Abstract
Background
Acute myocardial injury is associated with poor outcomes in patients with acute ischemic stroke, but its prognostic significance in patients with spontaneous intracerebral hemorrhage remains unclear. We investigated whether acute myocardial injury and the direction of the cardiac troponin I (cTnI) change (rising versus falling) affect post‐intracerebral hemorrhage outcomes.
Methods and Results
We re‐analyzed the FAST (Factor‐Seven‐for‐Acute‐Hemorrhagic‐Stroke) trial. Acute myocardial injury was defined as at least 1 cTnI value above the upper reference limit with a rise/fall of >20%. Logistic regression tested for associations (1) between acute myocardial injury (presence versus absence) and poor outcome (modified Rankin Scale 4–6) and mortality at 15 and 90 days; (2) among 3 groups (rising versus falling versus no acute myocardial injury) and outcomes. Among the 841 FAST participants, 785 patients were included. Acute myocardial injury was detected in 29% (n=227); 170 had rising cTnI. At 15 and 90 days, respectively, those with acute myocardial injury had higher odds of poor outcome (adjusted odds ratio) ([aOR] 2.3 [95% CI, 1.3–3.9]); and adjusted odds ratio 2.5 [95% CI, 1.6–3.9];, and higher odds of mortality (adjusted odds ratio 2.4 [95% CI, 1.4–4.3]; and adjusted odds ratio 2.2 [CI, 1.3–3.6]) than patients without. There was no interaction between FAST group assignment and myocardial injury, and associations between myocardial injury and outcomes were consistent across group assignments. Rising cTnI was associated with the highest risk of poor outcomes and mortality.
Conclusions
In this secondary analysis of the FAST trial, acute myocardial injury was common and associated with poor outcomes. The direction of the cTnI change might provide additional risk stratification after intracerebral hemorrhage.
Keywords: cardiac complications, cardiac troponin, disability, hemorrhagic stroke, mortality
Subject Categories: Intracranial Hemorrhage
Nonstandard Abbreviations and Acronyms
- cTn
cardiac troponin
- FAST
Factor Seven for Acute Hemorrhagic Stroke
- ICH
intracerebral hemorrhage
- mRS
modified Rankin Scale
- NIHSS
National Institutes of Health Stroke Scale
- rFVIIa
recombinant activated factor VII
Clinical Perspective.
What Is New?
Our secondary analysis of the FAST (Factor‐Seven‐for‐Acute‐Hemorrhagic‐Stroke) trial shows that acute myocardial injury is common in patients with spontaneous intracerebral hemorrhage, and it is associated with poor outcomes and mortality.
Patients with a rising troponin pattern have higher odds of poor outcomes and mortality compared with those with a falling troponin pattern, whose odds are similar to patients without acute myocardial injury.
What Are the Clinical Implications?
Serial cardiac troponin measurements appear to be valuable for risk stratification in patients with spontaneous intracerebral hemorrhage.
Troponin that is rising between baseline and follow‐up measurements (rising pattern) carries a heightened risk of poor outcome and mortality and may be useful as a marker of unfavorable prognosis in patients with intracerebral hemorrhage.
There is a lack of established diagnostic and treatment strategies for patients with intracerebral hemorrhage who have acute myocardial injury, which requires case‐by‐case management strategies and merits further research.
Among major stroke subtypes, intracerebral hemorrhage (ICH) is associated with the highest disability burden and mortality, accounting for more than two‐thirds of all deaths in patients with stroke. 1 , 2 ICH volume, expansion, location, perihematomal edema volume, and presence of intraventricular hemorrhage are well‐studied factors influencing post‐ICH outcomes. 3 , 4 However, in‐hospital cardiac complications are also associated with increased in‐hospital mortality and longer hospital stay, but are understudied. 5 , 6 For the early detection of concomitant cardiac events, current American Heart Association/American Stroke Association ICH guidelines recommend measuring cardiac troponin (cTn), a biomarker of myocardial injury, in all patients presenting with ICH. 7 Elevated cTn is detected in up to 20% to 30% of patients with ICH and correlates with poor outcomes. 5 , 8 , 9 , 10 However, a single elevated cTn does not identify the timing of the myocardial injury. Serial cTn measurements are required to differentiate acute myocardial injury (elevated cTn with a rise or fall of >20% from baseline measurement), from chronic conditions. 11 , 12 While in patients with acute ischemic stroke, the presence of acute myocardial injury is associated with worse outcomes compared with patients with elevated but stable cTn values or normal cTn, 13 , 14 the prognostic role of acute myocardial injury in patients with ICH remains unclear.
We investigated whether acute myocardial injury is associated with unfavorable outcomes after ICH using prospectively collected data from the FAST (Factor Seven for Acute Hemorrhagic Stroke) trial, a randomized controlled trial where patients with spontaneous ICH were randomized to receive recombinant activated factor VII (rFVIIa) or placebo. 15 We hypothesized that the presence of acute myocardial injury would increase the odds of poor outcomes and mortality at 15 and 90 days, independent of treatment arm (high dose versus low dose rFVIIa versus placebo). In addition, we investigated whether the direction of the cTn change (rising versus falling) would affect mortality and outcomes post‐ICH.
Methods
Data Availability
Anonymized data from the FAST trial can be requested through the Virtual International Stroke Trials Archive (VISTA, www.virtualtrialsarchive.org).
Study Design and Participants
We performed a secondary observational analysis of FAST, a multicenter, randomized, double‐blind, placebo‐controlled trial of rFVIIa for the treatment of spontaneous ICH. 15 Patients presenting within 3 hours of symptom onset were enrolled and exclusion criteria are listed in Data S1. The study protocol mandated obtaining centrally measured cTnI levels for all enrolled patients. A total of 841 patients were enrolled at 122 sites across 22 countries from May 2005 to February 2007. Study participants were randomized to receive placebo, 20 or 80 μg/kg of rFVIIa intravenously within 4 hours of ICH onset. In our analysis, we excluded patients without serial cTn measurements or with missing data on our primary outcome measures (Figure 1).
Figure 1. Flowchart of patient selection.
FAST indicates Factor Seven for Acute Hemorrhagic Stroke trial; and ICH, intracerebral hemorrhage.
Institutional review board approval was obtained at each enrolling trial site. Written informed consent for trial participation was provided by each patient or their legally authorized representative. Because only de‐identified and publicly available data were used, our secondary analysis was exempt from additional local Institutional Review Board approval. Results were reported in adherence to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. 16
Clinical Assessments
Clinical assessments (National Institutes of Health Stroke Scale [NIHSS], and modified Rankin Scale [mRS]) were performed at the time of FAST trial enrollment, 24 hours after drug administration, on days 2, 3, and 15, of hospitalization (or at discharge if earlier), and on day 90 after the index ICH. By convention, hematoma expansion was defined as growth in hematoma volume by either ≥33% or by ≥6 mL comparing baseline to 24‐hour computed tomography brain scans. 17
Exposures: Types of Myocardial Injury
All patients included in our analysis had at least 2 centrally analyzed cTn‐I values, 1 obtained at the time of FAST trial enrollment, and at least 1 more at either 24 hours or at 48 hours after administration of the investigational product. Acute myocardial injury was defined as at least 1 cTnI value above the upper reference limit with a rise/fall of >20% on serial measurements (if >2 values were available, the difference between peak and trough levels were used), based on the 2018 Fourth Universal Definition of Myocardial Infarction. 12 If acute myocardial injury was identified, the direction of the change was classified as rising or falling. Patients were categorized in 2 ways. First, they were dichotomized based on presence or absence of acute myocardial injury. Second, they were categorized in 3 groups based on cTn patterns and since we hypothesized an ordered risk of association of cTn patterns and unfavorable outcomes, we ranked the cTn patterns as follows: (1) rising cTn pattern, having highest risk for unfavorable outcomes (identifying progressing acute myocardial injury); (2) falling cTn pattern, having intermediate risk (identifying nonsevere or resolving acute myocardial injury); (3) no acute myocardial injury, having lowest risk (identifying a chronic myocardial injury or no myocardial injury).
Outcomes
Outcomes of interest were poor functional outcome (defined as mRS 4–6) and mortality at 15 days and at 90 days. The mRS was assessed via in‐person follow‐up visit or by a structured telephone interview.
Statistical Analysis
Continuous variables were reported as mean and SD for normally distributed variables, and as median with interquartile range for skewed data. Categorical variables were presented as frequencies. No imputation was performed for missing data. When data were missing, we showed the denominator of the group with available data. In univariable analysis, patients with ICH with and without acute myocardial injury were compared using an independent sample t test for continuous normally distributed variables, Mann–Whitney U test for continuous non‐normally distributed or ordinal variables, and χ2 for categorical variables. Multivariable logistic regression tested for a potential association between acute myocardial injury (presence versus absence) and the clinical outcomes. Covariates in the regression models were selected a priori and included sex, age, medical history of chronic kidney disease, coronary artery disease, congestive heart failure, atrial fibrillation, FAST trial arm assignment, systolic blood pressure at admission, ICH volume at baseline, ICH location (lobar versus deep versus infratentorial), NIHSS, and mRS before the index ICH. To provide additional information on changes across the range of the mRS scale, generalized ordered logistic regression was conducted to estimate the association of acute myocardial injury and a shift toward increased disability at 15 and 90 days (higher category of mRS). Univariable analyses were also performed for 3 groups (rising versus falling versus no acute myocardial injury). Normally distributed continuous data were compared using 1‐way ANOVA; Kruskal–Wallis test was used for skewed continuous data and ordinal data. Categorical variables among the groups were compared using χ2 test. Logistic regression tested for associations among 3 groups (rising versus falling versus no acute myocardial injury) and outcomes. Given the small number of outcome events for mortality at 15 days, sensitivity analyses were performed including only 5 covariates for adjustment (sex, age, study arm groups, ICH volume at baseline, and NIHSS at admission) to avoid overfitting. In addition, a hierarchical analysis plan stipulated that if the main outcomes did not differ significantly among treatment groups, we would explore the relationship between acute myocardial injury and cTn patterns and main outcomes, stratified by trial arm, using logistic regression, and that these results would be reported without claims of statistical significance. Finally, multivariable logistic regression tested for association of cTnI peak (defined as the highest cTn value detected in serial measurements) with clinical outcomes.
P values <0.05 were considered significant. Statistical analyses were performed with STATA 17.0 (StataCorp, College Station, TX).
Results
Cohort Characteristics
Among 841 participants enrolled in FAST, we included 785 with serial cTnI measurements (mean [SD] age 66 (13) years, 291 [37%] women, median [interquartile range] NIHSS at admission 13 [8–18]) (Figure 1). Of these, 227 (29%) were found to have acute myocardial injury. Among those with acute myocardial injury, 170 (75%) had a rising cTnI pattern and 57 (25%) had a falling pattern. Three cTn‐I measurements were obtained in 701 patients, and 2 cTn‐I measurements in 84 patients (for 39 patients cTn‐I was collected at the time of enrollment and at 24 hours, for 20 patients at the time of enrollment and at 48 hours, and for 25 patients at 24 and 48 hours).
Patients with acute myocardial injury compared with those without myocardial injury more often had a history of congestive heart failure, a larger ICH volume at baseline, received the higher rFVIIa dose more frequently, and were on average 2 years older (Table 1). Baseline characteristics for patients categorized in 3 groups (rising versus falling versus no acute myocardial injury) are shown in Table S1.
Table 1.
Baseline characteristics
| Acute myocardial injury (n=227) | No acute myocardial injury (n=558) | P value | |
|---|---|---|---|
| Demographic | |||
| Mean age, y | 66±13 | 64±13 | 0.06 |
| Sex (female) | 78 (34%) | 213 (38%) | 0.31 |
| Comorbidities | |||
| Hypertension | 195/213 (92%) | 467/497 (94%) | 0.36 |
| Diabetes | 23/213 (11%) | 64/497 (13%) | 0.40 |
| Dyslipidemia | 60/213 (28%) | 154/497 (31%) | 0.45 |
| Smoking (prior/current) | 7/213 (3%) | 21/497 (4%) | 0.56 |
| Chronic kidney disease | 3/213 (1%) | 5/497 (1%) | 0.64 |
| Coronary artery disease | 16/213 (8%) | 23/497 (5%) | 0.12 |
| Chronic heart failure | 7/213 (3%) | 5/497 (1%) | 0.03 |
| Atrial fibrillation/flutter | 13/213 (6%) | 16/497 (3%) | 0.07 |
| mRS pre‐admission | 0 [0–0] | 0 [0–0] | 0.48 |
| Systolic blood pressure | 182±31 | 180±30 | 0.37 |
| Diastolic blood pressure | 98±21 | 99±20 | 0.40 |
| Mean arterial pr essure | 126±21 | 126±21 | 0.91 |
| Heart rate | 79±15 | 78±15 | 0.82 |
| NIHSS | 14 [9–18] | 13 [8–18] | 0.12 |
| ICH characteristics | |||
| ICH volume baseline, mL | 14 [7–39] | 13 [6–28] | 0.04 |
| Localization | |||
| Deep | 173/221 (78%) | 439/534 (82%) | |
| Lobar | 36/221 (16%) | 69/534 (13%) | |
| Infratentorial | 12/221 (6%) | 26/534 (5%) | 0.43 |
| ICH expansion at 24 h | 60/217 (28%) | 126/542 (23%) | 0.20 |
| Study arm groups | |||
| Placebo | 60 (27%) | 188 (34%) | |
| 20 μg/kg | 64 (28%) | 189 (34%) | |
| 80 μg/kg | 103 (45%) | 181 (32%) | <0.01 |
Categorical variables are presented as frequency (column percent), continuous variables are presented as mean±SD, or median and interquartile range when non‐normally distributed. mRS indicates modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; and ICH, intracerebral hemorrhage. Bold values are statistically significant P values (P < 0.05).
Myocardial Injury and Outcomes
Patients with acute myocardial injury compared with those without acute myocardial injury had consistently worse outcomes (Table 2); they showed less neurological improvement (measured as change in NIHSS score from baseline to follow‐up) at day 15 (2 versus 4, P <0.01) and day 90 (4 versus 6, P <0.01), they more frequently had poor outcome at 15 days (86% versus 74%, P <0.01) and at 90 days (61% versus 41%, P <0.01), and they had greater mortality at 15 days (23% versus 11%, P <0.01) and at 90 days (29% versus 16%, P <0.01). The length of hospital stay was similar among the groups.
Table 2.
Cardiac troponin I values and outcomes categorized by presence of acute myocardial injury
| Acute myocardial injury (n=227) | No acute myocardial injury (n=558) | P value | |
|---|---|---|---|
| Cardiac troponin I | |||
| First cTnI, median (ng/mL) | 0.05 [0.05–0.1] | 0.05 [0.05–0.05] | <0.01 |
| Second cTnI, median | 0.1 [0.05–0.1] | 0.05 [0.05–0.06] | <0.01 |
| Third cTnI, median | 0.2 [0.1–0.9] | 0.05 [0.05–0.1] | <0.01 |
| Rising cTnI pattern | 170 (75%) | ||
| Length of stay (d) | 15 [7–31] | 15 [8–31] | 0.29 |
| Day 15 | |||
| NIHSS | 10 [5–20] | 7 [3–14] | <0.01 |
| Change from baseline NIHSS | 2 [−3–5] | 4 [1–7] | <0.01 |
| mRS | 4 [4–5] | 4 [3–5] | <0.01 |
| Poor outcomes (mRS 4–6) | 195 (86%) | 411 (74%) | <0.01 |
| Mortality | 53 (23%) | 63 (11%) | <0.01 |
| Day 90 | |||
| NIHSS | 6 [2–19] | 4 [2–9] | <0.01 |
| Change from baseline NIHSS | 4 [0–8] | 6 [2–10] | <0.01 |
| mRS | 4 [3–6] | 3 [2–4] | <0.01 |
| Poor outcomes (mRS 4–6) | 138 (61%) | 229 (41%) | <0.01 |
| Mortality | 65 (29%) | 89 (16%) | <0.01 |
Categorical variables are presented as frequency (column percent), non‐normally distributed continuous variables are presented as median and interquartile range. cTnI indicates cardiac troponin I; mRS, modified Rankin Scale; and NIHSS, National Institutes of Health Stroke Scale. Bold values are statistically significant P values (P < 0.05).
In multivariable logistic regression, patients with acute myocardial injury compared with those without myocardial injury had greater odds of poor outcomes at 15 days (adjusted odds ratio [aOR] 2.3 [95% CI, 1.3–3.9] and at 90 days (aOR, 2.5 [95% CI, 1.6–3.9]), and higher odds of mortality at 15 days (aOR, 2.4 [95% CI, 1.4–4.3]) and at 90 days (aOR, 2.2 [95% CI, 1.3–3.6]) (Table 3). Sensitivity analysis with the restricted model showed similar results (Table S2). Shift analysis showed worse disability (higher mRS scores) at 15 days (aOR, 2.0 [95% CI, 1.5–2.8]) and at 90 days (aOR, 1.8 [95% CI, 1.3–2.5]) in those with acute myocardial injury (Figure 2). Similar associations between acute myocardial injury and the main outcomes were observed across the 3 FAST treatment arms, and no evidence of heterogeneity of treatment effect was observed (Table S3).
Table 3.
Unadjusted and adjusted logistic regression analysis of association of acute myocardial injury and main outcomes
| Predictor variable: acute myocardial injury | Model | OR | 95% CI | P value |
|---|---|---|---|---|
| Poor outcomes at 15 d | Unadjusted | 2.2 | 1.4–3.3 | <0.01 |
| Adjusted* | 2.3 | 1.3‐3.9 | <0.01 | |
| Mortality at 15 d | Unadjusted | 2.4 | 1.6–3.6 | <0.01 |
| Adjusted* | 2.4 | 1.4‐4.3 | <0.01 | |
| Poor outcomes at 90 d | Unadjusted | 2.2 | 1.6–3.0 | <0.01 |
| Adjusted* | 2.5 | 1.6‐3.9 | <0.01 | |
| Mortality at 90 d | Unadjusted | 2.1 | 1.5–3.0 | <0.01 |
| Adjusted* | 2.2 | 1.3‐3.6 | <0.01 |
Odds ratios (OR) and corresponding 95% CI for association of acute myocardial injury with poor outcomes (modified Rankin Scale 4–6) and mortality at 15 and 90 days. Bold values are statistically significant P values (P < 0.05).
Adjusted for sex, age, medical history of chronic kidney disease, coronary artery disease, congestive heart failure, atrial fibrillation, study arm groups, systolic blood pressure at admission, intracerebral hemorrhage (ICH) volume at baseline, ICH localization, National Institutes of Health Stroke Scale at admission, and modified Rankin Scale pre‐index ICH.
Figure 2. Generalized ordered logistic regression analysis for the association of acute myocardial injury and a shift toward increased disability at 15 and 90 days (higher category of modified Rankin Scale).
*Adjusted for sex, age, study arm, systolic blood pressure at admission, intracerebral hemorrhage (ICH) volume at baseline, ICH localization, National Institutes of Health Stroke Scale at admission. aOR indicates adjusted odds ratios; mRS indicates modified Rankin Scale; and OR, odds ratio.
Troponin Patterns and Outcomes
Univariable analyses for patients classified in 3 groups (rising versus falling versus no acute myocardial injury) are reported in Table S4. In multivariable logistic regression analysis (Table 4), a rising cTn pattern was associated with greater odds of poor outcomes at 15 days (rising cTn: aOR, 2.7 [95% CI, 1.3–5.2]; falling cTn: aOR, 1.7 [CI, 95%, 0.7–4.0]; no acute myocardial injury as reference) and at 90 days (rising cTn: aOR, 2.9 [95% CI, 1.8–4.8]; falling cTn: aOR, 1.5 [95% CI, 0.7–3.3]).
Table 4.
Association of cardiac troponin patterns with main outcomes
| Outcomes | Model | cTnI Patterns | OR | 95% CI | P value |
|---|---|---|---|---|---|
| Poor outcomes at 15 d | Adjusted* | No acute myocardial injury | 1 | Reference | |
| Falling | 1.7 | 0.7–4.0 | 0.25 | ||
| Rising | 2.7 | 1.3–5.2 | <0.01 | ||
| Mortality at 15 d | Adjusted* | No acute myocardial injury | 1 | Reference | |
| Falling | 1.2 | 0.4–3.4 | 0.79 | ||
| Rising | 3 | 1.6–5.7 | <0.01 | ||
| Poor outcomes at 90 d | Adjusted* | No acute myocardial injury | 1 | Reference | |
| Falling | 1.5 | 0.7–3.3 | 0.34 | ||
| Rising | 2.9 | 1.8–4.8 | <0.01 | ||
| Mortality at 90 d | Adjusted* | No acute myocardial injury | 1 | Reference | |
| Falling | 1.6 | 0.6–4.3 | 0.34 | ||
| Rising | 2.3 | 1.3–4.1 | <0.01 |
Odds ratios (OR) and corresponding 95% CI for association of cardiac troponin (cTn) patterns with poor outcomes (modified Rankin Scale [mRS] 4–6) and mortality at 15 and 90 days. Bold values are statistically significant P values (P < 0.05).
Adjusted for sex, age, medical history of chronic kidney disease, coronary artery disease, congestive heart failure, atrial fibrillation, study arm groups, systolic blood pressure at admission, intracerebral hemorrhage (ICH) volume at baseline, ICH localization, National Institutes of Health Stroke Scale at admission, and mRS pre‐index ICH.
Patients with rising cTn had the highest risk of mortality at 15 days (rising cTn: aOR, 3.0 [95% CI, 1.6–5.7]; falling cTn: aOR, 1.2 [95% CI, 0.4–3.4]); and at 90 days (rising cTn: aOR, 2.3 [95% CI, 1.3–4.1]; falling cTn: aOR, 1.6 [95% CI, 0.6–4.3]). Sensitivity analysis with the restricted model showed similar results (Table S5).
Subgroup analyses examining the FAST treatment arms separately showed similar odds ratios in the placebo group for rising cTn pattern and the main outcomes; as in the prior subgroup analysis (Table S3), no evidence of heterogeneity of treatment effect was observed (Table S6). No associations between cTnI peak values and clinical outcomes were observed (Table S7).
Discussion
In this secondary observational analysis using data from the FAST trial, we found that patients with ICH with acute myocardial injury had higher risks of poor outcomes and higher mortality at 15 and 90 days, compared with patients with ICH without acute cardiac injury. In addition, those with a rising cTn pattern had higher odds of poor outcomes and mortality compared with those with a falling cTn pattern, whose odds were similar to patients without acute myocardial injury.
In patients with ischemic stroke, elevated cTn levels, especially when a dynamic change is detected, are a known prognostic factor for poor outcomes and early mortality. 13 , 18 , 19 , 20 Similarly, in patients with ICH an independent association of elevated troponin at admission with in‐hospital mortality and increased disability has been reported. 5 , 8 , 21 , 22 However, the relationship between acute myocardial injury and cTnI trends with outcomes in patients with ICH remain unclear, because the available investigations have not analyzed serial cTn measurements. Furthermore, previous studies on the role of elevated troponin in ICH are single‐centered, retrospective, or contain small sample sizes. Our findings, obtained from a carefully adjusted prespecified post hoc analysis of data from a large, multicenter, prospective randomized trial, with centrally analyzed and serial cTnI measurements, contribute novel insights by elucidating the prognostic significance of cTnI patterns in patients with spontaneous ICH.
Acute myocardial injury, present in nearly one third of participants, was surprisingly common in the FAST cohort; and the exclusion of patients with thrombotic or occlusive vascular disease within the month before FAST enrollment (Data S1) suggests that this myocardial injury was not pre‐existing, albeit a past medical history of congestive heart failure was slightly more frequent in patients with acute myocardial injury. Consistent with a prior post hoc analysis of the FAST trial, showing that higher doses of rFVIIa were associated with a small increased risk of non‐life‐threatening cardiac events (non‐ST‐segment elevation myocardial infarction or isolated cTnI elevation), our study showed that patients with acute myocardial injury more frequently received the high dose of rFVIIa. 23 However, the frequency of life‐threatening cardiac complications, particularly ST‐segment elevation myocardial infarction, was overall low and similar between study arms (1%). 23 All of our analyses were adjusted by FAST treatment assignment, and there was no evidence of heterogeneity of treatment effect on our main outcomes, demonstrating that our main findings (the associations between acute myocardial injury and outcomes) were not confounded by the administration of rFVIIa.
Cardiology guidelines consider any dynamic cTn change >20%, regardless of its direction, as specific to acute myocardial injury. Among patients with signs or symptoms of ischemia consistent with coronary thrombosis, early revascularization improves outcomes. 12 The situation in patients with ICH and acute myocardial injury is different from patients with acute coronary syndrome as primary diagnosis, without concomitant brain injury. Decreased level of consciousness in ICH may limit the identification and assessment of cardiac symptoms. Invasive cardiac diagnostic and therapeutic procedures are frequently deferred because patients with ICH may be unstable, and the use of antithrombotic therapy for acute coronary syndrome is contraindicated. 7 Therefore, existing cardiology recommendations are not fully applicable to the ICH population, for which a tailored interpretation of troponin elevation and patterns for risk stratification and management is needed. While atherosclerotic mechanisms represent the main cause of acute myocardial injury and dynamic troponin elevation in patients presenting with acute coronary syndrome, 24 post‐ICH cardiac complications may include other pathophysiological mechanisms, such as brain–heart autonomic axis disruption. 25 To be sure, poorly controlled cardiovascular risk factors that led to the initial ICH may represent the major cause of acute myocardial injury after all, but this assumption will have to be tested in future studies. 26
With our findings, we suggest that the direction of the cTn change provides additional risk stratification in patients with ICH, because rising and falling patterns reflect different phases of myocardial injury. 27
Strengths of our study are the exclusion of patients with angina or myocardial infarction within 30 days before ICH onset (reducing the likelihood that our study detected acute myocardial injury that preceded the index ICH), the availability of centrally analyzed serial cTnI measurements, and the short ICH onset to admission and cTnI measurement time intervals.
However, our study also has important limitations. First, this is a secondary observational analysis of a randomized controlled trial that was powered to detect differences in outcomes among treatment groups, which increases the risk of type 1 error in post hoc analyses. In addition, the risk of false positive associations is also increased because no adjustment of the P value threshold for multiple comparisons was performed in our exploratory analysis. Second, the data made available to us did not include types and timing of thromboembolic serious adverse events that were collected in the original study. Therefore, we could not assess the association between different cTnI patterns and types or severity of cardiac events, nor could we identify acute noncardiac conditions (pulmonary embolism or deep vein thrombosis) that could have affected cTn levels. Cardiac testing results and causes of mortality were also not included in our data set. Third, because the time interval between serial cTnI measurements in the FAST trial is wide (first value was obtained at randomization and the following at 24 and/or 48 hours), we cannot exclude misclassification of troponin patterns, because the cTnI peak of some patients might have occurred between measurements and therefore was missed. Fourth, although there was no statistically significant difference in outcomes between patients with ICH with falling pattern and those without acute myocardial injury, the smaller sample size of the falling pattern group (n=57, 7% of the total cohort) limited statistical power. Fifth, detailed ICH localization was not available, and the association between specific areas involved in the control of the central autonomic network (such as insular cortex) with cTn patterns and outcomes could not be assessed. Moreover, high‐sensitivity cardiac troponin assays, now considered the criterion standard for the detection of myocardial injury, 28 were not available at the time of the FAST trial. Lastly, findings from interventional trial cohorts may not be generalizable to the larger “real world” ICH population.
Conclusions
In conclusion, acute myocardial injury was common in the FAST trial cohort consisting of patients with spontaneous ICH admitted and neuro‐imaged within 6 hours of symptom onset, and myocardial injury was associated with short‐ and longer‐term mortality and poor outcomes. An early rising cardiac troponin pattern was also associated with poor outcomes and may be useful as a marker of an unfavorable prognosis.
The role of high‐sensitivity cardiac troponin with possibly greater prognostic value than old troponin assays remains to be investigated in future studies in patients with ICH. In addition, characterization of types of cardiac events associated with different cTn patterns might be relevant for future diagnostic and therapeutic approaches.
Sources of Funding
None.
Disclosures
Dr. Scheitz has received speaker honoraria from Bristol‐Myers Squibb‐Pfizer, and AstraZeneca, outside the submitted work. Dr Mayer has received consulting fees from CSL Behring, AstraZeneca, and MaxQ AI and grant support from the NIH (IMSM) for the FASTEST trial (5U01NS110772–02). Dr. Kasner has received grant funding from Bayer, Bristol‐Myers Squibb, Genentech, Medtronic, and Diamedica (all paid to institution); consulting fees from AstraZeneca, NovoNordisk, and Medtronic; and royalties from UpToDate. Dr. Witsch has received grant funding from the American Heart Association (Career Development Award, https://doi.org/10.58275/AHA.23CDA1053561.pc.gr.168057), and has received fees for medicolegal consulting, and royalties from Springer Nature for editing a textbook on stroke. The remaining authors have no disclosures to report.
Supporting information
Data S1
Tables S1–S7
This manuscript was sent to Jose R. Romero, MD, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.124.035053
For Sources of Funding and Disclosures, see page 8.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1
Tables S1–S7
Data Availability Statement
Anonymized data from the FAST trial can be requested through the Virtual International Stroke Trials Archive (VISTA, www.virtualtrialsarchive.org).