Intravenous Thrombolysis for Acute Ischemic Stroke

Fig. 6.1

History of clinical trials of IV thrombolysis

Finally, following the publication of the ECASS-III study in 2008, the time window for administration of intravenous (IV) thrombolysis was expanded from 3 to 4.5 h of symptom onset. It has to be emphasized that even though patients treated within 3 to 4.5 h after symptom onset benefit from r-tPA therapy, their outcome was worse than those treated within 3 h underlining once more the time dependency of the treatment.

6.3.2 Clinical Use

IV thrombolysis is usually only administered in hospitals. Within 10–20 min after arrival, the stroke-suspected patient should be sent for emergency imaging. Most centers use CT of the brain for exclusion of hemorrhage. The decision for IV thrombolysis is based on the result of the laboratory test, given that the time from symptom onset is less than 4.5 h, and potential contraindications regarding the use of IV thrombolysis have been ruled out. Contraindications against r-tPA use are discussed below (see Contraindications). Once the decision is made, treatment should be applied immediately on-site, striving for a “door-to-needle time” of less than 60 min. A CT angiography or other means of vascular imaging are not required for IV thrombolysis. Perfusion imaging will be helpful under special conditions, e.g., wake-up stroke, but it is also not mandatory. If performed, none of these should delay administration of treatment.

6.3.3 Dosage and Application

Alteplase¹ is the only preparation of r-tPA available for clinical use. Up to 100 kg body weight (BW), dosage is weight-dependent (0.9 mg r-tPA/kgBW; maximum dose: 90 mg). Ten percent of the calculated dose is given as a bolus, and the rest is continuously infused over 1 h. The infusible solution has to be prepared right before IV—delivery by dissolving lyophilized r-tPA in a solution containing L-arginine. In Japan, r-tPA was approved only for the dosing of 0.6 mg/kgBW. Recent study failed to demonstrate the non-inferiority of 0.6 mg r-tPA/kgBW compared to 0.9 mg r-tPA/kgBW [6]. For this reason, there are no general recommendations regarding the use of this lower dosage in the USA and Europe.

6.3.4 Contraindications

There are numerous formal contraindications to the utilization of IV r-tPA. Most of them were coined in analogy to the exclusion criteria defined by experts in the NINDS trial. Some of these criteria, as suitable as they may have been in the context of a clinical trial, have been shown to unreasonably limit the use of alteplase in clinical practice. For this reason, guidelines established by major stroke societies have been developed and adjusted over the last decades. The following section will give a short overview over some of the most relevant contraindications. For a comprehensive and more detailed review, it is strongly advised to consult national and/or international guidelines (e.g., American Heart Association/American Stroke Association [7], German Neurological Society [8], Japan Stroke Society [9]) (Table 6.1).

Table 6.1

Contraindications of administration IV r-tPA

	Exclusion criteria
Patients with acute stroke within 3 h from symptom onset	History of intracranial hemorrhage
	Severe hypertension (systolic > 185 mm Hg or diastolic > 110 mm Hg)
	Previous serious head trauma in previous 3 months
	Prior ischemic stroke in previous 3 months (AHA/ASA) or 1 month (Japan Stroke Society)
	Coagulopathy/thrombocytopenia
	• Coagulopathy: INR > 1.7, aPTT > 40 s, or PT > 15 s
	• Thrombocytopenia: a low platelet count (<100,000/mm³)
	Use of anticoagulants
	• Current use of vitamin K antagonist with an INR > 1.7
	• Heparin received within 48 h, with elevated aPTT
	• Current use of LMWH within 24 h
	• Current use of direct thrombin inhibitors or factor Xa inhibitors within 48 h, with elevated coagulation tests (such as aPTT, INR, platelet count, and ECT; TT; or appropriate factor Xa activity assays)
	Severe hypoglycemia or hyperglycemia
	• Blood glucose concentration <50 mg/dL (2.7 mmol/L) but considerable if symptoms do not improve rapidly after correction of glucose level
	Extensive hypoattenuation on CT scan (>1/3 cerebral hemisphere)
	Only minor or rapidly improving stroke symptoms (clearing spontaneously)
Additional criteria of patients with acute stroke within 3–4.5 h from symptom onset	Advanced age (>80 years)
	Severe stroke (NIHSS > 25)
	Current use of oral anticoagulant regardless of INR
	History of both diabetes and prior ischemic stroke

6.3.4.1 Intracranial Hemorrhage

Acute intracranial hemorrhage of any kind is an absolute contraindication to IV thrombolysis. Likewise, the history of ICH formally is an absolute contraindication. IV thrombolysis may be considered in these patients based on clinical judgment bearing in mind relevant factors (e.g., time passed since ICH, cause of ICH, extension of residual defect, recurrence of bleeding).

6.3.4.2 Severe Hypertension

Systolic blood pressure over 185 mm Hg and diastolic blood pressure over 110 mm Hg are contraindications to IV r-tPA therapy. If the blood pressure can be controlled and lowered below the defined thresholds prior to application, the use of alteplase can be considered safe.

6.3.4.3 Previous Serious Head Trauma

IV thrombolysis is not recommended by the AHA/ASA guidelines in patients with serious head trauma within the preceding 3 months.

6.3.4.4 Previous Stroke

IV thrombolysis is not recommended by the AHA/ASA guidelines in patients with ischemic stroke within the last 3 months and by the guidelines of the Japan Stroke Society within 1 month after the index event.

6.3.4.5 Coagulopathy/Thrombocytopenia/Use of Anticoagulants

IV thrombolysis is not recommended in patients with platelet counts <100,000/mm³, INR > 1.7, aPTT > 40 s, or PT > 15 s as safety and efficacy of treatment is unknown in this population. IV thrombolysis is also contraindicated in patients with a low platelet count (<100,000/mm³). The evidence supporting this is very weak as there are only few published case reports. As unsuspected abnormal platelet counts seems to be extremely unlikely, it is not recommended to postpone IV thrombolysis waiting for the results of the platelet count. Regarding those patients taking vitamin K antagonist, current AHA/ASA guidelines suggest an INR of 1.7 as cutoff for IV thrombolysis: while in patients with an INR ≤ 1.7 treatment might be justified, it is contraindicated in those with an INR > 1.7. IV thrombolysis is not recommended by the AHA/ASA in patients who received LMWH for anticoagulation purpose in the last 24 h.

6.3.4.6 Oral Direct Thrombin Inhibitors and Factor Xa Inhibitors

Direct oral anticoagulants (DOAC) have shown to be at least as effective as warfarin in the prevention of stroke in patients with atrial fibrillation.Together with the simpler handling, this has led to a rapid increase of their prescription over the past years. Unfortunately, there is still no standardized way of addressing some of the major problems that come with their use. Most importantly, standard coagulation test (INR, Quick, aPTT) are not reliable enough to discriminate if the DOAC is still active or not. Even though direct Xa inhibitors may alter prothrombin time (PT) and activated partial thromboplastin time (aPTT) and direct thrombin inhibitors pTT and INR, there are no cutoffs defined. Furthermore, in patients with renal failure, the elimination half-life of oral direct thrombin inhibitors as well as factor Xa inhibitors is increased. Thrombin time may be a sensitive indicator for ongoing direct thrombin inhibitor activity. Similarly, assays directly measuring factor Xa activity may be useful in the case of factor Xa inhibitors [10].

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