Cardiac troponins predict mortality and cardiovascular outcomes in patients with peripheral artery disease: A systematic review and meta‐analysis of adjusted observational studies

Abstract Background A significant proportion of patients (pts) with peripheral artery disease (PAD) have concomitant coronary artery disease and polyvascular involvement contributes to increased risk of death and unfavorable cardiovascular events. Hypothesis Cardiac troponins are associated with adverse cardiovascular outcomes in PAD pts. Methods We systematically searched Medline and Scopus to identify all observational cohort studies published before June 2021 (combining terms “troponin,” “peripheral artery disease,” “peripheral arterial disease,” “intermittent claudication,” and “critical limb ischemia”) that evaluated the prognostic impact of troponin rise on admission on all‐cause mortality and/or major cardiovascular events (MACEs; composite of myocardial infarction, stroke, and cardiovascular death) in PAD pts followed up at least 6 months. A meta‐analysis was conducted using the generic inverse variance method. Heterogeneity between studies was investigated using Cochrane's Q test and I 2 statistic. Results Eight studies were included in the final analysis (5313 pts) with a median follow‐up of 27 months (interquartile range: 12–59 months). The prevalence of troponin positivity was 5.3% (range: 4.4%–8.7%) in pts with intermittent claudication, and 62.6% (range: 33.6%–85%) in critical limb ischemia. Elevated troponins were significantly associated with an increased risk of all‐cause mortality (hazard ratio [HR]: 2.85, 95% confidence interval [CI]: 2.28–3.57; I 2 = 50.97%), and MACE (HR: 2.58, 95% CI: 2.04–3.26; I 2 = 4.00%) without publication bias (p = .24 and p = .10, respectively). Conclusion Troponin rise on admission is associated with adverse long‐term cardiovascular outcomes in symptomatic PAD.


| Search strategy
This meta-analysis was performed in accordance with the PRISMA statement. 7 We performed a systematic literature search of Medline and Scopus for all studies published before June 2021 without language restriction, using the following medical subject headings: "troponin," "peripheral artery disease," "peripheral arterial disease," "intermittent claudication," and "critical limb ischemia." Additional studies were identified by manual search of references of original studies or review studies.
Ethical approval or patient consent were not required because this study retrieved and synthesized data from already published studies.

| Study inclusion and outcomes
We included observational cohort studies that evaluated the prog-

| Data extraction and quality assessment
Study selection and data extraction were conducted independently by two investigators (M. V. and A. V. P.). Any disagreements or differences in the data extraction between the two authors were harmonized by consensus after rechecking the source data. Study quality was assessed using the validated Newcastle-Ottawa Scale for assessment of nonrandomized and observational studies, and studies were evaluated based on subject selection, comparability of study groups, and assessment of the outcome. 8 Risk of bias was evaluated for each study according to the ROBINS-I tool. 9 Completed database contained the following data: name of the first author, year of publication, country of origin, the total number of patients in each study, mean age of a population, the percentage of males, study design, troponin cutoff value and diagnostic assay, percentage of patients with elevated troponin levels, the proportion of patients with hypertension, diabetes, CAD, and CLI, the use of antiplatelet drugs and statins, the percentage of patients who died and experienced MACE, the follow-up period, adjusted hazard ratios (HRs), and confounding factors. Heterogeneity between studies was investigated using the Cochrane's Q test and I 2 statistic. Statistically significant heterogeneity was considered present at p < .10 and I 2 > 50%. Sensitivity analyses were performed by excluding studies one at a time to test the contribution of each study to the pooled estimates. Publication bias was assessed graphically using a funnel plot. Analyses were conducted using MedCalc Statistical Software version 20.011.

| Selected studies and baseline characteristics
Overall, 91 documents were initially identified from electronic search.

Multivariate statistical analysis was performed in all the studies.
Studies reported variable rates of increased troponin levels, ranging from 4.4% in claudicants up to 85% in patients with CLI. In a subgroup of patients with intermittent claudication the overall prevalence of troponin positivity was 5.3% (range: 4.4%-8.7%), while 62.6% (range: 33.6%-85%) of CLI patients had elevated troponin levels.

| Quantitative data synthesis
In pooled analysis, there was a significant association between elevated troponin levels and all-cause mortality (HR: 2.85, 95% con-  Figure 2B). Sensitivity analyses revealed that one study 15 had a significant impact on between-study heterogeneity ( Table 2). Only one study investigated the amputation risk according to troponin increased level. 14 Peripheral vascular patients with elevated troponins had an increased rate of amputation compared to those with normal values (adjusted HR: 3.71, 95% CI: 1.33-10.3).

| DISCUSSION
The prognostic role of cardiac troponin, a well-established biomarker in daily cardiology practice was not comprehensively studied in symptomatic PAD. According to our meta-analysis that included more than five thousand PAD patients, elevated troponins on admission were associated with an increased risk of all-cause mortality and major adverse cardiovascular events during a follow-up period of more than 2 years. In addition, troponin positivity was more frequently detected in patients with CLI compared to those with intermittent claudication.
Due to the systemic nature of atherosclerosis, multisite artery disease is common in patients with PAD and is associated with worse clinical outcomes. 3 However, screening for other sites of   Among patients with PAD in our meta-analysis the overall prevalence of CAD was 57%, what is in accordance with the previous epidemiological data. 2 In the vast majority of studies (seven out of eight) the effect estimates of Cox regression analyses were adjusted for CAD as a confounding variable. Also, in five out of eight studies recent acute coronary syndrome before enrollment or other acute cardiac diseases that may cause an increase of cardiac troponins were clearly indicated as exclusion criteria. 11,13,14,16,17 In addition, risk of bias was evaluated for each study according to ROBINS-I tool that included bias due to confounding. Two studies included in our systematic review reported receiver operating characteristic analysis for optimal cardiac troponin cutoff values in predicting adverse outcomes. In a study of patients with CLI Cimaglia et al. 17 reported cardiac troponin cutoff of >40 ng/L for the prediction of MACE and >42 ng/L for all-cause mortality. Clemens et al. 15 in a population of claudicants identified the optimal troponin cutoff value of 9 ng/L for the prediction of mortality. In the West of Scotland Coronary Prevention Study with a follow-up of 15 years, high concentrations of cardiac troponins (≥5.2 ng/L) were associated with an increased risk of coronary heart disease and cardiovascular death in middle-aged hypercholesterolemic men without a history of myocardial infarction. 24 Of note, cardiac troponin concentrations were reduced by statin treatment and those reductions were associated with better outcomes independent of LDL cholesterol lowering. In our meta-analysis, overall 80% of PAD patients were on statin therapy. The oldest study that was included in our meta-analysis 11 reported the lowest use of statins (26%). However, Spark et al. 11 in their study adjusted for statin treatment (among other confounders) in the multivariate analysis of factors predicting adverse outcomes. Unfortunately, patients with PAD still receive suboptimal medical therapy (including statins) when compared to patients with CAD. This may be due to the clinical inertia, atypical symptoms of PAD, or a focus on limb-related rather than cardiovascular outcomes. The recent guidelines recommend statin therapy for all patients with PAD on the basis of reduced cardiovascular morbidity and mortality (Class 1 recommendation). 2 Moreover, a recent meta-analysis with 138 060 PAD patients (35% were treated with statins) showed that statin treatment reduced major adverse limb events by 30% and amputations by 35%. 25

| CONCLUSION
Troponin positivity is common in symptomatic PAD patients, especially in those with CLI. Elevated cardiac troponins on admission are independently associated with an increased risk of MACEs and allcause mortality in symptomatic peripheral vascular disease during a long-term follow-up.

SUPPORTING INFORMATION
Additional supporting information may be found in the online version of the article at the publisher's website.