The tPA vs PCI for STEMI Slapdown – The STREAM trial 1-year mortality follow-up

Early last year the folks at Boehringer-Ingelheim (who manufacture and sell tenecteplase) sponsored the STREAM trial, which I have previously discussed in detail here. Recapping the greatest hits:

• n = 939 + 943 randomised interventional trial
• Inclusion = Adults with STEMI presenting < 3 hrs but can’t get to PCI < 1 hr
• Group 1 = tPA immediately and then delayed PCI (median 17 hrs)
• Group 2 = PCI as soon as possible (median 3 hrs)
• Outcome measure = cardiac death or MACE at 30 days
• No difference in these outcomes between the two groups
• 5 x rate of ICH in tPA group
• 2 x rate of CABG required in tPA group
• 36% of tPA group required immediate rescue PCI in order to achieve the “equal” outcomes

The one-year follow-up looks at mortality from cardiac and all causes a bit further down the track:

• Follow-up was pretty damn good – 99.2% and 99.3% of patients in each group were included
• All-cause mortality = 6.7% (tPA) vs 5.9% (PCI)
• Cardiac mortality = 4.0% (tPA) vs 4.1% (PCI)
• Altogether only 63 people died in the follow-up period
• 42 of them died of non-cardiac causes – 25 (tPA) vs 17 (PCI)
• In the 30-day to 1-year period, non-cardiac deaths were 13 (tPA) vs 7 (PCI)
• 9 died of stroke or ICH (tPA) vs 4 (PCI)
• 5% absolute increase in risk of death from ICH if over 75 yrs old & got tPA*

That last point is interesting. During the early stages of the trial, they noticed an excess mortality from ICH in patients > 75 yrs of age in the tPA group. After the first ~20% of patients were enrolled, they amended their protocol such that those people > 75 yrs old received a half-dose of tPA instead of the standard dose. The difference was about 5% (absolute mortality risk, not relative) and I have included the survival curves for “before and after” the protocol amendement below:

So if you’re over 75, have a STEMI and someone gives you tPA for it, you’re over twice as likely (10% vs 5%) to drop dead of an ICH if they don’t adjust the dose. Handy to know.

At the end of the day, mortality from cardiac causes was indeed pretty much exactly the same, though it’s worth remembering, again, that 36% of the tPA group required urgent rescue PCI to reach this equivalency of outcome.

It’s the mortality from non-cardiac causes that catches my attention, however. There is very little attention drawn to it in the paper; it is reported (briefly) in the results section, but the authors focus much more on the all-cause, overall mortality (which was closer to equal, though there was a trend for greater mortality in the tPA group) and cardiac mortality (which was the same). Far be it from me to suggest the presence of any impropriety or bias, but…

Overlooked as they are by the authors, pulling the actual numbers for non-cardiac deaths out of the paper is instructive:

• Non-cardiac deaths in the tPA group = 25+13 = 38 / 944 patients = 4.03%
• Non-cardiac deaths in the PCI group = 17 + 7 = 24 / 948 patients = 2.53 %

This equates to:

• 40 deaths per 1,000 patients in the tPA group
• 25 deaths per 1,000 patients in the PCI group

Given the power of this study, that is a significant difference. Statistically significant, and therefore likely to be “real”. And, subsequently and far more importantly, clinically significant / relevant.We hang our metaphorical hats on treatment effects and adverse effects of that magnitude (and smaller) every day (have a look at the size of the benefit margin for TXA in trauma, tPA in STEMI (where PCI is unavailable), aspirin in cardio/cerebrovascular disease, etc… you may or may not be surprised).

SUMMARY

For a remote STEMI patient that can get to the cath lab within around 3 hours:

• No additional benefit in thrombolysing them before/during transport
• Thrombolysis has only a 74% chance of achieving reperfusion compared to PCI
• If you do thrombolyse the old folk > 75 yrs, halve the dose or cop a 200% increase in risk of lethal ICH
• Thrombolysing & delaying PCI results in 15 excess non-cardiac deaths per 1,000 patients treated at 1 year

The original (30 day follow-up) STREAM trial can be found in the NEJM here: http://www.nejm.org/doi/full/10.1056/NEJMoa1301092

The latest (1 year follow-up) paper can be found in Circulation here: http://www.ncbi.nlm.nih.gov/pubmed/25161043