Chapter 31 Prevention and Treatment of Stroke

Medical management of stroke encompasses a wide range of therapies that include interventions directed at reducing the extent of acute injury, managing physiological parameters in the acute phase, and preventing recurrent strokes. Ischemic stroke is the most common form of cerebrovascular disease and will be the focus of this chapter, which will overview acute treatments and prevention measures. Only a brief mention of primary intracerebral hemorrhage (ICH) in regard to acute management and secondary prevention will be included.

Acute ischemic stroke (AIS) occurs after occlusion of an intracranial or extracranial vessel by a thrombus that in most cases has embolized from the heart or a more proximal vessel. Unlike acute myocardial infarction (AMI), in situ thrombosis is uncommon. As a consequence of acute vascular occlusion, a cascade of intracellular events (Fig. 31-1) is initiated; over varying periods of time, they lead to irreversible tissue injury such as infarction.¹ The temporal development of infarction within the ischemic brain region is quite variable, and portions of the ischemic brain tissue may not be irreversibly injured for many hours after the initial vascular occlusion.² Ischemic brain tissue that remains viable and potentially amenable to salvage with timely initiation of therapeutic interventions is called the ischemic penumbra, and this potentially salvageable tissue is the target of AIS therapies.^3,4 The basic concept underlying AIS therapy is that reducing the extent of brain infarction should translate into improved clinical outcome, as measured by commonly used outcome scales such as the modified Rankin Scale (mRS) or Barthel Index.⁵

Figure 31-1 Depiction of the major events that encompass the ischemic cascade of cellular injury.

DNA, deoxyribonucleic acid; NO, nitric oxide.

(Courtesy Dr. Wolf-Rudiger Schaebitz.)

The most important factor predisposing ischemic brain tissue to infarction is the severity of cerebral blood flow (CBF) decline.⁶ Regions with little or no residual CBF will evolve into infarction rapidly and are not the target of AIS therapies because reperfusion cannot in most cases be performed rapidly enough to salvage this ischemic core region. In the ischemic penumbra, CBF decline is more modest, and this ischemic tissue progresses more slowly toward infarction, providing a time window for intervention that can salvage tissue to some extent. A variety of definitions for the ischemic penumbra were suggested over time and are outlined in Box 31-1. Besides the severity of CBF decline, other factors that affect evolution of ischemic injury include temperature, glucose, blood pressure, and other metabolic factors.^7,8 The implication of these factors that contribute to the evolution of ischemic injury is that individual AIS patients have quite variable therapeutic time windows for successful therapeutic intervention, and that the earlier a therapy is initiated, the more likely it is to be beneficial. Acute ischemic stroke therapy can be divided into two broad areas: (1) recanalization/reperfusion approaches directed at improving altered CBF within ischemic tissue and (2) neuroprotection designed to impede the cellular consequences of ischemic injury. The focus of this chapter will be on the former because no neuroprotection strategies have been demonstrated to be of significant benefit. Recanalization/reperfusion can be accomplished with intravenous (IV) or intraarterial (IA) thrombolytics as well as mechanical devices. These approaches comprise the currently available AIS treatments.

Acute Stroke Therapy

The only AIS treatment currently approved by regulatory agencies is IV tPA initiated within 3 hours after stroke onset. Approval of this treatment was based on results of the NINDS tPA trial that demonstrated a highly significant improvement in 90-day outcome on various outcome measures including mRS, Barthel Index, and NIHSS.³³ The benefit was observed in different stroke subtypes and in patients with various ranges of baseline stroke severity, ranging from relatively mild to fairly severe.³⁴ Despite a risk of 6.4% for symptomatic intracranial hemorrhage with IV tPA treatment observed in the NINDS trial, the overall treatment effect was highly significant. Following the NINDS trial, several other studies of IV tPA were performed that tried to extend the therapeutic time window to 6 hours from stroke onset.^35–37 None of these demonstrated a significant benefit on the primary outcome measure chosen for the trial. However, a combined analysis of the European Cooperative Acute Stroke Studies (ECASS) I and II as well as the ATLANTIS trial demonstrated a significant treatment effect with IV tPA out to 4.5 hours from stroke onset.³⁸ This observation suggested that the therapeutic time window for IV tPA could be extended and was evaluated in the ECASS III trial. The study evaluated AIS patients between 3 and 4.5 hours after onset and reflected the European license for tPA: excluding patients over 80, those with very severe strokes, history of prior stroke, diabetes, and use of anticoagulants prior to stroke.³⁹ The ECASS III study demonstrated that 52.4% of tPA-treated patients achieved a favorable outcome of 0 to 1 on the mRS, compared to 45.2% with placebo treatment (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.02-1.76; P = 0.04). The results of ECASS III led to recommendations from the American Heart Association (AHA) and other groups that the use of IV tPA be extended to 4.5 hours in selected AIS patients.⁴⁰ Subgroup analysis of the ECASS III data suggested that patients older than 65 and those with more severe strokes had less benefit than younger patients or those with milder deficits⁴¹ (Box 31-3). Unfortunately, only standard CT scans were employed in the ECASS III trial, so it is unclear how more modern imaging techniques such as diffusion/perfusion magnetic resonance imaging (MRI) or perfusion CT may contribute to identifying AIS patients more or less likely to benefit from IV tPA in this extended time window when ischemic penumbral survival tends to wane.

Box 31-3 Subgroup Analysis of the ECASS III Trial of Intravenous tPA in the 3- to 4.5-Hour Time Window

Patient Characteristics Associated with Modest or No Benefit with tPA

Females

Age >65*

Moderate baseline stroke severity*

Diabetes mellitus

Hypertension*

Atrial fibrillation*

tPa, tissue plasminogen activator.

Adapted from Bluhmki E, Chamorro A, Dávalos A, et al: Stroke treatment with alteplase given 3.0-4.5 h after onset of ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol 8:1095–1102, 2009.⁴²

^* Denotes patients with an increased risk for symptomatic intracerebral hemorrhage (ICH).

Currently, IA thrombolysis remains an unproven therapy for AIS patients, despite its widespread use at larger centers. The only phase III trial that evaluated this therapeutic approach was the PROACT-III trial that compared prourokinase (n = 121) to placebo (n = 59) in severely compromised patients with angiographically confirmed large-vessel occlusion treated up to 6 hours after stroke onset.⁴² A prior safety trial demonstrated a reasonable safety profile. In the PROACT-II trial, 40% of treated patients achieved a favorable outcome, defined as an mRS score of 0 to 2, compared to 25% in the placebo group (P = 0.04). The rates of partial or complete recanalization were 66% and 18%, respectively. Symptomatic ICH was increased in the prourokinase group, but not significantly. The trial showed that IA therapy could be beneficial up to 6 hours from stroke onset in patients with large intracranial vascular occlusions. Prourokinase was not approved by regulatory agencies based upon this one modestly sized trial, and a second confirmatory trial was never performed. Prourokinase is not available for clinical use.

Studies of the IA use of tPA are limited to combination trials with initial IV tPA use followed by subsequent IA treatment. In the IMS I trial, the combined use of tPA both IV and IA was observed to carry a similar risk for ICH as IV tPA alone in the NINDS IV trial.⁴³ In the IMS II trial, patients initially received IV tPA within 3 hours of stroke onset. An angiogram was then performed, and if a clot was observed, IA therapy was initiated either through a standard catheter or an EKOS microinfusion catheter.⁴⁴ Among 81 patients included in the trial, 26 received IV tPA alone, 33 IV plus IA tPA via the EKOS catheter, and 19 the combination IA via a standard catheter. There was no control group, but when compared to the placebo group in the NINDS trial, this combined treatment approach tended to have a more favorable outcome. IMS III, a much larger trial comparing IV tPA with various combined IV and IA therapies, is ongoing, but recruitment has lagged. A European study comparing IV versus IA tPA is also ongoing.

The use of urokinase given IA was studied in the Japanese MELT trial that randomized 114 patients with angiographically confirmed middle cerebral artery (MCA) occlusion to active therapy or standard medical therapy within 6 hours of stroke onset.⁴⁵ The IA urokinase group achieved a favorable outcome (mRS 0-2) in 49.1% of patients, compared to 38.6% in the control group, a nonsignificant trend toward benefit in an underpowered trial. A detailed analysis of the randomized IA thrombolytic trials concluded that there was no evidence of proven benefit with this treatment approach when compared with the expected rate in a prognostic model.⁴⁶

Device recanalization was evaluated with both the MERCI retriever and PENUMBRA device. Both of these devices received U.S. Food and Drug Administration (FDA) clearance to remove clots in intracranial blood vessels but are not approved to treat AIS, a curious paradox when considering why a device would be used to remove a clot. Approval of the MERCI retriever was based upon an open nonrandomized trial in 141 AIS patients, most with anterior circulation occlusions, treated up to 8 hours after stroke onset who did not receive tPA.⁴⁷ These treated patients were then compared to historical controls, the placebo group from the PROACT-II trial. Partial or complete recanalization occurred in 48% of the patients treated with the MERCI retriever, but only 27.1% achieved an mRS score of 0 to 2 at 90 days, essentially the same as the 25% rate of mRS observed in the control group in the PROACT-II trial. Serious adverse events related to employment of the device occurred in 7.1% of the patients, but this did not include an additional 7.8% of patients who developed symptomatic ICH.

A second open-label study of a subsequent generation of the MERCI retriever, the Multi-MERCI study, was reported, but this study is difficult to interpret because concomitant use of IV and/or IA tPA was allowed and occurred in the majority of the patients in the study.⁴⁸ The partial or complete recanalization rate was slightly higher (57.3%), as was the rate of patients achieving a 90-day mRS score of 0 to 2 (36%). Symptomatic ICH occurred in 9.8% of patients, and serious adverse events occurred in 7.9%. The PENUMBRA device was also evaluated in an open trial and compared to historical controls from the PROACT II trial.⁴⁹ In this study, 125 patients were treated with the device up to 8 hours after stroke onset. Partial or complete recanalization occurred in 82% of the patients, device-related serious adverse events in 1.6%, and symptomatic ICH in 11.2%. At day 90, 25% of the patients achieved an mRS of 0 to 2, identical to the control group in the PROACT II trial.

Based on these two open studies that compared the device outcomes to historical controls from PROACT II, the devices both received clearance from the FDA for removal of intracranial clots. The trials do demonstrate that both devices effectively induce partial/complete vessel recanalization when employed up to 8 hours after stroke onset. However, the recanalization was not associated with improved clinical outcome, insofar as both trials demonstrated clinical outcomes essentially identical to the control group of untreated patients in PROACT II, and the rate of symptomatic ICH was concerning.

Despite the lack of proven clinical benefit, both IA tPA and device clot removal are used in some centers up to 8 hours and beyond after stroke onset. The lack of clinical benefit is concerning because both therapeutic approaches clearly induce recanalization of occluded vessels in the majority of patients treated, and this should translate into clinical improvement based upon the earlier time window IV tPA trials. The implication is that despite successful opening of occluded vessels in many patients, clinical benefit was not derived because not enough ischemic tissue was salvaged at the late time points evaluated, especially in the two device trials. Additionally, the rate of symptomatic hemorrhage rate seen in the MERCI and PENUMBRA studies may have detracted from potential clinical improvements. The results suggest that late recanalization alone is not sufficient for inducing clinical benefit, and those other factors such as tissue salvage at such late time points must be considered to demonstrate clinical efficacy.

In addition to recanalization therapies that have demonstrated clear benefit when initiated within 4.5 hours of stroke onset, the only other acute intervention with a documented significant improvement in outcome is the use of specialized stroke care units. In acute coronary care, specialized units have a long-standing history and proven track record. For AIS, the development and use of specialized care units is much more recent, and efficacy was documented later than for coronary care units. Several studies found that admission of AIS patients to stroke care units reduces mortality and disability when compared to care on general medical units with stroke team consultation.^50,51 The precise reasons for these benefits are uncertain but likely relate to stricter adherence to care guidelines, better blood pressure and glucose management, and earlier mobilization.⁵² Additionally, it is now apparent that management guidelines such as the AHA “Get with the Guidelines” recommendations reduce complications after AIS, and that these guidelines should be implemented both in stroke units and general hospital units if at all possible.⁵³

The other approach to AIS treatment besides recanalization/reperfusion is neuroprotection, or reduction of infarction by treatments targeting the manifold cellular consequences of focal brain ischemia, which has a long and undistinguished track record. In animal stroke models, many categories of neuroprotective drugs reduce infarct size, and some also improve functional outcome^54,55 (Box 31-4). The reduction of infarct size for many neuroprotective drugs occurred without reperfusion, implying that enough of the drug reached the ischemic penumbra in sufficient concentration to impede development of infarction. This can occur because there is sufficient residual CBF in the penumbral region to deliver the neuroprotective drug and allow this tissue to survive.

Box 31-4 Types of Neuroprotective Drugs That Have Been Evaluated as Potential Treatments for Acute Ischemic Stroke

NMDA antagonists

AMPA antagonists

Free radical scavengers

Growth factors

Calcium channel antagonists

GABA agonists

Serotonin antagonists

Potassium channel activator

Antiinflammatory agents

AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate.

Adapted from Schabitz WR, Fisher M: Perspectives on neuroprotective stroke therapy. Biochem Soc Trans 34:1271–1276, 2006; and Donnan GA: A new road map for neuroprotection. Stroke 39:242–248, 2008.^55,56

Based on preclinical data of varying quality and extensiveness, many neuroprotective drugs went into clinical development, including phase III trials in some cases.⁵⁶ None of the neuroprotective drugs demonstrated significant efficacy, and currently no neuroprotective drug is available for AIS treatment. Many reasons for the multitude of neuroprotective drug development programs were proposed regarding both the preclinical assessment of these agents and the clinical development programs⁵⁷ (Box 31-5). Neuroprotection as an AIS treatment strategy remains appealing either as monotherapy or in combination with reperfusion. A safe and modestly effective neuroprotective drug with clear stand-alone efficacy for improving outcome after AIS could be widely used, especially in hospitals without the adequate infrastructure for giving even IV tPA. Combining neuroprotection with reperfusion therapy can be envisioned in several ways. Very early initiation of a neuroprotectant could potentially extend survival of the ischemic penumbra, allowing for later deployment of an IV or IA reperfusion therapy. In animals, both high-flow 100% oxygen delivery and granulocyte colony stimulating factor (GCSF) have the capability to extend penumbral survival, but this approach has not yet been tested in clinical trials.^58,59 Another potential combination of neuroprotection with reperfusion would be to use an appropriate agent to reduce potential deleterious tissue consequences of successful reperfusion (i.e., reperfusion injury).⁶⁰ Neuroprotective drugs that affect free radicals or reduce the recruitment of inflammatory white blood cells (WBCs) may be particularly suited to reduce reperfusion injury, and clinical development programs with such agents after successful reperfusion should be considered.

Box 31-5 Potential Preclinical and Clinical Trials Flaws That May Have Hampered Neuroprotective Drug Development

Preclinical Testing Flaws

Inadequate sample sizes in treatment experiments

Lack of adequate physiological monitoring

Lack of blinding to treatment outcomes

Not testing the drug in animals that were female, aged, or had relevant comorbidities

Only testing the study drug in rodents

Only evaluating histological endpoints and not behavioral outcomes

Lack of determining effects on both ischemic gray and white matter

Clinical Trial Flaws

Treating patients too long after stroke onset

Including stroke subtypes not likely to respond to treatment, such as lacunar stroke patients

Moving to phase III trials without adequate assessment of the study drug’s pharmacology

Side effects precluded reaching the therapeutic blood level shown to be effective in animals

Inadequately powered phase III trials to detect a modest but clinically meaningful treatment effect

Using an insensitive or flawed primary outcome measure

Adapted from Gladstone DJ, Black SE, Hakim AM: Toward wisdom from failure: lessons from neuroprotective stroke trials and new directions. Stroke 33:2123–2136, 2002.⁵⁸

A final consideration for future neuroprotection development programs would be to use agents that reduce infarct size when given early after AIS, but also enhance the natural recovery processes that occurs weeks and months later.⁶¹ This combination approach is appealing because both the reduction of infarct size engendered by the neuroprotective effect and the recovery-enhancing effect will contribute to improved stroke outcome. Current pessimism related to neuroprotection for AIS could be replaced by guarded optimism, but the organization and conduct of clinical trials will be more complex and difficult than in the past.

The most important future directions for AIS therapy are to extend the treatment window beyond the currently proven 4.5 hours from onset with IV tPA and to maximize the therapeutic benefit of this treatment within the currently documented time-to-treatment window. An attractive hypothesis for accomplishing both objectives is to use advanced imaging to identify AIS patients with extensive, persistent ischemic penumbra, the target of acute stroke therapy.³ Two imaging modalities, diffusion- or perfusion-weighted MRI (DWI/PWI; Fig. 31-2) and perfusion CT (Fig. 31-3) may be appropriate for this task.^62,63 With DWI, regions of high-energy metabolism failure that developed cytotoxic edema can be readily identified and quantified as regions of hyperintensity that can be easily differentiated from normal brain regions. On PWI, various methods can be used to identify hypoperfused tissue, but approaches such as mean transit time mapping, time to peak mapping, and CBF mapping all have deficiencies in reliably differentiating among the ischemic core with very low CBF, the ischemic penumbra with moderate CBF, reductions, and oligemic tissue that is not destined for infarction.^64,65 Currently, it is suggested that Tmax mapping that corrects for the arterial input of contrast in normal brain contralateral to the ischemic region likely provides the best distinction among these three ischemic regions. The ischemic penumbra is thought to be represented by regions that are abnormal on PWI by Tmax thresholding but are normal on DWI, the so-called DWI/PWI mismatch.⁶⁶ Preliminary data support this concept because without therapy this DWI/PWI mismatch region is highly likely to demonstrate infarction on delayed T2 or fluid-attenuated inversion recovery (FLAIR) imaging. Magnetic resonance angiography (MRA) can also be acquired along with DWI and PWI and can depict the location of occlusion in large and medium-sized vessels.

Figure 31-2 Example of a diffusion and perfusion mismatch on an acute magnetic resonance imaging (MRI) scan.

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