Question

the inclusion and exclusion criteria for thrombolytic therapy. Explain why each criteria listed is important.

Answer 1

Ans) Current literature, it is clear that the levels
of evidence supporting individual exclusion criteria for intravenous alteplase vary widely.

- Some exclusions and myths already have extensive scientific study such as the clear ben-
efit of alteplase treatment in elderly stroke patients, in those with severe stroke, in those with diabetes mellitus and hyperglycemia, and in those with minor EICs evident on CT.

- Some exclusions such as recent intracranial surgery are likely based on common sense and very likely will never have a randomized, clinical trial to evaluate safety.

- Most contraindications or warnings range somewhere in between. However, the dif-
ferential impact of each exclusion factor varies not only with the evidence base behind it but also with the frequency of the exclusion within the stroke population, the probability of the
coexistence of multiple exclusion factors in a single patient, and the variation in practice among treating clinicians.

1. Alteplase treatment of patients with mild ischemic stroke. On the basis of surveys of stroke centers and experts and a review of the literature, there is good evidence for clinical equipoise, a suggestion of potential benefit, and wide practice variation, in combination with likely a lower-than-average risk associated with
treatment. The PRISMS trial is currently enrolling patients to evaluate this concept.470 The inclusion of milder patients, if proven beneficial, has great potential to broadly increase the number of ischemic stroke
patients eligible for alteplase. We would consider patients with “rapidly improving symptoms” who have improved to only having minor deficits within this category of mild symptoms. Our group has a strong con-
sensus that patients with improving symptoms but still with significant deficits that are otherwise eligible for alteplase should be treated.
2. Multimodal cerebral imaging to identify treatment candidates among previously alteplase-ineligible patients.
The promise of developing a “tissue clock” based on tissue viability rather than an arbitrary time window is extremely appealing. This is especially relevant to patients who wake up with their deficits (≈20% of ischemic stroke patients) and it is very unclear when
the stroke actually occurred. However, for multimodal imaging to significantly affect alteplase eligibility, the time window must be substantially lengthened, likely >8 to 12 hours from onset. Small increments in length-
ening the time window are not likely to significantly increase the numbers of eligible patients on the basis of the patterns of patient arrival to medical attention.
These multimodal imaging techniques clearly warrant further study, especially in terms of the natural history of infarct appearance in these imaging techniques as the infarct progresses and standardization of imaging techniques.
3. International consensus/harmonization of guidelines for alteplase inclusion/exclusion. As mentioned in the methodology section, we intentionally did not address the varying exclusion criteria and restrictions across theworld and instead focused on the FDA regulations and AHA/ASA guidelines. However, we believe that harmonization of the guidelines for use would be valuable and potentially could reduce confusion about the differences between guideline statements. We suggest that an international task force to harmonize the alteplase treatment guidelines would be an appropriate first step.
4. Alteplase treatment of patients with ischemic stroke who may be anticoagulated. As the population ages, use of anticoagulation will continue to increase, making a thorough understanding of the risks and benefits
of alteplase treatment in the setting of anticoagulation even more important. The introduction of novel anticoagulants has further complicated this issue, and the risks
associated with these newer agents are largely unknown.
5. Alteplase treatment of patients with periprocedural or perioperative ischemic stroke. We note that in general patients undergoing procedures are typically at a higher risk for ischemic stroke but are also at higher risk for
bleeding complications after a surgical procedure. To further complicate matters, each individual procedure likely has its own individual bleeding risks, making the study of a homogeneous population nearly impossible.
However, more frequent surgical and endovascular surgical or interventional procedures among patients at risk
for stroke would be a reasonable place to start evaluating the risks of treatment such as coronary bypass surgery or peripheral vascular disease repair. In addition, studies of
stroke prevention strategies during the perioperative and periprocedural period, including the risks of stopping antithrombotic medications, would be ideal.
6. Alteplase treatment of patients with acute ischemic stroke who have had recent ischemic stroke. The existing evidence appears not to justify totally excluding patients with a history of any size and severity of isch-emic stroke in the preceding 3 months from receiving
intravenous alteplase for an acute ischemic stroke. It currently is unknown how soon after stroke it is relatively safe to administer intravenous alteplase for an acute ischemic stroke (1 day, 1 week, 1 month, or 3
months) and how best to quantitatively and qualitatively estimate the potential of increased risk of sICH on the basis of the duration of time since the prior stroke, infarct volume, infarct severity, location of prior stroke, and neurovascular imaging characteristics. Studies to address these questions would further the field’s collective understanding of the scientific rationale behind this particular contraindication.
7. Alteplase treatment of patients with preexisting disabilities and dementia who sustain an acute ischemic stroke. Obtaining a better understanding of the complex
interactions that affect patient outcome after thrombolysis should be a priority for future research. Clearly, age alone should not be an exclusion, nor should a preexisting extremely mild dementia, for example.
However, as more and more comorbidities are added to a patient’s history, the likelihood of a good outcome probably becomes less and less. There are several risk prediction scores currently in the literature, but many of these are predictive Of only hemorrhagic transformation risk. Any risk prediction modeling research would need to include both the risk of hemorrhagic transformation and the chances
of an improved outcome after intravenous alteplase and would need to be prospectively validated in a controlled study rather than implemented purely on the basis of
epidemiological data.
The writing group suggests that the following topics are of lower yield for increasing/improving access or eligibility for
alteplase treatment:
1. Evaluation of treatment of elderly stroke patients.
Although there is good consensus about the benefit of alteplase in the elderly stroke patient among stroke experts in the United States, this consensus does not extend to other countries and is still listed as a caution on the FDA package insert. However, our group
believes that the literature supporting treatment in the elderly is substantial, and further study would not likely add much to this evidence. Instead, our group suggests further education of the medical community about this
literature to dispel the myth that elderly patients do not benefit from alteplase.
2. Uncommon exclusions from alteplase. Although it would be ideal to have definitive science behind every single eligibility criteria for alteplase treatment of acute ischemic stroke, we recognize that the most uncommon exclusions will likely never be feasible to study, and we suggest focusing limited resources on other, higher-priority research questions. We would add several criteria to this list of rarer exclusions, including but not limited to small, asymptomatic, unruptured intracranial aneurysms and small, asymptomatic, incidentally discovered benign intracranial neoplasms, that is, meningioma.