Abstract
Background:
Use of phosphodiesterase-5 inhibitors for Groups 2 and 3 pulmonary hypertension is rising nationally, despite guidelines recommending against this low-value practice. Although receiving care across healthcare systems is encouraged to increase Veterans’ access to specialists critical for pulmonary hypertension management, receiving care in two systems may increase risk of guideline-discordant prescribing. We sought to identify factors associated with prescribing of phosphodiesterase-5 inhibitors for Groups 2/3 pulmonary hypertension; particularly, to test the hypothesis that Veterans prescribed phosphodiesterase-5 inhibitors for pulmonary hypertension in the community (through Medicare) will have increased risk of subsequently receiving potentially inappropriate treatment in VA.
Methods and Results:
We constructed a retrospective cohort of 34,775 Medicare-eligible Veterans with Groups 2/3 pulmonary hypertension by linking national patient-level data from VA and Medicare from 2006–2015. We calculated adjusted odds ratios of receiving daily phosphodiesterase-5 inhibitor treatment for pulmonary hypertension in VA using multivariable models with facility-specific random effects. 1,556 Veterans received VA prescriptions for phosphodiesterase-5 inhibitor treatment for Groups 2/3 PH. Supporting our primary hypothesis, the variable most strongly associated with phosphodiesterase-5 inhibitor treatment in VA for Groups 2/3 PH was prior treatment through Medicare (OR 6.5 [95% CI 4.9–8.7]). Other variables strongly associated with increased likelihood of VA treatment included more severe disease as indicated by recent right heart failure (OR 3.3 [2.8–3.9]) or respiratory failure (OR 3.7 [3.1–4.4]); and prior right heart catheterization (OR 3.8 [3.4–4.3]).
Conclusions:
Our data suggests a missed opportunity to re-assess treatment appropriateness when pulmonary hypertension patients seek prescriptions from VA, a relevant finding given policies promoting shared care across VA and community settings. Interventions are needed to reinforce awareness that pulmonary vasodilators are unlikely to benefit Groups 2/3 pulmonary hypertension patients and may cause harm.
Providing patient-centered, high-value care is a fundamental goal of clinicians and health systems. Yet, an estimated 30% of all medical spending in the United States is wasteful and does not add value.1 One significant contributor to waste—overuse or misuse of medications—can result in adverse drug effects, decreased quality of life, increased hospitalizations, and even death.2, 3 The American Board of Internal Medicine’s Choosing Wisely Campaign identifies low-value practices, including inappropriate prescribing, to curb overuse and mitigate patient harm.4 Within this campaign, the American College of Chest Physicians and American Thoracic Society identified routine use of pulmonary vasodilators for Groups 2 and 3 pulmonary hypertension (PH) as one such practice.5
PH is a challenging condition to manage, with high morbidity and mortality. While patients with Group 1 PH (also known as pulmonary arterial hypertension) clearly benefit from treatment with pulmonary vasodilators, patients with the most common forms of PH – PH secondary to underlying left-sided heart disease (Group 2 PH) or chronic hypoxic lung disease (Group 3 PH) – have no established benefit from treatment.6–8 In fact, some studies suggest serious harm for patients with Groups 2 and 3 PH treated with vasodilators, including worsened hypoxemia, renal failure, right-sided heart failure, shock, and potentially higher mortality.9–12 Given the lack of benefit and potential for harm, clinical practice guidelines recommend against routine use of pulmonary vasodilators for Groups 2 and 3 PH and instead direct clinicians to optimize treatment for the underlying cardiac or pulmonary condition.13, 14
Despite these recommendations, use of pulmonary vasodilators, particularly phosphodiesterase-5 inhibitors (PDE5i), for Groups 2/3 PH is increasing over time.15, 16 Given the high cost of these medications, Veterans who share care across the Veterans Health Administration (VA) and community settings may seek to fill PDE5i prescriptions from VA, where co-pays tend to be substantially lower.17 With a growing national trend towards shared care for Veterans,18, 19 co-management of PH patients is also likely to increase. While shared care may increase Veterans’ access to specialty care critical for PH management, it also increases the potential for care fragmentation and the risk of guideline-discordant care. 20, 21 To understand the influences on potentially inappropriate PDE5i prescribing for PH in VA, and in particular the impact of shared care, we performed a national retrospective cohort study of Veterans diagnosed with Groups 2 or 3 PH over a decade. Our primary hypothesis was that Veterans with Groups 2/3 PH initiated on PDE5i treatment via Medicare would be at increased risk for subsequently receiving potentially inappropriate prescriptions in VA.
METHODS
Because of the sensitive nature of the data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to the study PI, Dr. Renda Wiener, at the Center for Healthcare Organization & Implementation Research (renda.wiener@va.gov).
Study Design and Data Source
We conducted a retrospective cohort analysis of all Medicare-eligible Veterans with Groups 2/3 PH diagnosed between January 1, 2006 to December 31, 2015, linking national patient-level data from the VA and Centers for Medicare and Medicaid Services. The Edith Nourse Rogers Memorial VA Hospital institutional review board approved this study.
Study Population
From the population of Veterans who used VA services during the study period, we identified all patients with incident PH between 2006–2015, defined by at least two International Classification of Diseases, 9th or 10th Revision diagnosis codes for PH (416.xx or I27.x) occurring either in VA or Medicare. We defined the incident PH date as the date of the first PH code. Those with a PH code between October 1, 1999 (the inception of the VA Corporate Data Warehouse) and December 31, 2005 were excluded. We restricted our sample to Medicare-eligible (age ≥ 65 years or in the Medicare denominator file) Veterans who were active pharmacy users (excluding those with no VA or Medicare prescriptions in the year before PH diagnosis). We also excluded Veterans who received PH care exclusively outside VA (i.e., no PH-associated outpatient visits in VA during the study period). Finally, we narrowed our sample to Veterans with Groups 2/3 PH using a previously validated algorithm designed to exclude Veterans with pulmonary arterial hypertension, other PH groups, or uncertain etiology of PH, which demonstrated a high positive predictive value for identifying Group 2/3 PH.15 In order to maximize the specificity of Groups 2/3 PH, the validated algorithm erred on the side of labeling patients as Group 1 over Group 2/3. For example, patients with diagnosis codes for both Group 1 PH-associated diagnoses and Groups 2 or 3 diagnoses were classified as Group 1 PH. The derivation of our study cohort is shown in Figure 1.
Figure 1:
Sample derivation of Medicare-eligible Veterans with groups 2 and 3 PH.
Definitions of abbreviations: PH = pulmonary hypertension; VA = Veterans Health Administration
Primary Outcome
The goal of our analysis was to identify patient- and facility-level factors associated with the probability of receiving PDE5i treatment of Groups 2/3 PH in VA. Our primary outcome was a binary indicator of treatment with daily PDE5i, defined by one or more VA prescriptions for daily PDE5i (sildenafil, vardenafil, or tadalafil) treatment, supplied for at least 15 days per month. We selected this algorithm as indicative of PDE5i treatment for PH based on: 1) our prior validation against gold standard medical record abstraction,15 during which we noted that prescriptions often included instructions to cut pills in half; 2) VA policy restricting PDE5i for treatment of erectile dysfunction to ≤4 doses per month.
Exposure variables
All exposure variables were derived using all available data from VA and Medicare. Variables were measured at the index date, defined as the initiation of daily PDE5i treatment in VA (date of first VA prescription) for cases, or for a calculated “phantom” prescription date for patients who did not receive VA treatment, as described below and shown in Figure 2.
Figure 2:
Timeline for definition of study variables. *Look-back period differs depending on exposure; for example, primary exposure of prior PDE5i treatment in Medicare looks back from index date to incident PH diagnosis, whereas acute organ failure variables look back only 3 months prior to index date. Full details of look-back period for each variable are available in Supplemental Table I of the online data supplement.
Following our primary hypothesis, our primary exposure variable was prior daily PDE5i treatment for Groups 2/3 PH through Medicare. We also evaluated other patient- and facility-level exposures we hypothesized might be associated with prescribing of PDE5i for Groups 2/3 PH based on clinical experience and prior literature on inappropriate prescribing in other contexts, as defined below. Exposures were identified by their presence during a defined look-back period from the index date (Figure 2); details of the look-back period for each variable are shown in Supplemental Table I of the online data supplement.
Additional patient-level exposures:
We included demographic characteristics (age, gender, race, marital status, and VA enrollment priority status, which is a proxy for level of disability and VA benefits22); factors related to PH etiology, severity, or management (underlying conditions associated with Groups 2/3 PH, recent right heart or respiratory failure, performance of a right heart catheterization, receipt of other pulmonary vasodilators); contraindications to PDE5i use (co-prescription of nitrates), acute and chronic comorbidities and vital status changes indicative of general health, and markers of healthcare utilization including long-term care, emergency department visits, hospitalizations, and intensive care unit stays in the prior year (see Supplemental Table I in the online data supplement for full list and definitions of all variables).
Additional facility-level exposures:
Patients were assigned to VA medical centers (facilities) based on the location of the most recent PH-associated visit on or before the date of the daily PDE5i prescription or phantom prescription date. For each VA facility, we calculated rates of daily PDE5i prescribing among all patients with Groups 2/3 PH seen at the facility, excluding facilities with a volume of less than 25 Groups 2/3 PH patients seen over the study period (one VA facility excluded). We then considered VA facility-level characteristics that may influence PDE5i prescribing for PH. These included factors relevant to PH care (volume of PH patients seen annually, volume of right heart catheterizations performed annually, presence of specialty pulmonary or cardiology care [defined by outpatient clinic stop codes]); geographic factors (US census region, rurality [defined by VA urban or rural designation23]), and facility complexity rating, which is comprised of patient volume and risk, level of teaching and research, number of specialists, and presence of intensive care units within the facility.24
Statistical Analysis
Our statistical analyses proceeded in two stages. In the first stage we imputed “phantom” prescription dates by estimating the number of days since PH diagnosis for patients who never received PDE5i treatment in VA. To do so, we developed a prediction model for the number of days between PH diagnosis and VA PDE5i prescription among those prescribed daily PDE5i in VA based on a comprehensive list of demographic and clinical variables. The fit of this model was then applied to the cohort who never received VA PDE5i treatment to obtain the imputed phantom prediction dates. This imputation model was created by fitting a gradient boosted tree25 for the time since PH diagnosis until VA PDE5i prescription. The approach of imputing phantom prescription dates has close connections to estimating missing disease onset dates in cohort studies.26, 27
In the second stage we modeled a binary indicator of VA PDE5i prescription based on the full cohort as a function of covariate information at the time of PDE5i initiation in VA for the treated patients and the phantom prescription dates for patients who did not receive PDE5i treatment in VA. We considered two models. First, we modeled VA PDE5i prescription as an ordinary multivariable logistic regression depending on the patient and facility exposures described above. Second, we extended the logistic regression model to include normally distributed facility-specific random effects. To address potential issues of multi-collinearity among the patient-level predictors, we computed variance inflation factors for each predictor in the model.28 No variables had a variance inflation factor greater than 10, a conventional threshold for collinearity concerns, suggesting that collinearity was not problematic. Missing data for weight difference were imputed using median values. All analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc, Cary, NC).
Sensitivity Analysis
We performed three sensitivity analyses to check the validity of our conclusions about factors associated with PDE5i prescribing for Groups 2/3 PH in VA. First, to ensure our population reflected active VA pharmacy users, we repeated our analyses excluding Veterans who received no VA prescriptions of any kind during the study period. Second, to increase our confidence that PDE5i prescriptions were intended for PH and not erectile dysfunction, we repeated our primary analyses excluding Veterans with an International Classification of Diseases code for sexual impotence and those with a prescription for PDE5i with a pill per month ratio <15 (indicating less than daily use). Finally, we determined the level of residual confounding necessary to nullify the effect of our primary exposure (prior daily PDE5i in Medicare).29
RESULTS
Study Population
We identified 34,775 Medicare-eligible Veterans with Groups 2/3 PH in our cohort. The mean age was 74.0 years; 97.4% were men and 79.4% were non-Hispanic white (Table 1). Veterans in our cohort had high rates of comorbid conditions, most commonly substance use disorders and underlying pulmonary, cardiac, or chronic kidney disease. Most Veterans were seen at urban facilities with high complexity ratings and both pulmonary and cardiology specialty care available.
Table 1.
Characteristics of Veterans and facilities by status of treatment with phosphodiesterase-5 inhibitor in VA
| Treatment status in VA | ||
|---|---|---|
| Treated (n = 1,556) | Untreated (n = 33,219) | |
| Patient characteristics | ||
| Demographics | ||
| Age, year, mean (SD) | 70.7 (9.2) | 74.2 (9.6) |
| Female sex | 23 (1.5%) | 890 (2.7%) |
| Race | ||
| White | 1163 (74.7%) | 26,455 (79.6%) |
| Black | 266 (17.1%) | 4,483 (13.5%) |
| Hispanic | 48 (3.1%) | 987 (2.9%) |
| Other | 79 (5.1%) | 1,334 (4.0%) |
| Married | 923 (59.3%) | 17,492 (52.7%) |
| VA benefits (priority status) | ||
| Highly disabled | 478 (30.7%) | 9,288 (28.0%) |
| Low/moderately disabled | 238 (15.3%) | 4,824 (14.5%) |
| Limited with copayments | 167 (10.7%) | 2,864 (8.6%) |
| Poverty/no copayments | 673 (43.3%) | 16,243 (48.9%) |
| PH diagnosis and management | ||
| Other pulmonary vasodilator | 35 (2.2%) | 100 (0.3%) |
| Calcium channel blockers | 858 (55.1%) | 19,861 (59.8%) |
| Right heart catheterization | 818 (52.6%) | 8,104 (24.4%) |
| Year of first PDE5i prescription | ||
| 2006 | 69 (4.4%) | 65 (0.2%) |
| 2007 | 98 (6.3%) | 1,661 (5.0%) |
| 2008 | 129 (8.3%) | 3,152 (9.5%) |
| 2009 | 162 (10.4%) | 3,784 (11.4%) |
| 2010 | 173 (11.1%) | 4,105 (12.4%) |
| 2011 | 141 (9.1%) | 4,639 (14.0%) |
| 2012 | 189 (12.1%) | 4,464 (13.4%) |
| 2013 | 187 (12.0%) | 3,972 (12.0%) |
| 2014 | 191 (12.3%) | 3,733 (11.2%) |
| 2015 | 175 (11.2%) | 3,646 (11.0%) |
| General health measures | ||
| Underlying PH condition associated with | ||
| Group 2 PH | ||
| Ischemic heart disease | 395 (25.4%) | 10,641 (32.0%) |
| Heart failure | 908 (58.4%) | 21,139 (63.6%) |
| Arrhythmia | 704 (45.2%) | 17,949 (54%) |
| Underlying PH condition associated with | ||
| Group 3 PH | ||
| Chronic lung disease* | 993 (63.8%) | 20,239 (60.9%) |
| Interstitial lung disease | 339 (21.8%) | 4,682 (14.1%) |
| Obstructive sleep apnea | 355 (22.8%) | 6,274 (18.9%) |
| Other comorbid conditions | ||
| Stroke or transient ischemic attack | 206 (13.2%) | 6,365 (19.2%) |
| Chronic kidney disease | 876 (56.3%) | 21,344 (64.3%) |
| Dialysis dependency | 109 (7.0%) | 2,496 (7.5%) |
| Chronic liver disease | 96 (6.2%) | 1,730 (5.2%) |
| Hepatitis C | 72 (4.6%) | 2,603 (7.8%) |
| Malignancy | 248 (15.9%) | 6,727 (20.3%) |
| Neurological disorder† | 27 (1.7%) | 2,002 (6.0%) |
| Mental health disorder‡ | 37 (2.4%) | 1,357 (4.1%) |
| Substance abuse | 579 (37.2%) | 16,104 (48.5%) |
| Oxygen dependency | 597 (38.4%) | 9,888 (29.8%) |
| Ventilator dependency | 42 (2.7%) | 837 (2.5%) |
| Medications for comorbidities | ||
| Opioids | 864 (55.5%) | 17,084 (51.4%) |
| Low dose PDE5i | 509 (32.7%) | 6,890 (20.7%) |
| Recent organ failures§ | ||
| Renal failure | 50 (3.2%) | 785 (2.4%) |
| Liver failure | 1 (0.1%) | 22 (0.1%) |
| Neurologic failure | 18 (1.2%) | 344 (1.0%) |
| Hematologic failure | 21 (1.3%) | 198 (0.6%) |
| Metabolic failure | 4 (0.3%) | 37 (0.1%) |
| Circulatory failure | 36 (2.3%) | 575 (1.7%) |
| Respiratory failure | 230 (14.8%) | 1,316 (4.0%) |
| Right heart failure | 310 (19.9%) | 2,579 (7.8%) |
| Vital sign changes | ||
| Change in weight in pounds, mean (SD) | −2.7 (11.5) | −1.1 (11.4) |
| Dual VA and community care | ||
| Daily PDE5i in Medicare | 102 (6.6%) | 232 (0.7%) |
| Contraindications to PDE5i | ||
| Nitrates | 97 (6.2%) | 2,317 (7.0%) |
| Healthcare utilization | ||
| Outpatient visit days, mean (SD) | 54.1 (46.5) | 52.0 (49.4) |
| Long term care | 13 (0.8%) | 315 (0.9%) |
| Emergency room visit days, mean (SD) | 1.4 (1.2) | 1.4 (1.2) |
| Hospitalizations, mean (SD) | 2.0 (2.8) | 2.1 (2.9) |
| Intensive care unit stays, mean (SD) | 0.5 (0.9) | 0.4 (0.8) |
| Facility characteristics | ||
| Geographic location¶ | ||
| North Atlantic | 263 (16.9%) | 8,617 (25.9%) |
| Southeast | 370 (23.8%) | 5,889 (17.7%) |
| Midwest | 323 (20.8%) | 8,084 (24.3%) |
| Continental | 283 (18.2%) | 4,755 (14.3%) |
| Pacific | 317 (20.4%) | 5,874 (17.7%) |
| Rurality | ||
| Rural | 83 (5.3%) | 2,244 (6.8%) |
| Urban | 1,428 (91.8%) | 30,443 (91.6%) |
| Unknown | 45 (2.9%) | 532 (1.6%) |
| Specialty care at the facility | ||
| Pulmonary | 1,518 (97.6%) | 32,464 (97.7%) |
| Cardiology | 1,538 (98.8%) | 32,991 (99.3%) |
| Complexity rating** | ||
| 1a | 767 (49.3%) | 14,470 (43.6%) |
| 1b | 276 (17.7%) | 6,593 (19.8%) |
| 1c | 191 (12.3%) | 5,112 (15.4%) |
| 2 | 159 (10.2%) | 4,129 (12.4%) |
| 3 | 118 (7.6%) | 2,383 (7.2%) |
| Volume of PH patients by quartile | ||
| Q4 – highest quartile | 685 (44.0%) | 17,594 (53.0%) |
| Q3 | 480 (30.8%) | 8,601 (25.9%) |
| Q2 | 259 (16.6%) | 5,021 (15.1%) |
| Q1 – lowest quartile | 132 (8.5%) | 2,003 (6.0%) |
| Volume of right heart catheterization by quartile | ||
| Q4 – highest quartile | 665 (42.7%) | 14,421 (43.4%) |
| Q3 | 487 (31.3%) | 9,963 (30.0%) |
| Q2 | 122 (7.8%) | 2,379 (7.2%) |
| Q1 – lowest quartile | 282 (18.1%) | 6,456 (19.4%) |
Definition of abbreviations: PDE5i = phosphodiesterase-5 inhibitor; PH = pulmonary hypertension; VA = Veterans Health Administration
Data presented as n (%) unless otherwise noted
Variables with missing data: change in weight (2.5% missing), marital status (0.3% missing), race (1.8% missing)
Includes COPD, bronchiectasis, asthma, hypersensitivity pneumonitis, pneumoconiosis
Incudes multiple sclerosis, Parkinson’s disease, dementia
Includes bipolar disorder and schizophrenia
Within 90 days prior to index date
Weight difference between most recently recorded weight and prior weight at least three months earlier
North Atlantic = Connecticut, Delaware, District of Columbia, Maine, Maryland, Massachusetts, New Hampshire, New Jersey, New York, North Carolina, Pennsylvania, Rhode Island, Vermont, Virginia, West Virginia; Southeast = Alabama, Florida, Georgia, Kentucky, Puerto Rico, South Carolina, Tennessee; Midwest = Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, Ohio, South Dakota, Wisconsin; Continental = Arkansas, Colorado, Louisiana, Mississippi, Montana, Oklahoma, Texas, Utah, Wyoming; Pacific = Alaska, Arizona, California, Hawaii, Idaho, Nevada, New Mexico, Oregon, Washington
1a-1c: high complexity of patient volume and risk, high volume of teaching and research; 2: moderate complexity of patient volume and risk; some teaching and research; 3: low complexity of patient volume and risk, little or no teaching or research
Relative to the multivariable logistic regression, the model with random effects was significantly more predictive (p<0.001) based on a likelihood ratio test for the random effects variance greater than zero.30, 31 We therefore report our findings based on the random effects logistic regressions. Odds ratios (OR) from these models adjust for the estimated facility-level random effects.
Factors associated with PDE5i prescribing for Groups 2/3 PH
1,556 (4.5%) Veterans received VA prescriptions for PDE5i treatment for Groups 2/3 PH. Of 334 Veterans who had received PDE5i treatment in the community, 31% had them continued in the VA. Supporting our primary hypothesis, by far the strongest predictor of PDE5i prescribing for Groups 2/3 PH in VA was prior PDE5i treatment in the community (OR 6.5, 95% CI [4.9–8.7]); Figure 3.
Figure 3:
Significant patient and facility factors associated with VA prescriptions of PDE5i for groups 2/3 PH. Definitions of abbreviations: CI=confidence interval; OR=odds ratio; PDE5i=phosphodiesterase-5 inhibitor; PH=pulmonary hypertension; VA=Veterans Health Administration
*Bolded OR are significant
†As Indicated by acute organ failure within 90 days of index date
‡North Atlantic = Connecticut, Delaware, District of Columbia, Maine, Maryland, Massachusetts, New Hampshire, New Jersey, New York, North Carolina, Pennsylvania, Rhode Island, Vermont, Virginia, West Virginia; Southeast = Alabama, Florida, Georgia, Kentucky, Puerto Rico, South Carolina, Tennessee; Midwest = Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, Ohio, South Dakota, Wisconsin; Continental = Arkansas, Colorado, Louisiana, Mississippi, Montana, Oklahoma, Texas, Utah, Wyoming; Pacific = Alaska, Arizona, California, Hawaii, Idaho, Nevada, New Mexico, Oregon, Washington
Patient-level factors:
PH severity and active management of PH were also associated with VA PDE5i prescribing for Groups 2/3 PH; Figure 3. Veterans with more severe PH disease as indicated by recent episodes of right heart failure (OR 3.3 [2.8–3.9]) or acute respiratory failure (OR 3.7 [3.0–4.4]) were more likely to be treated. Veterans who had previously received PH-specific interventions including right heart catheterization (OR 3.8, [3.4–4.3]) or treatment with other pulmonary vasodilators (OR 3.3, [2.1–5.2]) were also more likely to receive PDE5i for Groups 2/3 PH. Among our cohort, Veterans with conditions associated with Group 2 PH (underlying cardiac disease) were less likely to receive PDE5i treatment while Veterans with conditions associated with Group 3 PH (underlying lung disease, particularly interstitial lung disease) were more likely to receive treatment. Veterans with age ≥75 years and those with indications of poor general health were less likely to receive PDE5i treatment.
Facility-level factors:
We found substantial variation across facilities in rates of PDE5i prescribing for Groups 2/3 PH in VA, ranging from 0 to 35% (Figure 4). Relative to facilities in the Northeast, facilities in the Southeast (OR 2.0 [1.4–2.9]), Continental (OR 1.5 [1.1–2.2]), and Pacific regions (OR 1.6 [1.1–2.3]) were all associated with increased odds of VA PDE5i treatment (Figure 3). Facilities with lower PH patient volume had lower odds of VA prescriptions for PDE5i treatment of Groups 2/3 PH. The intraclass correlation for the random effects model is 0.076, suggesting that very little of the total variation is attributable to facility effects.32, 33
Figure 4:
Variation in VA prescribing of PDE5i for groups 2/3 PH by facility.
Definitions of abbreviations: PDE5i = phosphodiesterase-5 inhibitor; PH = pulmonary hypertension; VA = Veterans Health Administration
*Excludes VA facilities with volume of less than 25 groups 2/3 PH patients seen over the study period (n=1)
Sensitivity Analyses
There was little change in the direction of our main findings in our sensitivity analyses (See Supplemental Tables II and III in the online data supplement). Of note, in our model excluding Veterans potentially treated with PDE5i for erectile dysfunction, the effect of prior PDE5i treatment through Medicare was even stronger (OR 12.1, 95% CI [8.5–17.1]). For our primary exposure of prior daily PDE5i treatment for PH in Medicare, to nullify our observed OR of 6.5, an unmeasured confounder would need be associated with our exposure variable with a relative risk of 20, and with our primary outcome with a relative risk of at least 10.
DISCUSSION
Two recent international conferences of PH experts issued consensus statements raising concern about increasing indiscriminate use of pulmonary vasodilators for Groups 2 and 3 PH.34–36 To develop interventions to mitigate this problem, it is critical to understand factors driving potentially inappropriate treatment. While we found overall rates of PDE5i prescribing for Groups 2/3 PH were relatively low in VA (approximately 5%), some VA facilities were dispensing PDE5i prescriptions to nearly 35% of their patients with Groups 2/3 PH, exposing these patients to potential harm and wasting resources. At a cost of $10,000 to $13,000 to treat one patient for one year,37 the burden to the healthcare system of unnecessary PDE5i treatment for Groups 2/3 PH could be substantial. Furthermore, rates of potentially inappropriate treatment may actually be higher for patients treated in non-VA settings as VA has already taken steps to restrict PDE5i prescribing, such as requiring pharmacy review and approval to fill daily PDE5i prescriptions. Importantly, the factors we identified as associated with PDE5i treatment for Groups 2/3 PH in VA speak to larger issues that may drive inappropriate prescribing in other contexts, such as prescribing inertia, lack of provider awareness, workplace culture, subspecialty influences, and care fragmentation (Figure 5).
Figure 5:
Pathways influencing potentially inappropriate prescribing of phosphodiesterase-5 inhibitors for groups 2/3 PH in VA. Definitions of abbreviations: PDE5i = phosphodiesterase-5 inhibitor; PH = pulmonary hypertension; VA = Veterans Health Administration
The strongest predictor of treatment with PDE5i in VA was prior treatment initiated in the community, representing a missed opportunity to re-evaluate appropriateness of treatment and discontinue guideline-discordant prescriptions. The tendency to continue prescriptions initiated by another provider, even when potentially inappropriate, likely reflects multiple factors at the patient, provider, and system levels. Providers who inherit the prescribing of a medication may not always apply the same level of scrutiny as when initiating the medication themselves,38, 39 tending instead to respect their colleagues’ prescribing autonomy even when there is little evidence to support using the medication.40 Providers may be reluctant to discontinue treatment for a complex condition like PH, particularly if they have limited experience managing the condition, concerned that doing so may worsen symptoms or worsen clinical status.41 Similarly, patients may be resistant to change, pressuring a new provider into continuing a medication that was started by another clinician the patient trusts.42 Finally, inadequate care coordination across VA and non-VA systems may contribute to reluctance to discontinue medications.43 For example, VA providers with incomplete documentation of care received in the community may give their colleagues the benefit of the doubt in continuing a potentially inappropriate medication. With recent policy changes such as the Veterans Choice and MISSION acts, more Veterans can be expected to share care in the future,18, 19 raising the importance of educating VA providers on the need to carefully consider the appropriateness of prescriptions initiated in the community rather than defaulting to continuing them without much scrutiny.
In addition to our primary exposure of prior treatment in the community, we identified several other clinically relevant patient factors associated with higher odds of PDE5i treatment for Groups 2/3 PH. Veterans with more severe PH, as indicated by recent right heart failure or acute respiratory failure, were more likely to be treated. Patients with Groups 2 and 3 PH experience high mortality with significant symptom burden and poor prognosis.44 Though a provider may understand guideline recommendations at the population level, those beliefs may not always translate to how they manage individuals, particularly when faced with a patient with severe or end-stage disease.45 In particular, when providers perceive they have nothing else to offer, they are more likely to turn to low-value practices as a last resort to try to alleviate symptoms of a very sick patient.46 Indeed, in our study we found that among Veterans with Groups 2/3 PH, patients with interstitial lung disease were more likely to be treated with daily PDE5i while patients with underlying cardiac disease (Group 2 PH) were less likely to receive daily PDE5i treatment. This may reflect the limited options for treatment of interstitial lung disease as compared to a wider range of effective options for treatment of cardiac disease. This willingness to use pulmonary vasodilators for patients with interstitial lung disease despite established benefit and potential for harm was previously identified in a survey of pulmonary physicians.47
Prior management for PH, including right heart catheterization or treatment with other pulmonary vasodilators, also increased the odds of treatment with PDE5i. It is possible that these patients represent the subset of Groups 2/3 PH for whom guidelines allow trials of pulmonary vasodilators on a case-by-case basis—those whose symptoms and hemodynamics are “out of proportion” to their underlying heart or lung disease.13, 14 Alternatively, once providers have committed to seeking the diagnosis of PH with a right heart catheterization, they may be more prone to treat PH if the diagnosis is confirmed, regardless of whether the hemodynamics support the use of pulmonary vasodilators.
We also identified several facility factors associated with PDE5i treatment. Veterans receiving care in facilities with higher volume of PH patients were more likely to be treated, likely reflecting providers’ familiarity with the disease and the medications, as well as increased access to PH specialists. While some of these prescriptions may reflect appropriate trials of daily PDE5i for patients with Groups 2/3 PH out-of-proportion to the underlying disease, other cases may represent a “spillover” effect in which the threshold for treatment even for Groups 2/3 PH is lower in PH specialty clinics where providers routinely use pulmonary vasodilators for pulmonary arterial hypertension and are more comfortable using these medications. Indeed, prior survey data show that a majority of PH expert referral centers use pulmonary vasodilators for Groups 2 and 3 PH, despite limited evidence to support this practice.48
Our findings may inform the design of multi-level interventions to de-implement guideline-discordant prescribing of PDE5i for Groups 2/3 PH, preventing patient harm and waste of resources. At the system level, open sharing of patient records across systems, clearly defined provider roles, and bi-directional communication between community and VA providers are all necessary to improve co-management and appropriate prescribing.49, 50 Additional resources such as dedicated care trackers, patient navigators, and records administrators may be necessary to help bridge divides across systems.50 At the provider level, effective strategies to limit inappropriate prescribing in other contexts include focused educational sessions, audit and feedback, and clinical decision support integrated in the electronic medical record.51, 52 Pharmacist-led provider education and integration of pharmacists into clinical teams can also mitigate inappropriate prescribing, particularly when pharmacists are empowered to challenge potentially inappropriate prescriptions.53–55 Finally, as previously suggested, establishing appropriate use criteria may also help to reform this current practice.56
Our study has limitations. First, our retrospective analysis of administrative claims data cannot capture the nuanced thought processes of prescribers and there are likely additional influences on prescribing that we could not capture with this study design. Second, administrative data cannot assess physiologic data, without which we cannot definitively determine the appropriateness of prescriptions. Additionally, while more recent consensus statements definitively recommend against treatment of Groups 2/3 PH, earlier guidelines released during the study period were less clear and allowed for treatment in Groups 2/3 PH with a pre-capillary component. Because our validated algorithm15 was conservatively designed to increase specificity for identifying patients with Groups 2/3 PH, our results likely represent an underestimate of the rate of potentially inappropriate PDE5i prescribing. Third, while we sought to comprehensively capture both VA and community care by using VA and Medicare data and restricting our cohort to Medicare-eligible Veterans, we may have missed information about prescriptions or care received and reimbursed through other insurers. Finally, because our analysis is focused on Medicare-eligible Veterans, our results may not be generalizable to factors affecting treatment among non-Veterans or younger patients.
Given the growing rates of use of pulmonary vasodilators for Groups 2 and 3 PH and the recent calls by PH expert conferences to reduce this practice, the time is now to intervene to de-implement this low-value, high-cost, potentially harmful practice. Our study identifies previously unknown influences on potentially inappropriate PDE5i prescribing for PH and suggests concrete solutions to address them.
Supplementary Material
What is Known
Despite US and European guidelines recommending against routine use of pulmonary vasodilators such as phosphodiesterase-5-inhibitors (PDE5i) in pulmonary hypertension secondary to left heart disease (Group 2 PH) and chronic lung disease (Group 3 PH), use is rising over time, exposing patients to harm and increasing costs.
A growing national trend towards shared care for Veterans may increase the potential for care fragmentation and risk of guideline-discordant treatment with PDE5i for Groups 2 and 3 PH.
What this Study Adds
The strongest predictor of PDE5i treatment in VA for Groups 2/3 PH was prior treatment in the community, with an odds ratio of 6.5.
Other factors associated with PDE5i treatment for Groups 2/3 PH included more severe PH disease, prior right heart catheterization, and higher facility PH volume.
Understanding these factors associated with use of PDE5i for Groups 2/3 PH may help address larger issues driving inappropriate prescribing in other contexts, such as prescribing inertia, lack of provider awareness, workplace culture, subspecialty influences, and care fragmentation.
Acknowledgments.
Sources of funding:
This work was supported by VA HSR&D IIR 15-115 and by resources from the Edith Nourse Rogers Memorial Veterans Hospital and the VA Boston Healthcare System. In addition, Dr. Gillmeyer receives support through an NIH Institutional Training Grant, T32 HL007035; Dr. Maron receives support though NIH grants R56HL131787, 1R01HL139613-01, R21HL145420, 1U01HL125215-01, the cardiovascular medical research and education foundation (CMREF), and National Scleroderma Foundation; Dr. Rinne was funded through a Parker B. Francis Fellowship and a VISN 1 Career Development Award.
Footnotes
Disclosures:
The authors have no conflicts of interest to report. The views expressed in this article do not necessarily represent the views of the Department of Veterans Affairs or the United States Government.
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