Long term follow up on IST-3

I read this a few months back and forgot to post something on it. It’s not headline data the way IST 3 was but it’s worth knowing it’s out there. This is the long term (by which they mean 18 month) follow up on IST 3. The original trial has been written about and discussed fairly extensively on the FOAMed sites.

What they found:

  • they got around 2000 or so because only certain countries did follow up.
  • for those available they managed to follow up on the vast majority
  • the follow up was mainly phone and postal so not that great.
  • 30% knew which drug they got which they try to play down but given that the supposed benefit is so small then any recall may cause the difference
  • they do find about a 3.6% difference in alive and independent at 18 months favouring tPA (as pointed out by Brandon in the comments)
  • there’s a great Kaplan Meier curve showing early harm from TPA and then completely flat with placebo from then on. It’s behind the pay wall unfortunately but worth looking at
  • there was no difference in alive and independent at 18 months

“the unadjusted absolute difference in the number of patients alive and independent at 18 months was not significant”

So just to summarise that. A third of the patients knew which group they were in (nothing versus the fancy new drug) and ultimately there was no difference at 18 months.

Reference:

“Effect of Thrombolysis with Alteplase Within 6 H of Acute Ischaemic Stroke on Long-Term Outcomes (the Third International Stroke Trial [IST-3]): 18-Month Follow-Up of a Randomised Controlled Trial.” The Lancet Neurology (June 2013). PMID 23791822

Thrombolysis for stroke head to head in the BMJ

Hat tip to Domhnall for the heads up on this one.

The BMJ runs a series of head to head articles where two sides of a debate are presented. They tend to be written by the main players and always make for interesting reading. Following on from the recent controversy over their piece on guidelines for thrombolysis in stroke it seems that the BMJ have taken on stroke lytics as a suitably contested issue to justify a head to head. The head to head is definitely worth a read.

I’ve written before on lytics for stroke but find my sceptical position to be the minority  among my local colleagues and certainly amongst the wider medical establishment.

It’s nice to see the debate getting a wider audience

There’s also an associated poll where you can vote on whether harms outweigh benefits. As of today (wednesday 5th at 17:30) there’s a slight majority 52% suggesting harms outweigh benefits. This isn’t the x-factor remember but it’s nice to take your chance to have your say so I suggest head over now. (it’s at the bottom left corner of the home page)

PCI for stroke trials

OK, so I admit PCI for stroke is something I made up, but I think it’s a reasonable analogy. Given that treatment for STEMI moved from tPA to PCI then it’s hardly surprising to see a similar trend in the stroke world.

The idea is to remove (or sometimes lyse intrarterially) the cerebral arterial occlusion using interventional radiology. Whatever you make it’s certainly pretty cool and ambitious technology. There are a number of trials and devices out there for this type of thing, perhaps the most famous being the MERCI device.

Below is a review of two recent studies that compared new devices against the MERCI device.

Nogueira, Raul G, Helmi L Lutsep, Rishi Gupta, Tudor G Jovin, Gregory W Albers, Gary A Walker, David S Liebeskind, Wade S Smith, TREVO 2 Trialists. “Trevo Versus Merci Retrievers for Thrombectomy Revascularisation of Large Vessel Occlusions in Acute Ischaemic Stroke (TREVO 2): a Randomised Trial..” Lancet 380, no. 9849: 1231–1240. doi:10.1016/S0140-6736(12)61299-9.

METHODS

  • big sponsored trial to prove that the TREVO is better than MERCI device. Stryker makes both interestingly…
  • both are retrieval devices where the coil goes distal and the clot is withdrawn (there are others called micro aspiration)
  • all had to have failed tPA or be ineligible for it. (ALERT – lots of cherry picking can be done here)
  • lots of exclusion criteria (excluded 80% of those screened)
  • end point was revascualrisation NOT clinical outcome; hardly unsurprising though

RESULTS

  • 180 pts
  • The TREVO (the new device) did better in both the reperfusion and the clinical outcomes.
  • more died in the TREVO group at 90 days (24% v 34%) they somehow neglect to mention this…

———

Saver, Jeffrey L, Reza Jahan, Elad I Levy, Tudor G Jovin, Blaise Baxter, Raul G Nogueira, Wayne Clark, Ronald Budzik, Osama O Zaidat, SWIFT Trialists. “Solitaire Flow Restoration Device Versus the Merci Retriever in Patients with Acute Ischaemic Stroke (SWIFT): a Randomised, Parallel-Group, Non-Inferiority Trial..” Lancet 380, no. 9849: 1241–1249. doi:10.1016/S0140-6736(12)61384-1.

METHODS

  • a Dublin made device being trialled in the US against the only currently approved device
  • similar criteria as the previous trial – either failed tPA or contraindications and within 8 hrs
  • primary outcome was recanalisation NOT clinical outcome

RESULTS

  • total 120 pts
  • excluded 80% assessed
  • stopped early for benefit (always a shame…)
  • solitaire device was better on everything (even mortality in this tiny trial)
  • of note mortality was 44% in the MERCI group and 18% in the Solitaire group. Think about that for a second – in the MERCI group almost half died – that seems a bit off to me – most strokes don’t die in numbers like this – at least not by 90 days. They certainly didn’t die in these rates in the lytic trials.

 

Some thoughts

These are all very selected patients – so this is the best possible picture of the results. This is NOT a treatment that will be available to all your stroke patients. Often it will be limited by anatomy but it’s also only gonna be done in the younger patients with a better chance of outcome. The key will be (as with most things) being able to work out who might actually benefit from this sort of thing.

This may over the next 20 years become like PCI for STEMIs. But i doubt it, for the same reasons I’m dubious about lytics in stroke.

  1. diagnostically stroke is a much more difficult disease than STEMI
  2. the brain and its circulation is a lot more complex and tenuous than the heart (we have a circle of willis for a reason  - a built in collateral circuit in case of failure of flow.)

For added value I’ve added a demonstration video for all 3 devices below. See if you can spot the differences.

On IST-3 and why we still don’t have the answer we were looking for…

OK so IST-3 is out. It’s a big and important trial so make sure and read it. Stroke lytics get a lot of attention from EM folks, if only because we seem the only ones not convinced of its efficacy. Jerry Hoffman is probably the most important contentious voice but he’s by no means alone. Ryan Radecki has also some good stuff online and in print about it. I’ve even got my own compendium on it.

When I heard IST-3 was underway and almost ready to report I was quite excited to see someone finally answering the question in a rigorous way – do lytics in acute stroke improve outcomes? The trial that is still cited is the original NINDS trial. It showed a benefit but it was small (comparatively) and there were baseline differences between the groups that may have biased the trial in favour of tPA. This could have been answered by repeating the trial and replicating the results (a fairly common practice). This has never been done and unfortunately IST-3 is not the one to do it either. Now that’s hardly surprising – it was never the question the authors set out to answer.

If you don’t fancy reading the more detailed analysis below here’s the three major problems my point of view.

  1. this is an open label trial – It was blinded at assessment but in hospital following treatment everyone knew who got tPA and who didn’t and they were treated differently. This is a potential source of bias
  2. it only randomised people currently outside the licence for tPA so it’s testing an entirely different bunch from NINDS. See here for which patients were randomised.
  3. it was a negative trial by its primary outcome. Something the authors don’t acknowledge in the conclusion in the abstract.

There are lots of other problems that I’ve highlighted below. I’d be interested in your thoughts.

METHODS

  • multicentre international RCT
  • a pilot phase (<10% total) was blinded and then in the main trial it was open label. They don’t explain why the main trial was open label but presumably it’s cheaper and easier to do.
  • Randomised on basis of uncertainty principle. Basically if you’re unsure whether or not you should give it based on current guidelines then randomise
  • all kinds of follow-up but mainly via GP or phone or mailed questionnaire
  • originally planned for 6000 but recruitment insufficient so recalculated their power and changed the statistical plan.
  • realised that there were big differences in the sub-groups at baseline (mainly on time and stroke severity) and had to apply logistic regression to adjust for them. Seeing as the only +ve results in the trial were in the sub-groups it makes me further question their significance if they were adjusted to compensate for base-line imbalances.

RESULTS

  • 3000 over 10 years (which is very slow) 300/yr split between 150 centres means 2/yr/centre
  • half over 80 years old
  • virtually all outside the current european licence (which is the point of the trial)
  • mainly treated at 4.2hrs
  • pts who got tPA more likely to go to HDU (24%v17%) than those who didn’t. For this you could perhaps make the assumption that pts who got tPA got better nursing care…
  • big spike in early deaths (11% v 7%) but then improved by 6 months (16% v 20%). Overall mortality was identical at 6 months
  • found a 2% benefit in primary outcome (alive and independent, 35% v 37%) at 6 months. A difference this small of course did not reach statistical significance. You could call this an NNT of 50 if it was real.

Click for source

  • significant ICH 7% v 1%
  • oddly an increase in fatal swelling (odd because if tPA works then the infarct would be smaller and the swelling would be less) of infarcts in tPA group of 47 pts v 25 pts. This is played down as inconsistent with prior studies in the paper. UPDATE: it was pointed out to me by a fine neurologist that when you lyse the clot you get reperfusion oedema so this is actually a sign the tPA does breakdown clot. It makes sense. It’s still a problem if the reperfusion oedema kills people, but it’s not oedema simply from a big infarct.
  • they have a whole ream of things in the forest plot of secondary outcomes (these are the adjusted ones) and only one approaches significance – age >80 yrs. Unfortunately as Ryan points out – if it’s better for those greater than 80 then it’s worse for those <80 – which is the precise opposite of prior trials.

Below is a video of the lead author talking about the results if you’re interested

The paper itself lives here

In the same issue the same authors have published an updated systematic review and meta-analysis that now includes these results. One of the concerns that has been pointed out before is perhaps this heterogeneous data set (now up to 12 very differently ran trials) aren’t actually appropriate to meta-analyse.

There’s a glowing editorial about the trial that makes the slightly odd and even reckless statement that:

Every stroke patient should therefore be classed as a candidate for thrombolysis

This seems a little bit of a stretch seeing as the IST-3 trial used these criteria and excluded lots of pts:

Click for source

My suspicion as always, is that tPA does work for some patients with stroke, but certainly not all and until we can pick out the ones who benefit then I suspect that we shouldn’t have adopted this as wholeheartedly as we already have.

UPDATE – if you look at page 4 of the supplementary appendix there’s a list of the drug treatments that varied between the 2 groups. The two groups were treated differently 

UPDATE – there’s been some discussion of the technique of ‘ordinal analysis’ that was used in the trial and pushed by the authors as a way of seeing this as a positive trial. EM Nerd has written a great little piece on it if you want to know more

Tenectaplase for stroke

Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012 Mar. 22;366(12):1099–1107. PMID 22435369

See Ryan’s review of this paper published a few days ago.

This paper has, of course, got some slightly hyperbolic press that Domhnall pointed me towards.

METHODS

  • RCT, open label; alteplase vs tenectaplase at two doses (BI make both but guess which one wil run out of patent first…)
  • usual stroke lysis criteria but additional CT perfusing criteria needed.
  • Enrolled only 3% of those assessed within 6 hrs; vast majority excluded for “standard CI to alteplase”. Some others were excluded because of criteria specific to this trial.
  • “co-primary outcomes” which is a weird thing, I thought there should be one, being primary and all that… Anyway one of the primary outcomes was an imaging based one and the other was improvement in NIHSS at 24hrs. Note that these are different from the standard outcomes in other papers which is a delayed mRS score.

 

RESULTS

  • n = 75 split over 3 groups
  • tenectaplase was better at everything, better recovery and lower bleed rates. Though with numbers this small and selection criteria this tight and outcomes that aren’t the same as other trials it’s very hard to know if any of it means anything.

WHAT DOES IT MEAN

  • maybe… with all the fancy technology we can now pick out better the people who do well with stroke. In NINDS the mRS 0-1 was 26% and 39% for an NIHSS of 14 whereas here the mRS of 0-1 was 40% and 54% for an NIHSS of 14. Something is getting better it seems. And there’s good evidence that stroke care is better, it’s just not clear that the tPA is making the difference
  • or maybe… it’s just  a typical trial of something new in the early stages of its research where initial results look wonderful but over time it doesn’t quite pan out.

Note there was a previous prematurely terminated trial (for slow enrolment) of this a while back which didn’t find any difference between alteplase and tenectaplase. It had 112 pts by the way…

I’ll review it when I’ve gone through more of the details. Reference below:

Haley EC, Thompson JLP, Grotta JC, Lyden PD, Hemmen TG, Brown DL, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010 Apr.;41(4):707–711. PMC2860601