Abstract
The only treatment that has been proven to improve outcome after ischemic stroke is to reperfuse the brain by removing the arterial obstruction. All animal and clinical studies show that brain tissue exposed to the reduced blood flow inherent after an arterial occlusion dies quickly, in proportion to the reduction of flow. Brain tissue where there is the most profound reduction of flow (the ischemic “core”) dies within minutes. In areas where flow is less severely reduced (the ischemic “penumbra”), tissue death occurs more gradually, dependent on the adequacy of collateral flow. The faster that normal flow can be re-established, the less tissue death and the less consequent disability occurs. This chapter deals with systemic thrombolysis.
The only treatment that has been proven to improve outcome after ischemic stroke is to reperfuse the brain by removing the arterial obstruction. All animal and clinical studies show that brain tissue exposed to the reduced blood flow inherent after an arterial occlusion dies quickly, in proportion to the reduction of flow. Brain tissue where there is the most profound reduction of flow (the ischemic “core”) dies within minutes. In areas where flow is less severely reduced (the ischemic “penumbra”), tissue death occurs more gradually, dependent on the adequacy of collateral flow. The faster that normal flow can be re-established, the less tissue death and the less consequent disability occurs. This chapter deals with systemic thrombolysis. Endovascular thrombectomy is discussed in Chapter 6.
Intravenous tPA is the only FDA-approved medical therapy for acute ischemic stroke, based on the pivotal NINDS tPA Stroke Study.1 Since its approval in 1996, the utilization of tPA has steadily increased worldwide. In the US, the thrombolysis rate of all strokes went from 4% in 2003 to 7% in 2011.2
The first and most important step in stroke treatment is to recognize that a stroke is occurring, which has been covered in the previous chapters. However, because acute ischemic stroke is a clinical diagnosis and there is no rapid laboratory test with high sensitivity and specificity to confirm its presence, treatment with tPA is often carried out in patients where the diagnosis is not certain. Reassuringly, treatment of stroke “mimics” rarely produces hemorrhagic complications.3 In most series in experienced stroke centers, the stroke-mimic treatment rate is 10–20%, but no higher.
The second step then is appropriate selection of stroke patients for tPA. Intravenous tPA is indicated for acute ischemic strokes of all types, e.g. due to embolism from the heart or proximal arteries, or thrombosis of large or small intracranial arteries, of all degrees of severity, and with most comorbidities. But within this broad umbrella, patient selection is critical. If guidelines are followed, there are substantial benefits and the risks are minimized. On the other hand, if these are violated, then the risks begin to outweigh the benefits. Many of the original contraindications to IV tPA have been relaxed in light of accruing evidence of safety and benefit. This is reflected in the most recent guidelines4 and alteplase package insert.5 As a result, there is some variability in how strictly the published exclusion criteria are applied in practice. For the most part, the indications and contraindications we list below follow published guidelines. We have indicated beneath each guideline where we might allow some flexibility in interpreting these criteria. As a general rule of thumb, the less severe and disabling the stroke, the less likely we are to ignore relative contraindications, and vice versa.
The other critical step in tPA treatment is to administer the drug as quickly as possible. The most effective way to improve results with tPA is by administering the drug as soon as possible after symptom onset – “time is brain” – with best results occurring when treatment is started within 90 minutes of symptom onset. Gradually decreasing benefit is seen as time elapses up to 4.5 hours, so that all causes of treatment delay, including unnecessary diagnostic tests, should be identified and eliminated (Figure 5.1). A handful of studies are under way to assess whether the time window of tPA administration can safely be extended to patients presenting late or those with stroke symptoms upon awakening. We will cover this topic later in the chapter.
Figure 5.1 Model of favorable outcome at 3 months as a function of time to start of IV tPA treatment.
tPA Indications
1. Age 18 or older – There are no data to guide treatment in children. However, there are case reports of older children being treated with tPA using adult criteria.
2. Clinical diagnosis of ischemic stroke causing a measurable neurological deficit – In most but not all cases, NIHSS ≥ 3. However, there is no absolute lower NIHSS cutoff, remembering that the NIHSS does not measure disability. We use the criterion, “Would the neurological deficit be at all disabling if it were to persist?”
3. Onset of stroke symptoms well established to be less than 180 minutes (or 270 minutes [4.5 hours] in Europe and some US centers) before treatment would begin – We have addressed the importance of establishing the time of onset in Chapter 2. Intravenous tPA between 3 and 4.5 hours after stroke onset has been demonstrated to be effective in a randomized clinical trial in Europe, the ECASS III trial,7 and is incorporated in the AHA guideline recommendations. It is approved in Europe but not yet approved by the FDA in the USA.
tPA Contraindications
Strong Contraindications
1. Known history of intracranial hemorrhage – The alteplase package insert recommends only to “use caution” in treating patients with recent ICH, but it remains an absolute contraindication in the AHA/ASA guidelines. We would treat a patient with a remote (> 3 months old) ICH as long as the cause of the bleeding was no longer present.
2. Symptoms suggestive of subarachnoid hemorrhage – However, in a patient with “the worst headache of my life,” if careful reading of the CT shows no SAH, and the patient otherwise has a clinical presentation consistent with focal ischemic stroke, then treatment with tPA should be given.
3. Any evidence of bleeding on the pretreatment head CT – If there is any bleeding seen on the CT, the patient should not be treated. The CT should be carefully reviewed and any lesions suggestive of bleeding would exclude treatment. Remember that isodense subdural hematomas can be easily overlooked. It is uncertain whether patients with the parenchymal “microbleeds” often seen with amyloid angiopathy that are seen on gradient-echo MRI (and not CT) can be safely treated. The available data suggest that the risk of symptomatic ICH after tPA is increased and long-term functional outcome worse in patients who have > 10 cortical microbleeds on a baseline MRI. It is unclear whether the benefit of tPA in this patient population outweighs the risk of bleeding. We do not recommend a screening MRI in patients prior to tPA, though it might be reasonable in a patient with a relatively minor stroke and strong suspicion of underlying amyloid angiopathy.
4. Intracranial neoplasm, untreated arteriovenous malformation (AVM), or aneurysm that is at risk of bleeding – If the patient has an aneurysm or AVM that has been surgically clipped or repaired more than 3 months ago, we would probably allow treatment, though, if quickly available, we might do a CTA first to confirm obliteration of the lesion. The current guidelines state that it is probably reasonable to treat patients with unsecured unruptured aneurysms < 10 mm in size. No recommendation is made about larger aneurysms. Untreated AVMs should not be treated. Many patients with benign brain tumors such as meningiomas have been treated without complications. However, patients with more aggressive parenchymal brain tumors such as gliomas or metastases should not be treated.
5. Significant hypodensity or mass effect on pretreatment CT – Early ischemic changes on the CT are not a contraindication. However, clearly demarcated hypodensity suggesting that the stroke is more than 3 hours old would argue against treatment. Mass effect with compression of the ventricle or midline structures would suggest a non-stroke etiology.
6. Previous intracranial surgery, or serious head trauma within the past 3 months.
7. Sustained systolic blood pressure > 185 mmHg (with warning for > 175 mmHg, per the alteplase package insert), or sustained diastolic blood pressure > 110 mmHg – Aggressive treatment is necessary to lower blood pressure to these levels (see comments on blood-pressure control, below).
8. Active internal bleeding.
9. Received heparin within 48 hours AND has an elevated PTT.
10. Platelet count < 100 000. A platelet count is not necessary unless there is a clinical suspicion of thrombocytopenia. The 100 000 level, while in the guidelines, is arbitrary and it may be safe to treat patients with platelet counts of > 50 000 as long as there is no history of clinical bleeding. Again, stroke severity will play into this decision.
11. INR > 1.7 or known bleeding diathesis – We tend to be a little more conservative than published guidelines about the INR level that would allow treatment with IV tPA. In the NINDS trial, the cutoff used was a prothrombin time (PT) of 15 seconds. There is debate as to what INR level correlates with this level of PT. However, we know that increased bleeding occurs when patients treated with warfarin reach an INR of 1.7 or higher. In a patient with an INR of 1.6, we would consider omitting tPA and going for endovascular thrombectomy (EVT) if it is immediately available and the patient has an intracranial large-vessel occlusion (LVO). Even with these considerations, it should be emphasized that an INR is not required prior to treatment if the patient is not on warfarin or there is no reason to suspect abnormal liver function or coagulopathy.
12. Known bleeding diathesis.
13. Use of direct thrombin inhibitors or factor Xa inhibitors within the last 48 hours or if coagulation tests are abnormal (e.g., aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate factor Xa activity assays). There have been case reports where patients with acute ischemic stroke occurring within 48 hours of taking dabigatran are given the immediately acting reversal agent idarucizumab and then successfully and safely given tPA.8 The same may be true with andexanet alpha for patients on Xa inhibitors now that it is available. However, more clinical experience with this practice is needed before it can be routinely recommended. Again, patients on direct thrombin inhibitors or Xa inhibitors might be better candidates for EVT if they also harbor an LVO.
14. Suspected or known aortic arch dissection – This should be considered in patients presenting with chest pain or hypotension.
15. Suspected or known septic embolization/infective endocarditis – Embolic cerebral infarcts from endocarditis may have a high rate of spontaneous hemorrhagic conversion. Thrombolysis in this setting is expected to have a higher hemorrhage rate.
Relative Contraindications
1. Minor or rapidly improving symptoms – This scenario presents one of the most difficult decisions in treating patients with tPA and is the second most frequent cause for non-treatment of otherwise eligible patients (the first is being outside the established time window of 3–4.5 hours from onset). Guidelines state not to treat a patient who is rapidly improving. However, many such patients recover substantially but are still left with a disabling deficit. Even patients with very mild strokes benefit from tPA treatment, and intracranial bleeding complications in such patients are very rare. Therefore, instead of automatically excluding all patients who are improving or have minor deficits, we would still treat the minor or improving patient whose deficit, at the time you are ready to treat, would be disabling if it persisted. The PRISMS trial, which was terminated early because of slow recruitment and was therefore underpowered, did not show any benefit in treating non-disabling minor strokes.9
2. Ischemic stroke in the last 3 months – The current guidelines recommend against treating with IV tPA in this population. The alteplase package insert removed the exclusion. Because the highest risk of stroke recurrence is within the first 3 months, it is common that patients present with this relative “contraindication.” The risk of tPA treatment in these patients is creating hemorrhagic transformation of the previous stroke. Here in particular the severity of the previous and incident strokes, and the elapsed interval between them, is important. The smaller and more remote the previous stroke, and the more severe the incident stroke, the more likely we are to allow tPA treatment.
3. Gastrointestinal or urinary tract hemorrhage within the last 21 days – In some cases, we are not so rigid with regard to time intervals for GI and GU bleeding, allowing for clinical judgment based on the severity of the anticipated risk versus the possible benefit. For instance, one might be willing to treat a patient with a very severe stroke who has had some recent GI bleeding, knowing that this complication might occur, but also knowing that without treatment the outcome is likely to be very poor. This risk would be less acceptable in a patient with a milder stroke. The main caveat is that if the patient is actively bleeding, as evidenced by a low hemoglobin/hematocrit, that patient should not be treated. If you do treat a patient with risk of bleeding, then consultation with the appropriate surgical consultant who could help manage the hemorrhagic complication should be obtained at the time of treatment, in anticipation of, and not after, the complication occurs.
4. Major surgery or serious extracranial trauma within previous 14 days – again, severity of potential complications must be weighed against severity of the stroke. Obtaining a surgical consult prior to tPA administration is recommended.
5. Arterial puncture at a non-compressible site, or lumbar puncture – Guidelines state that tPA should not be given within 7 days of such punctures, but clinical judgment is necessary. Usually, 24 hours should be a sufficient interval if there is no evidence of an especially traumatic puncture.
6. Seizure at the onset of stroke – Patients with seizures were excluded from the initial studies of tPA because they made it difficult to assess how much of the neurological deficit was due to the seizure and how much due to the stroke. This is important when carrying out a clinical trial, but less important in clinical practice. If you are sure that a stroke has occurred that is causing a disabling deficit, even if the patient has had a seizure, it is appropriate to treat that patient if he or she qualifies by other criteria (particularly no evidence of head trauma with the seizure, and no mass effect on CT). CTA showing arterial occlusion, or DWI showing acute ischemic damage, can help in this situation if either can be carried out quickly. CT perfusion showing hyperemia may also point to a seizure rather than a stroke.
7. Blood glucose < 50 mg/dL or > 400 mg/dL – A patient who remains symptomatic after a high or low glucose is treated and normalized need not be excluded.
8. Hemorrhagic eye disorder, and other conditions likely to cause disability if bleeding occurs – Recent ocular surgery such as for cataracts, and other minor surgery, are not necessarily contraindications. Judgment is needed. Treatment of a patient with some ocular conditions, such as a recently detached retina, might pose too great a risk of visual loss, especially if the stroke is relatively mild. The best course is to try to reach the specialist consultant and ask for an opinion about bleeding risk.
9. Myocardial infarction in the previous 3 months – Judgment should be utilized in interpreting this exclusion. Both the time interval from the MI and the severity of the MI should be taken into consideration. Per the guidelines, it is reasonable to treat recent NSTEMI and STEMI involving the right or inferior myocardium, whereas it may be reasonable to treat left anterior STEMI. The main risk here is hemorrhagic pericarditis and pericardial tamponade. This would certainly be a risk with a recent transmural MI or open-heart surgery, but a smaller MI, even if recent, would not be considered a contraindication. Concurrent acute ischemic stroke and acute MI is not a contraindication to tPA.
10. Pregnancy – The concern with the use of tPA in pregnancy is the risk of uterine bleeding, not a teratogenic effect (class C). Additionally, tPA is too large a molecule to cross the placenta. The benefit to the mother of using tPA, especially taking into consideration the severity of the stroke, must be weighed against the risk of uterine bleeding, especially in high-risk patients (e.g., placental abruption, intrapartum bleeding). EVT might be an alternative but exposes the fetus to radiation. As a side note, tPA can probably be safely administered during lactation because it is broken down by the infant’s GI tract and its large size does not allow it to cross the gut–blood barrier.
11. Intracranial arterial dissection – the efficacy and safety of tPA administration in the setting of a known or suspected intracranial arterial dissection are not well studied and remain unclear. It should not be given if there is any associated subarachnoid bleeding on the CT. Patients with extracranial dissection can be safely treated, since most strokes in this setting result from emboli to the intracranial arteries.
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