Cardiovascular disease (CVD) is the leading cause of death worldwide.1 According to the World Health Organization, 17.7 million people died from CVD in 2015, representing 31 % of overall global mortality, of whom 7.4 million died directly from coronary disease.2 In Europe, CVD is responsible for 3.9 million deaths each year; it is estimated that one in six men, and one in seven women, will die from myocardial infarction (MI).3,4 In Portugal, mortality from CVD has fallen over the years, but it remains the leading cause of death, accounting for 29.7 % of overall mortality in 2015.5

Ischemic heart disease has the highest mortality of all CVD,1 particularly ST-elevation myocardial infarction (STEMI), in both the acute phase and in follow-up. Among the available therapeutic options for this condition, primary percutaneous coronary intervention (PCI) has been shown to be more effective than thrombolysis in reducing mortality and adverse cardiac events, as well as being safer, as it is less likely to be associated with severe bleeding complications.

Whichever method of coronary reperfusion is chosen, it should be performed as rapidly as possible. The patient’s prognosis depends on the extent of infarction, which in turn depends on the time from symptom onset to reperfusion of the myocardial tissue.6 Rapid restoration of coronary flow reduces infarct size and reduces morbidity and mortality.7

Most hospitals in Portugal do not possess a catheterization laboratory, and thus patients with STEMI must be transferred to a referral hospital with this facility. The impact on prognosis in STEMI of delays associated with interhospital transfer has been the subject of considerable research in Europe and efforts have been made to reduce these delays.8,9 Development of clearly defined regional protocols has helped to increase the proportion of patients treated within the specified time windows.10,11 Nevertheless, if a patient goes to a center without a catheterization laboratory and is then transferred to a PCI-capable hospital, reperfusion can be significantly delayed,12,13 which can increase morbidity and mortality. Ideally, all STEMI patients should be taken by the emergency medical services to a hospital capable of performing PCI immediately. However, in practice, many patients travel by their own means to a hospital without a catheterization laboratory, thereby delaying initiation of treatment that is known to reduce mortality.12,13

The aim of this study is to compare treatment delay in patients with STEMI undergoing interhospital transfer and in those admitted directly to Hospital de Braga, and to assess its impact on mortality, in order to obtain data on which to base discussion and development of measures to improve prognosis of STEMI patients in the Minho region of Portugal.

The results obtained in the present study for the two components of total ischemic time (symptom onset-FMC and FMC-reperfusion) can be considered to be generally acceptable. Although significant differences do exist, patients in both groups were prompt in seeking assistance from the health system following symptom onset, with a median delay of 76.5min (40.3–150) in the direct admission group and 91.0min (50–180) in the interhospital transfer group (Figure 2A). However, these medians cannot conceal the fact that a significant proportion of patients are unacceptably late in contacting the health services, with times in the last quartile of 150 and 180min, respectively, in the direct admission and interhospital transfer groups. There is an urgent need to improve this situation, potentially through large-scale ongoing public information campaigns aiming to alert the general population to the symptoms of MI and to the actions that should be taken when it occurs.8,24

Regarding FMC-reperfusion time, the direct admission group presented good results, with a median of 87.5min (69.0–114), and 78.8 % of patients being treated within the maximum time recommended by the guidelines (120min). By contrast, in the interhospital transfer group, the median FMC-reperfusion time was 145min (115–199), and only 30.9 % were treated within the recommended 120min (Figure 2B), a modest result compared to the direct admission group. However, considering all the logistical difficulties involved in transferring a patient with STEMI, an additional 56.5min can be taken to be acceptable, especially when compared to results from other series.7,25,26–28 There are, nevertheless, several aspects that could be improved. Efforts to reduce system delays for STEMI patients should focus on two points. Firstly, FMC-reperfusion time could be reducing through faster diagnosis of STEMI, with an electrocardiogram performed by a cardiopulmonary technician associated with assessment by the Manchester triage system in all patients with chest or abdominal pain.29 Secondly, patient transfer protocols should be established in centers without PCI facilities that include immediate availability of ambulances (either local or belonging to the national emergency medical services), staffed by a physician and a nurse, that can safely and rapidly transport the patient directly to the catheterization laboratory, avoiding the delays that currently occur due to the need to wait for an ambulance, lack of availability of emergency medical staff, and other factors.10 In addition, the above-mentioned public campaigns should educate the population that when the signs and symptoms of MI are detected, they should call the national emergency number immediately, thereby bypassing centers without PCI capability. This would lead to considerable gains in terms of reducing ischemic time.8,24

Adding the time taken to transport patients between hospitals to total ischemic time would be expected to result in increased mortality in these patients. However, one-year mortality was no higher in the interhospital transfer group in our population, with no statistically significant difference between the groups (11.7 % vs. 9.2 %, p=0.193). In our opinion, the main reason for this is the marked differences between the groups in terms of Killip class IV at admission, which was almost twice as frequent in the direct admission group as in the interhospital transfer group (5.8 % vs. 3.2 %, p=0.049) (Table 1). This finding is unexpected, given that the baseline characteristics of the two groups did not differ significantly. It is possible, although we have no specific evidence to support the idea, that the difference in Killip class may have been due to a subgroup of patients with severe STEMI who were first attended in centers without PCI capability, developed cardiogenic shock and died before or during transfer to the catheterization laboratory. Since these patients would not have been included in our analysis, they may have constituted a source of positive selection bias in the interhospital transfer group, leading to underestimation of the prevalence of Killip class IV and mortality in this group.

Support for this idea comes from the multivariate analysis (Table 3), which shows that the strongest predictor of one-year mortality was in fact Killip class IV at admission (HR 11.2, 95 % CI 6.35–19.8, p<0.001). Another predictor was age, and although there was no significant difference in overall age between the two groups, in the subgroup aged ≥75 years there were significantly more older patients in the direct admission group (Table 1). This could also help explain the absence of difference in one-year mortality between the groups.

Treatment delays in STEMI patients and their effect on mortality have been the subject of much analysis by a range of research groups and PCI programs, with conflicting results.10,11,25 Although the concept that ‘time is muscle’ is important, and current guidelines strongly recommend that FMC-reperfusion time should be kept below 120min, primary PCI after this time has undoubted benefits.29–32 Furthermore, data from high-volume primary angioplasty centers with well-organized patient transfer systems tend to show that the additional delay caused by interhospital transfer has a limited effect on patient prognosis.33 Since the referring hospitals in the Minho region are all close to Hospital de Braga and its catheterization laboratory, and are all linked by fast road networks, delays due to interhospital transfer in this case are likely to be less than in other regions, with correspondingly less impact on one-year mortality. Analysis of the graphic showing the relationship between FMC-reperfusion time and one-year mortality (Figure 4) supports this idea; mortality increased only slightly for the first 210min, and then more sharply thereafter. It can thus be assumed that the additional time required for interhospital transfer has little impact on patients who do in fact arrive at the catheterization laboratory and undergo primary PCI (<0.5 % difference in one-year mortality).

Analysis of the relationship between one-year mortality and Killip class IV during hospital stay (Figure 5) shows that over half of deaths in the direct admission group occurred in patients in cardiogenic shock during hospital stay, while in the interhospital transfer group this figure was lower, although the difference did not reach statistical significance (52.8 vs. 40.8 %, p=0.253). Another finding from this analysis was the high mortality of patients in cardiogenic shock, which exceeded 60 % in both groups (62.2 % vs. 64.4 %, p>0.999) (Figure 5). Although these figures are in line with those in the literature,34,35 they are still a cause for concern, as they demonstrate that in such cases it is not sufficient to perform successful PCI: these are highly unstable patients who often deteriorate immediately after PCI and need close monitoring. Their very high risk, frequently accompanied by multiple organ failure, necessitates a range of treatments (including circulatory support, mechanical ventilation, renal replacement therapy and others) and a multidisciplinary therapeutic approach. If these are applied promptly, they can help to reduce the high mortality seen in these patients.36,12

Although this study is the largest ever carried out in STEMI patients in Portugal in terms of both number of patients and time period covered, it has certain limitations that should be borne in mind. Firstly, it was a retrospective observational study in a single catheterization laboratory and is thus subject to the limitations and biases inherent to retrospective single-center studies. Secondly, it was not possible to analyze cardiovascular mortality separately from overall mortality, and thus the possibility cannot be excluded that some patients died from causes unrelated to STEMI. Thirdly, as stated above, the lack of information on patients who died before reaching the catheterization laboratory – in the referring hospitals, during transfer, or in our hospital – hampers interpretation of the true relationship between Killip class and mortality. Finally, our results pertain to the Minho and, given the particular geographic and sociodemographic characteristics of the region, as well as its well-developed road network, they may not be applicable to the rest of the country.

In conclusion, it is fair to say that results obtained by the primary PCI program of the Minho region during the five-year study period were acceptable in terms of the time taken to treat STEMI patients.

Most patients undergoing primary PCI in the catheterization laboratory of Hospital de Braga come from other hospitals in the region. Although the time taken to transfer them significantly delayed reperfusion therapy, this delay did not increase one-year mortality in these patients. However, the significant difference in the proportion of patients admitted in Killip class IV in two groups with similar baseline characteristics leads us to believe that some patients transferred from referring hospitals may have died before arrival at the catheterization laboratory, thus affecting mortality in the interhospital transfer group.

We have also identified weak points in the patient pathway from symptom onset to reperfusion, and have discussed measures that could help to resolve them.