William M. Feinberg Award for Excellence in Clinical Stroke High Explosive Treatment for Ultra-Acute Stroke: Hype of Hope

Proven treatments for acute stroke can be categorized by target population (ischemic stroke [IS], intracerebral hemorrhage [ICH], or both), utility (proportion of patients who can be treated), magnitude of efficacy, and cost. In general, high-cost interventions need to have high efficacy for health economic reasons; examples include intravenous alteplase, mechanical thrombectomy, and hemicraniectomy. Conversely, low-cost interventions, such as aspirin, typically have low efficacy. Having a medium-to-high efficacy intervention that was inexpensive and could be used worldwide in both IS and ICH would be a major advantage.

High blood pressure (BP) is common in acute stroke and associated independently with poor functional outcome, increased death, and early recurrence (IS) and hematoma expansion (ICH).1,2 Although debated since 1985,3 it was only recently demonstrated in the INTERACT-2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial-2) trial that intensive BP lowering was beneficial,4 as now promoted in international guidelines.5,6 In contrast, whether BP should be lowered acutely in IS remains unclear.7–9

Nitric oxide (NO) is a diatomic gaseous molecule of nitrogen and oxygen that is highly reactive and short lived. However, it is a fundamental physiological control and defense molecule that may have been used by early organisms as far back as 3 billion years.10 In human physiology, it has vascular regulatory, neurotransmitter, anti-infection, and reproductive roles. NO is synthesized from the amino acid L-arginine by 3 enzymes: endothelial, inducible, and neuronal NO synthase. Many effects of NO are mediated through the second messenger cGMP, which is catalyzed by guanylate cyclase from guanylate triphosphate. cGMP levels may be maintained by phosphodiesterase-5 inhibitors such as dipyridamole. NO is inactivated through oxidation to nitrite then nitrate; this reaction may be reversed and it now appears that NO may be synthesized from nitrate …

P roven treatments for acute stroke can be categorized by target population (ischemic stroke [IS], intracerebral hemorrhage [ICH], or both), utility (proportion of patients who can be treated), magnitude of efficacy, and cost. In general, high-cost interventions need to have high efficacy for health economic reasons; examples include intravenous alteplase, mechanical thrombectomy, and hemicraniectomy. Conversely, low-cost interventions, such as aspirin, typically have low efficacy. Having a medium-to-high efficacy intervention that was inexpensive and could be used worldwide in both IS and ICH would be a major advantage.
High blood pressure (BP) is common in acute stroke and associated independently with poor functional outcome, increased death, and early recurrence (IS) and hematoma expansion (ICH). 1,2 Although debated since 1985, 3 it was only recently demonstrated in the INTERACT-2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial-2) trial that intensive BP lowering was beneficial, 4 as now promoted in international guidelines. 5,6 In contrast, whether BP should be lowered acutely in IS remains unclear. [7][8][9] Nitric oxide (NO) is a diatomic gaseous molecule of nitrogen and oxygen that is highly reactive and short lived. However, it is a fundamental physiological control and defense molecule that may have been used by early organisms as far back as 3 billion years. 10 In human physiology, it has vascular regulatory, neurotransmitter, anti-infection, and reproductive roles. NO is synthesized from the amino acid L-arginine by 3 enzymes: endothelial, inducible, and neuronal NO synthase. Many effects of NO are mediated through the second messenger cGMP, which is catalyzed by guanylate cyclase from guanylate triphosphate. cGMP levels may be maintained by phosphodiesterase-5 inhibitors such as dipyridamole. NO is inactivated through oxidation to nitrite then nitrate; this reaction may be reversed and it now appears that NO may be synthesized from nitrate in humans (eg, from beetroot and green leafy vegetables). 11 The importance of NO in physiology was recognized in 1992 as molecule of the year, 12 and the awarding of Nobel prizes to Furchgott, Ignarro and Murad in 1998 for their contribution, along with that of Moncada, to the elucidation of NO as endothelium-derived relaxing factor and the mediation of its activity via cGMP. 13 NO levels are low in acute IS and even more so in ICH. 14,15 In view of the multiple potentially beneficial actions of NO, supplementation might then be beneficial. Preclinical studies of experimental stroke, many of these now rather dated, found that NO donors reduced lesion size, but only if administered early after stroke induction 16 ; NO also induced reperfusion in permanent models of ischemia. Clinically, NO can be administered as substrate (L-arginine or nitrate), as the gas (as done in neonatology), as a NO donating drug, 17 as a drug that stimulates endogenous NO synthesis (eg, statins), or as a drug that inhibits phosphodiesterase-5. Of these interventions, the most relevant for human study includes organic nitrates, such as glyceryl trinitrate (GTN, with transdermal, sublingual, or intravenous administration) and isosorbide mononitrate (oral), and the metal-NO complex, sodium nitroprusside (intravenous).
GTN is the medical name for nitroglycerin, a high explosive found in dynamite. 18 Alfred Nobel made his fortune in the late 1800s when he learnt to stabilize nitroglycerin and make its routine use feasible and safe; this fortune supports the prizes that are given his name. 19 Ironically, Nobel developed angina and used nitroglycerin for prophylaxis. Even more ironic, he died of a stroke (ICH) 19 ; so, if the GTN-stroke story told here is correct, he might have been able to treat himself with his own invention! Three phase II trials of transdermal GTN in patients with acute and subacute stroke found that this NO donor rapidly reduced peripheral and central BP, 24-hour BP, pulse pressure, and augmentation index (amounting to improved vascular compliance). [20][21][22] Although sodium nitroprusside, another NO donor, reduced platelet function, 23 GTN had no such effect 20 ; as a result, GTN may be given in ICH. When given to lower systolic BP by ≈10%, neither sodium nitroprusside nor GTN reduced cerebral blood flow or altered cerebral blood flow velocity. 21- 24 On the basis of the above data, the safety and efficacy of GTN was tested in 4011 patients with acute IS or ICH (within 48 hours of ictus 25  Oxide in Stroke). 26 GTN did not shift the modified Rankin Scale (adjusted common odds ratio 1.01; 95% confidence interval, 0.91-1.13). 9 However, GTN improved the modified Rankin Scale in patients randomized within 6 hours of stroke onset, a preplanned subgroup (called ENOS-early from here on). 9,27 Similarly, GTN improved the modified Rankin Scale in the small (n=41) phase II ambulance-based RIGHT (Rapid Intervention With Glyceryl Trinitrate in Hypertensive Stroke Trial) with paramedics performing screening, recruitment, consent, and treatment. 28,29 Data from all 5 GTN trials (4197 patients) were aggregated in an individual patient data meta-analysis. 30 These confirmed that GTN improved functional outcome if given within 6 hours but not later; time-dependent benefits were also seen for death, disability (Barthel Index), cognition (telephone Mini-Mental State Examination, telephone interview cognition scale, and verbal fluency), mood (Zung Depression Scale), and quality of life (Euro-QoL health utility status and Visual Analogue Scale). When administered within 6 hours, GTN was effective in IS and, potentially more so, in ICH; in IS, the benefit was seen in patients who received intravenous alteplase (either before or after GTN), and potentially in those who were not given thrombolysis. 30 The importance of low NO levels contributing to poor outcome after stroke is further highlighted by studies of diaspirin cross-linked hemoglobin, which increases levels of endothelin (a potent vasoconstrictor), and scavenges vascular NO. 31 In a small trial in patients with acute IS, treatment with diaspirin cross-linked hemoglobin was associated with a significant worsening of outcome, as measured using the modified Rankin Scale, Barthel Index, and National Institutes of Health Stroke Scale. 32 Hence, a model of vascular NO and stroke can be built whereby increasing age and vascular risk factors reduce NO levels, these falling further in acute IS, and particularly in acute ICH. Administering NO as GTN may improve outcome, whereas further lowering NO worsens outcome, as occurs through scavenging with diaspirin cross-linked hemoglobin ( Figure 1).
Two parallel streams of research are now ongoing. First, the existing preclinical data 16 need to be expanded with modern high-quality multicentre studies 33 involving appropriate randomization and blinding, eg, through the Multi-PART international consortium (http://www.dcn.ed.ac.uk/multipart/, accessed 18 June 2016). And second, further clinical trials are needed in the ultra-acute prehospital period after stroke. One trial of GTN is ongoing (RIGHT-2, http://right-2.ac.uk), and others will start shortly or are seeking funding.  If NO, say given as transdermal GTN, is eventually shown to be effective, it is likely that its effects will be mediated through several mechanisms. First, the time course whereby efficacy is inversely related to the time from onset to treatment mirrors that seen for proven reperfusion strategies based on intravenous alteplase and mechanical thrombectomy ( Figure 2). 34,35 That GTN might work through reperfusion is unsurprising in view of its known potent vasodilatory properties. Vasodilation might involve both enhancing collateral flow via surface pial arteries (ie, opening the backdoor 36 ) and main cerebral arteries (front door). Second, GTN might amplify the effects of alteplase, both through preparing patients for thrombolysis by lowering their systolic BP below 185 mm Hg before hospitalization, and by opening the artery around the occluding clot so as to improve access by fibrinolytic agents, whether endogenous or exogenous. Nonsignificant trends to more and earlier thrombolysis were seen in the RIGHT pilot trial. 29 Third, lowering BP might reduce hematoma expansion after ICH, 4 and early recurrence after IS. Fourth, GTN has cytoprotective and antiapoptotic properties 37 and might prevent ischemic cells from dying. Finally, other properties that might be of relevance include sympathetic stimulation and plasma volume expansion.
The apparent positive effects of GTN on multiple clinical outcomes suggest that future trials of NO donors need to factor in such measures to give a more holistic view of its effects. Furthermore, ambulance-based trials should assess the effect of the intervention on in-hospital treatments such as use of alteplase, which might increase and be started earlier. 29 In contrast, thrombectomy, hemicraniectomy, intensive care, and therapy might each be less necessary. For example, ENOS-early suggested that involvement by a physiotherapist might be reduced in patients randomized to GTN. 27 There is much to do to complete this story. Further trials of GTN (and possibly other NO donors) are needed because the existing data are small and largely come from a subgroup (ENOS-early) of a large neutral trial. Studies also need to be led by groups other than mine to expand the validity and diversity of data. Finally, stroke physicians may need to readjust their perspective that effective interventions have to be expensive; if GTN is effective, then it will break this link so that an easy to give intervention can be of relevance to both developed and developing countries, both major types of stroke, and cost <£5 (€6/$7) per patient. Ultimately, time will tell whether this developing story is hype or hope!