Stroke is the leading cause of disability and the third leading cause of death in the U.S. Approximately 700,000 new and recurrent strokes occur in the U.S. each year. While stroke is generally considered a disease of the elderly, up to 30% of stroke occur in people under the age of 55. And though stroke is felt to be preventable by controlling risk factors (smoking, hypertension, diabetes, hi cholesterol) the incidence of morbidity and mortality has not changed in recent years. Futhermore, the trend is not anticipated to change with the increasing numbers of elderly in the U.S.
Cost-benefit decisions for interventions for stroke need to be individualized. Stroke is one of the most feared events among people and many are willing to accept the risk of potential treatment-related complications to avoid being left in a dependent state because of stroke. In a survey of over 1200 persons at increased risk of stroke (prior TIA or non-disabling stroke, or major risk factors) nearly half (45%) of respondents considered major stroke to be a worse outcome than death. And more importantly 15% of respondents were willing to trade off little chance of or no survival to avoid a major stroke (Samsa). It naturally follows then that the resultant disabled state after failed attempted treatment for major stroke is the important determinant for patients desiring treatment, not the type of stroke (ischemic or hemorrhagic) leading to the disabled state.
Intravenous (IV) recombinant tissue plasminogen activator (tPA, alteplase) is currently the only treatment for acute ischemic stroke approved by the FDA. The use of IV tPA is based on the National Institutes of Neurological Disorders and Stroke (NINDS) studies (Parts I and II) that revolutionized the treatment of acute ischemic stroke. For the first time an effective and safe therapy for stroke was demonstrated. Patients treated with 0.9 mg/kg IV tPA within three hours of the onset of stroke had significantly lower NIH Stroke Scale scores(NIHSS) at 24 hours and were 30% more likely than placebo to have minimal or no disability at three months. Symptomatic hemorrhage was 6% in the tPA treated group compared to 0.6% in placebo but there was a non-significant reduction in mortality in the tPA treated group.
These results have been repeated throughout the US and Canada. The STARS trial, a phase IV multi-center open-label prospective study demonstrated similar efficacy and safety in 389 patients treated at 57 university and community centers. Numerous community and academic centers have reported similar experience with the use of t-PA for acute ischemic stroke using the NINDS study inclusion/exclusion criteria.
Although the benefit of the use of IV tPA is well established, there are still a considerable number of patients that do not respond to this treatment. In the NINDS study only 21% of patients with NIHSS> 10 achieved minimal or no disability at three months .This is likely due to low recanalization rates estimated to be 30-40% with iv t-PA. The site of occlusion is also important as larger more proximal vessel occlusions tend to be less responsive to thrombolysis (delZoppo).
The natural history of stroke can be best understood by looking at the placebo groups of multi-center trials evaluating acute ischemic stroke therapies. The NIH Stroke Scale (NIHSS) has been shown to be one of the best predictors of outcome from stroke. This is a scale of stroke severity based on neurologic exam findings. Higher numbers on the NIHSS indicate increased severity of stroke. Numerous groups have shown that stroke outcome is inversely proportional to stroke severity at presentation. For example in the placebo group of the TOAST trial over 85% of persons with NIHSS > 15 presenting with acute stroke had severe disability or were dead at 7 days. This is in contrast to only 22% of those with a NIHSS < 7 ending up with severe disability or death (Figure 1).
The NINDS study also demonstrated that stroke carries significant morbidity and mortality. Approximately 75% of patients with an NIHSS score >17 at baseline had a poor outcome. Nearly 40% of IV tPA treated patients had severe disability or died at three months compared to nearly 50% of the placebo group. Thus research has focused on using more effective and definitive therapies.
Intra-arterial thrombolytic therapy has many advantages over IV therapy. PROACT II was the first randomized, placebo-controlled study to confirm that intra-arterial therapy is effective for treatment of acute ischemic stroke and can be performed safely. This study demonstrated that patients treated with intra-arterial pro-urokinase within six hours of onset of symptoms were 15% more likely to achieve minimal or no disability at 3 months than patients treated with heparin alone. Furthermore though there was a 10% symptomatic hemorrhage rate in the treatment group compared to 2% in the placebo group, there was a non-significant decrease in mortality in the pro-urokinase group. Recanalization rates were significantly higher (66%) than those reported with intravenous t-PA (33%).
Though the PROACT II trial did not lead to approval of pro-urokinase by the FDA for the treatment of acute stroke, it confirmed that stroke could be successfully and safely treated up to six hours in a randomized controlled trial. Animal models of focal brain ischemia also support treatment of acute stroke up to 6 hours from onset. And in fact the International Stroke Trial III (IST-3) in the UK and Europe is enrolling patients for treatment of acute ischemic with IV tPA up to 6 hours from onset of symptoms.
Intra-arterial therapy for acute ischemic stroke has been used for years in selected centers throughout the world. Beneficial off-label use of urokinase or tPA has been reported in a number of uncontrolled, nonrandomized case series, and many neurointerventionalists have adopted this therapy, making it standard practice in many communities.
In a recent review of the safety and effectiveness of intra-arterial therapy, Lisboa et al. identified 27 studies with 852 patients treated with IAT (IA or combined IV/IA thrombolytic therapy) for acute ischemic stroke and 100 controls. Forty-one other studies were excluded due to small numbers (<10) or TIA patients were included. Most of the studies were either prospective or retrospective case-series. There were three randomized studies (2 placeo-controlled and one comparing IV/IA to IA alone). Only one was a large randomized, phase III trial.
The mean ages were 63.5 years in the IAT group and 65.3 in the control group. Baselin NIHSS scales were not available in all studies but clinical descriptions in most cases indicated that patients enrolled had severe strokes. The most commonly reported agent was urokinase (n=472) followed by tPA (185), prourokinase (134) and streptokinase (7). The majority (78%) of control patients received heparin. Arterial occlusions were found in the following vessels; 85 ICA (33cervical); 570 MCA (M1 or M2, 47 T-occlusions); 176 vertebrobasilar. Mean time to treatment was highly variable and depended on the study with 6, 8 12 and 24 hour treatment windows. Posterior circulation infarcts tended to be treated later up to 48 hrs. Recanalization rates varied from 35.5% to 100% with mean 72.2%.
Favorable outcomes (modified Rankin Score 0-2, Glasgow Outcome Scale =1, or Barthel Index >90) were significantly more common in the IAT treated group compared to the controls (41.5% vs 23%; P=0.002). There was a significantly highr rate of SICH in the treated group compared to controls (9.5% vs. 3%;P=0.046). Despite this excess hemorrhage rate, mortality was significantly lower in the IAT group compared to controls (27.2% vs. 40%: P=0.004).
| Outcomes |
IAT (n=852) |
Controls (n=100) |
OR |
P |
| Favorable Outcome |
41.5% |
23 |
2.4 |
0.002 |
| SICH |
9.5 |
3 |
3.4 |
0.046 |
| Death |
27.2 |
40 |
0.56 |
0.004 |
The use of combined therapy (IV + intra-arterial) may offer an advantage over intraarterial (IA) alone. The main advantage may be earlier administration of thrombolytics, as the IV portion is given without the need to wait for angiography. The Emergency Management of Stroke (EMS) study published in 1999 was the first randomized study to use this methodology. Thirty-five patients were randomized to receive IV/IA or placebo/IA within 3 hours from onset of symptoms. Recanalization was significantly greater in the IV/IA group compared to the placebo/IA group (81% vs. 50% TIMI 2 or 3). The lack of significant improvement despite higher recanalization rates in the IV//IA group has been attributed to the inordinate number of deaths in the IV/IA group, small study size and higher baseline stroke severity. Three of the 5 deaths in the IV/IA treated group were felt to be unrelated to the therapy they received: one patient had acute aortic dissection developed a fatal hemopericardium after administration of IV tPA; one patient pulled her femoral sheath and had enough blood loss to precipitate an acute myocardial infarction and arrest; the third patient died of breast cancer 87 days after treatment. Subsequent to the EMS study some centers have reported their successful and safe use of this combined therapy.
The results of the Interventional Management of Stroke (IMS) study were recently reported at the 27th International Stroke Conference in San Antonio Texas (February 2002). This was a multi-center safety and efficacy trial that enrolled 80 patients using this combined IV/IA therapy. Patients with NIHSS score > 10 received 0.6 mg/kg IV t-PA within 3 hours from onset of stroke and then were taken directly to angiography for the administration of 0.3 mg/kg intraarterial tPA. The results were then compared to the NINDS IV t-PA treated group and the placebo group. Baseline stroke severity was normalized by comparing the IMS results to those NINDS patients with NIHSS>10.
Clearly better outcomes were achieved with a similar acceptable 6% symptomatic hemorrhage rate (Table 2). Asymptomatic intracranial hemorrhage (ASICH) was higher in the IMS group compared to placebo and IV tPA but less than PROACT II. This is most likely attributable to patients with larger infarcts undergoing IA therapy, which have a higher spontaneous hemorrhage rate compared to smaller infarcts.
| Outcome |
IMS I 0.6 IV + IA N= 80 |
NINDS |
PROACT II |
||
| Placebo (N=211) NIHSS>10 |
0.9 IV t-PA N = 182 |
N=180 MCA < 6 hrs |
Placebo |
||
| Mortality @3mo. |
16% |
21%(24%) |
17%(21%) |
25% |
27% |
| SICH < 36° |
6 % |
1% |
6.7% |
10% |
2% |
| Serious systemic bleed |
3% |
0.5% |
1% |
||
| ASICH |
38% |
3% |
6% |
46% |
16% |
The IMS I study also showed that the odds of returning to normal or an independent state (mRankin Score 0-1;NIHSS 0-1) with combined IV-IA therapy were greater than 2.0 compared to IV tPA treated patients in the NINDS trial(Table 3). Furthermore clinical improvement parralleled radiographic improvement with more than 50% of patients treated with combined IV-IA achieving complete (TIMI 3) or near complete (TIMI 2) recanalization (Table 4).
| Outcome |
IMS I (N=80) |
NINDS Placebo (N=211) |
Odds Ratio (95%,CL) |
| mRankin 0-1 |
30% |
18% |
2.29 |
| mRankin 0-2 |
43% |
28% |
2.04 |
| NIHSS 0-1 |
25% |
15% |
2.24 |
| Outcome |
IMS |
PROACT II |
|
| Recanalization |
N=80 |
N=180 MCA < 6 hrs |
Placebo |
| TIMI 3 |
11% |
19% |
2% |
| TIMI 2 |
45% |
47% |
18% |
Newer third-generation thrombolytic drugs have been studied in the treatment of acute MI with varying success. Only one agent, reteplase (Retivase), has been studied for use in the treatment of acute stroke. Reteplase has shown greater efficacy than alteplase (tPA or Activase) for the treatment of acute MI, defined by higher recanalization rates and more complete recanalization. Reteplase is a modified form of alteplase. It is less fibrin selective and is thought to penetrate clot better due to this lower affinity. Additionally, reteplase has a longer half-life (15-18 min vs. 3-6min), which allows bolus dosing. Therefore reteplase is considered to be a better choice than alteplase for the treatment of acute ischemic stroke as more complete and earlier recanalization is expected to lead to better clinical recovery.
A few centers have reported the use of intra-arterial reteplase for treatment of acute ischemic stroke within 6 hours. Qureshi et al. treated patients considered poor candidates for IV tPA with 8 Units (U) of intra-arterial reteplase. Inclusion criteria included 1) time from onset > 3 hours, 2) severe stroke NIHSS > 16, and 3) recent major surgery (< 2 weeks). Fourteen of eighteen (88%) had complete or near complete recanalization. Seven of sixteen (44%) had significant neurologic improvement (> 4 point decrease on NIHSS) at 24 hours and 9 of 16 (56%) patients had improvement at 7 to 10 days. Symptomatic hemorrhage occurred in 1 patient. In this dose escalation study, it was also found that higher doses up to 8 U lead to higher recanalization, but two patients had recanalization before achieving the maximum dose of 8 U.
More recently Qureshi et al. reported that aggressive mechanical clot disruption with low-dose reteplase led to complete or near complete recanalization in 16 of 19 patients. Neurologic improvement (NIHSS lowering of > 4 points) was seen in 63% at 7 to 10 days after treament. Seven of 19 were functionally independent at follow-up. There were no SICHs and 3 ASICHs. Mortality was high at follow-up (10 of 19; 53%). Massive ischemic stroke was the cause in 6 of 10 mortalities (1 MI with cardiogenic shock) in the first 7 to 10 days. There were 2 withdrawals of care and one death due to severe medical complications (pneumonia, renal failure, respiratory failure).