- Email: [email protected]
kexin type 9 inhibitors in community practice
Journal of Clinical Lipidology (2019) -, -–-
Original Article
The patient journey with proprotein convertase subtilisin/kexin type 9 inhibitors in community practice Corey K. Bradley, MD*, Peter Shrader, MA, Robert J. Sanchez, PhD, Eric D. Peterson, MD, MPH, Ann Marie Navar, MD, PhD Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA (Drs Bradley, Shrader, Peterson, and Naver); and Medical Affairs, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA (Dr Sanchez) KEYWORDS: Proprotein convertase subtilisin/kexin type 9; PCSK9 inhibitor; Utilization; Cardiovascular disease; Prevention
BACKGROUND: Trials have demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective as an adjunct to statin therapy, but access and cost issues have limited their use in community practice. OBJECTIVE: The aim of the study was to better understand patients’ experiences when trying to obtain, fill, and use PCSK9 inhibitor therapy in community practice. METHODS: We conducted a patient survey to evaluate patient experiences with PCSK9 inhibitors including medication initiation, indication for treatment, insurance approval status, medication persistence, and reason for discontinuation. The survey was emailed to 4740 adults who used a patient access support program. RESULTS: Overall, 1327 of 4740 adults completed the survey (28.0% response rate). Of those, 75.0% were aged .60 years, 52.8% were male, and 92.4% were White. At the time of PCSK9 inhibitor prescription, 70.2% were not on a statin (with 84.4% of those not on a statin reporting statin intolerance). Overall, 74.6% of patients found the drug approval process to be ‘‘somewhat’’ or ‘‘very’’ burdensome. Among n 5 1216 patients who initiated treatment, 33.7% discontinued by the time of the survey, with 50.0% taking the drug for 1 to 6 months. Patient out-of-pocket costs were the leading reported reason for discontinuation. CONCLUSIONS: Most PCSK9 inhibitor users in community practice were not on a statin, presumably because of statin intolerance. The drug approval process and costs continue to be strong reasons for lower initiation of PCSK9 agents, as well as higher discontinuation rates. Ó 2019 National Lipid Association. All rights reserved.
Introduction In 2015, 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, were approved for patients with atherosclerotic cardiovascular * Corresponding author. Duke Clinical Research Institute, Duke University School of Medicine, 2400 Pratt Street, Durham, NC 27705, USA. E-mail address: [email protected] Submitted March 1, 2019. Accepted for publication June 21, 2019.
1933-2874/Ó 2019 National Lipid Association. All rights reserved. https://doi.org/10.1016/j.jacl.2019.06.008
disease (ASCVD) or heterozygous familial hypercholesterolemia who required additional lipid-lowering beyond maximally tolerated statin therapy. Subsequently, 2 large cardiovascular outcomes trials have demonstrated the efficacy of PCSK9 inhibitors in reducing cardiovascular disease events.1,2 Nevertheless, in the year following the approval of PCSK9 inhibitors, their use was low. Furthermore, only half of PCSK9 inhibitor prescriptions received payer approval, and up to a one-third of approved prescriptions were never filled. The reasons for these low rates are
2
Journal of Clinical Lipidology, Vol -, No -, - 2019
due in part to insurance barriers,3 which lead to high rates of payer rejections and increased out-of-pocket expenses for patients.4 To date, there is limited information on patients’ experiences when trying to obtain, fill, and use PCSK9 inhibitor therapy in community practice.
tolerability, and acceptability were shortened on the phone survey because of time constraints. Participants provided informed consent (electronic for the online survey and verbal for the phone survey), and the study received Institutional Review Board approval from Duke University.
Methods
Analysis
Patient population
Analyses were stratified by survey type, and comparisons of responses between the 2 survey types were performed to assess representativeness of the sample. Patient characteristics were compared between groups based on use and approval status. In descriptive analyses, categorical variables were summarized using percentages and compared using chi-squared tests. Patients who had missing data to questions about medication prescription, use status, or approval status were excluded from the final analyses. All statistical analyses were performed using SAS version 9.4 (SAS, Cary, NC).
We conducted a survey of all patients who had participated in a company-sponsored patient support program for PCSK9 inhibitor therapy; when agreeing to participate in the portal, these patients consented to being contacted for research purposes. The support program provided patients with information about therapy and provided assistance with medication initiation. A total of 4740 adults who consented to being contacted and had a valid email addresses were sent a link to complete an online survey between March 7, 2017, and November 2, 2017. Among adults who consented to be contacted for research purposes and had a valid phone number, a further unique subset of adults was randomly selected to participate in a phone-based survey. The phone-based survey was conducted, given the anticipated lower response rate for the email-based survey compared with what expected using a telephone contact, as well as potential differences in the population of patients willing to respond to a phone-based vs email-based survey. The goal sample size for the phone survey was 500 adults. A centralized call center at the Duke Clinical Research Institute contacted eligible adults between August 23, 2017, and December 20, 2017, until a final sample size of 500 were reached. Because calls were made in ‘‘batches,’’ the final sample size was 503 adults.
Survey characteristics The online survey included participant self-report of demographics, clinical characteristics, PCSK9 inhibitor use and approval status, drug persistence behaviors, and patient beliefs about the medication. Patient beliefs about the medication were assessed using concepts from the Injection-Treatment Acceptance Questionnaire, including all questions from the domains ‘‘perceived efficacy’’ and ‘‘injection self-efficacy’’ and a subset of questions of the domains ‘‘acceptance of side effects,’’ ‘‘injection convenience,’’ and ‘‘overall acceptance.’’5,6 The phone survey included similar questions to the online survey with 2 exceptions: (1) additional questions were added to clarify the presence of ASCVD and the timing of statin discontinuation (if applicable) based on preliminary results from the online survey; and (2) questions in the online survey addressing the burden of the approval process and patient beliefs about drug efficacy,
Results Of the 4740 patients contacted via email, 1023 (21.6% click rate) clicked on the email link to access the survey, of whom 85.9% (n 5 879) completed the consent process. After reading the consent, 55 patients declined to participate, leaving 824 who completed the survey, for an email response rate of 17.4%. In the phone survey, a total of 752 adults were contacted, of whom 503 (66.9% response rate) agreed to participate in the survey (Supplemental Figs. 1 and 2). Table 1 describes the characteristics of all patients who consented to take the survey. There were slight differences in the demographic characteristics of adults who took the survey via email and phone (Table 1), with those completing the survey via email being slightly younger, more likely to report being White or Caucasian race, having government insurance (eg, Medicare and Medicaid), higher education, and higher income. There were also differences in the reported indication for treatment. Patients could have been referred to the patient support program from which we identified the sample without having a prescription for a PCSK9 inhibitor. Of adults who consented to take the survey, 21 in the email survey and 34 in the phone survey reported never being prescribed a PCSK9 inhibitor (or did not remember being prescribed one) and were excluded from subsequent analyses. The final sample size of adults prescribed a PCSK9 inhibitor who completed the survey was 1269 (803 email and 466 phone).
Patients prescribed PCSK9 inhibitors Table 2 lists characteristics of adults prescribed a PCSK9 inhibitor who completed a survey. Most adults
Bradley et al Table 1
The patient journey with PCSK9 inhibitors
3
Characteristics of survey respondents overall and by survey type
Patients’ characteristics Age (y) ,40 40–59 60–79 .80 Sex (% male) Race Caucasian/White Black Other Education High school or less At least some college Graduate degree Household income ,$30,000 $30,000–$69,999 .$70,000 Insurance type Private Government None
Overall (N 5 1327), n (%)
Email consent (n 5 824), n (%)
Phone consent (n 5 503), n (%)
21 290 852 81 52.8
17 (2.2) 190 (24.4) 537 (68.9) 35 (4.5) 54.0
4 (0.9) 100 (21.5) 315 (67.7) 46 (9.9) 50.9
1132 (92.4) 46 (3.8) 47 (3.8)
721 (94.1) 20 (2.6) 25 (3.3)
411 (89.5) 26 (5.7) 22 (4.8)
193 (20.1) 350 (36.5) 415 (43.3)
105 (16.5) 239 (37.6) 291 (45.8)
88 (27.2) 111 (34.4) 124 (38.4)
224 (18.1) 753 (60.9) 259 (21.0)
89 (11.4) 490 (63.0) 199 (25.6)
135 (29.5) 263 (57.4) 60 (13.1)
746 (56.5) 462 (35.0) 87 (6.6)
446 (54.3) 312 (38.0) 50 (6.1)
300 (60.0) 150 (30.0) 37 (7.4)
P difference .0007
(1.7) (23.3) (68.5) (6.5)
.29 .009
.0004
,.0001
.02
were aged .60 years (75.0%), reported White or Caucasian race (92.4%), and had at least some college education or a graduate degree (81.9%). There was a slight majority of males (52.9%) and adults with private insurance (59.0%). The leading patient-reported indication for therapy was ASCVD (n 5 459, 36.2%) or ASCVD and heterozygous familial hypercholesterolemia (31.2%); however, 14.1% of patients did not know their indication, had missing data, or reported their indication as ‘‘other.’’ Although cardiologists were the most common prescribing provider type, primary care physicians were responsible for 12.9% of all PCSK9 prescriptions. Overall, statin utilization was low; only 29.8% of those surveyed were taking a statin, and 15.5% were taking a high-intensity statin (defined as atorvastatin 40 or 80 mg, and rosuvastatin 20 or 40 mg). Similarly, very few (19.3% overall) of those prescribed a PCSK9 inhibitor were taking ezetimibe. Very few adults (n 5 13) reported never trying a statin; most adults who were not on a statin had previously tried one, but discontinued because of the side effects (84.9%; Table 1).
PCSK9 inhibitor initiation and self-reported persistence and adherence Figure 1 demonstrates the breakdown of treatment status at the time of the survey. Of the 1263 adults with data on current PCSK9 inhibitor utilization, n 5 1216 (96.3%) subjects had received at least 1 dose of PCSK9 inhibitor. Among the 1216 who initiated therapy, n 5 779 (61.3%)
were still on treatment at the time of the survey, whereas n 5 428 (33.7%) had discontinued therapy by the time they completed the survey. Figure 2 shows patient-reported reasons for never initiating PCSK9 inhibitor therapy (among n 5 47 adults who were prescribed, but never received therapy) or discontinuing therapy (among n 5 428 adults who initiated but discontinued treatment). In both groups, the leading patient-reported reasons for lack of PCSK9 inhibitor utilization was lack of insurance approval (54.3% of those who never initiated therapy and 34.4% of those who stopped therapy), followed by high costs to the patient (39.1% of those who never initiated therapy and 38.2% of those who stopped therapy). Among those who discontinued treatment, 24.4% reported discontinuing because of perceived side effects. Rates of discontinuation were similar among those with a reported history of statin intolerance (20.4%) and those without statin intolerance (26.8% discontinued PCSK9 inhibitor). Among patients who started a PCSK9 inhibitor, slightly more than half (64.1%, n 5 779) were still taking their prescribed PCSK9 inhibitor at the time of the survey. Table 3 shows drug adherence and persistence behavior by patient PCSK9 inhibitor use status. There were no significant differences between those currently on therapy and those who had discontinued therapy based on age, race, or insurance type. Nevertheless, those on therapy were more likely to be male (57.0% vs 45.3%, P 5 .0005), report a graduate degree (22.9% vs 16.8%, P 5 .02), and have a higher household income. Among current users, 85.3%
Journal of Clinical Lipidology, Vol -, No -, - 2019
4 Table 2 Characteristics of patients prescribed PCSK9 inhibitor
Patients’ characteristics
All patients prescribed PCSK9 inhibitors (n 5 1269)*, n (%)
Age (y) ,40 21 (1.7) 40–59 290 (23.3) 60–79 851 (68.5) .80 81 (6.5) Sex (% male) 657 (52.9) Race Caucasian/White 1131 (92.4) Black 46 (3.8) Other 47 (3.8) Education High school or less 224 (18.1) At least some college 752 (60.9) Graduate degree 259 (21.0) Household income ,$30,000 193 (20.2) $30,000–$69,999 350 (36.5) .$70,000 415 (43.3) Insurance type Private 745 (59.0) Government 462 (36.6) None 30 (2.4) Insurance medication coverage Full 824 (66.9) Partial 356 (28.9) None 51 (4.1) Clinical characteristics† HeFH only 235 (18.5) ASCVD only 459 (36.2) ASCVD and HeFH 396 (31.2) Other/no response/missing 179 (14.1) Currently taking any statin 376 (29.8) Currently taking high-intensity statin 190 (15.5) Not taking statin 884 (70.2) Currently taking ezetimibe 236 (19.3) Not taking statin Phone: reason for not taking statin‡ Side effects 284 (85.8) Other 37 (11.2) Never took a statin 10 (3.0) Email: reason for not taking statinx Side effects 462 (84.3) Stopped when starting PCSK9 44 (8.0) inhibitor Other 39 (7.1) Never took a statin 3 (0.6) Prescribing doctor Cardiologist 963 (76.3) Endocrinologist 93 (7.4) Primary care 163 (12.9) Other 44 (3.5) Patient involvement in approval{ Completing paperwork 276 (23.3) (continued on next page)
Table 2
(continued )
Patients’ characteristics Getting paperwork to provider Calling insurer None of the above Burden of approval process# Not at all burdensome Somewhat burdensome Very burdensome
All patients prescribed PCSK9 inhibitors (n 5 1269)*, n (%) 441 (37.2) 340 (28.7) 84 (6.6) (n 5 496) 126 (25.4) 199 (40.1) 171 (34.5)
ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hyperlipidemia; PCSK9, proprotein convertase subtilisin/kexin type 9 inhibitors. *134 respondents were prescribed PCSK9 inhibitors but had subsequent missing data or did not know their approval status. †In the phone survey, ASCVD was assessed by asking patients about a history of stroke, heart attack, coronary stent, or heart bypass. In the email survey, this was broadened to include coronary artery disease, angina, abdominal aortic aneurysm, and transient ischemic attacks. ‡Phone survey only. xEmail survey only. {Patient involvement options are not mutually exclusive. # The question of if patients stopped statin after initiating PCSK9 inhibitors was not asked on phone survey to prevent potentially prompting patients to stop therapy inappropriately after seeing high rates of this on the first email survey.
had been on therapy for more than 6 months. Of those who discontinued therapy, 50.0% stopped the medication after 1 to 6 months, whereas 42.6% stopped after $6 months. Patients currently on therapy reported missing a dose or having a delay to dose of more than 1 week significantly more than those who had discontinued therapy (28.2% of those on therapy vs 9.3% of those who discontinued, P # .0001) or forgotten to take their medication on the day it was due (36.7% vs 22.2%, P # .0001). Although many reported skipping a prescription fill because of the price (17.7% of those on therapy vs 49.4% of those who discontinued), few reported intentionally spacing out doses to make the prescription last longer (6.1% vs 4.8%, P 5 .37). Table 4 compares patient-reported beliefs about disease risk and PCSK9 inhibitors between those who were still on therapy and those who had discontinued or did not initiate treatment for the subset of patients who completed the email survey. Of email responses, the majority of both groups reported confidence in drug efficacy, reporting they were ‘‘quite’’ or ‘‘very confident’’ in the drug treating condition (89.6%, P 5 .0001), although those on therapy did have higher overall confidence in treatment effectiveness than those who discontinued. Similarly, those currently on therapy had higher beliefs in the safety of PCSK9 inhibitors and acceptability of therapy; 82.6% of current users found therapy side effects ‘‘acceptable’’ or ‘‘very acceptable’’ compared with 55.7% of former users (P # .0001), and 94.0% vs 84.8% reported the drug to be overall
Bradley et al
The patient journey with PCSK9 inhibitors
5
Figure 1 Patient response to survey. Patient response to survey contact and PCSK9 inhibitor prescription. PCSK9, proprotein convertase subtilisin/kexin type 9 inhibitor.
‘‘acceptable’’ or ‘‘very acceptable’’ (current vs nonusers, respectively, P 5 .002). Drug administration was well tolerated; 92.9% overall reported it was ‘‘easy’’ or ‘‘very easy’’ to give the injection.
Insurance approval and patient process experience Not all those who were on therapy or had discontinued therapy received insurance approval. Among adults who had started PCSK9 inhibitor therapy and for whom approval status was known, the approval rate was 74.9%. Of those still on therapy, 631 (81.0%) reported receiving approval, 95 (12.2%) reported not receiving approval, and approval status was missing or unknown in 53 adults (6.8%). Of those who never initiated or discontinued therapy (n 5 475), 205 (43.2%) had
received approval, 204 (42.9%) had not received approval, and approval status was unknown for 66 adults (13.9%). Characteristics of patients according to approval status are described in Supplemental Table 1. Those who received approval were older and more likely to report government insurance and an indication of ASCVD than those who did not receive approval. There was no difference in education or income by approval status nor was statin utilization different among those who received approval and those who did not. Most patients were engaged in the prior authorization process in some capacity, with the most cited method being getting paperwork to/from the doctor or pharmacy (37.2%). There were similar rates of participation in the prior authorization process across approval and utilization status (Table 1). The majority of all groups found the process to be ‘‘somewhat’’ or ‘‘very’’ burdensome (74.6%).
34.4
Not approved
54.3 38.2 39.1
Too expensive Perceived side effects/fear of side effects
24.4 10.9
Discon nued drug
1.5 4.4
Did not want/like injec on
Never received drug
2.0 2.2
Did not think it was needed
25.9
Other
15.2
0.0
10.0
20.0
30.0
40.0
50.0
60.0
% of Respondents
Figure 2 Reason for not currently using PCSK9 inhibitors. Reason for not currently using PCSK9 inhibitors and whether the drug was discontinued or never received. PCSK9, proprotein convertase subtilisin/kexin type 9 inhibitor.
Journal of Clinical Lipidology, Vol -, No -, - 2019
6 Table 3
Patient persistence and adherence with PCSK-9 inhibitors by use status
Patient persistence and adherence* Age (y) ,40 40–59 60–79 .80 Sex (% male) Race Caucasian/White Black Other Education High school or less At least some college Graduate degree Household income ,$30,000 $30,000–$69,999 .$70,000 Insurance type Private Government None Insurance medication coverage Full Partial None Clinical characteristics HeFH only ASCVD only ASCVD and HeFH Other/no response/missing Months using drug ,1 mo 1–6 mo .6 mo Medication adherence (% yes) Missed or delayed doses by 1 wk Forgotten to take dose Intentionally spaced doses Skipped filling because of price None of the above
On therapy (n 5 779), n (%)
Discontinued therapy (n 5 428), n (%)
12 193 521 45 443
6 86 297 36 193
P value .13
(1.5) (24.8) (67.1) (5.8) (57.0)
(1.4) (20.2) (69.7) (8.5) (45.3)
706 (91.0) 25 (3.2) 28 (3.6)
380 (89.8) 21 (5.0) 19 (4.5)
128 (16.8) 461 (60.3) 175 (22.9)
89 (21.0) 264 (62.3) 71 (16.8)
97 (12.6) 211 (27.4) 288 (37.4)
92 (22.0) 123 (29.4) 107 (25.5)
459 (59.3) 290 (37.5) 9 (1.2)
257 (60.2) 155 (36.3) 6 (1.4)
512 (65.9) 222 (28.6) 29 (3.7)
281 (66.0) 119 (27.9) 22 (5.2)
138 288 269 84
87 149 115 77
.0005 .10
.02
,.0001
.97
.43
.01 (17.7) (37.0) (34.5) (10.8)
(20.3) (34.8) (26.9) (18.0) ,.0001
2 (0.3) 111 (14.4) 658 (85.3)
31 (7.4) 210 (50.0) 179 (42.6)
218 283 47 130 309
39 93 20 203 164
(28.2) (36.7) (6.1) (17.7) (39.8)
(9.3) (22.2) (4.8) (49.4) (39.0)
,.0001 ,.0001 .37 ,.0001 .78
ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hyperlipidemia. *Nine respondents answered the question about receiving therapy, but had subsequent missing data.
Discussion Although the provider experience with PCSK9 inhibitor therapy has been documented,7 the patient experience (including the approval process and use) has not previously been well described. In this survey, we identified first that PCSK9 inhibitor utilization has been largely confined to patients with statin intolerance, rather than patients with high on-statin low-density lipoprotein cholesterol (LDL-C) levels. Next, we reconfirmed that cost and lack of insurance
approval decreased patient initiation of therapy. Finally, we identified that even among patients who receive therapy, persistence is suboptimal, with discontinuation driven by cost and insurance approval, as well as patient-perceived side effects. Large outcomes trials have demonstrated the safety and efficacy of PCSK9 inhibitors in reducing the risk of cardiovascular events when added to a background of statin therapy,1,2 and at the time of the study, the Food and Drug Administration label states that PCSK9 inhibitors are to be
Bradley et al Table 4
The patient journey with PCSK9 inhibitors
7
Patients’ beliefs about PCSK9 inhibitors by use status*
Patients’ beliefs Drug effectiveness Confidence in drug treating condition Not at all confident A little confident Somewhat confident Quite confident Very confident Injection effectiveness in treating condition Not at all effective A little effective Somewhat effective Quite effective Very effective Drug safety Acceptability of side effects Very unacceptable Unacceptable Neither acceptable nor unacceptable Acceptable Very acceptable Drug delivery Acceptability of pain at injection site Very unacceptable Unacceptable Neither acceptable nor unacceptable Acceptable Very acceptable Confidence in ability to give injection Not at all confident A little confident Somewhat confident Quite confident Very confident Ease of giving injection Very difficult Difficult Neither difficult nor easy Easy Very easy Drug acceptability Overall acceptability of treatment Very unacceptable Unacceptable Neither acceptable nor unacceptable Acceptable Very acceptable
Overall (N 5 520), n (%)
On therapy with approval (n 5 406), n (%)
Discontinued/did not initiate with approval (n 5 114), n (%)
6 8 37 85 355
(1.2) (1.6) (7.5) (17.3) (72.3)
0 6 29 68 288
(0.0) (1.5) (7.4) (17.4) (73.7)
6 2 8 17 67
(6.0) (2.0) (8.0) (17.0) (67.0)
5 8 26 68 327
(1.2) (1.8) (6.0) (15.7) (75.4)
1 4 19 49 264
(0.3) (1.2) (5.6) (14.5) (78.3)
4 4 7 19 63
(4.1) (4.1) (7.2) (19.6) (65.0)
42 18 53 114 262
(8.6) (3.7) (10.8) (23.3) (53.6)
18 4 45 94 224
(4.7) (1.0) (11.7) (24.4) (58.2)
24 14 8 20 38
(23.1) (13.5) (7.7) (19.2) (36.5)
19 9 45 131 299
(3.8) (1.8) (9.0) (26.0) (59.4)
15 3 35 102 246
(3.7) (0.8) (8.7) (25.4) (61.4)
4 6 10 29 53
(3.9) (5.9) (9.8) (28.4) (52.0)
3 5 13 59 422
(0.6) (1.0) (2.6) (11.8) (84.1)
3 4 11 37 345
(0.8) (1.0) (2.8) (9.3) (86.3)
0 1 2 22 77
(0.0) (1.0) (2.0) (21.6) (75.5)
1 8 27 86 381
(0.2) (1.6) (5.4) (17.1) (75.8)
1 6 25 62 307
(0.3) (1.5) (6.2) (15.5) (76.6)
0 2 2 24 74
(0.0) (2.0) (2.0) (23.5) (72.6)
15 6 19 98 366
(3.0) (1.2) (3.8) (19.4) (72.6)
9 1 14 72 303
(2.3) (0.3) (3.5) (18.1) (75.9)
6 5 5 26 63
(5.7) (4.8) (4.8) (24.8) (60.0)
P value ,.0001
.003
,.0001
.009
.01
.17
.0001
PCSK9, proprotein convertase subtilisin/kexin type 9 inhibitors. *Email survey only.
used in addition to maximally tolerated doses of statin.8 Yet, despite existing evidence and indication, most patients in this study who had been prescribed a PCSK9 inhibitor were not on a statin, and 84.4% of those patients reported statin intolerance. Whether these patients meet strict
criteria for statin intolerance is unknown, but at minimum, it appears that most those who are being prescribed a PCSK9 inhibitor self-reported being statin intolerant. Our rate of statin utilization (29.8%) was slightly lower than what was shown by Rane et al., who reported that only
8 40.5% of patients prescribed PCSK9 inhibitors were currently using a statin by physician report, and similar to what was found in a large national analysis of pharmacy claims data, whereas 76.9% of those prescribed PCSK9 inhibitors were not on a statin.4,9 Importantly, these prescriptions were not inappropriate: those who are statin intolerant are at high risk of recurrent events10,11 and PCSK9 inhibitors have been shown to be effective in lowering LDL-C in those with statin intolerance.12,13 The demand for lipidlowering therapy options for statin-intolerant patients may have driven uptake, given the lack of previously available therapeutic options; however, efforts to increase uptake of PCSK9 inhibitor therapy should now focus on those with ASCVD who are at high risk for recurrent events and persistently high LDL-C despite maximally tolerated therapy, as studied in the trials. Furthermore, there was a small subset of patients in our study who reported stopping statins following PCSK9 inhibitor initiation. Providers should continue to emphasize to patients that the benefits of PCSK9 inhibitor therapy are in addition to statins and encourage continued statin therapy while on PCSK9 inhibitors. Continuing statin therapy after starting PCSK9 inhibitors is also important to maintain insurance coverage for therapy; many insurance companies require documentation of LDL-C lowering on PCSK9 inhibitors. If patients stop statin therapy after starting PCSK9 inhibitors, then their apparent LDL-C lowering on PCSK9 inhibitor will be reduced, and they may not be able to obtain reauthorization for ongoing therapy. Our study also found a low rate of ezetimibe use in those prescribed PCSK9 inhibitors (19.3%). This survey did not further evaluate the reason for the lack of ezetimibe use. However, at the time, the survey guidelines did not recommend using ezetimibe before initiating PCSK9 inhibitor, and payer requirements for ezetimibe as a stepthrough therapy also varied.14 Whether the recommendation to try ezetimibe first in the latest lipid guidelines leads to an increase in ezetimibe use in those prescribed PCSK9 inhibitors remains to be seen. At the time of the survey, we found that even among patients who were enrolled in a company-sponsored patient portal with access to support for navigating the prior authorization process, only 66.9% of patients prescribed PCSK9 inhibitors had received insurance approval. Lack of payer approval was a leading reason that patients did not start or discontinued therapy; however, even among those who received approval and were still on therapy, most patients reported the approval process to be ‘‘burdensome’’ or ‘‘very burdensome.’’ As shown in prior studies, a key barrier to patient utilization of PCSK9 inhibitors was cost, which was cited by nearly 40% of those who discontinued or did not initiate treatment. Patient out-of-pocket costs are strongly correlated with primary non-adherence, or lack of patients’ filling a prescription even after approval. This survey reveals that costs also appear to impact patient’s longterm persistence to treatment. There is hope in the fact that
Journal of Clinical Lipidology, Vol -, No -, - 2019 the recently announced 60% decrease in price of both drugs may translate into reduced out-of-pocket costs for those with government insurance.15,16 For those that are still unable to afford the prescription, enhancing access to patient assistance programs may help improve long-term adherence to PCSK9 inhibitor therapy. Largely because of cost and lack of insurance approval, 1 in 3 adults who initiated a PCSK9 inhibitor discontinued therapy, with 24.4% of those who discontinued treatment citing side effects from PCSK9 inhibitor therapy as the reason (representing around 8% of those who initiated therapy). This number was slightly higher than what was seen in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) trials, in which 628 of 13,784 (4.6%) and 362 of 9462 (3.8%), respectively, discontinued therapy because of adverse events.1,2 Importantly, in both trials, similar numbers of participants in the placebo arm also discontinued because of adverse events (4.2% [n 5 581] of 13,780 in FOURIER, and 3.7% [n 5 347] of 9462 in ODYSSEY OUTCOMES),1,2 which suggests that much of the intolerance to PCSK9 inhibitors in clinical trials may be unrelated to the active therapy or may reflect a ‘‘nocebo effect’’ as seen commonly in statin clinical trials. Our study was not designed to obtain detailed information on patient-perceived side effects nor was it designed to determine whether patient-reported side effects were because of a true causal link vs a nocebo effect. However, it is important to note that studies evaluating treatment acceptance suggest a high level of drug acceptance,5,6,17 and multiple studies have shown that evolocumab and alirocumab have been well tolerated by patients.18,19 Clinicians should monitor patients for both real and perceived side effects and help determine if side effects may be related to PCSK9 inhibitors. Both patients and providers should report any potential PCSK9 inhibitor–related side effects to the Food and Drug Administration’s MedWatch program. Nevertheless, despite the side effect rates reported in this survey, most patients found PCSK9 inhibitors acceptable and believe that they are effective. Even patients who had discontinued therapy reported high rates of confidence in drug efficacy and tolerability. Identifying and addressing barriers to long-term persistence to PCSK9 inhibitors is critical to achieve the population health benefits of the medication; in clinical trials, the event rates between the treated and placebo arms did not separate for the first 6 to 12 months.1,2 This study has several limitations. First, the subsample of patients who chose to enroll in the patient portal may not be representative of the overall population. For example, patients less satisfied with their experience with PCSK9 inhibitors or who did not feel the medication was effective may have been less likely to participate in the patient portal or survey. Second, indication for therapy was self-reported in this survey, which is inherently subject to recall bias and
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may not have been well understood by patients at the time of the survey. Third, this study identified patients referred to a company-sponsored support program for alirocumab. As a result, the results likely apply more to patients prescribed alirocumab. Because patients may be prescribed 1 brand and then switched to another or were prescribed both pending insurance approval, we asked patients about therapy as a class and did not evaluate differences by therapy type. Importantly, this survey was conducted before the results of the FOURIER and ODYSSEY OUTCOMES trials, after which new agreements with payers have been undertaken with the goal to lower the bar to approval. In addition, the cost of both PCSK9 inhibitors has been significantly decreased since the time of this survey. Finally, arrangements between the manufacturers and health plans have changed since the survey. For example, Express Scripts, Inc, which is a large pharmacy benefits manager in the United States, announced they will pass a portion of their rebates to the patients who are effectively lowering out-of-pocket expenses.20 Also, companies have worked with payers to lower the prior authorization requirements for providers. Further exploration is needed to better understand the impact of these changes on patient initiation and persistence to PCSK9 inhibitors.
Conclusion In conclusion, in contrast to what was studied in trials, PCSK9 inhibitors appear to be prescribed more commonly in adults with statin intolerance than those on high-intensity statins. Efforts to expand utilization of PCSK9 inhibitors should focus on high-risk adults with persistently high LDL-C, despite statin therapy. Lack of insurance approval and high out-of-pocket costs are consistent barriers to both initiation and long-term persistence to PCSK9 inhibitor therapy. Continued efforts between payers and pharmaceutical companies to decrease access barriers will be critical to ensure the maximal effectiveness of PCSK9 inhibitors to reduce the burden of ASCVD.
Acknowledgments Erin Campbell, MS, of the Duke Clinical Research Institute provided editorial assistance. This study was supported by Sanofi and Regeneron Pharmaceuticals, Inc., United States A.M.N. receives support from the NHLBI, United States (K01HL133416). Authors’ contributions: A.M.N. and P.S. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. C.K.B., R.J.S., E.D.P., and A.M.N. were responsible for study concept and design. P.S. and A.M.N. were responsible for data analysis. C.K.B., R.J.S., E.D.P., and A.M.N. were responsible for interpretation of data. C.K.B. was responsible for drafting the article. C.K.B., R.J.S., E.D.P., and A.M.N. were responsible for critically revising the article.
9
Disclosure C.K.B. and P.S. reports no relevant disclosures. R.J.S. reports employment with Regeneron Pharmaceuticals, Inc. E.D.P. reports research grants (significant) from Amgen, Sanofi, Astrazeneca, Merck; consultant/advisory board (modest) from Amgen; consultant/advisory board (significant) from AstraZeneca, Merck, and Sanofi Aventis. A.M.N. reports research grants (significant) from Amgen, Sanofi, Amarin, Janssen, and Regeneron; consultant/advisory board (modest) for Amgen, Regeneron, NovoNordisk, AstraZeneca, and Sanofi.
Supplementary data Supplementary data related to this article can be found online at https://dx.doi.org/10.1016/j.jacl.2019.06.008.
References 1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017; 376:1713–1722. 2. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379: 2097–2107. 3. Doshi JA, Puckett JT, Parmacek MS, Rader DJ. Prior authorization requirements for proprotein convertase subtilisin/kexin type 9 inhibitors across US private and public payers. Circ Cardiovasc Qual Outcomes. 2018;11:e003939. 4. Navar AM, Taylor B, Mulder H, et al. Association of prior authorization and out-of-pocket costs with patient access to PCSK9 inhibitor therapy. JAMA Cardiol. 2017;2:1217–1225. 5. Tatlock S, Grant L, Spertus JA, et al. Development and content validity testing of a patient-reported treatment acceptance measure for use in patients receiving treatment via subcutaneous injection. Value Health. 2015;18:1000–1007. 6. Tatlock S, Arbuckle R, Sanchez R, et al. Psychometric evaluation of a treatment acceptance measure for use in patients receiving treatment via subcutaneous injection. Value Health. 2017;20: 430–440. 7. Cohen JD, Cziraky MJ, Jacobson TA, Maki KC, Karalis DG. Barriers to PCSK9 inhibitor prescriptions for patients with high cardiovascular risk: results of a healthcare provider survey conducted by the National Lipid Association. J Clin Lipidol. 2017;11:891–900. 8. Young K, Krumholz HM. FDA Approves Praluent to Treat Certain Patients with High Cholesterol. NEJM J Watch; 2015Available at: https://www.jwatch.org/na38684/2015/08/03/fda-approves-pcsk9-in hibitor-reduce-cholesterol. Accessed January 9, 2019. 9. Rane PB, Patel J, Harrison DJ, et al. Patient characteristics and realworld treatment patterns among early users of PCSK9 inhibitors. Am J Cardiovasc Drugs. 2018;18:103–108. 10. Serban MC, Colantonio LD, Manthripragada AD, et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol. 2017;69: 1386–1395. 11. Graham JH, Sanchez RJ, Saseen JJ, Mallya UG, Panaccio MP, Evans MA. Clinical and economic consequences of statin intolerance in the United States: results from an integrated health system. J Clin Lipidol. 2017;11:70–79.e1. 12. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the
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GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2541–2548. Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9:758–769. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73:3168–3209. PR Newswire. Amgen Makes RepathaÒ (Evolocumab) Available in the US at a 60 Percent Reduced List Price. AMGEN; 2018Available at: https://www.amgen.com/media/news-releases/2018/10/amgen-makesrepatha-evolocumab-available-in-the-us-at-a-60-percent-reduced-listprice/. Accessed January 9, 2019. PR Newswire. Sanofi and Regeneron Offer PraluentÒ (alirocumab) at a New Reduced U.S. List Price. PR Newswire; 2019Available at: http://www.news.sanofi.us/2019-02-11-Sanofi-and-Regeneron-offer-
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Praluent-R-alirocumab-at-a-new-reduced-U-S-list-price. Accessed February 20, 2019. Leiter LA, Cariou B, M€uller-Wieland D, et al. Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: the ODYSSEY DMINSULIN randomized trial. Diabetes Obes Metab. 2017;19: 1781–1792. Zhang XL, Zhu QQ, Zhu L, et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med. 2015;13:123. Stoekenbroek RM, Hartgers ML, Rutte R, de Wijer DD, Stroes ESG, Hovingh GK. PCSK9 inhibitors in clinical practice: delivering on the promise? Atherosclerosis. 2018;270:205–210. PR Newswire. Sanofi and Regeneron to Lower Net Price of PraluentÒ (Alirocumab) Injection in Exchange for Straightforward, More Affordable Patient Access for Express Scripts Patients. PR Newswire; 2018Available at: https://newsroom.regeneron.com/news-releases/ news-release-details/regeneron-and-sanofi-lower-net-price-praluentralirocumab. Accessed January 9, 2019.
Original Article
The patient journey with proprotein convertase subtilisin/kexin type 9 inhibitors in community practice Corey K. Bradley, MD*, Peter Shrader, MA, Robert J. Sanchez, PhD, Eric D. Peterson, MD, MPH, Ann Marie Navar, MD, PhD Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA (Drs Bradley, Shrader, Peterson, and Naver); and Medical Affairs, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA (Dr Sanchez) KEYWORDS: Proprotein convertase subtilisin/kexin type 9; PCSK9 inhibitor; Utilization; Cardiovascular disease; Prevention
BACKGROUND: Trials have demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective as an adjunct to statin therapy, but access and cost issues have limited their use in community practice. OBJECTIVE: The aim of the study was to better understand patients’ experiences when trying to obtain, fill, and use PCSK9 inhibitor therapy in community practice. METHODS: We conducted a patient survey to evaluate patient experiences with PCSK9 inhibitors including medication initiation, indication for treatment, insurance approval status, medication persistence, and reason for discontinuation. The survey was emailed to 4740 adults who used a patient access support program. RESULTS: Overall, 1327 of 4740 adults completed the survey (28.0% response rate). Of those, 75.0% were aged .60 years, 52.8% were male, and 92.4% were White. At the time of PCSK9 inhibitor prescription, 70.2% were not on a statin (with 84.4% of those not on a statin reporting statin intolerance). Overall, 74.6% of patients found the drug approval process to be ‘‘somewhat’’ or ‘‘very’’ burdensome. Among n 5 1216 patients who initiated treatment, 33.7% discontinued by the time of the survey, with 50.0% taking the drug for 1 to 6 months. Patient out-of-pocket costs were the leading reported reason for discontinuation. CONCLUSIONS: Most PCSK9 inhibitor users in community practice were not on a statin, presumably because of statin intolerance. The drug approval process and costs continue to be strong reasons for lower initiation of PCSK9 agents, as well as higher discontinuation rates. Ó 2019 National Lipid Association. All rights reserved.
Introduction In 2015, 2 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, were approved for patients with atherosclerotic cardiovascular * Corresponding author. Duke Clinical Research Institute, Duke University School of Medicine, 2400 Pratt Street, Durham, NC 27705, USA. E-mail address: [email protected] Submitted March 1, 2019. Accepted for publication June 21, 2019.
1933-2874/Ó 2019 National Lipid Association. All rights reserved. https://doi.org/10.1016/j.jacl.2019.06.008
disease (ASCVD) or heterozygous familial hypercholesterolemia who required additional lipid-lowering beyond maximally tolerated statin therapy. Subsequently, 2 large cardiovascular outcomes trials have demonstrated the efficacy of PCSK9 inhibitors in reducing cardiovascular disease events.1,2 Nevertheless, in the year following the approval of PCSK9 inhibitors, their use was low. Furthermore, only half of PCSK9 inhibitor prescriptions received payer approval, and up to a one-third of approved prescriptions were never filled. The reasons for these low rates are
2
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due in part to insurance barriers,3 which lead to high rates of payer rejections and increased out-of-pocket expenses for patients.4 To date, there is limited information on patients’ experiences when trying to obtain, fill, and use PCSK9 inhibitor therapy in community practice.
tolerability, and acceptability were shortened on the phone survey because of time constraints. Participants provided informed consent (electronic for the online survey and verbal for the phone survey), and the study received Institutional Review Board approval from Duke University.
Methods
Analysis
Patient population
Analyses were stratified by survey type, and comparisons of responses between the 2 survey types were performed to assess representativeness of the sample. Patient characteristics were compared between groups based on use and approval status. In descriptive analyses, categorical variables were summarized using percentages and compared using chi-squared tests. Patients who had missing data to questions about medication prescription, use status, or approval status were excluded from the final analyses. All statistical analyses were performed using SAS version 9.4 (SAS, Cary, NC).
We conducted a survey of all patients who had participated in a company-sponsored patient support program for PCSK9 inhibitor therapy; when agreeing to participate in the portal, these patients consented to being contacted for research purposes. The support program provided patients with information about therapy and provided assistance with medication initiation. A total of 4740 adults who consented to being contacted and had a valid email addresses were sent a link to complete an online survey between March 7, 2017, and November 2, 2017. Among adults who consented to be contacted for research purposes and had a valid phone number, a further unique subset of adults was randomly selected to participate in a phone-based survey. The phone-based survey was conducted, given the anticipated lower response rate for the email-based survey compared with what expected using a telephone contact, as well as potential differences in the population of patients willing to respond to a phone-based vs email-based survey. The goal sample size for the phone survey was 500 adults. A centralized call center at the Duke Clinical Research Institute contacted eligible adults between August 23, 2017, and December 20, 2017, until a final sample size of 500 were reached. Because calls were made in ‘‘batches,’’ the final sample size was 503 adults.
Survey characteristics The online survey included participant self-report of demographics, clinical characteristics, PCSK9 inhibitor use and approval status, drug persistence behaviors, and patient beliefs about the medication. Patient beliefs about the medication were assessed using concepts from the Injection-Treatment Acceptance Questionnaire, including all questions from the domains ‘‘perceived efficacy’’ and ‘‘injection self-efficacy’’ and a subset of questions of the domains ‘‘acceptance of side effects,’’ ‘‘injection convenience,’’ and ‘‘overall acceptance.’’5,6 The phone survey included similar questions to the online survey with 2 exceptions: (1) additional questions were added to clarify the presence of ASCVD and the timing of statin discontinuation (if applicable) based on preliminary results from the online survey; and (2) questions in the online survey addressing the burden of the approval process and patient beliefs about drug efficacy,
Results Of the 4740 patients contacted via email, 1023 (21.6% click rate) clicked on the email link to access the survey, of whom 85.9% (n 5 879) completed the consent process. After reading the consent, 55 patients declined to participate, leaving 824 who completed the survey, for an email response rate of 17.4%. In the phone survey, a total of 752 adults were contacted, of whom 503 (66.9% response rate) agreed to participate in the survey (Supplemental Figs. 1 and 2). Table 1 describes the characteristics of all patients who consented to take the survey. There were slight differences in the demographic characteristics of adults who took the survey via email and phone (Table 1), with those completing the survey via email being slightly younger, more likely to report being White or Caucasian race, having government insurance (eg, Medicare and Medicaid), higher education, and higher income. There were also differences in the reported indication for treatment. Patients could have been referred to the patient support program from which we identified the sample without having a prescription for a PCSK9 inhibitor. Of adults who consented to take the survey, 21 in the email survey and 34 in the phone survey reported never being prescribed a PCSK9 inhibitor (or did not remember being prescribed one) and were excluded from subsequent analyses. The final sample size of adults prescribed a PCSK9 inhibitor who completed the survey was 1269 (803 email and 466 phone).
Patients prescribed PCSK9 inhibitors Table 2 lists characteristics of adults prescribed a PCSK9 inhibitor who completed a survey. Most adults
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3
Characteristics of survey respondents overall and by survey type
Patients’ characteristics Age (y) ,40 40–59 60–79 .80 Sex (% male) Race Caucasian/White Black Other Education High school or less At least some college Graduate degree Household income ,$30,000 $30,000–$69,999 .$70,000 Insurance type Private Government None
Overall (N 5 1327), n (%)
Email consent (n 5 824), n (%)
Phone consent (n 5 503), n (%)
21 290 852 81 52.8
17 (2.2) 190 (24.4) 537 (68.9) 35 (4.5) 54.0
4 (0.9) 100 (21.5) 315 (67.7) 46 (9.9) 50.9
1132 (92.4) 46 (3.8) 47 (3.8)
721 (94.1) 20 (2.6) 25 (3.3)
411 (89.5) 26 (5.7) 22 (4.8)
193 (20.1) 350 (36.5) 415 (43.3)
105 (16.5) 239 (37.6) 291 (45.8)
88 (27.2) 111 (34.4) 124 (38.4)
224 (18.1) 753 (60.9) 259 (21.0)
89 (11.4) 490 (63.0) 199 (25.6)
135 (29.5) 263 (57.4) 60 (13.1)
746 (56.5) 462 (35.0) 87 (6.6)
446 (54.3) 312 (38.0) 50 (6.1)
300 (60.0) 150 (30.0) 37 (7.4)
P difference .0007
(1.7) (23.3) (68.5) (6.5)
.29 .009
.0004
,.0001
.02
were aged .60 years (75.0%), reported White or Caucasian race (92.4%), and had at least some college education or a graduate degree (81.9%). There was a slight majority of males (52.9%) and adults with private insurance (59.0%). The leading patient-reported indication for therapy was ASCVD (n 5 459, 36.2%) or ASCVD and heterozygous familial hypercholesterolemia (31.2%); however, 14.1% of patients did not know their indication, had missing data, or reported their indication as ‘‘other.’’ Although cardiologists were the most common prescribing provider type, primary care physicians were responsible for 12.9% of all PCSK9 prescriptions. Overall, statin utilization was low; only 29.8% of those surveyed were taking a statin, and 15.5% were taking a high-intensity statin (defined as atorvastatin 40 or 80 mg, and rosuvastatin 20 or 40 mg). Similarly, very few (19.3% overall) of those prescribed a PCSK9 inhibitor were taking ezetimibe. Very few adults (n 5 13) reported never trying a statin; most adults who were not on a statin had previously tried one, but discontinued because of the side effects (84.9%; Table 1).
PCSK9 inhibitor initiation and self-reported persistence and adherence Figure 1 demonstrates the breakdown of treatment status at the time of the survey. Of the 1263 adults with data on current PCSK9 inhibitor utilization, n 5 1216 (96.3%) subjects had received at least 1 dose of PCSK9 inhibitor. Among the 1216 who initiated therapy, n 5 779 (61.3%)
were still on treatment at the time of the survey, whereas n 5 428 (33.7%) had discontinued therapy by the time they completed the survey. Figure 2 shows patient-reported reasons for never initiating PCSK9 inhibitor therapy (among n 5 47 adults who were prescribed, but never received therapy) or discontinuing therapy (among n 5 428 adults who initiated but discontinued treatment). In both groups, the leading patient-reported reasons for lack of PCSK9 inhibitor utilization was lack of insurance approval (54.3% of those who never initiated therapy and 34.4% of those who stopped therapy), followed by high costs to the patient (39.1% of those who never initiated therapy and 38.2% of those who stopped therapy). Among those who discontinued treatment, 24.4% reported discontinuing because of perceived side effects. Rates of discontinuation were similar among those with a reported history of statin intolerance (20.4%) and those without statin intolerance (26.8% discontinued PCSK9 inhibitor). Among patients who started a PCSK9 inhibitor, slightly more than half (64.1%, n 5 779) were still taking their prescribed PCSK9 inhibitor at the time of the survey. Table 3 shows drug adherence and persistence behavior by patient PCSK9 inhibitor use status. There were no significant differences between those currently on therapy and those who had discontinued therapy based on age, race, or insurance type. Nevertheless, those on therapy were more likely to be male (57.0% vs 45.3%, P 5 .0005), report a graduate degree (22.9% vs 16.8%, P 5 .02), and have a higher household income. Among current users, 85.3%
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4 Table 2 Characteristics of patients prescribed PCSK9 inhibitor
Patients’ characteristics
All patients prescribed PCSK9 inhibitors (n 5 1269)*, n (%)
Age (y) ,40 21 (1.7) 40–59 290 (23.3) 60–79 851 (68.5) .80 81 (6.5) Sex (% male) 657 (52.9) Race Caucasian/White 1131 (92.4) Black 46 (3.8) Other 47 (3.8) Education High school or less 224 (18.1) At least some college 752 (60.9) Graduate degree 259 (21.0) Household income ,$30,000 193 (20.2) $30,000–$69,999 350 (36.5) .$70,000 415 (43.3) Insurance type Private 745 (59.0) Government 462 (36.6) None 30 (2.4) Insurance medication coverage Full 824 (66.9) Partial 356 (28.9) None 51 (4.1) Clinical characteristics† HeFH only 235 (18.5) ASCVD only 459 (36.2) ASCVD and HeFH 396 (31.2) Other/no response/missing 179 (14.1) Currently taking any statin 376 (29.8) Currently taking high-intensity statin 190 (15.5) Not taking statin 884 (70.2) Currently taking ezetimibe 236 (19.3) Not taking statin Phone: reason for not taking statin‡ Side effects 284 (85.8) Other 37 (11.2) Never took a statin 10 (3.0) Email: reason for not taking statinx Side effects 462 (84.3) Stopped when starting PCSK9 44 (8.0) inhibitor Other 39 (7.1) Never took a statin 3 (0.6) Prescribing doctor Cardiologist 963 (76.3) Endocrinologist 93 (7.4) Primary care 163 (12.9) Other 44 (3.5) Patient involvement in approval{ Completing paperwork 276 (23.3) (continued on next page)
Table 2
(continued )
Patients’ characteristics Getting paperwork to provider Calling insurer None of the above Burden of approval process# Not at all burdensome Somewhat burdensome Very burdensome
All patients prescribed PCSK9 inhibitors (n 5 1269)*, n (%) 441 (37.2) 340 (28.7) 84 (6.6) (n 5 496) 126 (25.4) 199 (40.1) 171 (34.5)
ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hyperlipidemia; PCSK9, proprotein convertase subtilisin/kexin type 9 inhibitors. *134 respondents were prescribed PCSK9 inhibitors but had subsequent missing data or did not know their approval status. †In the phone survey, ASCVD was assessed by asking patients about a history of stroke, heart attack, coronary stent, or heart bypass. In the email survey, this was broadened to include coronary artery disease, angina, abdominal aortic aneurysm, and transient ischemic attacks. ‡Phone survey only. xEmail survey only. {Patient involvement options are not mutually exclusive. # The question of if patients stopped statin after initiating PCSK9 inhibitors was not asked on phone survey to prevent potentially prompting patients to stop therapy inappropriately after seeing high rates of this on the first email survey.
had been on therapy for more than 6 months. Of those who discontinued therapy, 50.0% stopped the medication after 1 to 6 months, whereas 42.6% stopped after $6 months. Patients currently on therapy reported missing a dose or having a delay to dose of more than 1 week significantly more than those who had discontinued therapy (28.2% of those on therapy vs 9.3% of those who discontinued, P # .0001) or forgotten to take their medication on the day it was due (36.7% vs 22.2%, P # .0001). Although many reported skipping a prescription fill because of the price (17.7% of those on therapy vs 49.4% of those who discontinued), few reported intentionally spacing out doses to make the prescription last longer (6.1% vs 4.8%, P 5 .37). Table 4 compares patient-reported beliefs about disease risk and PCSK9 inhibitors between those who were still on therapy and those who had discontinued or did not initiate treatment for the subset of patients who completed the email survey. Of email responses, the majority of both groups reported confidence in drug efficacy, reporting they were ‘‘quite’’ or ‘‘very confident’’ in the drug treating condition (89.6%, P 5 .0001), although those on therapy did have higher overall confidence in treatment effectiveness than those who discontinued. Similarly, those currently on therapy had higher beliefs in the safety of PCSK9 inhibitors and acceptability of therapy; 82.6% of current users found therapy side effects ‘‘acceptable’’ or ‘‘very acceptable’’ compared with 55.7% of former users (P # .0001), and 94.0% vs 84.8% reported the drug to be overall
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5
Figure 1 Patient response to survey. Patient response to survey contact and PCSK9 inhibitor prescription. PCSK9, proprotein convertase subtilisin/kexin type 9 inhibitor.
‘‘acceptable’’ or ‘‘very acceptable’’ (current vs nonusers, respectively, P 5 .002). Drug administration was well tolerated; 92.9% overall reported it was ‘‘easy’’ or ‘‘very easy’’ to give the injection.
Insurance approval and patient process experience Not all those who were on therapy or had discontinued therapy received insurance approval. Among adults who had started PCSK9 inhibitor therapy and for whom approval status was known, the approval rate was 74.9%. Of those still on therapy, 631 (81.0%) reported receiving approval, 95 (12.2%) reported not receiving approval, and approval status was missing or unknown in 53 adults (6.8%). Of those who never initiated or discontinued therapy (n 5 475), 205 (43.2%) had
received approval, 204 (42.9%) had not received approval, and approval status was unknown for 66 adults (13.9%). Characteristics of patients according to approval status are described in Supplemental Table 1. Those who received approval were older and more likely to report government insurance and an indication of ASCVD than those who did not receive approval. There was no difference in education or income by approval status nor was statin utilization different among those who received approval and those who did not. Most patients were engaged in the prior authorization process in some capacity, with the most cited method being getting paperwork to/from the doctor or pharmacy (37.2%). There were similar rates of participation in the prior authorization process across approval and utilization status (Table 1). The majority of all groups found the process to be ‘‘somewhat’’ or ‘‘very’’ burdensome (74.6%).
34.4
Not approved
54.3 38.2 39.1
Too expensive Perceived side effects/fear of side effects
24.4 10.9
Discon nued drug
1.5 4.4
Did not want/like injec on
Never received drug
2.0 2.2
Did not think it was needed
25.9
Other
15.2
0.0
10.0
20.0
30.0
40.0
50.0
60.0
% of Respondents
Figure 2 Reason for not currently using PCSK9 inhibitors. Reason for not currently using PCSK9 inhibitors and whether the drug was discontinued or never received. PCSK9, proprotein convertase subtilisin/kexin type 9 inhibitor.
Journal of Clinical Lipidology, Vol -, No -, - 2019
6 Table 3
Patient persistence and adherence with PCSK-9 inhibitors by use status
Patient persistence and adherence* Age (y) ,40 40–59 60–79 .80 Sex (% male) Race Caucasian/White Black Other Education High school or less At least some college Graduate degree Household income ,$30,000 $30,000–$69,999 .$70,000 Insurance type Private Government None Insurance medication coverage Full Partial None Clinical characteristics HeFH only ASCVD only ASCVD and HeFH Other/no response/missing Months using drug ,1 mo 1–6 mo .6 mo Medication adherence (% yes) Missed or delayed doses by 1 wk Forgotten to take dose Intentionally spaced doses Skipped filling because of price None of the above
On therapy (n 5 779), n (%)
Discontinued therapy (n 5 428), n (%)
12 193 521 45 443
6 86 297 36 193
P value .13
(1.5) (24.8) (67.1) (5.8) (57.0)
(1.4) (20.2) (69.7) (8.5) (45.3)
706 (91.0) 25 (3.2) 28 (3.6)
380 (89.8) 21 (5.0) 19 (4.5)
128 (16.8) 461 (60.3) 175 (22.9)
89 (21.0) 264 (62.3) 71 (16.8)
97 (12.6) 211 (27.4) 288 (37.4)
92 (22.0) 123 (29.4) 107 (25.5)
459 (59.3) 290 (37.5) 9 (1.2)
257 (60.2) 155 (36.3) 6 (1.4)
512 (65.9) 222 (28.6) 29 (3.7)
281 (66.0) 119 (27.9) 22 (5.2)
138 288 269 84
87 149 115 77
.0005 .10
.02
,.0001
.97
.43
.01 (17.7) (37.0) (34.5) (10.8)
(20.3) (34.8) (26.9) (18.0) ,.0001
2 (0.3) 111 (14.4) 658 (85.3)
31 (7.4) 210 (50.0) 179 (42.6)
218 283 47 130 309
39 93 20 203 164
(28.2) (36.7) (6.1) (17.7) (39.8)
(9.3) (22.2) (4.8) (49.4) (39.0)
,.0001 ,.0001 .37 ,.0001 .78
ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hyperlipidemia. *Nine respondents answered the question about receiving therapy, but had subsequent missing data.
Discussion Although the provider experience with PCSK9 inhibitor therapy has been documented,7 the patient experience (including the approval process and use) has not previously been well described. In this survey, we identified first that PCSK9 inhibitor utilization has been largely confined to patients with statin intolerance, rather than patients with high on-statin low-density lipoprotein cholesterol (LDL-C) levels. Next, we reconfirmed that cost and lack of insurance
approval decreased patient initiation of therapy. Finally, we identified that even among patients who receive therapy, persistence is suboptimal, with discontinuation driven by cost and insurance approval, as well as patient-perceived side effects. Large outcomes trials have demonstrated the safety and efficacy of PCSK9 inhibitors in reducing the risk of cardiovascular events when added to a background of statin therapy,1,2 and at the time of the study, the Food and Drug Administration label states that PCSK9 inhibitors are to be
Bradley et al Table 4
The patient journey with PCSK9 inhibitors
7
Patients’ beliefs about PCSK9 inhibitors by use status*
Patients’ beliefs Drug effectiveness Confidence in drug treating condition Not at all confident A little confident Somewhat confident Quite confident Very confident Injection effectiveness in treating condition Not at all effective A little effective Somewhat effective Quite effective Very effective Drug safety Acceptability of side effects Very unacceptable Unacceptable Neither acceptable nor unacceptable Acceptable Very acceptable Drug delivery Acceptability of pain at injection site Very unacceptable Unacceptable Neither acceptable nor unacceptable Acceptable Very acceptable Confidence in ability to give injection Not at all confident A little confident Somewhat confident Quite confident Very confident Ease of giving injection Very difficult Difficult Neither difficult nor easy Easy Very easy Drug acceptability Overall acceptability of treatment Very unacceptable Unacceptable Neither acceptable nor unacceptable Acceptable Very acceptable
Overall (N 5 520), n (%)
On therapy with approval (n 5 406), n (%)
Discontinued/did not initiate with approval (n 5 114), n (%)
6 8 37 85 355
(1.2) (1.6) (7.5) (17.3) (72.3)
0 6 29 68 288
(0.0) (1.5) (7.4) (17.4) (73.7)
6 2 8 17 67
(6.0) (2.0) (8.0) (17.0) (67.0)
5 8 26 68 327
(1.2) (1.8) (6.0) (15.7) (75.4)
1 4 19 49 264
(0.3) (1.2) (5.6) (14.5) (78.3)
4 4 7 19 63
(4.1) (4.1) (7.2) (19.6) (65.0)
42 18 53 114 262
(8.6) (3.7) (10.8) (23.3) (53.6)
18 4 45 94 224
(4.7) (1.0) (11.7) (24.4) (58.2)
24 14 8 20 38
(23.1) (13.5) (7.7) (19.2) (36.5)
19 9 45 131 299
(3.8) (1.8) (9.0) (26.0) (59.4)
15 3 35 102 246
(3.7) (0.8) (8.7) (25.4) (61.4)
4 6 10 29 53
(3.9) (5.9) (9.8) (28.4) (52.0)
3 5 13 59 422
(0.6) (1.0) (2.6) (11.8) (84.1)
3 4 11 37 345
(0.8) (1.0) (2.8) (9.3) (86.3)
0 1 2 22 77
(0.0) (1.0) (2.0) (21.6) (75.5)
1 8 27 86 381
(0.2) (1.6) (5.4) (17.1) (75.8)
1 6 25 62 307
(0.3) (1.5) (6.2) (15.5) (76.6)
0 2 2 24 74
(0.0) (2.0) (2.0) (23.5) (72.6)
15 6 19 98 366
(3.0) (1.2) (3.8) (19.4) (72.6)
9 1 14 72 303
(2.3) (0.3) (3.5) (18.1) (75.9)
6 5 5 26 63
(5.7) (4.8) (4.8) (24.8) (60.0)
P value ,.0001
.003
,.0001
.009
.01
.17
.0001
PCSK9, proprotein convertase subtilisin/kexin type 9 inhibitors. *Email survey only.
used in addition to maximally tolerated doses of statin.8 Yet, despite existing evidence and indication, most patients in this study who had been prescribed a PCSK9 inhibitor were not on a statin, and 84.4% of those patients reported statin intolerance. Whether these patients meet strict
criteria for statin intolerance is unknown, but at minimum, it appears that most those who are being prescribed a PCSK9 inhibitor self-reported being statin intolerant. Our rate of statin utilization (29.8%) was slightly lower than what was shown by Rane et al., who reported that only
8 40.5% of patients prescribed PCSK9 inhibitors were currently using a statin by physician report, and similar to what was found in a large national analysis of pharmacy claims data, whereas 76.9% of those prescribed PCSK9 inhibitors were not on a statin.4,9 Importantly, these prescriptions were not inappropriate: those who are statin intolerant are at high risk of recurrent events10,11 and PCSK9 inhibitors have been shown to be effective in lowering LDL-C in those with statin intolerance.12,13 The demand for lipidlowering therapy options for statin-intolerant patients may have driven uptake, given the lack of previously available therapeutic options; however, efforts to increase uptake of PCSK9 inhibitor therapy should now focus on those with ASCVD who are at high risk for recurrent events and persistently high LDL-C despite maximally tolerated therapy, as studied in the trials. Furthermore, there was a small subset of patients in our study who reported stopping statins following PCSK9 inhibitor initiation. Providers should continue to emphasize to patients that the benefits of PCSK9 inhibitor therapy are in addition to statins and encourage continued statin therapy while on PCSK9 inhibitors. Continuing statin therapy after starting PCSK9 inhibitors is also important to maintain insurance coverage for therapy; many insurance companies require documentation of LDL-C lowering on PCSK9 inhibitors. If patients stop statin therapy after starting PCSK9 inhibitors, then their apparent LDL-C lowering on PCSK9 inhibitor will be reduced, and they may not be able to obtain reauthorization for ongoing therapy. Our study also found a low rate of ezetimibe use in those prescribed PCSK9 inhibitors (19.3%). This survey did not further evaluate the reason for the lack of ezetimibe use. However, at the time, the survey guidelines did not recommend using ezetimibe before initiating PCSK9 inhibitor, and payer requirements for ezetimibe as a stepthrough therapy also varied.14 Whether the recommendation to try ezetimibe first in the latest lipid guidelines leads to an increase in ezetimibe use in those prescribed PCSK9 inhibitors remains to be seen. At the time of the survey, we found that even among patients who were enrolled in a company-sponsored patient portal with access to support for navigating the prior authorization process, only 66.9% of patients prescribed PCSK9 inhibitors had received insurance approval. Lack of payer approval was a leading reason that patients did not start or discontinued therapy; however, even among those who received approval and were still on therapy, most patients reported the approval process to be ‘‘burdensome’’ or ‘‘very burdensome.’’ As shown in prior studies, a key barrier to patient utilization of PCSK9 inhibitors was cost, which was cited by nearly 40% of those who discontinued or did not initiate treatment. Patient out-of-pocket costs are strongly correlated with primary non-adherence, or lack of patients’ filling a prescription even after approval. This survey reveals that costs also appear to impact patient’s longterm persistence to treatment. There is hope in the fact that
Journal of Clinical Lipidology, Vol -, No -, - 2019 the recently announced 60% decrease in price of both drugs may translate into reduced out-of-pocket costs for those with government insurance.15,16 For those that are still unable to afford the prescription, enhancing access to patient assistance programs may help improve long-term adherence to PCSK9 inhibitor therapy. Largely because of cost and lack of insurance approval, 1 in 3 adults who initiated a PCSK9 inhibitor discontinued therapy, with 24.4% of those who discontinued treatment citing side effects from PCSK9 inhibitor therapy as the reason (representing around 8% of those who initiated therapy). This number was slightly higher than what was seen in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) trials, in which 628 of 13,784 (4.6%) and 362 of 9462 (3.8%), respectively, discontinued therapy because of adverse events.1,2 Importantly, in both trials, similar numbers of participants in the placebo arm also discontinued because of adverse events (4.2% [n 5 581] of 13,780 in FOURIER, and 3.7% [n 5 347] of 9462 in ODYSSEY OUTCOMES),1,2 which suggests that much of the intolerance to PCSK9 inhibitors in clinical trials may be unrelated to the active therapy or may reflect a ‘‘nocebo effect’’ as seen commonly in statin clinical trials. Our study was not designed to obtain detailed information on patient-perceived side effects nor was it designed to determine whether patient-reported side effects were because of a true causal link vs a nocebo effect. However, it is important to note that studies evaluating treatment acceptance suggest a high level of drug acceptance,5,6,17 and multiple studies have shown that evolocumab and alirocumab have been well tolerated by patients.18,19 Clinicians should monitor patients for both real and perceived side effects and help determine if side effects may be related to PCSK9 inhibitors. Both patients and providers should report any potential PCSK9 inhibitor–related side effects to the Food and Drug Administration’s MedWatch program. Nevertheless, despite the side effect rates reported in this survey, most patients found PCSK9 inhibitors acceptable and believe that they are effective. Even patients who had discontinued therapy reported high rates of confidence in drug efficacy and tolerability. Identifying and addressing barriers to long-term persistence to PCSK9 inhibitors is critical to achieve the population health benefits of the medication; in clinical trials, the event rates between the treated and placebo arms did not separate for the first 6 to 12 months.1,2 This study has several limitations. First, the subsample of patients who chose to enroll in the patient portal may not be representative of the overall population. For example, patients less satisfied with their experience with PCSK9 inhibitors or who did not feel the medication was effective may have been less likely to participate in the patient portal or survey. Second, indication for therapy was self-reported in this survey, which is inherently subject to recall bias and
Bradley et al
The patient journey with PCSK9 inhibitors
may not have been well understood by patients at the time of the survey. Third, this study identified patients referred to a company-sponsored support program for alirocumab. As a result, the results likely apply more to patients prescribed alirocumab. Because patients may be prescribed 1 brand and then switched to another or were prescribed both pending insurance approval, we asked patients about therapy as a class and did not evaluate differences by therapy type. Importantly, this survey was conducted before the results of the FOURIER and ODYSSEY OUTCOMES trials, after which new agreements with payers have been undertaken with the goal to lower the bar to approval. In addition, the cost of both PCSK9 inhibitors has been significantly decreased since the time of this survey. Finally, arrangements between the manufacturers and health plans have changed since the survey. For example, Express Scripts, Inc, which is a large pharmacy benefits manager in the United States, announced they will pass a portion of their rebates to the patients who are effectively lowering out-of-pocket expenses.20 Also, companies have worked with payers to lower the prior authorization requirements for providers. Further exploration is needed to better understand the impact of these changes on patient initiation and persistence to PCSK9 inhibitors.
Conclusion In conclusion, in contrast to what was studied in trials, PCSK9 inhibitors appear to be prescribed more commonly in adults with statin intolerance than those on high-intensity statins. Efforts to expand utilization of PCSK9 inhibitors should focus on high-risk adults with persistently high LDL-C, despite statin therapy. Lack of insurance approval and high out-of-pocket costs are consistent barriers to both initiation and long-term persistence to PCSK9 inhibitor therapy. Continued efforts between payers and pharmaceutical companies to decrease access barriers will be critical to ensure the maximal effectiveness of PCSK9 inhibitors to reduce the burden of ASCVD.
Acknowledgments Erin Campbell, MS, of the Duke Clinical Research Institute provided editorial assistance. This study was supported by Sanofi and Regeneron Pharmaceuticals, Inc., United States A.M.N. receives support from the NHLBI, United States (K01HL133416). Authors’ contributions: A.M.N. and P.S. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. C.K.B., R.J.S., E.D.P., and A.M.N. were responsible for study concept and design. P.S. and A.M.N. were responsible for data analysis. C.K.B., R.J.S., E.D.P., and A.M.N. were responsible for interpretation of data. C.K.B. was responsible for drafting the article. C.K.B., R.J.S., E.D.P., and A.M.N. were responsible for critically revising the article.
9
Disclosure C.K.B. and P.S. reports no relevant disclosures. R.J.S. reports employment with Regeneron Pharmaceuticals, Inc. E.D.P. reports research grants (significant) from Amgen, Sanofi, Astrazeneca, Merck; consultant/advisory board (modest) from Amgen; consultant/advisory board (significant) from AstraZeneca, Merck, and Sanofi Aventis. A.M.N. reports research grants (significant) from Amgen, Sanofi, Amarin, Janssen, and Regeneron; consultant/advisory board (modest) for Amgen, Regeneron, NovoNordisk, AstraZeneca, and Sanofi.
Supplementary data Supplementary data related to this article can be found online at https://dx.doi.org/10.1016/j.jacl.2019.06.008.
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