Omecamtiv Mecarbil in Black Patients With Heart Failure and Reduced Ejection Fraction Insights From GALACTIC-HF

BACKGROUND Omecamtiv mecarbil improves cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Consistency of drug bene ﬁ t across race is a key public health topic. OBJECTIVES The purpose of this study was to evaluate the effect of omecamtiv mecarbil among self-identi ﬁ ed Black patients. METHODS In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) patients with symptomatic HF, elevated natriuretic peptides, and left ventricular ejection fraction (LVEF) # 35% were randomized to omecamtiv mecarbil or placebo. The primary outcome was a composite of time to ﬁ rst event of HF or cardiovascular death. The authors analyzed treatment effects in Black vs White patients in countries contributing at least 10 Black participants. RESULTS Black patients accounted for 6.8% (n ¼ 562) of overall enrollment and 29% of U.S. enrollment. Most Black patients enrolled in the United States, South Africa, and Brazil (n ¼ 535, 95%). Compared with White patients enrolled from these

H eart failure (HF) is a well-known global health issue that disproportionately affects Black patients whose risk of developing HF has been estimated as high as 20 times that of White patients, 1 and who bear a disproportionate burden in terms of prevalence, hospitalization rates, and mortality. 2,3Exacerbating this disparity is the under-representation of Black patients in biomedical research, 4,5 including pivotal drug trials. 6A recent systematic review indicated that, even as late as 2019, only about half of clinical trials reported race data and that average participation of Black patients remains approximately 5%, 7 with similar estimates of participation rates seen for HF-specific trials. 8[12] The GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) trial evaluated the effects of omecamtiv mecarbil, a first-in-class myosin activator, in patients with HF and reduced ejection fraction (EF).Omecamtiv mecarbil augments myosinactin cross-bridges resulting in increased contractility. 13This novel approach avoids the increases in intracellular calcium levels and myocardial oxygen demand commonly associated with adverse effects of traditional inotropes (calcitropes), such as myocardial ischemia, ventricular arrhythmias, and death. 14,15The GALACTIC-HF trial demonstrated an 8% lower relative risk (HR: 0.92 [95% CI: 0.86-0.99];P ¼ 0.025) of a composite primary outcome of time to first event of HF or death from cardiovascular causes without increased risk of myocardial ischemic events, ventricular arrhythmias, or death from cardiovascular causes. 16The primary results reported the race subgroup analysis of the primary endpoint compared across 4 groups (White, Black, Asian, and other) showing no statistically significant difference in effect estimates for Black vs White patients. 16The current study performed a more complete and detailed evaluation of the efficacy and safety of omecamtiv mecarbil among self-identified Black patients compared with White patients participating in GALACTIC-HF.

METHODS
PATIENTS AND TRIAL.7][18] Briefly, the GALACTIC-HF trial randomized patients between 18  were the largest single race group in the overall trial as well as within the 3 countries included in the current analysis (n ¼ 1,129).Alternative approaches such as using composite race groups (eg, non-Black or non-White) were not pursued as they are inherently less informative (due to conflating distinct race groups) and because there is recent consensus that this approach is not the preferred method of reporting and analyzing race data. 19,20ATISTICAL ANALYSIS.Continuous variables were summarized by mean AE SD or median (IQR), as appropriate.Categorical variables were summarized with counts and percentages.Potential differences in treatment effects across race groups were assessed using interaction tests comparing the estimated effects of omecamtiv mecarbil (vs placebo) in Black compared with White patients.Time-to-event outcomes were analyzed using Kaplan-Meier estimates and Cox proportional hazards models.We also per-

RESULTS
The GALACTIC-HF trial analyzed a total of 8,232 patients, all of whom had race data available.Among these, 562 (6.8%) self-identified as Black. 16The mean   1. Black patients were more often female, younger, had lower LVEF, were more likely to have hypertension, and were less likely to have atrial arrhythmias or ischemic etiology compared with their White counterparts (all P # 0.001).At baseline, Black patients had higher systolic blood pressure, lower Nterminal pro-B-type natriuretic peptide (NT-proBNP) levels, higher cardiac troponin I levels, and higher estimated glomerular filtration rate.Treatments for HF varied substantially across race as well.At the time of enrollment, Black patients were more likely to be prescribed each aspect of guideline-directed medical therapy, including renin-angiotensin-blocking therapies, beta-blockers, and mineralocorticoid receptor antagonists (all P < 0.05).However, Black patients were less likely than White patients to have an implanted defibrillator or cardiac resynchronization therapy (P < 0.001).Sensitivity analyses based on Fine-Gray competing risk models produced consistent results (Supplemental Table 1).
Regardless of randomization assignment, Black patients had higher rates of the primary outcome than White patients (Table 2).The primary event rate in Black patients was 38 per 100 patient-years compared with 31 per 100 patient-years in White patients (P ¼ 0.017).When adjusted for age, sex, and country, the HR for the primary event in Black vs White patients was 1.33 (95% CI: 1.13-1.56).Similarly, there was greater risk of HF hospitalization among Black patients, with an adjusted HR of 1.38 (95% CI: 1.15-1.65).
On the other hand, there was no significant difference detected in terms of the risk of cardiovascular mortality in the adjusted model (HR: 0.87, 95% CI: 0.67-1.13).We also performed sensitivity analyses stratified by U.S. (n ¼ 1,177, 357 Black patients and 820 White patients) or non-U.S.enrollment (n ¼ 487, 178 Black patients and 309 White patients), summarized in Supplemental Table 2. Black patients from U.S. sites had higher rates of the primary outcome compared with White U.S. patients (adjusted HR: 1.37, 95% CI: 1.14-1.64),whereas Black patients outside the United States (ie, Brazil and South Africa, n ¼ 178) showed a directionally similar but statistically nonsignificant trend toward higher primary event rates when compared with their White counterparts (adjusted HR: 1.18, 95% CI: 0.83-1.67).

EFFECT OF OMECAMTIV MECARBIL IN BLACK PATIENTS
COMPARED WITH WHITE PATIENTS.The overall results of treatment with omecamtiv mecarbil were broadly consistent between Black and White patients (Central Illustration).The primary, secondary, and biomarker outcomes in Black patients compared with White patients are summarized in Table 3.In testing the effect of omecamtiv mecarbil on the primary endpoint (time to cardiovascular death or first HF event) across race, we found no statistically significant difference between Black and White patients (Figure 1).The estimated treatment effect on the primary endpoint in Black patients (HR: 0.83, 95% CI: 0.65-1.06)was similar to that of White patients from the same countries (HR: 0.88, 95% CI: 0.73-1.05).In terms of absolute event rates, among Black patients the estimated effect of omecamtiv mecarbil was a reduction in the primary event rate of 7.7 events per 100 patient-years (95% CI: À17.9 to þ2.4), compared with saving 6.0 events per 100 patient-years in White patients (95% CI: -11.9 to 0.0).Similarly, the secondary endpoints of time to first HF hospitalization and time to cardiovascular death did not show any statistically significant interaction by race comparing Black and White patients (Figure 2).The estimated treatment effect on absolute event rates for HF hospitalization was saving 6.0 events per 100 patientyears in Black patients (95% CI: -14.9 to þ2.8) compared with saving 3.8 events per 100 patient-years in White patients (95% CI: -8.9 to þ1.2).Sensitivity analyses based on Fine-Gray competing risk models produced consistent results (Supplemental Table 3).
Examination of the effect of omecamtiv mecarbil on vital signs and biomarkers (measured as a change from baseline to 24 weeks and comparing omecamtiv mecarbil with placebo) revealed similar treatment effects in Black compared with White patients (Table 3).Changes in heart rate, troponin, and NT-proBNP appeared consistent across race with omecamtiv mecarbil treatment causing a decrease in heart rate and NT-proBNP levels, and a small increase in troponin I levels in both groups.Similarly, both race groups showed no association of omecamtiv mecarbil with changes in creatinine, potassium, or adverse events (Table 4).Among the numerous endpoints examined, the only nominally significant interaction of treatment with race was for blood pressure.Among Black patients, treatment with omecamtiv mecarbil was associated with a 3.4 mm Hg increase in systolic blood pressure (95% CI: 0.2-6.7),whereas among White patients there was no significant change in systolic blood pressure (-0.7 mm Hg, 95% CI: 2.6-1.3), with an unadjusted interaction P value of 0.02.
We performed sensitivity analyses of treatment effect stratified by U.S. (n ¼ 1,177, 357 Black patients and 820 White patients) or non-U.S.enrollment (n ¼ 487, 178 Black patients and 309 White patients).
There were no statistically significant differences by race in the effect of omecamtiv mecarbil on the primary outcome regardless of whether examining U.S.

DISCUSSION
Race should never be assumed to modify the treatment effect of medical therapies because this could contribute to discrimination or reduced access, [21][22][23][24] but, conversely, quantifying the treatment effects of medications in diverse racial groups is of high public health importance.Moreover, achieving equitable enrollment in clinical trials continues to be a challenge. 8The current data indicate that the GALACTIC-HF trial was successful in enrolling Black patients, and that Black patients who received omecamtiv mecarbil had a trend toward benefit in clinical outcomes that was not statistically different from that in White patients or the overall trial result.These data should provide reassurance for patients, providers, and policy-makers that Black patients should be treated similarly with respect to this novel medication.
The overall effect of omecamtiv mecarbil appeared consistent across the 2 race groups, including similar event and biomarker indicators of both efficacy and safety.Indeed, the primary endpoint effect estimates in this current analysis are numerically closer than those in the original race subgroup analysis included in the primary results. 16This subtle difference could theoretically be explained by geographic/regional differences confounding the effect of race, but this is statistically difficult to explore with so few Black patients in many participating countries/regions.
Although there was 1 statistically significant interaction by race (ie, change in systolic blood pressure), it is important to view this finding in the context of examining a wide variety of endpoints without adjustment for multiple comparisons.Blood pressure effects of omecamtiv mecarbil in Black patients may deserve further investigation, but additional evidence would be required before this could be accepted as a true difference.Reassuringly, for both Black and White patients, omecamtiv mecarbil was associated with statistically significant reductions in heart rate and NT-proBNP, and no significant adverse events.
Omecamtiv mecarbil had a consistent effect across the 2 race groups studied despite substantial differences in baseline patient characteristics and overall event rates between Black and White patients.The baseline characteristics of Black patients in this study were similar to those seen in previous studies, with Black patients with HF more likely to have comorbid hypertension, younger age, lower LVEF, and less likely to have atrial fibrillation or ischemic etiology. 3,25,26Notable among these differences are 2 key characteristics that are associated with differences in omecamtiv mecarbil benefit: atrial fibrillation and LVEF. 27For both characteristics, the differences by race (less atrial fibrillation and lower LVEF in Black patients) would be expected to associate with greater benefit of omecamtiv mecarbil. 27 findings were recently reported in both HF clinical trials and population studies. 26,31In the specific setting of GALACTIC-HF, the higher rate of medication use in Black patients could theoretically also reflect the higher prevalence of hypertension and higher baseline blood pressure among Black patients when compared with White patients.In contrast to medical therapy, there were disparities in the use of   implanted defibrillators and cardiac resynchronization therapies (both less frequent in Black patients), which have been described in previous registry and public data. 32,33These data also demonstrate higher overall event rates among Black patients with HF driven mostly by hospitalization.
Although the overall proportion of Black patients in GALACTIC-HF of 6  Black patients treated with omecamtiv mecarbil -85 years of age with symptomatic HF (New York Heart Association functional class II, III, or IV) and left ventricular ejection fraction (LVEF) #35%, elevated natriuretic peptides, and either were currently hospitalized for HF (inpatients) or had either made an urgent visit to the emergency department or been hospitalized for HF within 1 year before screening (outpatients).Key exclusion criteria included hemodynamic or clinically unstable state, mechanical circulatory support, renal failure (estimated glomerular filtration rate of <20 mL/min/1.73m 2 of body surface area), systolic blood pressure <85 mm Hg, or recent acute coronary syndrome.Patients were randomized 1:1 to receive omecamtiv mecarbil or placebo in addition to standard care using an interactive Webresponse or voice-response system and a sequestered, fixed randomized schedule.The omecamtiv mecarbil doses were 25 mg, 37.5 mg, or 50 mg twice daily, adjusted according to plasma levels of the drug in a double-blinded fashion.Postrandomization assessments (clinical and serum) were performed at weeks 2, 4, 6, 8, 12, 24, 36, and 48 and every 16 weeks thereafter.The study protocol was approved by the relevant ethics committees and all participants provided informed consent.The primary outcome was a composite of time to first HF event or death from cardiovascular causes.Additional endpoints of interest were components of the primary composite endpoint, stroke, biomarkers of treatment effect, and safety outcomes.The A B B R E V I A T I O N S A N D A C R O N Y M S EF = ejection fraction HF = heart failure LVEF = left ventricular ejection fraction NT-proBNP = N-terminal pro-B-type natriuretic peptide

FIGURE 1
FIGURE 1 Effect of OM on the Primary Outcome

STUDY LIMITATIONS.
Our work has a few limitations to note.Although the recruitment of Black patients into the study was substantial and compared favorably with contemporary studies, the trial was still not designed to be adequately powered for race-based stratified analyses of the primary and secondary endpoints.Additionally, we did not have data on socioeconomic status or other social determinants of health that may contribute to varying outcomes among participants, so these data cannot shed more light on specific questions related to these factors.Similarly, although subgroup analysis of race was prespecified, the full analytic detail for this work was determined after trial completion and this work still suffers all the inherent limitations in such analyses, including increased type I error risk.Despite these limitations, the favorable direction of the effect estimates and overall consistency of the results are reassuring.Furthermore, the strong enrollment of Black patients and inclusion of 260 primary events should be able to provide reasonable estimates of the treatment effect of omecamtiv mecarbil in this important patient population.Finally, to maintain sharp focus we did not consider ethnicity (Hispanic compared with non-Hispanic) or other race groups in the trial (eg, Asian patients).CONCLUSIONSGALACTIC-HF enrolled more Black patients than any contemporary HF trial.The effect of omecamtiv mecarbil in Black patients was similar to White counterparts from the same countries of enrollment.
of Cape Town, South Africa; h Wits Clinical Research, Johannesburg, South Africa; i TREAD Research, Cardiology Unit, Department of Internal Medicine, Tygerberg Hospital and Stellenbosch University, Parow, South Africa; j University Hospitals and Case Western Reserve University, Cleveland, Ohio, USA; k Estudios Clínicos Latino América, Rosario, Argentina; l Duke University School of Medicine and Duke Clinical Research Institute, Durham, North Carolina, USA; m British Heart Foundation Cardiovascular Research Centre, Glasgow, United Kingdom; n University of Brescia, Brescia, Italy; o Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; p Cytokinetics Inc, South San Francisco, California, USA; and the q San Francisco Veterans Affairs Medical Center and School of Medicine, University of California-San Francisco, San Francisco, California, USA.The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate.For more information, visit the Author Center.

TABLE 1
Baseline Characteristics of Black vs White Patients in GALACTIC-HF (Brazil, South Africa, and the United States) estimated glomerular filtration rate; GALACTIC-HF ¼ Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure; HF ¼ heart failure; ICD ¼ implantable cardioverter defibrillator; KCCQ ¼ Kansas City Cardiomyopathy Questionnaire; MRA ¼ mineralocorticoid receptor antagonist; NT-proBNP ¼ N-terminal pro-B-type natriuretic peptide; NYHA ¼ New York Heart Association; SBP ¼ systolic blood pressure.

TABLE 2
Primary and Secondary Endpoints in Black vs White Patients Regardless of CENTRAL ILLUSTRATION Effects of Omecamtiv Mecarbil in Black Compared With White Patients PlaceboP for interaction = 0.66 (Black vs White)

Incidence Rate (Per 100 Patient-Years)
Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure; PARAGON-HF ¼ Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction; PT ¼ patient; VICTORIA ¼ VerICiguaT GlObal Study in Subjects With Heart Failure With Reduced EjectIon FrAction.

TABLE 3
Outcomes of Omecamtiv Mecarbil Treatment (vs Placebo) in Black vs White Patients a Patients were from Brazil, South Africa, and the United States.b Measured baseline to 24 wk. a

TABLE 4
Safety Outcomes of Omecamtiv Mecarbil Treatment (vs Placebo) in Black vs White Patients Values are HR (95% CI) unless otherwise indicated.Patients were from Brazil, South Africa, and the United States.

TABLE 5
Black Patient Enrollment in Recent HF Clinical Trials Total Black Patients U.S. Black Enrollment Values are n (%). a North America (not United States only).DAPA-HF ¼ Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; EMPEROR-Reduced ¼ EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction; PARADIGM-HF ¼ Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure; PARAGON-HF ¼ Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction; PIONEER-HF ¼ comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode; VICTORIA ¼ VerICiguaT GlObal Study in Subjects With Heart Failure With Reduced EjectIon FrAction; other abbreviation as in Table 1.