a brief history of clot busting
The EM community had always been wary about the thrombolytics literature. Ken Milne (Canadian EM doc) posts a summary on ACEPNOW in September 2020. There is a long history of studies on clot busting.
| year | events |
|---|---|
| 1950s | streptokinase (from streptococcus) and urokinase (from human urine) used, but led to a lot of ICH |
| 1960s | diagnostic angiograms became a thing a study comparing plasmin, heparin, streptokinase and placebo showed SK did better |
| 1990s | MAST-E and MAST-I showed increased risk of SK leading to its abandonment NINDS I&II 1995 showed better outcomes at 3 months with tPA at < 3h (but also ↑ICH), lot of controversy in the ED literature about NINDS ECASS 1995 failed to show benefit at < 6h (which was blamed on protocol violations) FDA 1996 approves tPA for stroke up to 3h after onset ECASS II and ATLANTIS A (0-6h) and ATLANTIS B (3-5h) failed to show benefit, so we gave tPA up till 3h |
| 2008 | ECASS III showed benefit up to 4.5h with risk of ICH of 7.9% for tPA vs 3.5% for placebo. But in 2020… EPITHET 2008 tPA vs placebo in the 3-6h window + DWI/perfusion mismatch on MRI couldn’t reproduce the results, but tPA had better neurologic outcomes |
| 2009 | Meta-analysis of ECASS 1, 2 & 3 + ATLANTIS showed better mortality with tPA. AHA/ASA revise the stroke guidelines up to 4.5 hours DIAS-2 looked at 3-9 hours for desmoteplase (a fibrinolytic derived from bat saliva whic is more selective and a longer half life) with no benefit and increased brain bleeds. Reanalysis of NINDS data revealed imbalance in stroke severity at presentation in both groups. After controlling for these, the tPA efficacy was no longer statistically significant. (Hoffman 2009) |
| 2010 | Pooling of NINDS + EPITHET data (3670 patients) showed favorable outcomes at 4.5 hours |
| 2013 | AHA/ASA, AAN, ACEP, ANA and NCCS support use of tPA from 0-3h (level A) and 3-4.5h (level B) |
| 2013 | IST-3 trial tPA < 6h showed reduction in disability at 6 months (but no difference in mortality or independence after 6 months), stopped early from the 6000 patients at 3035 patients due to benefit. 4% increase in death at 1 week and 6% increase in ICH. Bhatt 2013: Of 40 malpractice cases, 38 were failure to give tPA and 2 were complications of tPA administration |
| 2014 | Cochran Review pooled 10,187 patients from 27 trials and showed 0-3h benefit better than 3-6h benefit. |
| 2015 | DIAS-3 looked at 3-9 hours with desmoteplase and showed no difference in benefit or harm. Tsivgoulis 2015: 8942 pt case series with 392 stroke mimics, the risk of ICH was lower in stroke mimics (0.3%) compared to stroke (0.5%) |
| 2019 | Powers 2019, stroke guidelines revised. Summary to come, but feel free to review the reference. |
| 2020 | Alper in BMJ reanalyzed the ECASS III data adjusting for baseline imbalances and didn’t find any significant benefits in the 3-4.5h range. |
So where does this leave us? Right now the standard of care is to give thrombolytics. Bhatt 2013 found that 38/40 stroke related malpractice cases were due to failure to give and only 2 from complications of tPA administration.
a brief history of endovascular clot busting
| year | events |
|---|---|
| 1999 | PROACT II showed IA pro-urokinase improved outcomes. Outside the study, they showed recanalization was improved by using the guidewire to disrupt the clot. |
| 2004 | MERCI clot retrieval device was approved (with or without IA tPA) |
| 2007 | Suction thrombectomy (Penumbra system) approved. It opened vessels but didn’t improve outcomes. |
| 2012 | SOLITAIRE and TREVEO “stent-triever” trials approved devices that allowed the next set of trials to occur in the setting of previously unsuccessful trials. |
| 2013 | IMS III (tPA vs tPA + EVT) MR RESCUE (tPA vs tPA + EVT) SYNTHESIS (tPA vs only EVT) none showed improvement of outcomes |
| 2014 | MR CLEAN, EXTEND-IA, ESCAPE, SWIFT PRIME, REVASCAT showed benefit of EVT over IV tPA alone. Many were cut short after MR CLEARN showed efficacy or they hit their end point early. (Some say early ending may artificially show benefit). |
patwari 