Journal of Thrombosis and Thrombolysis 1996;3:249-255 �9 Kluwer Academic Publishers, Boston. Printed in the Netherlands.

Time to Treatment: A Crucial Factor in Thrombolysis and Primary Angioplasty

Christopher P. Cannon Cardiovascular Division, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital Boston, Massachusetts

Abstract. Time to treatment with thrombolytic therapy has been recognized as an important factor in the treatment of patients with acute myocardial infarction: B y restoring infarct-related artery patency earlier, cl inical outcome is im- proved. Of the several components of t ime delay between the onset of pain to opening of the artery, in-hospital t ime delay (i.e., the door-to-needle time) is one that physicians can con- trol the most, with improvements being reported with the use of a myocardial infarction (MI) protocol like the one advocated by the National Hear t At tack Alert Program. These same principles apply to the alternate reperfusion strategy, primary angioplasty. Indeed, while primary angio- plasty has been shown to be beneficial in early clinical trials, it appears that the "door-to-balloon" time is a crucial compo- nent of the overall strategy. Thus, a growing body of evidence demonstrates that t ime to treatment is a crucial factor in both thrombolysis and primary angioplasty.

Key Words. thrombolysis, primary angioplasty, t ime to treat- ment, acute myocardial infarction

Thrombolytic therapy has dramatically reduced mor- tality following acute myocardial infarction, from ap- proximately 13% at 1 month in the early 1980s [1,2] to 6.3% in patients treated with current thrombolytic regimens [3]. Its benefit is related to early achieve- ment of infarct-related artery patency, whereby rapid coronary reperfusion limits infarct size, decreases left ventricular dysfunction, and improves survival [4,5]. Compared with placebo, thrombolysis achieves earlier and higher rates of infarct-related artery patency and lower mortality [6,7]. Similarly, more aggressive thrombolytic-antithrombotic regimens, such as front- loaded tissue plasminogen activator (t-PA) with in- travenous heparin and aspirin, achieve even earlier infarct-related artery patency and lower mortality fol- lowing acute MI [3,8,9]. An additional means of achieving earlier infarct-related artery patency and improve clinical outcome is earlier administration of thrombolytic therapy. As such, time is an important "adjunctive agent" to thrombolytic therapy.

acute myocardial infarction (MI): Early achievement of an open infarct-related artery is associated with improved outcome. Over the past decade, numerous angiographic studies lend support to this hypothesis, write the result that is has more recently been re- ferred to as the open artery theory [5]. Even in the earliest angiographic studies of thrombolytic therapy, patients who achieved early reperfusion have been found to a lower mortality compared with those who do not [10-12]. In TIMI 1, patients who achieved re- perfusion at 90 minutes following the start of throm- bolytic therapy had a much lower 1 year mortality, 8.1%, compared with 14.8% for patients who were oc- cluded at 90 minutes [11].

These early observations were expanded with the use of the TIMI flow grading system [13], which has been used in the TIMI [9,14,15], TAMI [16], GUSTO [8], and German angiographic trials [17]. In both the original report from TIMI 1 [14] and in an overview of these trials (Figure 1), patients with TIMI grade 3 flow had the lowest mortality, 3.6%, compared with 9.5% with patients with TIMI grade 0 or 1 flow (p < 0.00001) [18]. Patients with TIMI grade 2 flow had an intermediate mortality of 6.6%, which was siguifi- cantly better than an occluded artery [18].

A recent analysis from the GUSTO angiographic substudy, in which the mortality rates of patients with TIMI flow grades 2 and 3 were adjusted for differ- ences in baseline characteristics, also showed that, compared with patients with an occluded artery (TIMI grade 0 or 1), patients with TIMI grade 3 flow had the lowest mortality, while those with TIMI grade 2 flow had a mortality benefit of approximately half that of TIMI grade 3 flow [19]. Taken together, patients with an open infarct-related artery 90 min- utes after the start of thrombolytic therapy had a mortality of one-half that of those with persistent occlusion at 90 minutes (p < 0.00001) [18]. Thus, angi- ographic evidence in over 4000 patients indicates that rapid reperfusion following thrombolysis is associated with improved survival. As such, early reperfusion of

The Early Open Artery Theory

The open artery hypothesis is the paradigm by which thrombolytic therapy is understood to be beneficial in

Address for correspondence: Christopher P. Cannon, M.D., Cardio- vascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Email: cpcann~

249

250 Cannon

Relationship of Infarct-Related Artery TIMI Flow Grade at 90 Minutes to 30-42 Day Mortality

0

"0 od

TIMI I Trial

12 1

8

Overview of TIMI, TAMI, GUSTO, German Trials

N=4,281 1 ~,^.,~11 D,.,t~ t~tl/l/~4

21

0 TIMI 0/1 TIMI 2 TIMI 3 TIMI 0/1 TIMI 2 TIMI 3

TIMI 3 f low vs. TIMI 0,1,2 f low TIMI 2 v s . 0/1 f low TIMI 3 vs. 2 f low *p = 0.005 *p = 0.026 ** p = 0.0006

Fig. 1. The importance of rapid reperfusion: The relationship between mortality and TIMI flow grade 90 minutes following throm- bolytic therapy in the TIMI I trial and an overview of 15 angiographic trials. (Data from Flygenring et al. [14] and Cannon and Braunwald [18].)

the infarct-related artery is the primary goal in the treatment of acute MI.

I m p o r t a n c e o f T i m e to T r e a t m e n t

Support of the open artery theory also came from the mega trials: The importance of rapid time to treat- ment was highlighted first by the GISSI 1 trial, in which streptokinase was associated with a 19% reduc- tion in mortality compared with placebo [1]. However, in patients who were treated within 1 hour from the onset of symptoms, they had a 50% improvement of mortality [1]. In the TIMI 2 trial, it was observed that for each hour earlier that a patient was treated, there was a decrease in the absolute mortality by 1% (Fig- ure 2) [20]. This translates into an additional 10 lives saved per 1000 patients treated [18]. The lower mor- tality associated with earlier treatment was also seen in the GUSTO trial [21] and the National Registry of Myocardial Infarction [22]. This same relationship has been observed in patients treated with primary percu- taneous transluminal coronary angioplasty (PTCA), where earlier treatment relative to the onset of chest pain is associated with lower mortality [23] (Figure 2). Thus, for both thrombolysis and primary angioplasty, earlier treatment is associated with improved sur- viral, emphasizing the need to speed treatment [24].

I m p r o v i n g T i m e to T r e a t m e n t

In recognition of the importance of time to treatment, the National Heart, Lung, and Blood Institute estab- lished the National Heart Attack Alert Program

(NHAAP) in 1991, with the goal of reducing each com- ponent of delay in the time to treatment [25]. As shown in Figure 3, there are four components of time delay between the onset of chest pain (i.e., occlusion of the artery) to actually achieving reperfusion, that is, re-opening the artery. They are (1) patient delays, that is, the time between the onset of symptoms and the patient's seeking of medical advice; (2) transport delays, involving the time for the patient to present to medical attention, usually by ambulance; (3) the so-called door to needle time, the interval between the patient's arrival at the medical facility to the treat- ment with thrombolytic therapy; and (4) thrombolytic reperfusion time, the time between the administration of thrombolytic therapy and the achievement of reper- fusion [24,26]. Of all these time delays, the one physi- cians have most control over is the in-hospital delay, which became the focus of the NHAAP's initial effort [25]. In addition, the NHAAP has developed recom- mendations on how to reduce transport delays, as well as patient delays [27].

To help focus on the critical steps in the emergency department, Smith and members of the NHAAP Co- ordinating Committee coined the term, the 4 Ds: Door, Data, Decision, and Drug times. These are the four critical time points in evaluating the patient, for thrombolysis: the time between hospital arrival (Door) and the time the ECG is taken (Data), how long it takes the physician to decide whether the patient is eligible for thrombolysis (Decision), and how long it takes to have the drug mixed up and administered (Drug). Using the 4 Ds has been extremely useful in reducing in-hospital treatment delays, as evidenced by several recent reports [28-31] (Figure 4).

Time to Treatment 251

Effect of Time to Treatment on Mortality

o

Th rombolysis 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

P=O.05 6.2 6

Primary PTCA

15 ................................................

g 11.2 ~ lO o

~- 5 W o

v -

0 0 <1 h 1-2 h 2-3 h 3-4 h <2 h 2-6 h >6 h

Fig. 2. The relationship between time to treatment and mortality for thrombolytic therapy (from the TIMI 2 trial) and primary an- gioplasty. (Data from Timm et al. [20] and O'Keefe et al. [23].)

Time Delays in Achieving Reperfusion

i.Upat!er~t..~Tra.n.sp(~.~ .m..!n:hoSl~ita!... ~ . D r u g . . p . e r f u s i . o n ..........

Current I m 0 1 2 3 4 t Hours from Onset of Pain t

Onset of Chest Pain (Occlusion of Artery)

Opening of the Artery

Fig. 3. Components of time delays in achieving reperfnsion following acute MI. (Adapted from Cannon and Braunwald [18] and Gersh and Anderson [26], with permission.)

Drug Reperfusion Time

The fourth component of the time delay, drug reperfu- sion time, has been the focus of a great deal of re- search over the past decade. After streptokinase was found to be beneficial, trials with other agents began, with the focus on more rapid reperfusion. The TIMI 1 trial showed that t-PA opened approximately twice as many vessels as streptokinase by 90 minutes [13,32]. However, in the wake of GISSI 2 [33] and ISIS 3 [34], which showed no difference between t-PA, (using the 3-hour regimen without intravenous heparin), and streptokinase, the clinical value of rapid drug reperfusion was called into question.

The importance of rapid drug reperfusion was high- lighted by the GUSTO I and TIMI 4 trials, which found that the more aggressive thrombolytic regimen, front-loaded t-PA with intravenous heparin and aspi-

rin, achieved a higher rate of early reperfusion and was associated with improved survival and clinical outcome [3,9]. In light of this benefit, many new agents are currently under investigation, including TNK-tPA in the TIMI 10 trial [35] and r-PA [36] in the GUSTO 3 trial.

The most encouraging finding is that the beneficial effect of reducing time to t reatment and that of more rapid drug reperfusion are additive in improving sur- vival of patients with acute MI. As shown in Figure 5, in the GUSTO trial earlier t reatment was associ- ated with lower mortality. In addition, at each time period, use of a thrombolytic agent that opens arteries more rapidly (t-PA as compared with streptokinase) was associated with an added reduction in mortality. Thus, as would be expected based on the open ar tery theory, efforts to reduce time to treatment will work in concert with the use of more rapidly acting throm-

252 Cannon

Effect of MI Protocols on Door to Needle Times

100 a ~

8O

40

20

0 Pre

lOO I 1 ~ 1^^

80 7 6

Post Pre Post Pre Post Pre Post

Fig. 4. The beneficial effect of an acute MI protocol on in-hospital treatment times. (Data from Pel le t al. [42], Cannon et al. [28], Kopecky et al. [31], and Lambrew [29].)

~ Additive Effect of Improving Time to Treatment and Drug Reperfusion Time on Mortality

~ ' 1 0

Q

~ 5

a O ~ 0

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0-2h , 2-4h 4.6 i 5.6 5.5 6.5

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im SK

Fig. 5. The additive effect in reducing mortality of 1) improving time to treatment and 2) more rapid drug reperfusion time in the GUSTO I trial. (Data from Topol et al. [43].)

bolytic agents to together reduce mortality. Thus, as efforts to improve time to treatment continue on both hospital and national levels, they will have additive beneficial effects to the ongoing research efforts to find more effective thrombolytic agents [35,36].

Time to Reperfusion with Primary Angioplasty

Primary angioplasty is an alternative method of re- perfusion therapy for acute MI that is gaining wide acceptance and is growing in use. One advantage of primary angioplasty is that there is no drug reperfu-

sion time: Once the angioplasty balloon is inflated, the artery is open (Figure 6). However, it should be noted that the in-hospital phase has more components. In addition to taking the patient's history, obtaining the ECG, and assessing for suitability for primary angio- plasty, one must also assemble the cardiac catheter- ization team, transpoi% the patient to the catheteriza- tion laboratory, obtain arterial access, perform the diagnostic catheterization, and set up for and then perform the angioplasty (Figure 6). One must recall that in the acute MI setting, while all the steps are being carried out, the infarct-related artery is oc- cluded and myocardial necrosis is ongoing.

At experienced centers, these steps can be carried

Time to Treatment 253

Components in Time Delays with Thrombolysis vs. Primary PTCA

Thrombolysis

Primary PTCA

0 1 2 3 4 Hours from Onset of Pain

Fig. 6. Components of time delays for thrombolysis and primary angioplasty.

Time to Treatment and Outcome Following 1 ~ PTCA

Time Delay -- 60 mins Delay = 1 hour 44 mins

121 is P=O.O8

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IE

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Fig. 7. The beneficial effect of primary angioplasty with a rapid "door-to-balloon" time, but lack of benefit with a slower "door-to- balloon" time. (Data from Grines et al. [37] and Rogers et al. [41].)

out quickly, as in the initial PAMI and Netherlands trials, which had "door-to-balloon" times of only 60 minutes [37,38]. In this setting, primary angioplasty has been found to be beneficial compared with the 3-hour t-PA regimen and streptokinase, respectively (Figure 7). However, in current clinical practice, me- dian door to balloon times are approximately 2-21/2 hours [39,40]. In these reports, however, no benefit of primary angioplasty is observed [39-41] (Figure 7). Thus, it appears that time to treatment is a very ira- portant component of primary angioplasty, and hospi- tals that offer primary angioplasty should both moni- tor door-to-balloon times and develop protocols to minimize time delays in achieving reperfusion.

C o n c l u s i o n s

Thus, time is truly a crucial factor in reperfusion ther- apy for acute MI, with both thrombolysis and primary angioplasty. Physicians should refocus their efforts to ensure that time to treatment is as rapid as possible at their institutions. The use of acute MI protocols (i.e., critical pathways) for both thrombolysis and primary angioplasty should be a high priority for all institutions and lead to improved care for patients with acute MI.

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farto Miocardico (GISSI). Effectiveness of intravenous

254 Cannon

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Time to Treatment 255

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