NBS receives support from an unrestricted grant from AbbVie Inc. ARH has served as a consultant to Actelion, Bayer, Complexa and United Therapeutics. She has had grant funding from the NIH and CMREF. ADZ receives research support from Gilead Sciences, Inc. and Sanofi Inc. However, this study did not receive any funding and the noted author disclosures do not impact this study. These financial disclosures do not alter our adherence to PLOS ONE policies on sharing data and materials.
‡ These authors also contributed equally to this work.
Phosphodiesterase-5 inhibitors (PDE-5I) have demonstrated improvement in disease symptoms and quality of life for patients with pulmonary arterial hypertension (PAH). Despite these benefits, reported adherence to PDE-5I therapy is sub-optimal. Clinical pharmacists at an integrated practice site are in a unique position to mitigate barriers related to PAH therapy including medication adherence and costs. The primary objective of this study was to assess medication adherence to PDE-5I therapy within an integrated care model at an academic institution. The secondary objective was to assess the impact of out-of-pocket (OOP) cost, frequency of dosing, adverse events (AE) and PAH-related hospitalizations on medication adherence. We performed a retrospective cohort analysis of adult patients with PAH who were prescribed PDE-5I therapy by the center’s outpatient pulmonary clinic and who received medication management through the center’s specialty pharmacy. We defined optimal medication adherence as proportion of days covered (PDC) ≥ 80%. Clinical data including AEs and PAH-related hospitalizations were extracted from the electronic medical record, and financial data from pharmacy claims. Of the 131 patients meeting inclusion criteria, 94% achieved optimal adherence of ≥ 80% PDC. In this study population, 47% of patients experienced an AE and 27% had at least one hospitalization. The median monthly OOP cost was $0.62. Patients with PDC<80% were more likely to report an AE compared to patients with PDC≥ 80% (
Pulmonary hypertension (PH) is a chronic, progressive disease characterized by elevated pulmonary vascular pressure.[
Phosphodiesterase-5 inhibitors (PDE-5I) are a class of medications approved for the treatment of PAH.[
To improve patient outcomes such as medication adherence, a growing number of institutions have developed integrated pharmacy practice models that implement interdisciplinary team-based care. Embedded in the clinic, pharmacists are in a unique position to mitigate barriers related to PAH therapy.[
The primary objective of this study was to evaluate adherence to PDE-5I therapy for the management of World Health Organization (WHO) Group 1 PAH in patients within an integrated, multidisciplinary care model.[
We conducted a retrospective cohort analysis of patients with WHO Group 1 PAH prescribed a PDE-5I (sildenafil or tadalafil) by the center’s outpatient pulmonary clinic who received medication management through the center’s specialty pharmacy. Patients with less than three prescription claims during the study period were excluded given that measurement of adherence over a short period of time may lead to inaccuracy and at least three dispenses are recommended for a meaningful adherence calculation.[
Patients included in the study were adults aged 18 years or older, with an International Classification of Diseases, Tenth Revision Clinical Modification (ICD-10-CM) diagnosis codes for pulmonary hypertension (ICD10 I27.0 to I27.89). The EMR was reviewed to ensure only patients with a PAH diagnosis were included.
Medication adherence was measured using proportion of days covered (PDC), defined as the total days covered by medication fills divided by the total number of days the patient was prescribed the medication during the observation period.[
In addition, we captured financial and insurance information from VSP claims data. We assessed patients’ insurance type (Medicare, Medicaid or commercial), use of financial assistance programs (including co-pay cards, foundation assistance or Vanderbilt-specific medication assistance), as well as monthly OOP costs incurred during the study period.
We reviewed the EMR to collect patient demographics, patient-reported AEs, and PAH-related hospitalizations. Demographic data included gender, race, age, and smoking status. We defined a hospitalization as an in-patient stay greater than 24-hours secondary to a PAH-related cause. We determined a PAH-related cause to be a chief complaint or primary diagnosis of shortness of breath, hypervolemia, hypovolemia, syncope, medication AE or heart failure that resulted in hospital admission.
We described the study population using the number and percent for categorical variables, and means, standard deviations (SDs) and interquartile ranges (IQRs) for quantitative variables. Chi-squared tests and logistic regression were performed to test whether gender, race, smoking status, and insurance type would be associated with medication type (sildenafil vs. tadalafil) and dichotomized medication adherence with a cutoff of 80% (i.e., PDC<80% vs. PDC ≥ 80%).
Since the distribution of PDC values was highly skewed, commonly used statistical methods would not be appropriate to fit this data. Thus, we reversed the PDC values by taking 100 minus the PDC percent value as a measure of non-adherence (e.g., a PDC value of 95% corresponds with a 5% modified measure). We call it “modified non-adherence measure”, modified non-adherence measure (%) = 100 –PDC (%). The modified non-adherence measure allowed us to use a negative binomial (NB) regression model that would be useful to fit over-dispersed data with high proportion of zeros of the modified non-adherence measure (i.e., 100% PDC value). We selected candidate covariates from univariate analyses and the most important covariates were included in the final models considering the small sample size. We performed all statistical analyses using the programming language R version 3.4.3.
Of the 180 patients screened, we excluded 18 patients due to having less than three prescription claims through the specialty pharmacy. We excluded an additional 30 patients due to lack of a WHO Group 1 PAH diagnosis. We excluded one patient post-evaluation due to multiple pharmacy changes during study period, which made an accurate medication adherence calculation not feasible (see
WHO = World Health Organization; VSP = Vanderbilt Specialty Pharmacy; *One patient received both sildenafil and tadalafil during study period. We utilized pharmacy claims data for both medications and created a record for both sildenafil and tadalafil for this patient.
N (%) | |
---|---|
Median [IQR |
55 [45–62] |
Female | 92 (70.2) |
Male | 39 (29.8) |
Caucasian | 102 (77.9) |
African American | 28 (21.4) |
American Indian/Alaska Native | 1 (0.8) |
Commercial | 38 (29.0) |
Government Plan | 93 (70.9) |
Never smoked | 81 (61.8) |
Previous smoker | 38 (29.0) |
Current smoker | 12 (9.2) |
Sildenafil | 44 (33.6) |
Tadalafil | 86 (65.6) |
Sildenafil and tadalafil | 1 (0.8) |
Functional Class I | 10 (7.6) |
Functional Class II | 51 (38.9) |
Functional Class III | 66 (50.4) |
Functional Class IV | 4 (3.0) |
a Interquartile range
b World Health Organization
More than half (66%) of the study cohort received tadalafil. There was no significant difference in gender, race, smoking status, or insurance type between patients prescribed sildenafil compared to tadalafil. Of note, one patient switched therapy from sildenafil to tadalafil due to difficulty with three times a day administration of sildenafil. For this patient, we used an average PDC weighted by the number of days on each therapy, which resulted in a PDC value of 92%.
The overall average PDC for all patients was 96% (standard deviation = 0.092). Furthermore, 94% of patients achieved adherence of ≥ 80% PDC. Eight patients had a PDC value of less than 80%. Patients with PDC <80% were significantly more likely to report an AE compared to those with ≥ 80% PDC (χ2 = 9.48,
PDC< 80% |
PDC≥ 80% |
||
---|---|---|---|
0.786 | |||
Caucasian | 7 (5) | 95 (73) | |
African American | 1 (1) | 27 (21) | |
Alaska Native/American Indian | 0 | 1 (<1) | |
0.072 | |||
Never smoker | 8 (6) | 73 (56) | |
Previous smoker | 0 | 38 (29) | |
Current smoker | 0 | 12 (9) | |
0.576 | |||
Sildenafil | 2 (2) | 43 (33) | |
Tadalafil | 6 (5) | 81 (61) | |
Endothelin receptor antagonist | 4 (3) | 64 (49) | 0.91 |
Prostanoid | 4 (3) | 36 (27) | 0.22 |
Calcium channel blocker | 0 | 6 (5) | 0.52 |
Prostacyclin receptor agonist | 0 | 5 (4) | 0.56 |
0.002 | |||
Yes | 8 (6) | 54 (41) | |
No | 0 (0) | 69 (53) | |
0.910 | |||
Yes | 2 (2) | 33 (25) | |
No | 6 (5) | 90 (69) | |
0.838 | |||
$0 | 4 (3) | 45 (34) | |
>$0-$10 | 3 (2) | 55 (42) | |
>$10–100 | 1 (1) | 17 (13) | |
>$100 | 0 (0) | 6 (5) | |
0.062 | |||
Yes | 7 (5) | 66 (50) | |
No | 1 (<1) | 57 (44) |
a statistical significance tested by Pearson’s chi-squared test
b n = 132 as one patient received both sildenafil and tadalafil.
Patient data represented using jittered dots. Due to a high proportion of patients with 0% modified non-adherence (i.e., 100% raw PDC score), the 25th percentile and the median both overlap at 0%. The top of the box represents the 75th percentile of the data. The y-axis only extends up to 50% because the highest modified non-adherence value was 46%. Modified non-adherence was calculated as 100 –raw PDC value in percentage (%).
In this study population, 47% of patients experienced an AE during the study period. The mean PDC of the subset of patients reporting an AE was 94% (standard deviation = 0.123). The most common AE was headache (24%) with seven of the eight patients who had <80% PDC reporting a headache while on therapy. Other AEs included reflux (11%), diarrhea (11%), leg pain (6%) and nausea/vomiting (5%). Occurrence of an AE was not associated with medication type, age, race, gender, or smoking status in this cohort. In addition, there was no significant difference in AE between patients on sildenafil compared to those on tadalafil (
While the majority (73%) of patients in this study did not have a PAH-related hospitalization during the two-year period, 24% of the study population had 1 to 2 hospitalizations and 3% had ≥ 3 hospitalizations. Among the total 35 hospitalizations, the majority of patients (69%) were in functional class III. The most common chief complaint upon admission was shortness of breath (54%). One patient experienced diarrhea that led to hospitalization. From unadjusted analyses, females were less likely to be hospitalized when compared to males (unadjusted OR = 0.438, 95% CI 0.194–0.988,
The median monthly OOP medication cost was $0.62 (Range: $0 to $354.71; IQR: $0.00-$5.83), with 37% of patients having no monthly OOP cost. Of those who incurred a monthly OOP cost, 44% of patients paid less than $10 per month. Additionally, 14% of patients had a monthly OOP cost greater than $10 but less than $100, and 5% of patients had an OOP of greater than $100 per month. Patients with commercial insurance had a significantly higher OOP cost than patients with non-commercial insurance (median OOP $54 compared to $4.20,
More than half of patients (56%) used one or more financial assistance programs. Nineteen percent of patients received assistance through a manufacturer copay card, 34% of patients received assistance from a foundation, and 16% used the Vanderbilt Medication Assistance Program. More than half of Medicare beneficiaries as well as the majority of patients with commercial insurance required financial assistance (53% and 71%, respectively). Of those patients receiving assistance, 81% were on tadalafil and 19% were on sildenafil or Revatio. There was no difference in OOP cost between patients with financial assistance compared to those without it (
Overall, patients in this study cohort achieved high medication adherence (mean PDC of 96% for both sildenafil and tadalafil) over a two-year period. This value exceeds the adherence rates observed by Waxman et al. among specialty pharmacy users over a 6-month period (63.2% for Adcirca and 66.5% for Revatio).[
Using healthcare claims data, Copher and colleagues reported similarly high medication adherence to sildenafil with an average MPR of 0.96 in 247 patients.[
Nearly half of the study patients experienced a treatment-related AE, with headache being the most commonly reported. The occurrence of headache in this study cohort was at a similar rate compared to previous trials.[
The impact of PAH-related hospitalization on medication adherence was a novel covariate analyzed. Data from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a multicenter, observational, US-based registry designed to evaluate the longitudinal course of PAH, found that 56.8% of patients experienced a hospitalization and 52.4% of those hospitalizations were secondary to PAH.[
Previous studies have shown that greater length of time on targeted therapy and use of a compliance aid may be negatively associated with adherence in patients on PAH therapy.[
Given previous findings that frequency of dosing and medication cost may influence adherence to PDE-5I therapy, we examined each of these covariates to determine their potential effect on PDC.[
When comparing specialty pharmacy users paying different OOP co-payments, Waxman, et al. found a lower rate of adherence in the group paying $251+ compared to the $0-$50 group (53.9% vs. 67.4%,
Given the high medication adherence rates seen in this integrated model, we believe it vital to describe the care model provided to the cohort studied. Prior to the integration of a clinical pharmacist, provider burden, prior authorization requirements, and high OOP costs often delayed or interrupted treatment. In 2014, VSP collaborated with the clinic to incorporate a clinical pharmacist and pharmacy technician as patient care partners. These embedded services has streamlined medication access issues and increased coordination of care. Of note, specialty medications are not auto-filled within our model. Rather, a pharmacy technician and/or pharmacist must speak to the patient monthly prior to a refill shipment. Further, the clinical pharmacist provides patient education during clinic visits and collaborates with providers to determine cost-effective, optimal treatment regimens.
As a single-center, nonrandomized, retrospective cohort study, our findings may not be generalizable to all patients with PAH. In addition, because researchers only had access to VSP claims data, a comparator arm was not feasible. Furthermore, researchers could only capture AEs and hospitalizations if documented in the EMR. While it is an objective measure, PDC reflects prescription refills but not actual medication consumption.
Our sample size was small relative to a highly skewed distribution of adherence measures; hence, it is possible that the study was not be able to identify potentially important covariates associated with adherence due to insufficient power. Lastly, patients were required to have at least three prescription claims for inclusion to allow for an appropriate observance of patient adherence behavior.
Longitudinal studies conducted within an integrated pharmacy practice model would provide meaningful information about long-term relationship between medication adherence and health outcomes. Furthermore, studies comparing integrated specialty pharmacy models such as VSP with non-integrated models would be useful to assess the value-add of this care delivery model.
Although patients on combination therapy were not excluded from this study, we could not evaluate the effect of combination therapy on medication adherence as we did not have access to pharmacy claims data for non-PDE5I agents. Combination therapy is a strategy commonly used in PAH patients and has previously been noted to negatively impact adherence rates compared to patients on monotherapy.[
Patients receiving care within the high-touch, integrated VSP model maintained high rates of medication adherence over a two-year period. Furthermore, previous predictors of low medication adherence such as increased dosing frequency and medication cost did not have a negative impact on adherence in this cohort.
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The authors would like to thank Sarah Slack, PharmD for her involvement in design, Jacob Bell, BS, CPhT for data extraction, Drs. Meredith Pugh and Ivan Robbins for their collaboration with the VSP team, Rusty Hammonds, CPhT for his tireless work for PAH patients and Megan Peter, PhD for her help in the review process.