Dallas, TX - The 90-day results (the primary end point) of the ASSENT-4 study comparing full-dose TNK-facilitated PCI vs primary PCI alone still show a worse outcome in the facilitated group, but the mortality difference between the two arms is no longer significant.

And a subgroup analysis has shown that patients randomized in the ambulance did better than those randomized at hospital, and those given TNK in the ambulance actually had the lowest mortality in the whole trial, showing yet again the importance of early treatment in MI.

The ASSENT-4 investigators, led by Drs Frans Van de Werf (University of Leuven, Belgium) and Allan Ross (George Washington University, Washington, DC), were planning to randomize 4000 patients between the two strategies, but the trial was stopped in July of this year after 1667 patients had been enrolled because of a significantly higher mortality rate in the TNK-plus-PCI arm.

Van de Werf and Ross presented the 90-day results during this week's American Heart Association (AHA) Scientific Sessions 2005. The primary end point, a composite of death, heart failure, and cardiogenic shock, still showed a large and significant increase in the combination arm, but none of the individual components of the end point were now significantly different.

ASSENT-4 results at 90 days (primary end point)

End point	TNK+PCI (%)	PCI alone (%)	p
Death/CHF/cardiogenic shock	18.8	13.7	0.0055

Individual components of the primary end point

End point	TNK+PCI (%)	PCI alone (%)	p
Death	6.7	5.0	0.141
Cardiogenic shock	6.1	4.8	0.273
CHF	12.1	9.4	0.078

Van de Werf noted that recurrent MI and target vessel revascularization were also increased in the combination arm, and he highlighted the "highly significant" difference in strokes between the two strategies. He said the stroke rate in the TNK arm was consistent with previous TNK trials, but that it was surprising that there was only one stroke in the PCI arm.

ASSENT-4 secondary end points at 90 days

End point	TNK+PCI (%)	PCI alone (%)	p
Re-MI	6.1	3.5	0.020
Repeat TVR	6.6	3.6	0.006
Stroke	2.65	0.12	<0.0001
Intracranial hemorrhage	1.09	0.12	significant
Major bleeds (in hospital)	5.7	4.3	0.217

Ross presented data on the evolving mortality results from the time at which the trial was stopped to the 90-day results. This showed that the difference in mortality between the two groups diminished and became nonsignificant as more data became available.

ASSENT-4: Evolving mortality

Time point	Records, n	TNK+PCI (%)	PCI alone (%)	p
Trial stopped	1320	6.5	3.4	0.01
30 d	1663	6.0	3.8	0.04
90 d	1648	6.7	5.0	0.14

Ross also presented subgroup analyses, showing that those patients who were randomized in the ambulance received either TNK or PCI faster than patients randomized in either PCI hospitals or non-PCI hospitals, and that this translated into lower mortality rates.

Time in minutes from pain to randomization and from randomization to first reperfusion treatment according to whether randomized in a PCI hospital, a non-PCI hospital, or an ambulance                 

	PCI hospitals	PCI hospitals	Non-PCI hospitals	Non-PCI hospitals	Ambulance	Ambulance
Time (min)	TNK+PCI	PCI alone	TNK+PCI	PCI alone	TNK+PCI	PCI alone
Pain to randomization	160	160	130	135	105	105
Randomization to balloon		95		140		98
Randomization to TNK	10		12		10

Mortality rates according to place of randomization

Place of randomization	TNK+PCI (%)	PCI alone (%)
PCI hospital	8.5	5.2
Non-PCI hospital	5.3	4.8
Ambulance	3.1	4.1

Ross pointed out that the lowest mortality in the entire trial was seen in those patients randomized in the ambulance and assigned to TNK plus PCI.

He noted that the TIMI-3 patency data also supported treatment in the ambulance. The pre-PCI TIMI-3 patency rate in the whole TNK group, which has been reported previously, was a very low 43.5%, but this increased to 55% in patients treated in the ambulance, showing yet again the benefits of fast treatment.

Pre-PCI TIMI-3 flow according to place of randomization

Place of randomization	TIMI-3 flow (%)
PCI hospital	39
Non-PCI hospital	43
Ambulance	55

Ross concluded that it is not only the reperfusion regimen used that is important, but also the time and place of enrollment.

Van de Werf commented, "There appears to be a benefit of facilitated PCI with TNK if given in the ambulance," adding, "The decision to stop the trial at the time it was stopped was the right decision, but if we did the trial again, we would include more ambulances."

Lessons learned

Ross and Van de Werf again highlighted the short transfer times in this study, saying that they had expected the delay between TNK and PCI to be much longer than the 97 minutes reported in this study.

ASSENT 4: PCI delay

Randomization	Time (min)
Randomization to TNK	10
Randomization to first balloon	107
PCI-related delay	97

Van de Werf said: "The lytic up-front approach is more likely to be beneficial when the PCI delay is quite long. If we did this study again, we would not permit the inclusion of patients who would receive PCI so quickly."

Suboptimal dose of heparin

They also discussed again the possibility that a suboptimal dose of heparin may have been used. In the trial, a bolus dose of heparin was given (a slightly lower dose in the TNK group than in the PCI group, 60 vs 70 U/kg), and no infusion was given because of concerns about bleeding. Ross noted: "It is very clear that patients did not receive the highest possible dose of heparin. This is because we wanted to avoid excess bleeding, which has been seen in previous trials using a full dose of lytic and a full dose of heparin. If we did this trial again, we would pay more attention to the heparin dose."

Dr Paul Armstrong (University of Alberta, Edmonton), also a member of the ASSENT-4 steering committee, noted that another subgroup analysis had shown that the TNK group had a worse outcome only in those patients who went on to receive stents. "In this trial, the advantage of primary PCI alone was seen only in patients receiving stents—not in those who received balloon angioplasty." He suggested that this might be the result of putting a stent into a prothrombotic environment brought about by insufficient antithrombotic/antiplatelet therapy.

In an interview with heartwire, Armstrong said: "It seems clear that there is an intersection between the content of care and where that care is delivered, as the data from the three areas where patients entered the system are very different." He added: "A lot of lessons have been learned from this trial, but the most important one seems to be that time is the most important thing—whichever treatment you give, you must give it quickly."

He said the ASSENT investigators would like to do another trial, taking on board all the lessons learned from this trial, and he does not believe the strategy of facilitated PCI with full-dose lytic is dead yet. "There are lots of caveats but still lots of possibilities," he commented.

Transfer AMI still under way

In a separate session on facilitated PCI at the AHA meeting, Dr Magnus Ohman (Duke University, Durham, NC) noted that another trial with full-dose TNK is still under way. The Transfer AMI trial is a Canadian study similar to ASSENT-4 but with longer transfer times between the lytic and PCI. "This trial has randomized a few hundred patients and has not yet been stopped, so it may be that ASSENT-4 was a one-off," Ohman commented. He added that the ambulance data in ASSENT-4 were from a small subgroup but were "very provocative," noting that a European trial (CAPTIM) had shown similar results.

He also noted that "the trial everyone is now waiting for" is FINESSE, which is testing the facilitated-PCI regimens of half-dose reteplase plus abciximab or abciximab alone vs primary PCI alone. But results are not due until 2007.

In an interview with heartwire, Ohman said he thought the half-dose lytic strategy seemed like a better bet for facilitated angioplasty. "Using full-dose lytic seems to limit your options too much in terms of increasing the dose of antithrombotic and antiplatelet agents." But he added: "The key to improving the treatment of MI is to improve our systems to speed up treatment, rather than worrying too much about exactly which regimen we use."