FDA approves use of drug to reduce risk of cardiovascular events in certain adult patient groups

Background: In sickle cell disease (SCD), hemoglobin S (HbS) polymerizes upon deoxygenation, reducing red blood cell (RBC) deformability. RBC deformability can be measured over a gradient of oxygen tensions (pO2) with the Laser Optical Rotational Red Cell Analyzer (Lorrca) ektacytometer (RR Mechatronics). Oxygen gradient ektacytometry generates 3 key parameters: 1) EImax, RBC deformability at normoxia; 2) EImin, minimum RBC deformability upon deoxygenation; and 3) the point of sickling (PoS): the oxygen tension at which a 5% decrease in deformability is observed during deoxygenation, reflecting the patient-specific pO2 at which sickling begins (Figure 1A). Previously we showed that oxygen gradient ektacytometry-derived biomarkers correlate with measures of SCD disease severity and hemolytic rate (Rab et al. Blood 2018), and is associated with vaso-occlusive crisis (VOC) frequency (Rab et al, Blood 2019). In this study, we confirm these observations in 2 independent cohorts and extend it to occurrence of acute chest syndrome (ACS), stroke including silent cerebral infarction (SCI), and transcranial Doppler (TCD) outcome. Methods: We analyzed 2 cohorts of SCD patients; an adult patient cohort of 53 SCD patients, enrolled at either University Medical Center Utrecht, The Netherlands (UMCU, n=25) or Hospital Lyon France (LIBM, n=28), and a pediatric patient cohort of 190 SCD patients enrolled at Texas Children's Hospital, USA (TCH). Subjects were HbSS or HbS/β-thalassemia, with a substantial number of subjects on hydroxyurea (HU) therapy (adult cohort 66% and pediatric cohort 86%), and not on chronic transfusion therapy. Correlations between oxygen gradient ektacytometry-derived biomarkers and the clinical complications of stroke or silent infarcts (SCI), ACS, VOC were assessed in both pediatric and adult patients. Patient groups generally did not significantly differ significantly by age, gender or HU treatment in the adult cohort except for age, which was lower in the ACS+ group (25.3years (y) compared to 32.0y) and also lower in the VOC+ group (27.1y compared to 35.8y). In the pediatric cohort, patient groups differed significantly in the ACS+ group compared to the ACS- group by age (ACS- group 8.37, ACS+ group 10.9y) and HU treatment (ACS- group 76%, ACS+ group 93%). Similarly, age was significantly higher in the Stroke+ group compared to the Stroke- group (14.0y compared to 9.3y), which was also found when studying VOC (VOC+ group 11.6y, VOC- group 8.2y). Results: In the pediatric cohort, PoS was significantly higher in patients with ACS (mean 40.3 compared to 34.9 mmHg, p=0.0001, Figure 1B). In the adult cohort, PoS was also higher in those with ACS although this did not reach significance (p=0.053, Figure 1C). In the pediatric cohort, PoS was higher in patients with stroke or SI (mean 43.0 mmHg compared to mean 37.3 mmHg, p<0.05), Figure 1D). This finding was replicated in the adult cohort (p<0.05, Figure 1E). EImin and EImax in both cohorts were significantly lower in patients who experienced stroke or SCI (all p<0.05). PoS was higher and EImin and EImax lower in subjects with elevated TCD measurements (all p<0.01, Figure 1F and G). In the adult and pediatric patient cohort, PoS was higher in patients with recent VOC (both p<0.05, Figure 1H and I). Differences in mean PoS between pediatric and adult patient cohorts could be due to differences in treatment, age, genetic background or technical differences between Lorrca devices. Lower significance levels found in the adult patient cohort could be due to smaller sample size. Conclusion: We show that oxygen gradient ektacytometry provides functional, clinically relevant next generation biomarkers that are associated with ACS, stroke and VOC. This study therefore further validates the clinical usefulness of these biomarkers, in particular in relation to cerebral vasculopathy. Since our results merely describe an association and not causality further validation is warranted to establish how well oxygen gradient ektacytometry can assess disease severity. However, its parameters could already provide the clinician with information about patient RBC characteristics and sickling propensity that could aid in clinical decision making. Our results provide a rationale for further development of these biomarkers in the evaluation of novel therapies as part of clinical care, or clinical trial endpoints. Disclosures Rab: RR Mechatronics: Research Funding. Bos:RR Mechatronics: Research Funding. Cnossen:Takeda: Research Funding; Shire: Research Funding; Baxter: Research Funding; Bayer: Research Funding; Sobi: Research Funding; CSL behring: Research Funding; Nordic Pharma: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding. Wijk:Agios Pharmaceuticals Inc.: Research Funding; RR mechatronics: Research Funding. Sheehan:Emmaus: Research Funding; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. van Beers:Pfizer: Research Funding; RR mechatronics: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

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P1587Comparison of effects of lowering blood pressure in individuals with blood pressure <140/90 mmHg and hypertension guideline recommendations: a systematic review and meta-analysis of randomised trials

European Heart Journal ◽

10.1093/eurheartj/ehz748.0347 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

A Mohammad ◽

N Wang ◽

E Atkins ◽

R Kanukula ◽

M D Huffman ◽

...

Keyword(s):

Systematic Review ◽

Blood Pressure ◽

Cardiovascular Events ◽

Data Generation ◽

Hypertension Guideline ◽

Recommended Treatment ◽

Patient Groups ◽

Lowering Drug ◽

Meta Analyses

Abstract Background Implementation of evidence-based medicine requires minimising delays between data generation and guideline creation. We examined the temporal relationship between accumulating evidence from randomized controlled trials (RCTs) of blood pressure (BP) lowering drug therapy among individuals with SBP<140 mmHg, DBP<90 mmHg, or both, and hypertension guideline recommendations over time. Methods A systematic review was conducted by searching MEDLINE for RCTs between January 1966 and February 2018. Included trials randomized patients to BP lowering drug(s) vs placebo/no treatment or to more vs less BP lowering with at least 1000 patient-years of follow-up per treatment group, and provided data relevant to BP lowering in patients with SBP<140 mmHg, DBP<90 mmHg, or both (hereafter <140/90 mmHg). Included trials were classified according to major patient groups and whether all patients had baseline BP <140/90 mmHg, or most control group patients had BP <140/90 mmHg during follow-up, which was selected because this is the BP against which interventions were compared. Two reviewers independently extracted relevant data from included RCTs and hypertension guidelines. Cumulative meta-analyses of cardiovascular events were conducted and were compared to hypertension guideline recommendations. The primary outcome was major cardiovascular events. Results A total of 73 trials (n=300,805) were included, including 16 trials/subgroups with all participants baseline BP <140/90mmHg. Benefits of BP lowering in individuals with usual BP <140/90 mmHg began to emerge in the 1970s (Figure). Most evidence was from trials that included some or all patients with hypertension at baseline, but most patients had BP <140/90 mmHg during follow-up due to regression to the mean and background treatment. Starting from 1992, 22 trials reported results by baseline hypertension status with no difference in cardiovascular event relative risk reduction among those with and without hypertension (relative risk 0.87 [95% CI 0.84–0.90] vs 0.86 [0.83–0.90], respectively. Until 2017, no major guidelines recommended treatment initiation or intensification for patients with baseline BP <140/90 mmHg, apart from the periods during which some guidelines recommended treatment at lower thresholds for patients with diabetes and chronic kidney disease (Joint National Committee 1997 to 2014; European Society of Hypertension 2007 to 2009). Cumulative meta-analyses of trials Conclusions Evidence of benefits of BP lowering among individuals with usual BP <140/90 mmHg have been demonstrated for decades. However, there has been a substantial delay between data generation and guideline recommendations. This delay was may be due to the inappropriate emphasis on baseline rather than usual BP levels, and relatively narrow evidence synthesis, which does not fully account for evidence generated across various major patient groups.

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