Cardiovascular disease remains the most common cause of death in Europe, and is responsible for double the number of cancer-related deaths.1,2 Ischemic heart disease is the most common cause of death globally and in Europe and, although its incidence is decreasing in Europe, it is still growing worldwide.1–3 Similarly, although the incidence of ST-elevation myocardial infarction (STEMI) is falling, the incidence of non-ST-elevation myocardial infarction is rising.4,5 The diagnosis of myocardial infarction (MI) is based on evidence of necrosis of cardiac myocytes due to ischemia, specifically an increase in cardiac troponin level above the 99th percentile.6,7 Patients with STEMI can be treated using fibrinolysis or percutaneous coronary intervention (PCI), the latter being the method of choice.8,9 Regardless of reperfusion method, the main objective in STEMI is to minimize total ischemia time, which is defined as the time between symptom onset and the initiation of treatment. Current guidelines from the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) recommend that this time should be less than 120 min, and set targets of 90 min and 30 min for the time between first medical contact and reperfusion through PCI and fibrinolysis, respectively.7,10

The hospital network in Portugal, as in most countries, includes hospitals both with and without catheterization laboratories. Thus, patients with STEMI who are to be treated by PCI have to be screened and transported to centers with appropriate facilities.11 Several European clinical trials have shown that timely inter-hospital transfer for primary PCI is feasible and associated with lower mortality compared to fibrinolytic therapy.12,13 A critical factor in the inter-hospital transfer process is the time taken for hospitals without PCI facilities to refer patients with STEMI to centers capable of performing PCI. This parameter, called door in-door out (DIDO) time, is defined as the time from arrival to discharge at the first hospital.

DIDO time is increasingly considered an important measure in efforts to accelerate reperfusion. The ESC and ACC/AHA guidelines recommend that it should ideally be less than 30 min.7,14 Despite its importance, this parameter is still little studied. The relevance of patient characteristics and their relationship with DIDO time, as well as its effect on treatment and subsequent outcomes, are still uncertain.14 In a study of 14821 STEMI patients from several hospitals in the USA who were transferred to other centers for PCI, Wang et al. concluded that the majority did not achieve the target for DIDO time and that the shorter the time, the lower the adjusted mortality risk, thus demonstrating the importance of this parameter.15

This study aims to assess the DIDO time of hospitals transferring STEMI patients to a referral center for PCI, in addition to exploring the association of delays in reperfusion with morbidity and mortality in this population.

This was an observational, retrospective and analytical study based on a convenience sample consisting of patients with STEMI who underwent PCI in a cardiology department between January 1, 2013 and June 30, 2017 (n=1140), thus obtaining a minimum follow-up time of one year. Data were collected from the intervention cardiology database of the reference center.

From the initial set of patients, only those who had been transferred from other hospitals were selected. Those for whom not all data of interest for the study could be obtained, particularly DIDO time, those in whom the succession of events was imprecise or contradictory, those who underwent PCI after stabilization, those who received fibrinolytic therapy in the first hospital and those who with symptoms for longer than 12 hours, were excluded. A sample of 523 patients was thus obtained from the initial set of 832 transferred patients.

Patients included in the study population were classified according to DIDO time. Wang et al.,15 investigating the same parameter, chose to divide patients into two groups: those in whom DIDO time was ≤30 min, and those in whom it was >30 min. Since Wang et al.’s study was our reference, we initially intended to adopt the same method, however, this was not feasible. After the sample was collected, it was found that if this value was used to separate the patients, the sizes of the groups would be very different, thus compromising the statistical power of this work. Specifically, the group with DIDO time ≤30 min contained only seven individuals, while the other group contained 516. It was thus decided to divide the sample using 60 min as cutoff, thus obtaining two groups: estimated DIDO ≤60 min, n=129; and estimated DIDO >60 min, n=394.

Statistical analysis

The statistical analysis was performed using IBM SPSS Statistics®, version 23, for Windows. A significance level of 5% was established, with p-values ≤0.05 being considered statistically significant.

For the descriptive analysis of categorical variables, the frequency distribution and percentages were calculated. Continuous variables were described as means and standard deviation (SD). Medians and interquartile range (IQR) were used for the variable DIDO time since its distribution was highly asymmetrical.

The two groups, DIDO time ≤60 min and >60 min, were compared using the t test for independent samples, and the assumption of homogeneity of variances was assessed with Levene's test.23 Cohen's D (d) was calculated as an effect size measure, and the values 0.20, 0.50 and 0.80 were considered to represent a small, medium and large difference, respectively.22–27

The chi-square test or Fisher's exact test was used for qualitative variables.28 The effect size was calculated using phi (Φ) when the variables under analysis were dichotomous and Cramer's V (V) when at least one of the variables had more than two categories, and the values 0.10, 0.30 and 0.50 were considered to represent a small, medium and large effect size, respectively.27

A binary logistic regression analysis was performed to analyze predictors of in-hospital mortality. In the first phase, 14 predictors (including the variable under study, DIDO time) were included in the model, which were selected according to a previously validated mortality model that included age, gender, body mass index (BMI), diabetes, hypertension, dyslipidemia, smoking, previous MI, previous PCI, previous coronary artery bypass grafting (CABG), previous HF, previous stroke, dialysis and peripheral arterial disease (PAD).29 Considering the number of in-hospital deaths in the sample, the number of predictors of the model was reduced and the variables BMI, diabetes, hypertension, dyslipidemia, smoking, previous MI, previous PCI, previous CABG, previous HF and previous stroke were excluded, since they did not contribute significantly to the model. Thus, the most parsimonious possible predictive model was obtained.30 The assumptions for performing this analysis were tested, specifically the absence of multilinearity and the existence of outliers that could influence the regression model.

In terms of survival, Kaplan-Meier analysis was performed for mortality according to estimated DIDO time, obtaining two survival curves.

The Z-score of proportions was calculated to compare mortality up to the end of follow-up between the two study groups (Figure 1).

Figure 1.

Schematic representation of the study design. DIDO: door in-door out; PCI: percutaneous coronary intervention; STEMI: ST-elevation myocardial infarction.

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Among the 523 patients with STEMI transferred for primary PCI, the median DIDO time was 82 min (IQR 61–132 min). As shown in Figure 2, only seven patients (1.3%) were transferred in 30 min or less, thus achieving the recommended time. By contrast, 75.3% were transferred in more than 60 min and 42.1% in more than 90 min.

Figure 2.

Distribution of door in-door out time in the 523 patients with ST-elevation myocardial infarction transferred for primary percutaneous coronary intervention.

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The results of the descriptive study of estimated DIDO time for the two groups are summarized in Tables 1–4.

The demographic data and timings (Table 1) showed a predominance of male patients in both groups. In the ≤60 min group age ranged between 34 and 90 years (mean 59.3 years, SD 12) and in the >60 min group between 30 and 92 years (mean 61.5 years, SD 13.5). Statistically significant differences were found between the two groups in total ischemia time, with a mean of 222 min in the ≤60 min group and 344.2 min in the >60 min group [t(310.20)=−8.93, p<0.001, d=2.17], and in system delay, with shorter system delay in the ≤60 min group (mean 118.7 min, SD 31.6) compared to the >60 min group (mean 207.3 min, SD 121) [t (506.42)=−14.12, p<0.001, d=3.95].

Regarding medical history (Table 2), patients with estimated DIDO time ≤60 min were more likely to have a history of smoking [chi-square (2)=6.79, p=0.034, Φc=0.12] compared to the >60 min group. In contrast, the >60 min group were more likely to have hypertension [chi-square (1)=5.08, p=0.024, Φ=0.10]. No statistically significant differences were found between the groups regarding chronic kidney disease, chronic HF, transient ischemic attack/stroke, valvular disease, PAD, coronary heart disease, CABG, previous MI, previous PCI, diabetes or hypercholesterolemia.

Regarding complications associated with the event and the intervention, there were no statistically significant differences in any variables (Table 3).

In-hospital mortality was 0% in the ≤60 min group and 5.1% in the >60 min group, a statistically significant difference [chi-square (1)=6.81, p=0.006, Φ=0.11]. The groups did not differ significantly in relation to the other follow-up variables (Table 4).

Survival analysis

Kaplan-Meier analysis (Figure 3) produced a log-rank p-value of 0.011, so the differences in survival time between the two groups were statistically significant.

Figure 3.

Kaplan-Meier curves for the survival of patients with ST-elevation myocardial infarction according to door in-door out time.

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In addition to the differences in survival time, it was also observed that by the end of follow-up, the >60 min group presented higher mortality than the ≤60 min group, and these results were also statistically significant (Z=−2.41, p=0.016).

Patients with STEMI transferred for PCI often have delayed reperfusion and only a minority meet the target of 90 min or less for the time between first medical contact and PCI.31,32 Included in this timeline is DIDO time, an important parameter that if targets are achieved can reduce delays in reperfusion, besides being an indicator of the quality of referral in the first hospital. In this study, it was found that only 1.3% of the 523 patients included met the recommended time of 30 min or less.7 Additionally, 42.1% took more than 90 min to transfer, thus making the 90 min target for first medical contact to PCI impossible to reach. It was also found that patients with DIDO times >60 min had significantly longer system delays (207.3 min vs. 112.7 min) than patients with DIDO times ≤60 min. The 2011 retrospective study by Wang et al., which included 14821 STEMI patients from several hospitals in the USA transferred for primary PCI, revealed that 11% of patients met the predicted mark of 30 min or less in relation to DIDO time, and, similarly to this study, came to the conclusion that patients with DIDO times longer than 30 min had significantly longer system delays than those with times ≤30 min (median 127 min vs. 85 min; p<0.001).15 It is important to note that the authors of the above-mentioned article used a DIDO time of 30 min to separate patients into two groups, in contrast to the 60-minute cutoff used in our study.

The main objective of these targets is to obtain the shortest possible total ischemia time. Several studies have established a direct relationship between total ischemia time and the severity of myocardial injury and associated mortality, on the principle that “time is muscle”.33–35 In our study, patients in the >60 min group had significantly longer total ischemia times (344.2 min vs. 222 min) than patients who had DIDO times ≤60 min. The study also demonstrated a significantly increased risk of in-hospital mortality in patients in the >60 min group. This risk was maintained after variables that influence mortality in MI were included in the regression model. Similarly, Wang et al. found that in-hospital mortality was significantly higher in patients with DIDO times >30 min (5.9%) than in those with times ≤30 min (2.7%; p<0.001). After construction of a predictive model of in-hospital mortality, the influence of the variable under study remained (adjusted odds ratio 1.56, 95% CI 1.15–2.12).15 In addition to DIDO time, the regression model in our study demonstrated that age and PAD also increased the probability of in-hospital death, and were thus factors constituting to a poor prognosis, results corroborated by the literature.36,37

Regarding the survival analysis, Kaplan-Meier curves showed statistically significant differences, demonstrating that patients who were transferred in >60 min had shorter survival than those who were transferred in ≤60 min. In addition to the differences in survival time, it was also observed that by the end of follow-up, the >60 min group presented higher mortality than the ≤60 min group. To the best of our knowledge, this is the first study to explore the influence of DIDO time on the survival of patients with MI.

The recommended strategy for ensuring timely reperfusion is to promote people's awareness of the common symptoms of MI and to encourage prompt use of the emergency medical system. Emergency medical vehicles play a critical role in the initial management of patients with STEMI.38 If patients go to hospitals without PCI facilities, there should be mechanisms for rapidly addressing and screening patients with chest pain and for performing an immediate evacuation protocol when a diagnosis of STEMI is confirmed. During the lifetime of the Stent for Life initiative in Portugal, there were positive changes in patient delay indicators, especially a lower proportion of patients who attended non-PCI centers, but system delay did not change significantly over this period.39 It therefore remains essential for decision-makers and public health authorities to implement public health policies to monitor and alert health professionals to the need for early identification and referral of STEMI patients, similarly to the smoking ban in 2008, the salt reduction regulation in 2010 and the coronary fast track for acute coronary syndromes in 2007.40

The current ESC guidelines for the management of STEMI recommend that if the time to PCI is greater than 120 min, fibrinolysis should be used.7

When analyzing this study, it is important to consider its limitations. Because of its retrospective nature, it was not possible to ensure that the number of omitted cases in the statistical analysis of some variables was low. Second, due to the inaccurate recording of the time patients left the first hospital, the DIDO time had to be estimated, and thus does not necessarily correspond to the actual value. It is essential that in the future, hospitals record the entry and exit of patients with STEMI methodically and accurately, and that they use these records for periodic reviews targeting DIDO time.

DIDO time is considered an important parameter in the reperfusion of patients with STEMI who require inter-hospital transfer to undergo PCI.

This study demonstrated that DIDO times ≤60 min were associated with shorter reperfusion delays, lower adjusted in-hospital mortality, and longer survival times compared to patients who were transferred in >60 min. Additionally, it was found that most patients transferred did not meet the recommended 30-min target.

In view of these results, it is important to carry out future studies on hospitals without PCI facilities aiming to identify factors that contribute to non-compliance with targets established for DIDO time and, according to the findings of such studies, to implement appropriate interventions.

The authors have no conflicts of interest to declare.