New Study Supports the Reliability SCD Patient-Reports of VOC-Related Pain Crises

Karin Coyne, PhD, MPH

A new study examined the reliability of patient-reports of vaso-occlusive crises (VOC), or pain crises, using a sickle cell disease (SCD) diary. The results demonstrated that patients were able to describe their experiences of VOC-related pain crises accurately, and were able to differentiate these experiences from everyday pain.

A team of investigators led by Karin Coyne, PhD, MPH, Patient-Centered Research, Evidera, aimed to validate a daily patient-reported outcome for patients with sickle cell disease to accurately report their VOC status and experience of a pain crisis. VOC episodes have typically been assessed through medical utilization, excluding events managed at home.

The Role of VOCs in a Lifetime of SCD

Individuals with sickle cell disease experience VOCs frequently, as they can begin at any time. During a VOC, the blood vessels of the patient are obstructed which leads to ischemic tissue injury and severe pain. These episodes can increase morbidity and mortality, especially in older patients, as a result of the organ damage caused by repeated VOCs.

Investigators noted that pain crises are the most common reason that these patients visit the emergency department (ED) and are responsible for missed school, work, and decreased health-related quality of life (HRQoL). The impacts of decreased HRQoL include inhibited physical, emotional, and social functioning, and research has shown that impacts are worse among individuals with sickle cell disease compared to the general population and to some other chronic diseases.

The timing of VOC episodes are difficult to predict, investigators wrote. A reliable tracking method over long periods of time for these crises are needed. The current practice has physicians relying on patient recall and medical record documentation in order to get a history of the patient’s incidence and severity of a VOC episode. However, these records don’t include episodes that are managed at home–which is a majority of them.

Validating VOC Management At Home

Investigators believed that the medical utilization definition of a VOC likely only represents a subset of the overall patient experience with these crises. Actually, the frequency of SCD patient-reported crisis pain was higher than what was captured by their healthcare providers, and crisis pain was largely managed at home, according to results from The Pain in Sickle Cell Epidemiology Study (PiSCES).

“Requiring medical utilization for a VOC episode to be recorded underestimates patient burden of VOC and limits the ability to fully evaluate the benefit of new treatments. Thus, there is a need for a patient-reported outcome (PRO) measure to accurately capture and record VOCs,” investigators wrote.

The team performed the ELIPSIS study, which was non-interventional, longitudinal, and assessed novel biomarkers in order to identify and document the complete natural history of VOCs experienced by patients with sickle cell disease who had hemoglobin SS (HbSS) or S-β thalassemia (HbS- β) genotype. Patients were at least 12 years old and had a confirmed diagnosis of stable SCD.

Patients kept a daily SCD Diary where they responded to questions regarding their experiences with VOC, pain, tiredness, functioning, and medical utilization. The patients reported these entries on a secure, electronic, FDA compliant, handheld device.

In the SCD Diary, a description of a pain crisis was included that read: “People like yourself describe a pain crisis day as a day when your pain is more than usual, you cannot do what you would normally do, you may be more tired than usual, and often use extra pain medication to get by. Sometimes you may need to speak to or see a doctor or go to the emergency room or hospital, and other times you may treat yourself at home.”

The SCD Diary Provides Accurate, Comprehensive Insight

Of the 37 patients enrolled in the study, 35 completed it. The average age of the population was 24.7 ± 9.5 years and just over half were female (51.4%). Only 10 patients (28.6%) completed entries in their SCD Diary more than 80% of the time, making the average completion rate in this group 88.6% compared to the rest of the patients who had a 57.4% completion rate.

The SCD Diary items on the first day of a VOC event showed a strong correlation with one another (worst pain range: r = 0.574 to 0.584; tiredness range: r = 0.574 to 0.693; all p<0.0001). Additionally, the items for VOC days were also strongly correlated (worst pain range: r = 0.648 to 0.658; tiredness: r = 0.648 to 0.758; all p<0.0001). Due to the lack of responses reported on non-VOC days, correlations on these days did not converge.

Of the total patients, 31 (88.6%) reported at least 1 VOC day during the study. The mean number of VOC days experienced per patient within the 6 month observation period in the study was 9.9 ± 18.5 days. The average number of VOC days for patients who completed the diary at least 80% of the time was 19.9 ± 30.7 days and 5.9 ± 8.5 for non-completers.

Investigators noted the large discrepancy between the 2 groups as driven in part by an outlier in the completer group who reported 91 VOC days. Without this patient-report, the average number of VOC days for diary completers changed to 12.0 ± 18.9.

Investigators found that the mean severity of worst pain was higher on VOC days compared to non-VOC days (7.6 vs 2.6, respectively). The mean severity of tiredness was similarly higher on VOC days compared to non-VOC days (6.3 vs 4.1, respectively). As for the functioning items, mean impact scores were higher on VOC days (usual physical activities = 3.6; social activities = 2.6; daily activities = 3.5 self-care = 2.9) compared to non-VOC Days (usual physical activities = 2.6; social activities = 2.1; daily activities = 2.5; self-care = 1.8).

Results displayed that the magnitude of difference between VOC Days and non-VOC days for the functioning scores was smaller than the differences observed for worst pain and tiredness scores between VOC and non-VOC days.

“Previously reported results from ELIPSIS15 showed that the majority of VOC Events (62.3%) were treated at home, 18.4% culminated in a hospitalization, 17.5% resulted in direct healthcare utilization, while the remaining (1.8%) had indirect healthcare utilization. These results, in conjunction with results from the PiSCES14 study that found VOC pain was largely managed at home, indicate that relying on the medical utilization operational VOC definitions results in a substantial number of missed VOC episodes,” investigators wrote.

In response to this study, investigators called for the use of patient-reports to be adopted into clinical and investigative practices.

“Participants in the ELIPSIS study were able to use the SCD Diary to reliably report their VOC related pain crises,” they concluded. “Moreover, results from these analyses demonstrate that the SCD Diary is valid and can be implemented into clinical trials to capture the full patient experience of VOC-related pain crises. This finding is critical as it signals the ability to shift from a medical utilization definition of a VOC to a patient-reported definition.”

The study "Validation of Patient-reported Vaso-occlusive Crisis Day as an Endpoint in Sickle Cell Disease Studies" was published in European Journal of Haematology.