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Disease-modifying therapies for SCD
Riociguat®, has been shown to improve function (increased 6-minute walk distance) and decrease vascular resistance in patients with pulmonary hypertension with- out SCD (NCT00855465).87 The impact of this agent on pain and cardiopulmonary function is currently being test- ed in 100 people with SCD at multiple sites, in the Sterio- SCD study (NCT02633397).
As a class of drugs, ‘statins’ decrease systemic inflam- mation and improve vascular health in the general popu- lation. Twenty-five people with SCD were treated with low-dose atorvastatin for 1 month: changes were observed in cholesterol and some markers of vascular health, but no conclusive findings were made.88 In a dose- finding study, performed in 26 people with SCD over 3 weeks, simvastatin was safe and increased nitric oxide levels, while decreasing markers of inflammation (C-reac- tive protein and interleukin-6).89 A 3-month follow-up study in 19 people with SCD showed an excellent safety profile, an improvement in the rate but not the intensity of pain, and salutary effects on some but not all markers of inflammation and vascular health.90 This class of agents is not being actively tested at this time, but its excellent safety profile suggests that it may have a useful role in the management of selected patients with SCD.
Targeting platelet activation and hypercoagulability
SCD is a hypercoagulable state with an incidence of thromboembolism comparable to that in individuals with some inherited thrombophilias.12,13,91-93 Overactivation of hemostatic components, including platelets and coagula- tion factors, contributes to the vasculopathy of SCD through increased endothelial activation, platelet-leuko- cyte aggregates, and increased inflammation.13,94-96 As such, these factors are seen as potential targets for novel phar- maceutical interventions (Online Supplementary Table S2B).
Recent results of studies investigating antiplatelet agents targeting GPIIb/IIIa have been disappointing. A single- center, phase II, randomized, double-blind, placebo-con- trolled study (NCT00834899) found the reversible GPIIb/IIIa inhibitor eptifibatide to be safe but it did not improve time to resolution of vaso-occlusive episodes or hospital discharge.97 A secondary analysis of these data did, however, reveal that eptifibatide reduced ADP-depen- dent platelet aggregation, platelet-leukocyte aggregates, and inflammatory cytokines.98 Another GPIIb/IIIa- inhibitor, abciximab, was withdrawn from a patient-ori- ented study due to insufficient recruitment (NCT01932554). Prasugrel, an irreversible inhibitor of platelet aggregation through the P2Y12 class of ADP receptors has also been studied. A phase II, double-blind, randomized, multicenter trial (NCT01167023) found that prasugrel was safe, reduced markers of platelet activation including P-selectin, and was associated with a trend toward decreased pain when compared to placebo.99 While it was a negative study and patients 18 years or older were not included, the seminal phase III Determining Effects of Platelet Inhibition on Vaso- Occlusive Events (DOVE) trial was still informative as one of the largest multinational phase III trials in pediatric SCD and found that prasugrel did not reduce the rate of vaso-occlusive episodes in pediatric and adolescent patients up to 17 years of age when compared to place- bo.100 In addition, a phase II study (HESTIA2, NCT02482298) assessing the impact of ticagrelor, a reversible P2Y12 antagonist, found that the drug was safe
but did not reduce the number of diary-reported pain-free days in adults with SCD.101
While SCD is a procoagulant disorder, with chronic acti- vation of the coagulation system through increased thrombin generation and diminished anticoagulant pro- teins,12,102 the clinical benefit of routine anticoagulant use in SCD is still largely unknown. For instance, warfarin, a vitamin K antagonist, has been associated with decreased D-dimer levels in adult patients with vaso-occlusive episodes.103 However, a recent phase II study (NCT01036802) evaluating its use in patients with pul- monary hypertension, which in some adults may be due to in-situ thrombosis formation within the pulmonary vas- culature, was terminated early due to poor accrual. Similarly, a phase II feasibility study (NCT02098993) investigating unfractionated heparin in acute chest syn- drome was also terminated due to poor enrollment. Interestingly, a low-molecular weight heparin, tinzaparin, shortened the durations of vaso-occlusive episodes and hospitalization compared to those in placebo-treated patients in a randomized, double-blind trial.104 A phase III study (NCT02580773) evaluating the effectiveness of tin- zaparin on time to resolution of acute chest syndrome is currently recruiting participants. A randomized, double- blind, phase II study (NCT01419977) evaluating prophy- lactic dosing of a low molecular weight heparin, dal- teparin, during vaso-occlusive episodes has been complet- ed and preliminary results indicate an insignificant impact on markers of coagulation, while reducing pain scores in hospitalized patients given the trial drug compared to those given placebo.105 Novel anti-Xa oral agents, too, are under investigation. A phase II study (NCT02072668) evaluating the impact of rivaroxaban on inflammatory markers during the non-crisis steady state has recently been completed. A phase III, placebo-controlled trial (NCT02179177) investigating the effect of prophylactic dosing of apixaban on daily pain scores is recruiting. Defibrotide, a sodium salt of a single-stranded poly- deoxyribonucleotide with anti-thrombotic and anti- inflammatory properties, is currently being evaluated pri- marily for safety (grade III/IV allergic reaction or hemor- rhage) in a phase II study (NCT03805581) among adult patients with SCD and acute chest syndrome.
Targeting leukocytes, cytokines, and other inflammatory mediators
Patients with SCD are in a constant inflammatory state primarily due to vaso-occlusion-induced hypoxia-reperfu- sion, endothelial damage, and activated and aging leuko- cytes, in part regulated by the microbiome.10,106-108 As such, there has been a growing interest among investigators interested in targeting these inflammatory pathways for potential clinical benefit in adult patients with SCD (Online Supplementary Table S2C). Use of inhaled mometasone, a corticosteroid, is being tested in two phase II studies (NCT02061202 – IMPROVE, NCT03758950 – IMPROVE2) to determine its effectiveness in reducing pain and inflammation among patients without asthma. Recent results indicate that the use of inhaled mometasone is fea- sible and that it can reduce circulating soluble vascular cell adhesion molecule and markers of macrophage activation, while improving daily pain scores.109,110 Invariant natural killer T (iNKT) cell activation is increased in patients with SCD and is regulated by the adenosine A2A receptor.111 Regadenoson, a partially selective adenosine A2A receptor
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