System Delay and Timing of Intervention in Acute Myocardial Infarction (from the Danish Acute Myocardial Infarction-2 [DANAMI-2] Trial)

System Delay and Timing of Intervention in Acute Myocardial Infarction (from the Danish Acute Myocardial Infarction-2 [DANAMI-2] Trial) Peter H. Nielsen, MDa, Christian J. Terkelsen, MD, PhDa, Torsten T. Nielsen, MD, DMSca, Leif Thuesen, MD, DMSca, Lars R. Krusell, MDa, Per Thayssen, MD, DMScb, Henning Kelbæk, MD, DMScc, Ulrik Abildgaard, MDd, Anton B. Villadsen, MDe, Henning R. Andersen, MD, DMSca, and Michael Maeng, MD, PhDa,*, on behalf of the Danami-2 Investigators The interval from the first alert of the healthcare system to the initiation of reperfusion therapy (system delay) is associated with mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention (pPCI). The importance of system delay in patients treated with fibrinolysis versus pPCI has not been assessed. We obtained data on system delay from the Danish Acute Myocardial Infarction-2 study, which randomized 1,572 patients to fibrinolysis or pPCI. The study end points were 30-day and 8-year mortality. The short system delays were associated with reduced absolute mortality in both the fibrinolysis group (<1 hour, 5.6%; 1 to 2 hours, 6.9%; 2 to 3 hours, 9.5%; and >3 hours, 11.5%; test for trend, p ⴝ 0.08) and pPCI group (<1 hour, not assessed; 1 to 2 hours, 2.6%; 2 to 3 hours, 7.5%; >3 hours, 7.7%; test for trend, p ⴝ 0.02). The lowest 30-day mortality was obtained with pPCI and a system delay of 1 to 2 hours (vs fibrinolysis within <1 hour, adjusted hazard ratio 0.33; 95% confidence interval 0.10 to 1.10; p ⴝ 0.07; vs fibrinolysis within 1 to 2 hours, adjusted hazard ratio 0.37; 95% confidence interval 0.14 to 0.95; p ⴝ 0.04). pPCI and system delay >3 hours was associated with a similar 30-day and 8-year mortality as fibrinolysis within 1 to 2 hours. In conclusion, short system delays are associated with reduced mortality in patients with ST-segment elevation myocardial infarction treated with fibrinolysis as well as pPCI. pPCI performed with a system delay of <2 hours is associated with lower mortality than fibrinolysis performed with a faster or similar system delay. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:776 –781) The reduction in the interval to reperfusion is important to decrease mortality in patients with ST-elevation myocardial infarction (STEMI).1–5 Previous studies have focused on a reduction in patient delay (i.e., interval from symptom onset to when the patient alerts the healthcare system), but even large-scale media campaigns have failed to successfully achieve a reduction in patient delay or mortality.6,7 The current American and European guidelines have mainly focused on the door-to-balloon (D2B) or door-to-needle (D2N) time as indicators of the quality of care and predictors of mortality.8 –12 These intervals, however, are short compared to the cumulated time from symptom onset to the initiation of reperfusion therapy (i.e., treatment delay) and do not reflect the entire interval that can be modified by the

healthcare system. System delay (i.e., the interval from when the patient alerts the healthcare system to reperfusion therapy) might be more optimal as a performance measure, because it holds all the healthcare-related delay. We have recently shown that system delay was associated with mortality in a registry cohort of 6,209 patients with STEMI treated with primary percutaneous coronary intervention (pPCI).13 The importance of system delay in patients treated with fibrinolysis has neither been reported nor been compared to system delay with pPCI. Hence, the purpose of the present study was to compare the relative effect of system delay after fibrinolysis and pPCI as a predictor for 30-day mortality and long-term mortality. Methods

a

Department of Cardiology, Aarhus University Hospital, Skejby, Denmark; bDepartment of Cardiology, Odense University Hospital, Odense, Denmark; cDepartment of Cardiology, Gentofte University Hospital, Copenhagen, Denmark; dDepartment of Cardiology, Rigshospitalet, Copenhagen, Denmark; and eDepartment of Cardiology, Aarhus University Hospital, Aalborg, Denmark. Manuscript received February 11, 2011; manuscript received and accepted May 9, 2011. *Corresponding author: Tel: (⫹45) 8949-5566; fax: (⫹45) 8949-6025. E-mail address: [email protected] (M. Maeng). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.05.007

The study population included patients enrolled in the Danish Acute Myocardial Infarction-2 (DANAMI-2) trial. The DANAMI-2 trial randomly assigned 1,572 patients with STEMI to treatment with fibrinolysis or pPCI.14,15 Patients who emigrated during follow-up were included in the analyses and censored on the day of emigration. Allcause mortality data were acquired from the Danish Civil Registration System in March 2008. www.ajconline.org

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Figure 1. Treatment delay divided into patient delay, emergency medical service (EMS) delay, in-door-out-door delay, transfer delay, and D2N/D2B delay. Treatment delay ⫽ time from start of symptoms to start of fibrinolysis or first contrast injection; patient delay ⫽ time from start of symptoms to patient alerting healthcare system; EMS delay ⫽ time from alerting healthcare system to arrival at (first) hospital; system delay ⫽ time from patient alerting healthcare system to start of fibrinolysis or first contrast injection; D2N time ⫽ time from arrival at hospital to onset of fibrinolysis; in-door-out-door ⫽ time from arrival at local hospital to start of transfer to PCI center; transfer time ⫽ time of departure from referral hospital to arrival at PCI center; D2B time ⫽ time from arrival at PCI center to first contrast injection; pPCI-invasive ⫽ patient randomized to pPCI at PCI-capable hospital; pPCI-referral ⫽ patients randomized to pPCI at referral hospital. Numbers indicate median time in minutes. Table 1 Treatment time Variable

Fibrinolysis Group

pPCI-Invasive Group

pPCI-Referral Group

p Value

Patient delay Emergency medical service call to arrival at local hospital In-door-out-door at local hospital Transfer time Door-to-needle/door-to-balloon time System delay Treatment delay

53 (15–135) 35 (22–57)

48 (16–120) 40 (25–65)

55 (15–129) 40 (24–61)

0.70 0.03

— — 50 (40–70) 90 (70–130) 165 (110–269)

— — 81 (65–98) 127 (98–157) 183 (137–285)

57 (30–87) 31 (19–45) 14 (11–29) 148 (120–183) 215 (162–312)

— — ⬍0.001 ⬍0.001 ⬍0.001

Data are presented as median (interquartile range) in minutes. Door-to-balloon time ⫽ arrival at invasive hospital to first contrast injection; door-to-needle time ⫽ hospital arrival to start of fibrinolytic therapy; patient delay ⫽ symptom onset to emergency medical service call; system delay ⫽ emergency medical service call to initiation of reperfusion; transfer time ⫽ time of departure from referral hospital to arrival at PCI center; treatment delay ⫽ symptom onset to initiation of reperfusion.

The definitions of the intervals are given in Figure 1. The interval of the first balloon inflation is usually used as the time of reperfusion in pPCI; however, reperfusion often takes place before balloon inflation (e.g., during wiring or thrombectomy). Because data on the first wiring were not available and because the first contrast injection is followed within a few minutes by the first coronary intervention, we decided to use the first contrast injection as the interval of the first intervention. Acknowledging the widespread acceptance of the D2B delay as a performance measure, we decided to use the D2B delay synonymously with the time from arrival at the invasive center to the first contrast injection. The patients

were divided into 4 groups according to the system delay (⬍1, 1 to 2, 2 to 3, and ⬎3 hours). In the pPCI group, only 6 patients had a system delay time of ⬍1 hour. Therefore, these 6 patients were included in the 1 to 2-hour system delay group. The Pearson chi-square test was used for comparison of categorical variables. Continuous variables are reported as the median (interquartile range). The groups were compared using the analysis of variance when normally distributed and the Kruskal-Wallis rank-sum test if not normally distributed. Kaplan-Meier curves were used to illustrate the cumulative mortality and compared using the log-rank test. Multivariate Cox regression analysis,

0.30 ⬍0.001 0.46 0.88 0.99 3.9% 2.8% 76 (65–88) 140 (120–160) 54.7% 4.8% 2.0% 75 (60–88) 135 (120–155) 52.9% 4.3% 3.4% 70 (60–84) 136 (120–150) 52.6%

Figure 2. Absolute mortality by system delay. (A) 30-Day mortality. (B) Long-term mortality. Because only 6 patients were in pPCI group with system delay ⬍1 hour, they were added to group with system delay of 1 to 2 hours.

adjusting for age, heart rate at admission, and diabetes, was used to model survival.16 A p value of ⱕ0.05 was considered significant (2-sided testing). Data are presented as median (interquartile range) or percentages.

0.47 0.02 0.01 0.02 0.66 5.1% 10.3% 80 (70–88) 140 (120–160) 59.0% 2.9% 5.1% 74 (64–86) 139 (120–150) 53.3% 2.2% 3.3% 70 (60–84) 132 (111–150) 51.8% 1.9% 1.9% 70 (60–80) 135 (117–150) 50.5%

— — — — —

66 (55–74) 74.0% 13.9% 7.2% 52.5% 10.5% 62 (53–71) 70.6% 23.2% 9.2% 57.8% 11.5% 62 (53–71) 76.9% 18.9% 4.3% 63.0% 11.2% 0.02 0.04 0.19 0.59 0.11 0.02 63 (54–76) 78.2% 29.5% 6.1% 55.3% 20.5% 66 (56–76) 67.9% 20.4% 5.8% 55.3% 10.2% 63 (55–73) 72.4% 20.2% 6.9% 61.6% 9.7%

Age (years) Men Hypertension Diabetes mellitus Current smoker Previous acute myocardial infarction Previous coronary angioplasty Previous stroke Heart rate (beats/min) Systolic blood pressure (mm Hg) Anterior wall acute myocardial infarction

61 (50–69) 83.2% 16.8% 10.3% 52.8% 15.9%

— — — — — —

⬎3 (n ⫽ 181) 2–3 (n ⫽ 361) p Value ⬎3 (n ⫽ 78) 2–3 (n ⫽ 137) 0–1 (n ⫽ 107)

1–2 (n ⫽ 452)

0–1 (n ⫽ 0)

1–2 (n ⫽ 234)

pPCI Fibrinolysis (h) Variable

Table 2 Baseline variables versus system delay among patients randomized to fibrinolysis and primary percutaneus coronary intervention (pPCI)

0.17 0.43 0.01 ⬍0.001 0.53 0.85

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p Value

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Results Figure 1 illustrates the different intervals of treatment delay. The median treatment delay for all patients was 191 minutes (interquartile range 135 to 287) and differed among patients in the fibrinolysis, pPCI-invasive, and pPCI-referral groups (Table 1). The shortest treatment delay was observed in the fibrinolysis group and the longest treatment delay was in the pPCI-referral group. The patients treated with fibrinolysis and pPCI had similar patient delays (Table 1). The emergency medical service delay was slightly shorter in the fibrinolysis group than in the pPCI-invasive and pPCI-referral groups (Table 1). The median distance for transfer from the referral hospitals to the pPCI centers was 50 km (interquartile range 3 to 150). The system delay and D2N/ D2B time differed among the 3 treatment categories (Table 1), with fibrinolysis associated with the shortest delay and pPCI referral with the longest delay. Data on the treatment delay was missing for 21 patients, 1 patient had missing patient delay data, 22 had missing

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adjusted hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.10 to 1.19; p ⫽ 0.07) comparison to fibrinolysis within ⬍1 hour. Furthermore, pPCI within 1 to 2 hours was significantly better than fibrinolysis within 1 to 2 hours (2.6% vs 6.9%; adjusted HR 0.37, 95% CI 0.14 to 0.95; p ⫽ 0.04). A system delay ⬎3 hours in the pPCI group resulted in similar mortality as fibrinolysis started with a system delay of 1 to 2 hours (7.7% vs 6.9%; adjusted HR 0.97, 95% CI 0.52 to 1.83; p ⫽ 0.94). At the end of the follow-up period, 442 patients had died, 233 in the fibrinolysis group and 209 in the pPCI group. Figure 2 depicts the absolute mortality and Figure 3 the 8-year Kaplan-Meier curves for the system delay groups. In the fibrinolysis group, a longer system delay was associated with increased absolute mortality (test for trend, p ⫽ 0.02; Figure 2). In the pPCI group, a similar association between system delay and mortality was found (test for trend, p ⫽ 0.04; Figure 2). For 30-day mortality, treatment with pPCI within 1 to 2 hours had the best outcome of all examined delays and was associated with a trend toward lower reduced mortality (pPCI within 1 to 2 hours vs fibrinolysis within 1 hour, 21.8% vs 23.4%, adjusted HR 0.74, 95% CI 0.49 to 1.27, p ⫽ 0.31; pPCI within 1 to 2 hours vs fibrinolysis within 1 to 2 hours, 21.8% vs 29.4%, adjusted HR 0.74, 95% CI 0.53 to 1.03, p ⫽ 0.07). Similarly, a system delay ⬎3 hours in the pPCI group resulted in 8-year mortality similar to that after fibrinolysis with a system delay of 1 to 2 hours (29.3% vs 29.4%; adjusted HR 0.87, 95% CI 0.63 to 1.19, p ⫽ 0.38). Discussion Figure 3. Kaplan-Meier estimates of mortality according to intervals of system delay among (A) patients randomized for fibrinolysis and (B) patients randomized for pPCI. Because only 6 patients were in pPCI group with system delay ⬍1 hour, they were added to group with system delay of 1 to 2 hours.

system delay data, and 77 had missing D2N/D2B time data. The median follow-up interval was 7.8 years (interquartile range 7.1 to 8.5). The vital status at end of follow-up was unknown for 4 patients in the fibrinolysis group and for 4 patients in the pPCI group; all 8 of these patients emigrated during follow-up and were censored on the day of emigration. The baseline variables for the patients in the 4 different system delay groups are listed in Table 2. In the fibrinolysis group, the age, gender distribution, number of patients with previous myocardial infarction, number of patients with previous stroke, heart rate, and systolic blood pressure differed among the system delay groups. In the pPCI group, the number of patients with hypertension, diabetes, and previous stroke differed among the system delay groups. At 30 days of follow-up, 113 patients had died, 61 in the fibrinolysis group and 52 in the pPCI group. The system delay was associated with incremental mortality in the fibrinolysis group (test for trend, p ⫽ 0.08; Figure 2) and in the pPCI group (test for trend, p ⫽ 0.02; Figure 2). Treatment with pPCI within 1 to 2 hours was associated with a nonsignificant 67% reduced mortality rate (2.6% vs 5.6%;

In a recent analysis of 6,209 patients with STEMI treated with pPCI, we showed that mortality was associated with a relative increase of 10% for each hour longer system delay.13 The present study evaluated the association between system delay and mortality among patients randomly assigned to pPCI and fibrinolysis in the DANAMI-2 trial. The 30-day and long-term mortality data showed that patients treated with pPCI had numerically lower mortality than patients treated with fibrinolysis for all similar system delays. pPCI performed with a system delay of 1 to 2 hours was associated with a significantly lower mortality than fibrinolysis performed within 1 to 2 hours, with a trend toward lower 30-day mortality compared to fibrinolysis within 1 hour. The long-term mortality data showed that pPCI compared to fibrinolysis was associated with at least similar mortality rates despite an additional 1-hour system delay. If we accept the premise that any delay is associated with increased morbidity and mortality in patients with STEMI, the logical consequence is to organize the triage of these patients to reduce the interval from the first contact to the healthcare system to the initiation of therapy (i.e., we must reduce the system delay). The D2B time is an important quality of care parameter for monitoring hospital performance for patients admitted directly to a pPCI center. However, a strategy of prehospital diagnosis and rerouting of patients directly to the pPCI center, thus bypassing local hospitals, will tend to prolong the D2B time owing to a shorter staff mobilization time, even though the treatment

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delay and system delay will be reduced significantly.17 An indication of the importance of the staff mobilization time was shown in the present study, in which the D2B time was 81 minutes for patients admitted directly to a pPCI center and only 14 minutes for patients transferred for pPCI. However, other factors, primarily the interval to the diagnosis, could also have added to this difference. Our recent study introduced system delay as a complimentary parameter to the D2N/D2B time.13 The system delay does not have the aforementioned shortcoming of the D2N/D2B time. The system delay includes the transport delay, and it seems reasonable to use the system delay rather than the D2N/D2B time in the search for an acceptable pPCI-related delay in patients with STEMI diagnosed before reaching the hospital by the emergency medical service or in patients admitted to a referral hospital. Our study indicated that pPCI performed with a system delay of ⬍2 hours was associated with the lowest short- and long-term mortality. It also showed that it was acceptable, compared to the initiation of fibrinolysis within 1 hour, to have a delay of pPCI of ⱖ60 minutes. This finding is in accordance with the long-term results obtained in the DANAMI-2 trial, which concluded that pPCI should be offered to patients with STEMI when interhospital transport to an invasive hospital can be completed within 120 minutes.18 As shown in Figure 1, fibrinolysis was associated with the shortest delay and transfer for pPCI with the longest delay. However, we found that transfer for pPCI was associated with a significant mortality reduction after 8 years of follow-up compared to fibrinolysis given at the referral hospitals.18 Using the same recommended limits for fibrinolysis and pPCI, therefore, seem an incorrect simplification. Given the premise that fibrinolysis can be initiated within 1 hour after the first medical contact, our results are in line with the European STEMI guidelines, which recommend pPCI when performed within 2 hours of the first medical contact.19 However, only 14% of the patients randomized to fibrinolysis had a system delay of ⬍1 hour; also, when the system delay was 1 to 2 hours, pPCI with a system delay of ⬎3 hours gave the same short- and long-term results. Thus, if fibrinolysis cannot be initiated with a system delay of ⬍1 hour, pPCI performed with a system delay of ⬍2 hours will lead to a mortality reduction. Also, pPCI performed with a system delay of ⬎3 hours will not increase mortality, according to our findings. The current American guidelines on STEMI recommend fibrinolytic treatment if pPCI cannot be reliably performed within 90 minutes of the first medical contact.20 If, however, patients present at a referral (“non–PCI-capable”) hospital, the latest update of the American guidelines state that patients with STEMI should be triaged to fibrinolytic therapy or transferred for pPCI, according to the judgment of mortality risk, risk of fibrinolytic therapy, symptom duration, and estimated time of transfer to a pPCI-capable hospital.21 Again, our results indicate that pPCI should be the preferred strategy when it can be performed with a system delay of ⬍2 hours, a strategy that should be achievable for most citizens in the United States, where 80% of the adult population lives within 60 minutes of a pPCI-capable hospital.22 Our study is a post hoc analysis of the DANAMI-2 trial. However, it is unlikely that more reliable data are available, because the DANAMI-2 trial is the largest randomized

study comparing pPCI and fibrinolysis. Second, the DANAMI-2 trial was powered to compare a composite end point of death, reinfarction, or stroke. Therefore, the present analysis was limited by the power calculations related to the DANAMI-2 primary end point. Finally, unmeasured confounding factors might have hampered the association between time and mortality. 1. Boersma E. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J 2006;27:779 –788. 2. Brodie BR, Stuckey TD, Muncy DB, Hansen CJ, Wall TC, Pulsipher M, Gupta N. Importance of time-to-reperfusion in patients with acute myocardial infarction with and without cardiogenic shock treated with primary percutaneous coronary intervention. Am Heart J 2003;145: 708 –715. 3. De Luca G, Suryapranata H, Zijlstra F, van’t Hof AW, Hoorntje JC, Gosselink AT, Dambrink JH, de Boer MJ. Symptom-onset-to-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty. J Am Coll Cardiol 2003;42:991–997. 4. McNamara RL, Herrin J, Wang Y, Curtis JP, Bradley EH, Magid DJ, Rathore SS, Nallamothu BK, Peterson ED, Blaney ME, Frederick P, Krumholz H. Impact of delay in door-to-needle time on mortality in patients with ST-segment elevation myocardial infarction. Am J Cardiol 2007;100:1227–1232. 5. Zijlstra F, Patel A, Jones M, Grines CL, Ellis S, Garcia E, Grinfeld L, Gibbons RJ, Ribeiro EE, Ribichini F, Granger C, Akhras F, Weaver WD, Simes RJ. Clinical characteristics and outcome of patients with early (⬍2 h), intermediate (2– 4 h) and late (⬎4 h) presentation treated by primary coronary angioplasty or thrombolytic therapy for acute myocardial infarction. Eur Heart J 2002;23:550 –557. 6. Blohm MB, Hartford M, Karlson BW, Luepker RV, Herlitz J. An evaluation of the results of media and educational campaigns designed to shorten the time taken by patients with acute myocardial infarction to decide to go to hospital. Heart 1996;76:430 – 434. 7. Hedges JR, Feldman HA, Bittner V, Goldberg RJ, Zapka J, Osganian SK, Murray DM, Simons-Morton DG, Linares A, Williams J, Luepker RV, Eisenberg MS. Impact of community intervention to reduce patient delay time on use of reperfusion therapy for acute myocardial infarction: rapid early action for coronary treatment (REACT) trial. REACT Study Group. Acad Emerg Med 2000;7:862– 872. 8. Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French WJ, Gore JM, Weaver WD, Rogers WJ, Tiefenbrunn AJ. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000;283:2941–2947. 9. Boden WE, Eagle K, Granger CB. Reperfusion strategies in acute ST-segment elevation myocardial infarction: a comprehensive review of contemporary management options. J Am Coll Cardiol 2007;50: 917–929. 10. Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything? Am J Cardiol 2003;92:824 – 826. 11. Nallamothu B, Bradley E, Krumholz H. Time to treatment in primary percutaneous coronary intervention. N Engl J Med 2007;357:1631– 1638. 12. Ting HH, Bradley E, Wang Y, Nallamothu B, Gersh BJ, Roger VL, Lichtman JH, Curtis J, Krumholz H. Delay in presentation and reperfusion therapy in ST-elevation myocardial infarction. Am J Med 2008; 121:316 –323. 13. Terkelsen CJ, Sorensen JT, Maeng M, Jensen LO, Tilsted HH, Trautner S, Vach W, Johnsen SP, Thuesen L, Lassen JF. System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. JAMA 2010;304:763–771. 14. Andersen HR, Nielsen TT, Rasmussen K, Thuesen L, Kelbaek H, Thayssen P, Abildgaard U, Pedersen F, Madsen JK, Grande P, Villadsen AB, Krusell LR, Haghfelt T, Lomholt P, Husted SE, Vigholt E, Kjaergard HK, Mortensen LS. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733–742.

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