According to the AHA/ACC guidelines, full-dose thrombolytics is the recommended reperfusion strategy for patients with expected delay [23, 24]. Unfortunately, 26–36 % of patients will ultimately fail to reperfuse and will require transfer for rescue PCI [25]. Two studies published in 2003, the Danish trial in Acute Myocardial Infarction-2 (DANAMI-2) [26] and the Primary Angioplasty in Patients transferred from General Community Hospitals to Specialized PTCA Units with or without Emergency Thrombolysis-2 (PRAGUE-2) [27], compared the outcome of thrombolysis administered immediately at a non-PCI-capable hospital versus emergent transfer for primary PCI (Table 16.2). Patients in DANAMI-2 received tPA in the thrombolytic arm, and bare metal stents were used in 93 % of patients transferred for primary PCI. Mean total door-to-balloon (from referring hospital to balloon in receiving hospital) time was 112 min for patients transferred for PCI. The rate of primary composite end point of death, re-infarction, and disabling stroke at 30 days was lower in the transferred PCI group than in the thrombolysis group (8.0 % vs. 13.7 %, p = 0.002). This was largely driven by a reduction in the rate of re-infarction (1.6 % vs. 6.3 % in the thrombolytic arm, p < 0.001), but there was a trend towards lower mortality (6.6 % in the PCI group vs. 7.8 % in thrombolysis group, p = 0.35) and disabling stroke (1.1 % in the PCI group vs. 2 % in the thrombolysis group, p = 0.15). The trial was terminated early by the Data Safety and Monitoring Board after observation of a marked improvement in the clinical outcome of patients in the group with transfer for primary PCI.

In PRAGUE-2, patients received streptokinase in the thrombolytic arm and bare metal stents were employed in 63 % of patients transferred for primary PCI. Mean total door-to-balloon time was 97 min. The combined end point of a 30-day incidence of death, re-infarction, and stroke was significantly lower for the transfer for PCI group as compared to thrombolysis (8.4 % vs. 15.2 %, p < 0.003). This study found a similar trend towards reduction in mortality with transfer for primary PCI (6.8 % vs. 10 %, p = 0.12). An analysis based on treatment actually received, rather than intention to treat, demonstrated a statistically significant reduction in mortality for patients who were transferred for primary PCI (6 % vs. 10.4 %, p < 0.05). In addition, the subgroup of patients presenting greater than 3 h from onset of symptoms demonstrated a clear reduction in mortality with transfer for primary PCI (6 % vs. 15.3 %, p < 0.02) [27]. Both studies reported that interhospital transfer was safe with rare complications. Two deaths and three cases of successfully resuscitated ventricular fibrillation were reported during transportation in PRAGUE-2, while no deaths and eight cases of successfully resuscitated ventricular fibrillation were reported during transportation in DANAMI-2 [26, 27].

The only US randomized transfer trial, AIR-PAMI, randomized high-risk STEMI patients (ST elevation with one of the following criteria: age >70 years, heart rate >100 beats/min, systolic BP <100 mmHg, Killip class II/III, left bundle branch block or anterior MI) presenting to hospitals without PCI capability to either on-site thrombolysis or transfer for primary PCI. The trial was terminated early because of poor enrollment, but there was a trend towards a reduced 30-day mortality with transfer for PCI (8.4 % vs. 12.1 %, p = 0.46) [28].

A recent meta-analysis confirmed the benefit of transfer for primary PCI over thrombolysis, showing a reduction in 30-day mortality (5.6 % vs. 6.8 %, p = 0.02), re-infarction (2.1 % vs. 4.7 %, p < 0.001), and stroke (0.7 % vs. 1.7 %, p = 0.0005) [29]. These results indicate that transfer for primary PCI from non-PCI centers has advantages over thrombolysis similar to the benefits seen with primary PCI in patients presenting to a PCI center if performed in a timely manner (Table 16.3).

A major concern was whether the results from the European trials could be translated into clinical practice in the United States. The DANAMI-2 and PRAGUE-2 studies were performed in relatively small countries and the transfer distance ranged from 5 to 74 km in PRAGUE-2 and the mean distance was 35 miles in DANAMI-2 trial. The time for transportation from community hospital to PCI center was 32 min in the DANAMI-2 trial and 48 min in the PRAGUE-2 trial, and the door-to-balloon time averaged 26 min in both studies. Thus, overall time from emergency department admission at the non-PCI hospital to treatment (total door-to-balloon time) in these studies was only 95–108 min [26, 27]. In contrast, in AIR-PAMI, the median total door-to-balloon time was 155 min [28]. Moreover, the median total door-to-balloon time in transfer patients in the US national registry of myocardial infarction 3/4 was 180 min with only 4.2 % of patients treated within 90 min [22]. In 2007, Henry et al. at the Minneapolis Heart Institute reported the results of 1,345 patients treated in a regional program for transfer of patients with STEMI for PCI using a standardized protocol and an integrated transfer system. They demonstrated a median total D2B time of 95 min and transport time of 22 min for patients presenting within 60 miles of the PCI center. Compared to patients presenting at the PCI center (D2B time of 65 min), no difference in mortality, infarct size, or re-infarction was seen in patients transferred for primary PCI [30].

Facilitated PCI for STEMI is a strategy of using full-dose thrombolysis followed by immediate PCI. In the TRANSFER-AMI trial, 1,059 STEMI patients presenting to a non-PCI-capable facility within 12 h of symptom onset who had at least 1 high-risk marker were treated with full-dose fibrinolytic therapy and were then randomized to a facilitated strategy (immediate transfer for PCI within 6 h of fibrinolytic therapy) or to standard therapy which included rescue PCI as needed [31] (Table 16.4). Standard treatment patients who did not require rescue PCI remained at the initial hospital for at least 24 h, and coronary angiography was encouraged within the first 2 weeks. All patients received standard-dose tenecteplase, aspirin, and either unfractionated heparin or enoxaparin. Treatment with clopidogrel was strongly encouraged. Glycoprotein IIb/IIIa inhibitors (GPI) were administered at the PCI-capable hospitals according to institutional practice. The primary end point was a 30-day composite of the first occurrence of death, re-infarction, recurrent ischemia, new or worsening heart failure, or cardiogenic shock. The median time to administration of tenecteplase from onset of symptoms was approximately 2 h in both groups. The median time from tenecteplase to cardiac catheterization was significantly lower in the facilitated arm (2.8 h vs. 32.5 h). Coronary angiography was performed in 98.5 % vs. 88.7 % and PCI in 84.9 % vs. 67.4 % of the facilitated and standard treatment arms respectively. The primary end point occurred in 11.0 % of the facilitated group compared with 17.2 % of the standard therapy group (RR 0.64; 95 % CI 0.47–0.84; p = 0.004) Furthermore, there was no significant difference in the rate of TIMI major and minor bleeding or GUSTO moderate and severe bleeding between the groups although there was a higher incidence of GUSTO mild bleeding in the facilitated arm (13 % vs. 9 %; p = 0.036). The authors concluded that immediate transfer of high-risk STEMI patients after fibrinolytic therapy at non-PCI hospitals for coronary angiography and PCI resulted in improved outcomes [31].

As opposed to facilitated PCI, a pharmaco-invasive strategy for STEMI treatment is defined as reduced-dose thrombolysis in conjunction with immediate PCI. The CARESS-in-AMI trial included 600 STEMI patients 75 years of age or younger with at least 1 high risk feature (extensive ST segment elevation, new-onset left bundle branch block, previous MI, Killip class greater than 2, or left ventricular ejection fraction ≤35 %) who were treated initially at non-PCI hospitals with half-dose reteplase, abciximab, heparin, and ASA within 12 h of symptom onset [32] (Table 16.5). These patients were randomized to immediate transfer for PCI or to standard treatment with transfer for rescue PCI if needed. The majority of patients in the immediate transfer group (85.6 %) underwent PCI as compared to only 30.3 % in the rescue PCI group. As expected, there was a shorter median time from fibrinolytic therapy to transfer to a PCI-capable center in the immediate versus the rescue PCI group (110 vs. 180 min; p < 0.0001). Antiplatelet therapy with aspirin and clopidogrel was used less frequently in the rescue arm than in the immediate transfer arm. The primary end point (composite of all-cause mortality, re-infarction, and refractory myocardial ischemia within 30 days) was significantly lower in the immediate PCI group as compared to rescue PCI (4.4 % vs. 10.7 %, p = 0.004, NNT = 17). There were no significant differences in the rates of major bleeding at 30 days (3.4 % vs. 2.3 %; p = 0.47) or stroke (0.7 % vs. 1.3 %; p = 0.50) between the two groups. The authors concluded that high-risk STEMI patients presenting at non-PCI hospitals and treated with half-dose fibrinolytic therapy, abciximab, heparin, and aspirin have improved outcomes when transferred for immediate PCI rather than rescue PCI if thrombolysis fails.

Only 25 % of hospitals in the United States are capable of providing primary PCI and most are located in urban areas [20]. Regional STEMI transfer systems have subsequently been developed to improve timely access to primary PCI. The first of these systems was developed at the Minneapolis Heart Institute (MHI) in 2003, the Level 1 Program [30]. MHI had long-standing referral relationships with 33 hospitals up to 210 miles away. In this system, patients are assigned one of two strategies based on the distance from the PCI center. Zone 1 consists of referral hospitals within 60 miles and Zone 2 consists of referral hospitals 60–210 miles from MHI. A standardized protocol is implemented at each hospital. All patients receive ASA 325 mg, clopidogrel 600 mg, UFH 60U/kg intravenous load (maximum 4000U), and 12U/kg/h intravenous infusion (max 1,000 U/h) in the emergency department at the presenting hospital. Patients who present at the PCI hospital (MHI) or are transferred from a Zone 1 hospital undergo primary PCI. Patients transferred from Zone 2 hospitals undergo a pharmaco-invasive approach with half-dose fibrinolytic (tenecteplase most frequently) followed by emergency transfer for immediate PCI. This strategy was based on the TNK patency results described in TIMI 10A and TIMI 10B [33, 34] and the synergistic effects of clopidogrel with fibrinolytic agents described in CLARITY and COMMIT [35, 36]. Median door-to-balloon times were 62 min for those presenting directly to the PCI hospital, 94 min for those presenting to Zone 1 hospitals, and 122 min for pharmaco-invasively treated patients transferred from Zone 2 hospitals [37]. Pre-PCI patency (TIMI 2 or 3 flow) was found in 73.6 % of the pharmaco-invasive PCI-treated patients versus 40.3 % in primary PCI patients (p < 0.001). There was no significant difference in 30-day mortality (5.5 % vs. 5.6 %, p = 0.94), stroke (1.1 vs. 1.3 %, p = 0.66), major bleeding (1.5 % vs. 1.8 %, p = 0.65), or re-infarction/ischemia (1.2 % vs. 2.5 %, p = 0.088) in patients receiving a pharmaco-invasive strategy compared with patients presenting directly to the PCI center, despite a significantly longer door-to-balloon time.

The “late open artery” hypothesis suggested that late patency of an infarct artery is associated with improved LV function, increased electrical stability, and the provision of collateral vessels to other coronary beds for protection against future events. The Occluded Artery Trial (OAT) randomly assigned 2,166 patients with a totally occluded infarct artery 3–28 days after MI (approximately 20 % of whom had received fibrinolytic therapy) to optimal medical therapy and PCI with stenting or to optimal medical therapy alone [38]. Patients with class III or IV heart failure, rest angina, left main or 3-vessel disease, clinical instability, or significant inducible ischemia were excluded. The 4-year cumulative end point (composite of death, re-infarction, or class IV heart failure) was 17.2 % in the PCI group and 15.6 % in the medical therapy group (p = 0.20). Re-infarction rates tended to be higher in the PCI group. The authors concluded that PCI of a totally occluded infarct artery later than 24 h after STEMI should not be performed in asymptomatic patients with 1- or 2-vessel disease if patients are hemodynamically and electrically stable and do not have evidence of severe ischemia.

The clinical efficacy and safety of fondaparinux was evaluated in the OASIS (Organization for the Assessment of Strategies for Ischemic Syndromes)-6 trial, which randomly assigned 12,092 patients with STEMI to receive either treatment with fondaparinux (2.5 mg/day, started early and given for up to 8 days) or usual care (placebo for those for whom UFH was not indicated or UFH for up to 48 h followed by placebo for up to 8 days) [51

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