient sex was defined as either male or female. Variables of clinical importance included length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, admission to the intensive care unit (ICU), substance misuse, route of antibiotic administration, inpatient treatment of infectious endocarditis, and homelessness. Patient length of hospital stay, measured in days, was a continuous variable derived by subtracting the date of admission from date of discharge. Location of infection was a binary variable whereby infection was defined as either left-sided or bilateral infection or echo-negative vs right-sided infection. Infections that affected left-sided cardiac structures were defined as left-sided infective endocarditis and infections that affected right-sided cardiac structures were defined as right-sided infective endocarditis. If infection affected both left- and right-sided cardiac structures, the infection was defined as bilateral infective endocarditis. The majority of patients required the use of a peripherally inserted central catheter. Misuse of a patient's peripherally inserted central catheter to inject nonmedical drug treatments was documented by the medical team in the clinical record
and was defined as a categorical variable, whereby peripherally inserted central catheter misuse was defined as either no misuse, misuse, or no peripherally inserted central catheter in place. Referral to addiction services, surgical intervention, and admission to the ICU were each treated as binary variables. Routine postoperative admission to the ICU was not included. Substance misuse was a binary variable defined as either monosubstance misuse (either opioid or stimulant misuse) or polysubstance misuse of opioids and stimulants. Route of antibiotic administration was a categorical variable whereby administration was defined as either intravenous, oral, or other (both oral and intravenous or intramuscular). Long-acting injectable antibiotics for outpatient treatment were not available in Canada at the time of this study and thus were not included. A detailed analysis of the intravenous and oral antibiotic agents used to treat patients with infective endocarditis is shown in Supplementary Table 1 (available online). Inpatient treatment was a categorical variable whereby patients either received inpatient or outpatient treatment, or left against medical advice. Inpatient treatment was defined as those who received <14 days of outpatient antimicrobials or left against medical advice with <14 days left of the planned treatment regimen remaining.
Homelessness was a binary variable whereby patients were either housed or lacked a fixed address.
The outcome variables consisted of recurrent infective endocarditis and patient mortality. Recurrent infective endocarditis cases are defined as those occurring more than 6 months apart or, if within 6 months, caused by a different microorganism AND with a new vegetation, as described previously.
Single positive blood cultures with cutaneous commensal organisms were not included. Time at risk for recurrent infective endocarditis was defined as the time from hospital admission for the first admission until either readmission for a second episode of infective endocarditis, death, or last contact with the health care system. Patient mortality was identified through electronic medical records and obituary records.
Electronic medical records from acute care, psychiatric, or rehabilitation centers, as well as outpatient pharmacy, physician, radiology, and laboratory records were used to ascertain data on long-term patient follow-up.
Statistical Analysis
Data were coded as binary, categorical, or continuous. Binary data used the values of 0, indicating the absence of a characteristic, and 1, indicating the presence of the characteristic. Descriptive analysis was conducted to compare demographic and clinical characteristics between people who inject drugs who experienced a single episode of infective endocarditis and people who inject drugs who went on to experience recurrent infective endocarditis episodes (≥2 infective endocarditis episodes). Continuous data were presented using median and interquartile range, whereas binary and categorical data were presented using frequencies and percentages. The distribution of variables across strata were assessed for equivalency using the Wilcoxon rank sum test and Pearson's chi-squared tests for continuous and binary/categorical variables, respectively. Missing data were noted for all variables where applicable. Fine-Gray sub-distribution hazard regression analysis was conducted to assess the relationship between predictors of clinical importance (age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, admission to the ICU, substance misuse, route of antibiotic administration, inpatient treatment of infectious endocarditis, and homelessness) and infective endocarditis recurrence among people who inject drugs in the presence of death as a competing risk. Further, a multivariable time-dependent Cox proportional hazards regression analysis was conducted to evaluate the relationship between patient long-term mortality and predictors of clinical importance. Surgical intervention and recurrent infective endocarditis were treated as time-dependent covariates to account for the effects of immortal time bias.
Wald test statistics, 2-sided confidence intervals, and P values < .05 were used to indicate statistical significance. Statistical analyses were performed using Stata/IC 16.1.
Of the 564 patients with definite infective endocarditis, 310 were identified as people who inject drugs. Among these patients, 236 experienced only a single episode of infective endocarditis and 74 (23.9%) experienced recurrent infective endocarditis (≥2 episodes). Among patients who experienced a second episode of infective endocarditis, 39.2% (29/74) went on to experience a third episode and 17.2% (5/29) went on to experience a fourth episode of infective endocarditis. Patient follow-up was available for 98.4% (305/310) of the study population and used in subsequent analyses. The median (interquartile range) length of patient follow-up was observed to be 686.5 (68.0-1715.0) days. Compared with patients who experienced only a single episode of infective endocarditis, patients who went on to experience recurrent episodes were more likely to have a longer length of hospital stay, right-sided infection, intravenous antibiotic therapy, to have misused their peripherally inserted central catheter, and be referred to addiction services. A detailed comparison of baseline characteristics among patients who did and did not experience recurrent episodes of infective endocarditis is shown in Table 1.
Table 1Demographic Characteristics of People Who Inject Drugs from Initial Hospitalization Stratified by Recurrent Disease Status
Bivariate and multivariable Fine-Gray competing risks regression are shown in Table 2. When accounting for the effects of other predictors in the model, people who inject drugs who misused their peripherally inserted central catheter had a 2.41 (95% confidence interval [CI], 1.17-4.98; P = .02) higher rate of recurrent infective endocarditis, given they had not yet experienced a recurrent episode. In addition, outpatient treatment was observed to significantly increase the rate of infective endocarditis recurrence by 2.02 (95% CI, 1.12-3.66; P = .02).
Table 2Bivariate and Multivariable Fine-Gray Regression for Recurrent Infective Endocarditis in People Who Inject Drugs with Consideration for Death as a Competing Risk
Adjusted SHRs were generated from multivariable Fine-Gray regression models. The multivariable model was adjusted for age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, ICU admission, substances misused, route of antibiotic administration, inpatient treatment, and homelessness.
These values indicate statistical significance (P < .05).
Left against medical advice
1.61
0.70
0.68-3.79
.27
1.49
0.71
0.58-3.78
.41
Homelessness (ref = not homeless)
1.76
0.78
0.73-4.20
.21
1.43
0.70
0.55-3.71
.46
CI = confidence interval; ICU = intensive care unit; SE = standard error; SHR = sub-distribution hazard ratio.
Adjusted SHRs were generated from multivariable Fine-Gray regression models. The multivariable model was adjusted for age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, ICU admission, substances misused, route of antibiotic administration, inpatient treatment, and homelessness.
† These values indicate statistical significance (P < .05).
When assessing the association between referral to addiction services and infective endocarditis recurrence, we observed that patients who inject drugs and were referred to addiction services were found to have a significantly increased rate of recurrent infective endocarditis (sub-distribution hazard ratio = 1.69; 95% CI, 1.02-2.78; P = .04), under fully conditional specification assumptions (Supplementary Table 2, available online). Additionally, the significant increase in recurrence observed for outpatient treatment in the complete case analysis in Table 2 was observed to no longer be statistically significant (P = .07) under fully conditional specification assumptions. These discrepancies imply that the missing data reduced statistical power and led to biased results by excluding valuable information that was provided by incomplete observations and warrants further study.
Furthermore, baseline cumulative incidence of recurrent infective endocarditis among people who inject drugs, with consideration for death as a competing risk, was observed to be approximately 32.0% (95% CI, 25.0%-40.0%) at the last observable timepoint of 2863 days (Figure 1). Conversely, the traditional Kaplan-Meier model estimator for the cumulative incidence of infective endocarditis recurrence, which treats death as right-censored, was observed to be 41.0% (95% CI, 32.0%-52.0%) at 2863 days. Consequently, censoring death in the traditional Kaplan-Meier model, rather than considering its effects, as in the Fine-Gray model, resulted in a notable increase in cumulative incidence of infective endocarditis recurrence of 9.0%.
Figure 1Baseline cumulative incidence estimators for recurrent infective endocarditis. (A) Fine-Gray estimator in which the effects of death as a competing risk are accounted for in the determination of the cumulative incidence; (B) Kaplan-Meier estimator in which the effects of death are censored. Cumulative incidence of infective endocarditis recurrence is depicted on the y-axis, while time in months from discharge from hospital from first episode of endocarditis is depicted on the x-axis. Fine-Gray and traditional Kaplan-Meier model estimators for recurrent infective endocarditis incidence are shown at time = 2863 days. CI = confidence interval.
Mortality status was reported for 99.4% (308/310) of the study population. The overall mortality rate was observed to be 33.8% (104/308). Bivariate and multivariable time-dependent Cox proportional hazard regression are shown in Table 3. In the adjusted model, factors associated with increased mortality included admission to the ICU (hazard ratio [HR] 3.62; 95% CI, 2.11-6.20, P < .001), peripherally inserted central catheter misuse (HR 2.44; 95% CI, 1.15-5.17; P = .02), and lack of peripherally inserted central catheter in place (HR 8.60; 95% CI, 4.56-16.23; P < .001). Factors associated with reduced mortality included referral to addiction services (HR 0.39; 95% CI, 0.22-0.70; P = .002), use of oral antibiotics (vs intravenous therapy; HR 0.38; 95% CI, 0.16-0.91; P = .03) and outpatient treatment (HR 0.39; 95% CI, 0.19-0.82; P = .01).
Table 3Bivariate and Multivariable Time-Dependent Cox Proportional Hazards Regression for Long-Term Mortality in People Who Inject Drugs
Adjusted HRs were generated from time-dependent multivariable Cox proportional hazards regression models. The multivariable model was adjusted for age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, ICU admission, substances misused, route of antibiotic administration, inpatient treatment, and homelessness.
Values in bold indicate statistical significance (P < .05).
0.29
0.21
0.07-1.23
.09
Homelessness (ref = not homeless)
1.41
0.55
0.65-3.03
.38
2.18
0.97
0.91-5.20
.08
CI = confidence interval; HR = hazard ratio; ICU = intensive care unit; SE = standard error.
Adjusted HRs were generated from time-dependent multivariable Cox proportional hazards regression models. The multivariable model was adjusted for age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, ICU admission, substances misused, route of antibiotic administration, inpatient treatment, and homelessness.
† Values in bold indicate statistical significance (P < .05).
Supplementary Table 2Complete Case Analysis and Fully Conditional Specification Imputation Multivariable Fine-Gray Regressions for Recurrent Infective Endocarditis in Persons Who Inject Drugs with Consideration for Death as a Competing Risk
Adjusted SHRs were generated from multivariable Fine-Gray regression models. The multivariable model was adjusted for age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, ICU admission, substances misused, route of antibiotic administration, inpatient treatment, and homelessness.
Adjusted SHRs were generated from multivariable Fine-Gray regression models. The multivariable model was adjusted for age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, ICU admission, substances misused, route of antibiotic administration, inpatient treatment, and homelessness.
Std. Err.
95% CI
P Value
Age
1.00
0.01
0.97
1.03
0.92
1.00
0.14
0.97
1.03
0.92
Sex (ref = female)
1.37
0.42
0.75
2.50
0.31
1.18
0.34
0.67
2.06
0.56
Length of hospital stay
1.00
0.002
1.00
1.01
0.60
1.00
0.002
1.00
1.01
0.71
Left-sided or bilateral infection or echo-negative (ref = right-sided IE)
0.57
0.21
0.28
1.18
0.13
0.60
0.20
0.30
1.16
0.13
Peripherally inserted central catheter misuse (ref = no misuse)
Peripherally inserted central catheter misused
2.41
0.89
1.17
4.98
0.02
2.63
0.89
1.36
5.09
0.004
No peripherally inserted central catheter in place
0.27
0.30
0.03
2.26
0.23
0.17
0.18
0.21
1.37
0.10
Referral to addiction services (ref = not referred)
1.49
0.41
0.87
2.55
0.15
1.69
0.43
1.02
2.78
0.04
Surgical intervention (ref = no surgery)
1.16
0.45
0.54
2.50
0.70
1.19
0.42
0.59
2.39
0.63
Admission to the ICU (ref = not admitted)
1.04
0.36
0.53
2.04
0.91
1.19
0.36
0.67
2.14
0.55
Misuse of Opiates and Stimulants (ref = opiate or stimulant use only)
Values in bold indicate statistical significance (P<0.05).
Abbreviations: CCA, complete case analysis; SHR, sub-distribution hazard ratio; Std. Err., standard error; CI, confidence interval; ICU, intensive care unit.
Adjusted SHRs were generated from multivariable Fine-Gray regression models. The multivariable model was adjusted for age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, ICU admission, substances misused, route of antibiotic administration, inpatient treatment, and homelessness.
When assessing the association between non-right-sided infection and the mortality rate, we observed people who inject drugs who had non-right-sided infection were found to have a significantly increased rate of mortality (HR 1.63; 95% CI, 1.03-2.59; P = .04) under fully conditional specification assumptions (Supplementary Table 3, available online). This discrepancy implies that the missing data reduced statistical power and led to biased results by excluding valuable information that was provided by incomplete observations. Further study is warranted.
Supplementary Table 3Multivariable Complete Case Analysis and Fully Conditional Specification Time-Dependent Cox Proportional Hazards Regression for Long-term Mortality in Persons Who Inject Drugs
Adjusted HRs were generated from time-dependent multivariable Cox proportional hazards regression models. The multivariable model was adjusted for age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, ICU admission, substances misused, route of antibiotic administration, inpatient treatment, and homelessness.
Adjusted HRs were generated from time-dependent multivariable Cox proportional hazards regression models. The multivariable model was adjusted for age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, ICU admission, substances misused, route of antibiotic administration, inpatient treatment, and homelessness.
Std. Err.
95% CI
P Value
Age
1.02
0.01
0.99
1.04
0.17
1.01
0.01
0.99
1.03
0.27
Sex (ref = female)
1.08
0.27
0.66
1.75
0.76
1.08
0.24
0.69
1.67
0.74
Length of hospital stay
1.00
0.004
0.99
1.01
0.62
1.00
0.004
0.99
1.00
0.50
Left-sided or bilateral infection or echo-negative (ref = right-sided IE)
1.54
0.41
0.92
2.58
0.10
1.63
0.38
1.03
2.59
0.04
Peripherally inserted central catheter misuse (ref = no misuse)
Peripherally inserted central catheter line misused
2.44
0.93
1.15
5.17
0.02
2.13
0.76
1.05
4.29
0.04
No peripherally inserted central catheter in place
8.60
2.79
4.56
16.23
<0.001
9.11
2.59
5.22
15.89
<0.001
Referral to addiction services (ref = not referred)
0.39
0.12
0.22
0.70
0.002
0.39
0.11
0.22
0.69
0.001
Surgical intervention
1.16
0.48
0.51
2.62
0.73
1.25
0.44
0.62
2.51
0.53
Recurrent endocarditis
1.90
1.59
0.37
9.79
0.44
1.49
1.21
0.30
7.32
0.62
Admission to the ICU (ref = not admitted)
3.62
0.99
2.11
6.20
<0.001
3.38
0.86
2.06
5.56
<0.001
Misuse of Opiates and Stimulants (ref = opiate or stimulant use only)
Values in bold indicate statistical significance (P<0.05).
Abbreviations: CCA, complete case analysis; HR, hazard ratio; Std. Err., standard error; CI, confidence interval; ICU, intensive care unit.
Adjusted HRs were generated from time-dependent multivariable Cox proportional hazards regression models. The multivariable model was adjusted for age, sex, length of hospital stay, location of infection, peripherally inserted central catheter misuse, referral to addiction services, surgical intervention, ICU admission, substances misused, route of antibiotic administration, inpatient treatment, and homelessness.
This study consists of the largest case series of individuals who inject drugs identified by detailed chart review with the Modified Duke Criteria for definite infective endocarditis, and the largest study to date of recurrent infective endocarditis in subjects who inject drugs. As in previous studies of infective endocarditis in people who inject drugs,
we found a very high incidence rate of recurrent infective endocarditis; 74/310 (23.9%) having a second episode with a 32.0% cumulative incidence when considering death as a competing risk. Assessment of the risk for recurrent infective endocarditis is critical in order to focus prevention efforts and to inform decisions about patient eligibility for cardiac surgery, particularly due to the higher risk of mortality with prosthetic valve infective endocarditis. Previous studies assessing the risks associated with recurrent infective endocarditis did not account for issues of survival bias, which may confound the analysis.
This bias may lead risk factors for death to be paradoxically protective against recurrent infective endocarditis, as patients who succumb will not be available to be re-infected. Therefore, we performed a competing risk analysis that allowed a more robust assessment of risk factors for recurrent infective endocarditis.
observed a 10-year mortality rate of approximately 20.0% among individuals who inject drugs. Conversely, this study observed a 7.8-year mortality rate of 33.8% among the study population. The city-wide electronic medical record database used in the current study allowed for improved ability to obtain long-term patient follow-up, which may have allowed us to identify more patient deaths rather than attributing them to loss of follow-up.
We previously demonstrated that patient injection drug use while on treatment for infective endocarditis was very common and was independently associated with a higher rate of new bloodstream infections (HR 5.07; 95% CI, 2.68-9.60).
We hypothesized that injecting into the peripherally inserted central catheter, despite the routine advice given by providers in our institutions to avoid this, may be evidence of more severe addiction and thus associated with recurrent infective endocarditis or death. Peripherally inserted central catheter misuse was very common in our cohort (76/310 patients, 24.5%). We identified a significant association between peripherally inserted central catheter misuse and the rate of infective endocarditis recurrence (sub-distribution HR = 2.41, P = .02) and mortality (HR 2.44, P = .02). In order to prevent peripherally inserted central catheter line misuse, some clinicians choose to attempt treatment using only peripheral intravenous therapy. We found that intravenous therapy in the absence of a peripherally inserted central catheter line was associated with a higher risk of death (HR 8.60, P < .001). It thus appears that simply avoiding peripherally inserted central catheter line insertion in these patients did not improve outcomes. Furthermore, outcomes may have been worse in these patients, as this strategy was likely applied selectively in patients whom the clinicians felt had particularly risky injecting behavior.
We observed a significant association between outpatient treatment and an increased rate of infective endocarditis recurrence (HR 2.02, P = .02) but reduced mortality (HR 0.39, P = .01). This may be due to patients who were hemodynamically stable enough to leave the hospital, may be less likely to die, but also fit enough to continue their injecting and thus be at risk of recurrent endocarditis. However, when accounting for missing data using the fully conditional specification imputation method, outpatient treatment was observed to still demonstrate a trend, but no longer be statistically significantly associated with an increased risk of recurrence. Further studies need to be conducted to better understand the association between outpatient treatment and infective endocarditis recurrence among people who inject drugs.
Importantly, inpatient assessment by addiction services was associated with decreased mortality among people who inject drugs and have infective endocarditis. The fact that 64.8% (201/310) of patients did not receive this care remains a significant concern. Unfortunately, this lack of access to addiction treatment for medical inpatients remains a widespread problem despite recommendations to offer this potentially life-saving intervention.
Integrating treatment at the iintersection of opioid use disorder and iinfectious disease epidemics in medical settings: a call for action after a National Academies of Sciences, Engineering, and Medicine Workshop.
A recent study found that opiate substitution therapy reduced mortality in people who inject drugs and have infective endocarditis, but only while on therapy, and did not reduce overall mortality due to poor retention in the program.
Association of treatment with medications for opioid use disorder with mortality after hospitalization for injection drug use-associated infective endocarditis.
Our inpatient and outpatient addiction services are generally well coordinated and we believe that this led to longer-term benefit, although further studies will be necessary to confirm this.
Use of oral antibiotics was associated with a reduced risk of mortality (HR 0.38, P = .03). A recent review reported that oral regimens in people with endocarditis who don't inject drugs were associated with improved clinical cure rates and reduced mortality when compared with ongoing intravenous therapy.
In particular, The Partial Oral Treatment of Endocarditis trial demonstrated that treatment of left-sided infective endocarditis with oral therapy was noninferior to intravenous treatment.
However, data on people who inject drugs are sorely lacking. Our data suggest that the benefit of oral regimens may be particularly great among individuals who inject drugs and who are at risk for complications associated with misuse of intravenous lines. We are presently conducting a randomized controlled trial of oral vs intravenous therapy in this population that will help to clarify the efficacy and safety of oral therapy for infective endocarditis among people who inject drugs.
Location of infection is an important factor in the prognosis of people who inject drugs and have infective endocarditis. We identified non-right-sided infection as a factor for increased rate of mortality under fully conditional specification assumptions, which is consistent with current literature.
although a recent meta-analysis did not identify a difference in postoperative mortality after valve surgery for infective endocarditis between people who inject drugs and those who do not.
Notably, in our study, surgery was not associated with an increased risk for recurrent infective endocarditis, although this study may have been underpowered to identify such an association. The benefits and risks associated with surgical intervention in people who inject drugs and have infective endocarditis require further study.
As the vast majority of patients used opiates, we investigated whether those who also used stimulants would have a higher relapse or death rate due to the lack of options for stimulant replacement therapy during the course of this study.
Too few patients used stimulants alone to assess this, however, use of multiple substances (both opiates and stimulants) compared with either group alone was not associated with a greater risk of recurrence or death.
Although we found that peripherally inserted central catheter misuse was very common among patients in the 3 London, Ontario hospitals in this study, this behavior may be different in other contexts/locations. Patient misuse of intravenous catheters may be underestimated, as physicians are not always aware of this behavior and do not always document it. Nevertheless, the very high rate of the behavior noted during chart review (76/310, 24.5%) in our study suggests that underestimation was not likely widespread in our center.
As this study was based on retrospectively collected data, accuracy of information may be limited. Another limitation to this study is the lack of a standard score for acute severity of illness. This study observed a moderate but positive association between increased rate of infective endocarditis recurrence and referral to addiction services. However, despite having data on admission to the intensive care unit, this study lacked data on the severity of disability, including neurological compromise due to embolic stroke, which may influence this observation. It is possible that severely impaired patients were not referred to addiction services, as they were not at risk for ongoing injection behaviors and thus would be expected to have a lower endocarditis recurrence rate. A prospective study with detailed history that encompassed severity of disability including neurological compromise and details about frequency of injection and other addiction behaviors would be informative.
Conclusion
Inpatient addiction behaviors in people who inject drugs and have infective endocarditis, such as misuse of the peripherally inserted central catheter line, predict higher risk of recurrent infective endocarditis and death. Avoidance of peripherally inserted central catheter lines and use of intravenous peripheral therapy did not reduce mortality, but oral therapy was associated with reduced risk of death. Effective harm-reduction strategies to target these patients, including inpatient addiction counseling and linkage to outpatient ongoing services, need to be emphasized.
Acknowledgments
We would like to thank Dr. Susana Pearl for editing and Dr. Yayuan Zhu for her statistical input.
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Funding: No financial support was received for the research, authorship, or publication of this article.
Conflicts of Interest: The authors have no conflicts of interest to disclose.
Authorship: The concept and design of the manuscript was brought forth by MS. ES compiled the data and created the database. MS and TEM supervised the study. JA performed the data analyses. JA, TEM, and MS interpreted the data. JA drafted the manuscript. All authors had access to the data, contributed to writing and revisions of the paper, and read and approved the final manuscript.
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