Impact of a Pharmacoinvasive Strategy With Prolonged PCI Delays
It is generally accepted that P-PCI is the preferred reperfusion option for patients with STEMI but also appreciated that the benefit becomes attenuated the longer it takes to deliver P-PCI following symptom onset. Furthermore, historical comparisons of P-PCI with fibrinolysis have in general been compared with in-hospital lytic alone rather than a PI strategy.
The previously published STREAM 30-day results showed that the PI strategy was a useful alternative option producing similar clinical outcomes in patients who could not receive timely PCI (within prespecified 60 min from when fibrinolysis could be delivered). This paper specifically examines the relationships between time and outcomes and presents analyses of time-related delay not available in the original paper.
Much has been written on the importance of timing to initiation of reperfusion. Animal data demonstrated irreversible cell death after about 40 min. A derived time construct indicates that during the first 2–3 h after symptom onset, time to treatment critically determines reduction in mortality: thereafter, a lesser benefit occurs. In the current analysis, patients randomised to the PI strategy received treatment within 2.4 h (median 1.7 h) of symptom onset compared with 3.8 h (median 3 h) for those randomised to P-PCI.
Guideline standards have been set for optimal time delay metrics. Attaining within-guideline door-to-balloon times may be the easiest parameter to achieve, especially driven by in-hospital audits. Overall ischaemic time may have more importance. In a recent publication, the door-to-balloon times fell significantly from median 83 min (2005–2006) to median 67 min (p<0.001) in 2009–2010. However, the in-hospital 30-day mortality remained similar (4.8%) (p=0.64). This can be explained by recognising that the door-to-balloon delay is only one component of the patient's overall ischaemia time, and shortening the overall symptom to reperfusion time (the system delay) is the key to improving outcomes. Terkelsen has clearly demonstrated the impact of system delay, with excess mortality evident over a 7-year follow-up (p<0.001), especially when the system delays were >180 min. Guidelines promote networks to reduce system delays. However, despite worthy efforts, insurmountable system delays continue in many parts of the world (due to geography, hospital-to-patient population density ratios, climatic issues and traffic congestion in large urban areas). These and other circumstances indicate that system delays may not always readily be overcome. In such global circumstances, initiating early fibrinolysis with timely follow-on angiography (including provision for urgent rescue PCI) may be preferable in order to achieve best outcomes.
It is the relationship of time delay to outcomes for the two strategies that was the specific focus of this study. It should be noted that the design of the current study selected a STEMI patient population presenting within 3 h of symptom onset who were judged unable to receive P-PCI within 1 h. Against a background of loss of benefit of PCI over PI therapy when the site-related delay is >1 h, our results (figure 2) emphasise the potential overall benefit of PI as this time delay progressively increases. Although historical trials of fibrinolysis have shown excess intracranial bleeding compared with P-PCI, in the parent STREAM trial, this was not the case once the protocol amendment to reduce TNK by 50% in the over 75 year old had been implemented.
In this prespecified substudy, the 30-day STREAM outcomes were analysed according to P-RD recognising that our study design mandated at least a 60 min P-RD in accordance with the European Society of Cardiology guidelines. The most important finding was that in the PI arm there was no increased hazard across P-RD (p(trend)=0.292), whereas there was an increased hazard in the P-PCI arm (p(trend)=0.038). For the 30-day composite of death/CHF/cardiogenic shock/re-MI, the test for interaction between P-RD and study treatment approached statistical significance (p(interaction)=0.094). This potential effect on metrics of LV function is of interest and in agreement with the findings from the CAPTIM and WEST studies.
A substantial proportion of STREAM patients had a P-RD <60 min despite the protocol specifying that patients were only to be included if they could not undergo PCI within 60 min of first medical contact (Table 2 and figure 2). Their incidental inclusion confirms such patients appear well served by P-PCI. This relationship was also observed in the sensitivity analysis, which restricted the cohort to 20 patients per site (p(interaction)=0.049). Thus, while this exploratory analysis suggests that when the site-related delay is short (≤55 min), patients do slightly better with P-PCI, as P-RD increased, the advantage swings towards PI. Despite the strong trend towards an interaction between P-RD and treatment strategy on clinical outcomes, the directional nature of our findings should be interpreted with caution given the modest size of the sample. Notwithstanding this caveat, the outcome data in this very early treated STEMI population provide new insights into the importance of timely reperfusion and add support for employing the PI strategy in parts of the world where (guideline) timely P-PCI cannot be achieved.
Our results differ from other published data because of important differences in median treatment times as expected given our narrow 3 h randomisation inclusion window from symptom onset. In our total population, P-RD was greater largely due to a much shorter fibrinolytic initiation time of 78 min compared with ≥160 min DANAMI-2 trial highlighting the 'time advantage' of fibrinolysis in STREAM. For the same reasons, our findings also contrast with the PCAT-2 Trialists where the median time from symptom onset to in-hospital fibrinolysis was 162 min.
The parent STREAM study was designed as a proof-of-concept study. All statistical tests were of an exploratory nature, and the small numbers do not allow for robust analytical assessment of clinical endpoints, especially mortality. Thus, the results of this presented subgroup analysis should also be considered exploratory and hypothesis generating. We also acknowledge that there may be unmeasured confounders related to delay, treatment and outcomes. However, within this randomised trial we are able to provide insights into how time delays affect both treatment strategies. The timely performance of rescue PCI and excellent protocol mandated ancillary pharmacological therapy likely contributed to our positive PI results and may be challenging to achieve in some clinical domains. Finally, our results do not challenge the assertion that P-PCI is the preferred option for STEMI when delivered in an expedient and timely manner in an expert 24/7 facility.
Discussion
It is generally accepted that P-PCI is the preferred reperfusion option for patients with STEMI but also appreciated that the benefit becomes attenuated the longer it takes to deliver P-PCI following symptom onset. Furthermore, historical comparisons of P-PCI with fibrinolysis have in general been compared with in-hospital lytic alone rather than a PI strategy.
The previously published STREAM 30-day results showed that the PI strategy was a useful alternative option producing similar clinical outcomes in patients who could not receive timely PCI (within prespecified 60 min from when fibrinolysis could be delivered). This paper specifically examines the relationships between time and outcomes and presents analyses of time-related delay not available in the original paper.
Much has been written on the importance of timing to initiation of reperfusion. Animal data demonstrated irreversible cell death after about 40 min. A derived time construct indicates that during the first 2–3 h after symptom onset, time to treatment critically determines reduction in mortality: thereafter, a lesser benefit occurs. In the current analysis, patients randomised to the PI strategy received treatment within 2.4 h (median 1.7 h) of symptom onset compared with 3.8 h (median 3 h) for those randomised to P-PCI.
Guideline standards have been set for optimal time delay metrics. Attaining within-guideline door-to-balloon times may be the easiest parameter to achieve, especially driven by in-hospital audits. Overall ischaemic time may have more importance. In a recent publication, the door-to-balloon times fell significantly from median 83 min (2005–2006) to median 67 min (p<0.001) in 2009–2010. However, the in-hospital 30-day mortality remained similar (4.8%) (p=0.64). This can be explained by recognising that the door-to-balloon delay is only one component of the patient's overall ischaemia time, and shortening the overall symptom to reperfusion time (the system delay) is the key to improving outcomes. Terkelsen has clearly demonstrated the impact of system delay, with excess mortality evident over a 7-year follow-up (p<0.001), especially when the system delays were >180 min. Guidelines promote networks to reduce system delays. However, despite worthy efforts, insurmountable system delays continue in many parts of the world (due to geography, hospital-to-patient population density ratios, climatic issues and traffic congestion in large urban areas). These and other circumstances indicate that system delays may not always readily be overcome. In such global circumstances, initiating early fibrinolysis with timely follow-on angiography (including provision for urgent rescue PCI) may be preferable in order to achieve best outcomes.
It is the relationship of time delay to outcomes for the two strategies that was the specific focus of this study. It should be noted that the design of the current study selected a STEMI patient population presenting within 3 h of symptom onset who were judged unable to receive P-PCI within 1 h. Against a background of loss of benefit of PCI over PI therapy when the site-related delay is >1 h, our results (figure 2) emphasise the potential overall benefit of PI as this time delay progressively increases. Although historical trials of fibrinolysis have shown excess intracranial bleeding compared with P-PCI, in the parent STREAM trial, this was not the case once the protocol amendment to reduce TNK by 50% in the over 75 year old had been implemented.
In this prespecified substudy, the 30-day STREAM outcomes were analysed according to P-RD recognising that our study design mandated at least a 60 min P-RD in accordance with the European Society of Cardiology guidelines. The most important finding was that in the PI arm there was no increased hazard across P-RD (p(trend)=0.292), whereas there was an increased hazard in the P-PCI arm (p(trend)=0.038). For the 30-day composite of death/CHF/cardiogenic shock/re-MI, the test for interaction between P-RD and study treatment approached statistical significance (p(interaction)=0.094). This potential effect on metrics of LV function is of interest and in agreement with the findings from the CAPTIM and WEST studies.
A substantial proportion of STREAM patients had a P-RD <60 min despite the protocol specifying that patients were only to be included if they could not undergo PCI within 60 min of first medical contact (Table 2 and figure 2). Their incidental inclusion confirms such patients appear well served by P-PCI. This relationship was also observed in the sensitivity analysis, which restricted the cohort to 20 patients per site (p(interaction)=0.049). Thus, while this exploratory analysis suggests that when the site-related delay is short (≤55 min), patients do slightly better with P-PCI, as P-RD increased, the advantage swings towards PI. Despite the strong trend towards an interaction between P-RD and treatment strategy on clinical outcomes, the directional nature of our findings should be interpreted with caution given the modest size of the sample. Notwithstanding this caveat, the outcome data in this very early treated STEMI population provide new insights into the importance of timely reperfusion and add support for employing the PI strategy in parts of the world where (guideline) timely P-PCI cannot be achieved.
Our results differ from other published data because of important differences in median treatment times as expected given our narrow 3 h randomisation inclusion window from symptom onset. In our total population, P-RD was greater largely due to a much shorter fibrinolytic initiation time of 78 min compared with ≥160 min DANAMI-2 trial highlighting the 'time advantage' of fibrinolysis in STREAM. For the same reasons, our findings also contrast with the PCAT-2 Trialists where the median time from symptom onset to in-hospital fibrinolysis was 162 min.
Limitations
The parent STREAM study was designed as a proof-of-concept study. All statistical tests were of an exploratory nature, and the small numbers do not allow for robust analytical assessment of clinical endpoints, especially mortality. Thus, the results of this presented subgroup analysis should also be considered exploratory and hypothesis generating. We also acknowledge that there may be unmeasured confounders related to delay, treatment and outcomes. However, within this randomised trial we are able to provide insights into how time delays affect both treatment strategies. The timely performance of rescue PCI and excellent protocol mandated ancillary pharmacological therapy likely contributed to our positive PI results and may be challenging to achieve in some clinical domains. Finally, our results do not challenge the assertion that P-PCI is the preferred option for STEMI when delivered in an expedient and timely manner in an expert 24/7 facility.