Systematic Review of the Clinical Features of de Winter Syndrome and the Role of Thrombolytic Therapy in Resource-limited Settings

Despite significant efforts in prompt diagnosis and revascularisation, acute MI remains the leading cause of death worldwide.¹ With advances in cardiology and ever-evolving research, a range of ECGs do not present in the classic ST-segment elevation pattern, yet still indicate acute myocardial ischaemia that requires the same level of urgency for revascularisation.²

ST-elevation MI (STEMI) equivalents are less recognised by clinicians, mainly because of a lack of awareness of the ECG patterns, and the clinical features of these patients are not well-known, often resulting in delayed treatment and poorer clinical outcomes.³ A thorough understanding of the clinical features of patients is crucial for the prompt identification and management of STEMI equivalents. The de Winter sign is a type of STEMI-equivalent ECG pattern characterised by an upsloping ST-segment depression at the J-point in leads V1–V6 followed by a tall positive symmetrical T wave.⁴ It has a high predictive value for occlusion in the proximal left anterior descending artery and is associated with a high mortality rate.^4,5

Reducing the ischaemic time (from the onset of the symptoms to coronary reperfusion) in de Winter syndrome is associated with better clinical outcomes and a lower incidence of major adverse cardiovascular events.⁶ Currently, the international guidelines recommend a percutaneous coronary intervention (PCI) strategy for patients with clinical concerns of ongoing myocardial ischaemia with atypical ECG patterns. However, access to PCI continues to be a great challenge in some regions of the US and Europe. It is even more pronounced in low- to middle-income countries, where the availability of PCI is significantly limited.^7–11

Zubaid et al. demonstrated that a pharmacoinvasive strategy involving systemic thrombolytic therapy followed by early angiography and PCI had comparable outcomes in STEMI patients.¹² The role of systemic thrombolysis has been a long-standing issue for clinicians from non-PCI centres, and the lack of a systematic review of the existing evidence makes it more challenging.

Given the time-sensitive nature of de Winter syndrome and the potential for improved outcomes with early reperfusion, this is the first systematic review to thoroughly analyse and summarise patients’ clinical profiles from studies published worldwide, and to investigate the role of thrombolytic therapy in providing early reperfusion in the absence of PCI.

Methods

The study was conducted based on the Preferred Reporting Items for Systematic Review and Analysis Framework. The prespecified study protocol was registered in PROSPERO (CRD42022350346). Our main inclusion criteria were studies that reported on patients with de Winter syndrome who underwent emergent reperfusion therapy and reported on their clinical outcomes. We excluded overlapping/repetitive studies, literature reviews, non-English studies and patients aged <18 years. No restrictions were placed on the publication date, sample size or study design. We conducted a systematic search on PubMed, Embase, Scopus and Google Scholar up to July 2024. The authors applied medical search headings and open-text fields to search articles related to de Winter syndrome. The detailed search algorithm is presented in Supplementary Table 1.

The authors screened the references in two stages after removing duplicates. The authors initially reviewed the titles and abstracts, and removed those that did not meet the inclusion criteria. The authors then analysed the full text of the articles and excluded those that did not meet the inclusion criteria. All articles identified using our search strategy were screened by two authors (NP, HS), with any discrepancies adjudicated by a third author (FB). All relevant studies were merged into EndNote. We extracted the following information: patient demographics (i.e. sex and age), cardiovascular risk factors (i.e. diabetes, hypertension, smoking history, dyslipidaemia and previous heart disease), intervention (i.e. percutaneous coronary intervention, thrombolysis or conservative management) and clinical outcomes (i.e. any complications postreperfusion therapies, cardiac arrhythmias and mortality). A positive clinical outcome or successful revascularisation was defined as the resolution of the de Winter pattern on ECG, including the normalisation of upsloping ST-segment depression and tall, positive symmetrical T wave in leads V1–V6, accompanied by an improvement in chest pain.

The modified Newcastle–Ottawa scale was used to evaluate study quality. This tool evaluates the following five criteria. First, does the patient constitute all cases at the medical centre? Second, was the diagnosis accurately made? Third, were other diagnoses excluded? Fourth, were all important data provided in the report? Fifth, was the outcome correctly determined? Each question received a binary response. The quality of the report was determined as good (low risk of bias) when all five criteria were satisfied, moderate when four criteria were satisfied and poor (high risk of bias) when three or fewer criteria were fulfilled.

Descriptive statistics were used to calculate the frequency and percentage of the extracted data. Continuous data points are reported as the mean and SD, and categorical variables as percentages and numbers (n).

Results

In our systematic review, we initially identified 7,072 studies. Removal of duplicates and articles that did not match the topic of interest retrieved 251 studies. Among these, 38 studies were not in English, 35 studies could not be retrieved, and 47 did not meet our inclusion criteria and were therefore excluded. We included 131 studies to evaluate the clinical features of patients with de Winter syndrome. Among them, 17 studies were further assessed to determine the efficacy of thrombolytic therapy in de Winter syndrome (Figure 1). No randomised controlled trial was identified; among these 131 studies were three retrospective studies, two case series and 126 case reports. The studies included to assess the role of thrombolytic therapy were one retrospective study and 16 case reports (Supplementary Table 2).

Clinical Features of de Winter Syndrome

Overall, we included 131 studies, encompassing 191 patients. Patients presenting with de Winter pattern ECG were predominantly men (86%), with a mean age of 53 years. Most patients were from PCI centres (92%).

All patients presented to their healthcare facilities with chest pain. History of smoking was the most common cardiovascular risk factor, accounting for approximately 35%, followed by hypertension (19%), dyslipidaemia (13%), diabetes (12%) and previous heart disease (5%; Table 1). Upon admission, troponin I was elevated in 82 patients (43%) and normal in 16 patients (8%). Similarly, ejection fraction on echocardiography was reported to be ‘mildly reduced’ to ‘reduced’ in 32 patients (16%), whereas normal ejection fraction was reported for 31 patients (16%; Table 2).

Most patients underwent percutaneous coronary intervention (85%). For patients who underwent coronary angiogram, severe (>90% occlusion) to total occlusion was reported in 176 patients (93%). This study also sought to identify clinical predictors of complete coronary vessel occlusion. A higher prevalence of smoking, hypertension, dyslipidaemia and VF was observed among the patients. In addition, more patients with severe occlusion exhibited normal ejection fraction compared with those with total occlusion. The left anterior descending artery was the culprit vessel in most cases (73%), followed by multivessel (more than one vessel affected; 11%), left circumflex artery (3%) and left main coronary artery (3%). A total of 22 patients (11%) experienced cardiac arrhythmias during admission, with malignant ventricular arrhythmias accounting for approximately 9%, followed by supraventricular tachycardia (1%) and premature ventricular contractions (1%). Mortality during the same admission was reported in five patients (3%; Table 3).

Systemic Thrombolysis in de Winter Syndrome

A total of 17 studies (23 patients) were included to assess the efficacy of systemic thrombolytic therapy. Of the total number of patients in our study, 12% received systematic thrombolysis and 9% (n=17) received PCI after systematic thrombolysis. All patients presented with typical chest pain. The mean duration from symptom onset to thrombolysis was 3.07 hours. Most patients received intravenous streptokinase infusions (35%) followed by tenecteplase (22%), reteplase (17%) and prourokinase (9%; Table 4). Generally, the drug dosages administered were similar to those given for STEMI. A total of studies (19 patients) reported a degree of reperfusion after thrombolytic therapy (82%; Table 5). Failed thrombolysis was reported in four patients (17%). No major or minor bleeding or mortality events were reported in patients who underwent systemic thrombolysis. Three studies (three patients) reported reinfarction after successful reperfusion with systemic thrombolysis.^4,13,14 Table 6 shows the coronary angiography findings of patients who received thrombolytic therapy.

Discussion

Early revascularisation remains the cornerstone of successful management of patients with STEMI-equivalent ECGs. Despite being mentioned in the Fourth Universal Definition of MI as atypical acute myocardial ischaemia, and studies demonstrating that delay in prompt revascularisation in the de Winter pattern of ECG increases mortality risk, no consensus is currently available for patients who have no access to PCI.¹⁵ Furthermore, the lack of structured clinical profiling of these patients may further contribute to the underrecognition of this life-threatening ECG pattern, leading to poor clinical outcomes.

The mean age of patients with de Winter syndrome was much younger than the global mean age for STEMI (mean age of 55 years).¹⁶ This may represent a subgroup of patients with premature MI. Because of the different enteropathogenic and prognostic characteristics of coronary artery disease compared with older populations, these patients should also be examined for nontraditional risk factors, including genetic predisposition, in future studies. The most prevalent cardiovascular risk factor in our study was a history of smoking, followed by hypertension, dyslipidaemia and diabetes. These findings highlight the important role of classical cardiovascular risk factors in the development of atherosclerosis in these populations.¹⁷ Given that younger individuals are generally less aware of cardiovascular risk, younger cohorts are most likely to benefit from primary preventive care strategies.

Regarding cardiovascular outcomes, 9% of the patients with de Winter syndrome had malignant ventricular arrhythmia. This prevalence is similar to the rate of malignant ventricular arrhythmia reported in STEMI cases.¹⁸ The mechanism of arrhythmogenesis of these life-threatening arrhythmias in de Winter syndrome is similar to that of STEMI, in which the damaged myocardium produces a medium for re-entrant circuits. The mortality rate was 3%. We postulate that the rate may be underestimated, especially with limited clinical data from non-PCI centres. Coronary angiography revealed severe to total occlusion of at least one coronary vessel in 93% of cases, thereby reinforcing the high predictive value of acute ischaemia in patients with de Winter syndrome. The left anterior descending artery was the most commonly associated culprit vessel, which is similar to that reported in previous studies.⁴

Among the 11% of patients who received systemic thrombolytic therapy (mostly from non-PCI centres), 82% had successful reperfusion. The success rate of reperfusion was comparable to that of thrombolysis in STEMI reported by Lawi et al. in low- to middle-income countries.¹⁹ In addition to reinforcing that PCI is the first-line consideration for de Winter syndrome, this study hypothesises the potential advantages of thrombolytic therapy in facilitating early reperfusion in de Winter syndrome when PCI is inaccessible. Prospective studies are essential to establish the efficacy and safety of systemic thrombolysis as a pharmacoinvasive strategy for de Winter syndrome, and to verify clinical markers indicative of complete coronary occlusion.

Streptokinase, followed by tenecteplase, was commonly used as a thrombolytic agent in these patients. The vast cost difference compared with tenecteplase, which is threefold more expensive than streptokinase, may have been a concern for physicians when deciding on the thrombolytic agent. Except for three studies reporting reinfarction in a patient post-thrombolysis after successful reperfusion, no incidents of major or minor haemorrhage or hypersensitivity reactions were reported. From further analysis of studies reporting failed thrombolysis, we postulate that it may have resulted from a longer door-to-needle time. This delay may be partly attributed to the failure to recognise the life-threatening ECG pattern and the uncertainty regarding the use of thrombolysis in de Winter syndrome. Given the huge burden of cardiovascular disease in low- to middle-income countries with limited access to PCI, this study hypothesises that, in the absence of contraindications, systemic thrombolytic therapy may offer a valuable means of timely reperfusion for patients with de Winter syndrome who arrive in non-PCI hospitals with limited access to PCI.

We acknowledge that the sample size and potential publication bias in case reports and case series were the main challenges in this study. We have attempted to mitigate biases by ensuring a structured approach that ensures that high-quality relevant case reports are included to ensure the reliability of the conclusions. In addition, we developed a well-defined methodology to ensure reproducibility and minimise bias in the review process. De Winter syndrome is an inadequately acknowledged variant of acute MI, and high-quality evidence, such as randomised controlled trials and large cohort studies, may be impractical due to difficulties in recruiting sufficient patients. The limited availability of data made a metanalysis unfeasible. However, the study showed that >80% of patients who received systemic thrombolysis experienced clinical improvement and resolution of ECG changes, suggesting a promising degree of early reperfusion with systemic thrombolytic therapy. This should not be underestimated, particularly if it can reduce cardiovascular morbidity and mortality in patients with acute MI when the preferred treatment options are unavailable.

Although our study will not be able to show direct causal effects because of low-level evidence, we believe that this systematic review can fill the current knowledge gap by providing a comprehensive overview of the clinical features, potential treatments and outcomes that individual reports may not capture. Systematic reviews of case reports have been proven to be valuable in documenting clinical features and treatment outcomes for uncommon diseases to reduce disease mortality and morbidity.^20–23 Given the lack of consensus for non-PCI hospitals, we believe this systematic review can provide clinicians with actionable insights to make more informed decisions that may impact patient care. This study can serve as a valuable foundation for future clinical trials to evaluate the safety and efficacy of the intervention. It also highlights the need to establish an international registry to record the cases of de Winter syndrome and support patient recruitment for future research.

Conclusion

We believe that this is the first systematic review to provide a comprehensive overview of the clinical features of patients with de Winter syndrome and the role of thrombolytic therapy by including all available evidence with a focus on the most recent publications. It is of paramount importance for physicians to recognise this STEMI-equivalent cardiology emergency and promptly deliver appropriate revascularisation strategies. This study generates an important hypothesis regarding the role of thrombolytic therapy in de Winter syndrome when timely access to PCI is not feasible, suggesting that it may achieve a certain degree of early reperfusion. This hypothesis requires further verification in randomised clinical trials.

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