The budget impact of using enteric-coated aspirin 325 mg + immediate-release omeprazole 40 mg to prevent recurrent cardiovascular events

Abstract

Objective: Aspirin (acetylsalicylic acid; ASA) is commonly used for secondary prevention of cardiovascular (CV) events, but may be associated with gastrointestinal (GI) adverse events, which can reduce adherence. Use of ASA co-therapy with proton pump inhibitors in patients at risk may be suboptimal. PA32540 (Yosprala™) is a coordinated-delivery tablet combining EC-ASA 325 mg and immediate-release omeprazole 40 mg. The objective of this flexible budget impact model was to project the financial consequences of introducing PA32540 325 mg/40 mg to prevent recurrent CV events, while reducing ASA-associated GI events in US adults.

Methods: A Markov Model was employed to estimate health state transitions associated with ASA 75–325 mg, ASA 75–325 mg + generic delayed-release omeprazole 40 mg, PA32540, or clopidogrel 75 mg to prevent recurrent CV events. Health states included ulcers, GI bleeding, CV events, and death. Model inputs included demographics, treatment dosages, treatment costs, adverse GI and CV events, and premature death. Data from peer-reviewed literature and censuses enabled appropriate allocation of CV and GI disease prevalence and mortality. The PA32540 non-adherence rate was conservatively set at 20%. PA32540 market share was set to 50%.

Results: The model projected annual savings of $81.0 million to $190.9 million within 1–5 years after PA32540 introduction to the plan, which included 134,558 members at risk for recurrent CV events. These values translate into savings of $602 (year 5) to $1,419 (year 1) per patient per year, and $81 (year 5) to $191 (year 1) per member per year. These values were robust to variations in parameters under a deterministic sensitivity analysis.

Conclusion: PA32540 use to prevent recurrent CV events was associated with cost reductions in each year examined with the model. From a health plan perspective, PA32540 is likely to have a net overall effect, resulting in significant cost savings.

Keywords:

• Aspirin
• proton pump inhibitors
• secondary prevention
• cardiovascular events
• ulcer
• gastrointestinal bleeding

Introduction

Cardiovascular disease (CVD), including ischemic heart disease and cerebrovascular disease, is the leading cause of death worldwide¹. Nonetheless, age-adjusted mortality rates from CVD are decreasing, suggesting improved survival in individuals who experience a cardiovascular event^1,2. Among these individuals, secondary events continue to be a challenging problem. In the US, within 6 years after a recognized myocardial infarction, 18% of men and 35% of women will have another heart attack, 7% of men and 6% of women will experience sudden death, and 8% of men and 11% of women will have a stroke³.

Clinical guidelines recommend aspirin (acetylsalicylic acid; ASA) therapy for the prevention of secondary CVD and stroke^4–6. Despite the proven benefits of ASA therapy in the secondary prevention of CVD, ASA utilization and adherence remains suboptimal^7,8. Poor adherence with low-dose ASA therapy ranged from ∼10% to over 50%, and patient-initiated discontinuation of therapy occurred in up to 30% of patients⁹. The causes of ASA discontinuation are often multifactorial; however, side-effects, including gastrointestinal (GI) events, are among the most significant contributors^10–12. Moreover, many studies have shown that discontinuation of ASA therapy following a secondary CV event or stroke may result in significant morbidity and mortality^13–16.

The frequency of ASA discontinuation creates a challenging paradox. Those at risk of a CV event are often directed to take ASA; however, adherence to ASA therapy puts patients at risk of GI side-effects, which increase the risk of discontinuation. Discontinuation of ASA increases the risk of CV events compared to those who continue ASA therapy.

Although historical strategies for reducing the risk of GI complications include the use of lower ASA doses, buffered ASA, and/or enteric-coated (EC)-ASA formulations, these strategies do not appear to reduce the risk of GI bleeding complications^17–22. Consequently, for patients at risk of upper gastroduodenal adverse events (AEs), gastroprotection should be prescribed¹⁷.

Proton pump inhibitors (PPIs) are the preferred agents for the therapy and prophylaxis of non-steroidal anti-inflammatory drug (NSAID)- and ASA-associated GI injury¹⁷. Continuous PPI use with ASA therapy is associated with a lower risk of GI ulcers or bleeding compared with intermittent or no PPI use among adults with a high risk of GI events^23,24.

However, prescribing and adherence to ASA co-therapy with PPIs in patients at risk may be suboptimal^25,26. In one study, more than 50% of patients at increased risk for GI events with ASA were not sufficiently treated with concomitant PPI therapy²⁵. Among patients who did receive a concomitant PPI prescription, less than half were adherent in using the PPI, and almost one third did not take their PPI at all²⁶. These data indicate that strategies that provide GI protection while facilitating adherence, such as those that combine ASA and a PPI into a single pill, are needed.

PA32540 (Yosprala™) is a coordinated-delivery tablet combining 325 mg EC-ASA and 40 mg immediate-release omeprazole that has recently been approved by the US Food and Drug Administration²⁷. An additional formulation of Yosprala™ (PA8140) contains 81 mg EC-ASA and 40 mg immediate-release omeprazole. In clinical studies, PA32540 significantly reduced the incidence of gastric and/or duodenal ulcers, upper GI symptoms, and discontinuation due to pre-specified upper GI AEs compared to EC-ASA 325 mg alone²⁸. In this analysis, we projected the financial consequences of introducing PA32540 to prevent recurrent CVD events while reducing ASA-associated GI events in US adults using a flexible budget impact model.

Methods

Model design

We developed an adjustable Markov Model in Microsoft Excel (Microsoft Corporation; Redmond, WA) to estimate health state transitions associated with ASA 75–325 mg, ASA 75–325 mg + generic delayed-release omeprazole 40 mg in separate formulations, PA32540 at the 325 mg/40 mg dose, or clopidogrel 75 mg to prevent recurrent CVD events.

Model inputs

Relative efficacy, safety, rates of adherence, and discontinuation rates were derived from the relevant peer-reviewed clinical literature, including the results of Phase 3 studies evaluating the impact of PA32540²⁸, and census data. Peer-reviewed literature and census data also enabled appropriate allocation of the cost of treatments (other than PA32540), CVD prevalence, and GI and CVD mortality rates. Health states included ulcers, GI bleeding, CVD events, and death. Model inputs included demographics, treatment dosages, the costs of treatments, adverse GI and CVD events, and premature death. The primary study outcome was the relative annual difference in the cost of care between populations that do and do not use PA32540. End-points included total costs to a 1,000,000-member plan per year, cost per member per year, and cost per patient per year. Total costs included drug costs, the cost of their major side-effects (i.e. the costs of ulcers, GI bleeding, secondary CVD, and their management), and the cost of death.

As described in Figure 1, patients entered the model with the initiation of either ASA 75–325 mg, ASA 75–325 mg + generic delayed-release omeprazole 40 mg, PA32540, or clopidogrel 75 mg after a CVD event. All patients included in the model initiated one of these treatments. The model accounted for treatment compliance, the potential for a recurrent fatal or non-fatal CVD event, and the potential for developing an ulcer with or without significant GI bleeding. Significant GI bleeding could result in death or non-adherence. The model was developed from a US payer perspective across a 5-year time horizon.

Figure 1. Diagram of Markov model flow. ASA: aspirin (acetylsalicylic acid); CVD: cardiovascular disease; GI: gastrointestinal; PPI: proton pump inhibitor.

Clinical inputs

Estimates of rates of CVD recurrence, adherence, ulcers, and significant bleeding are summarized in Tables 1^29–34 and 2^{11,14,28,35–43}. Estimates on the impact of PA32540 were derived from the results of PA32540 Phase 3 studies. PA32540 was evaluated in two identical, 6-month, randomized, double-blind, parallel-group, multi-center controlled Phase 3 studies investigating the incidence of gastric ulcers in patients with established CVD or cerebrovascular disease who had been using ASA 325 mg/day for ≥3 months and were at risk for developing ASA-associated ulcers. In both studies, PA32540 was compared with EC-ASA 325 mg²⁸. The design and results of these studies have been published elsewhere²⁸.

Table 1. Population estimates and CVD prevalence estimates in individuals aged 40–79 years.

	Population estimate/CVD prevalence (%)	Source
Adult population with CVD*	32.62%	Blackwell et al.^29 (2014) US Census Data^30 (2015)
Adult population at risk for recurrent CVD events*	41.25%	Blackwell et al.^29 (2014) US Census Data^30 (2015)
Males with CVD	51.00%	AHA^31 (2015)
Females with CVD	48.55%	AHA^31 (2015)
Annual CVD death rate for males with CVD	4.49%	Xu et al.^32 (2016)
Annual CVD death rate for females with CVD	4.47%	Xu et al.^32 (2016)
Annual GI bleeding death rate for patients with GI bleeding**	2.13%	Abougergi et al.^33 (2015)
Annual ulcer death rate among patients with ulcers	1.71%	Ruigómez et al.^34 (2000)

* Aged 18 and over.

** Age not specified.

AHA: American Heart Association; CVD: cardiovascular disease; GI: gastrointestinal.

Table 2. Clinical event probabilities.

	ASA	ASA + PPI	PA32540	Clopidogrel	Sources
Annual rate of recurrent CVD on treatment	5.00%	4.68%	3.50%	4.68%	Carlton et al.^35 (2013) Nichols et al.^36 (2010) Whellan et al.^28 (2014)
Annual rate of recurrent CVD without treatment	15.00%	15.00%	15.00%	15.00%	Biondi-Zoccai et al.^14 (2006)
Annual rate of ulcers on treatment	25.19%	15.84%	6.49%	20.00%	CAPRIE^37 (1996) Herlitz et al.^38 (2010) Ng et al.^39 (2008) Whellan et al.^28 (2014) Yeomans et al.^40 (2005)
Annual rate of ulcers leading to significant GI bleeding	20.00%	10.90%	10.90%	20.00%	Khuroo et al.^41 (1997) Wilcox and Spenney^42 (1988)
Annual rate of recurrent CVD in patients with ulcers on treatment	5.00%	4.68%	3.50%	4.68%	Carlton et al.^35 (2013) Whellan et al.^28 (2014)
Annual non-adherence rate	20.00%	37.00%	20.00%	22.30%	Carlton et al.^35 (2013) Saini et al.^43 (2011) Whellan et al.^28 (2014)
Annual non-adherence rates in patients with ulcers	55.00%	55.00%	55.00%	55.00%	Pratt et al.^11 (2010)

ASA: aspirin (acetylsalicylic acid); CAPRIE: clopidogrel vs aspirin in patients at risk of ischemic events; CVD: cardiovascular disease; GI: gastrointestinal; PPI: proton pump inhibitor.

The primary efficacy end-point of these studies was the cumulative proportion of subjects who developed endoscopically-determined gastric ulceration (defined as a mucosal break of ≥3 mm in diameter with depth) during the 6 months of treatment. Major adverse cardiovascular events (MACEs) included CVD death, acute coronary syndrome (including non-fatal or fatal myocardial infarction), ischemic stroke, heart failure, and unplanned coronary artery bypass graft or percutaneous coronary intervention. The combined study population included 1049 subjects.

Rates of endoscopic gastric ulcers were significantly lower with PA32540 than with EC-ASA (3.2% vs 8.6%; p < .001). Overall incidences of MACEs were similar between groups (PA32540, 1.7%; EC-ASA, 2.5%). Discontinuation rates due to pre-specified upper GI AEs were 1.5% with PA32540 and 8.2% with EC-ASA (p < .001).

Adherence and cost estimates

The PA32540 non-adherence rate was conservatively set at 20% (vs 1.5% observed in the Phase 3 studies), while the PA32540 market share was set to 50% (Table 3) of plan members at risk for recurrent CVD events. Inflation and discount rates were set to 3.0%.

Table 3. Estimated patient share per treatment option.

Treatment option	Current practice (without PA32540)	Comparator practice (with PA32540)
ASA	32.00%	16.50%
ASA + PPI	62.00%	30.75%
PA32540	0.00%	50.00%
Clopidogrel	6.00%	2.75%

ASA: aspirin (acetylsalicylic acid); PPI: proton pump inhibitor.

Cost inputs and assumptions are summarized in Table 4^43,44. For ASA 75–325 mg, ASA 75–325 mg + generic delayed-release omeprazole 40 mg, or clopidogrel 75 mg, costs were obtained from publicly available pricing databases. The price of PA32540 was assumed to be a wholesale acquisition cost (WAC) of $150 per 30 days. Costs related to ulcers, GI bleeding, other side-effects, CVD events, and death were estimated from the literature (Table 5)^43,45–48. All monetary values used in this analysis were adjusted for inflation and reported in 2015 US dollars.

Table 4. Dosing, cost input, and assumptions.

Treatment options	Dosage	Drug cost per day	Source
ASA	ASA 75–325 mg	$0.06	Gaspoz et al.^44 (2002)
ASA + PPI (omeprazole)	ASA 75–325 mg + omeprazole 40 mg	$0.50	Saini et al.^43 (2011)
PA32540	EC-ASA 325 mg + immediate-release omeprazole 40 mg	$5.00*
Clopidogrel	300 mg loading dose followed by 75 mg/day	$4.45	Gaspoz et al.^44 (2002)

* The price of PA32540 was assumed to be a WAC of $150 for 30 days.

ASA: aspirin (acetylsalicylic acid); EC-ASA: enteric-coated aspirin; PPI, proton pump inhibitor.

Table 5. Treatment-associated cost inputs and assumptions.

	ASA	ASA + PPI	PA32540	Clopidogrel	Sources
Drug costs*	$22	$183	$1,825	$1,624
Ulcer-related costs	$23,847	$23,847	$23,847	$23,847	Bi et al.^45 (2014) Fashner and Gitu^46 (2015)
GI bleeding costs	$8,599	$8,599	$8,599	$8,599	Saini et al.^43 (2011)
Costs of other side-effects	$0	$0	$0	$0
CVD-related costs	$84,971	$84,971	$84,971	$84,971	Bonafede et al.^47 (2015)
Costs of mortality	$29,824	$29,824	$29,824	$29,824	Stranges et al.^48 (2009)

* The price of PA32540 was assumed to be a WAC of $150 for 30 days.

ASA: aspirin (acetylsalicylic acid); CVD: cardiovascular disease; GI: gastrointestinal; PPI, proton pump inhibitor.

Sensitivity analysis

Two-way sensitivity analyses were performed by varying the rates of recurrent CVD events, ulcers, GI bleeding from ulcers, and non-adherence by 5% in either direction and by varying the unit price of PA32540 by 10% in either direction.

Results

It was estimated that, in a plan including 1,000,000 patients, 134,558 adult patients were at risk for secondary CVD events. Among adults aged 40–79 years, 44,221 males and 45,101 females were at risk for secondary CVD events.

The model projected annual savings of $81.0 million to $190.9 million within 1–5 years after PA32540 introduction to the plan (Figure 2). At year 1, total costs were $1.02 billion after the introduction of PA32540 and $1.21 billion with current practice without PA32540. By year 5, total costs were $1.31 billion with PA32540 and $1.39 billion without PA32540. These values translate into savings of $81 (year 5) to $191 (year 1) per plan member per year (Figure 3(A)) and $602 (year 5) to $1,419 (year 1) per patient per year (Figure 3(B)). Savings were similar for men and women. Annual savings ranged from $26.5 billion (year 5) to $62.7 billion (year 1) for men and $27.0 billion to $64.0 billion for women.

Figure 2. Total costs per year with and without PA32540. Costs shown here are to a plan with 1,000,000 members.

Figure 3. Budget impact of PA32540: annual cost per member per year (A) and annual cost per patient per year (B).

These values were robust and resistant to variations in rates of CVD, ulcers, bleeding, and the cost of PA32540 under a deterministic sensitivity analysis (Figure 4).

Figure 4. Tornado plot of uncertainty analysis at year 5. ASA, aspirin (acetylsalicylic acid); CVD: cardiovascular disease; GIB: gastrointestinal bleeding.

Discussion and conclusions

Despite the significant benefits of ASA therapy in the prevention of secondary CVD events, adherence to ASA is sub-optimal. Rates of non-adherence to ASA therapy have ranged from 8–28%¹². Adherence rates decline in the presence of GI symptoms.

While PPIs reduce the rates of GI AEs with ASA and have been shown to be cost-effective in patients using ASA for secondary CVD prevention^43,49,50, these agents are not routinely prescribed when ASA is initiated in patients at risk⁵¹. When PPIs are prescribed, evidence suggests that less than half of patients are adherent to daily PPI use²⁶. PA32540 may improve adherence by reducing the complexity of the regimen and by reducing the GI AEs observed with ASA alone.

Results from two randomized, double-blind, 6-month Phase 3 studies have confirmed the efficacy and safety of PA32540 in patients with established CVD or cerebrovascular disease who had used ASA 325 mg/day for the previous 3 months^28,52. A pooled analysis of these trials confirmed that PA32540, compared to EC-ASA alone, significantly reduced the incidence of endoscopically determined gastric ulcers (3.2% vs 8.6%; p < .001), the combined incidence of gastric and duodenal ulcers (3.4% vs 11.6%; p < .001), and per a post-hoc analysis, the incidence of new or worsening erosive esophagitis (2.1% vs 15.8%; p < .001). In addition, significantly fewer subjects assigned to PA32540 discontinued the study due to pre-specified upper GI AEs compared to EC-ASA alone. At month 6, 8.2% of subjects assigned to EC-ASA alone discontinued the study due to pre-specified upper GI AEs, compared to 1.5% of subjects assigned to PA32540 (p < .001). Overall rates of secondary major adverse CV events were 2.5% with EC-ASA and 1.7% with PA32540 (p = NS).

Our budget impact model suggests that the use of PA32540 may be cost-effective. Our analysis demonstrated that substantial cost savings of up to $1,419 per patient per year could be achieved with the use of PA32540 in patients at risk for ASA-related upper GI adverse events, for a total of up to $190.9 million for a plan with 1,000,000 members within 1–5 years after the introduction of PA32540. Per member savings of up to $191 per year could also be attained with PA32540. Moreover, as the risk of AEs such as GI bleeding may not appreciably differ with different doses²¹, these results could be extrapolated to patients using either the 81-mg or the 325-mg EC-ASA dose.

As with any predictive modeling study, this analysis has several limitations. First, the reliability of the estimates of clinical event rates incorporated in the model depends on the relevance and reliability of the existing data. PA32540 has not been evaluated in a real-world setting, and the outcomes observed in the Phase 3 clinical trial program with PA32540 may not be generalizable to the overall population.

In summary, this model demonstrated that the use of PA32540 to prevent recurrent CVD events was associated with cost reductions in each year examined. From a health plan perspective, PA32540 is likely to have a net overall effect that is budget saving.

Transparency

Declaration of funding

Funded by Aralez Pharmaceuticals R&D Inc.

Declaration of financial or other interests

YH and WZ are WG Group employees. JGF, DS, and JPT are Aralez employees and stock shareholders. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Previous presentations

These findings have been presented at the AMCP Nexus Conference in National Harbor, Maryland, on October 3–6, 2016.

Acknowledgments

The authors thank Nicole Cooper of MedVal Scientific Information Services, LLC, for medical writing and editorial assistance, which was funded by Aralez Pharmaceuticals R&D Inc. This manuscript was prepared according to the International Society for Medical Publication Professionals’ ‘Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP3 Guidelines’.

Additional information

Funding

Funded by Aralez Pharmaceuticals R&D Inc. The WG Group (part of Grey Healthcare Group and WPP group) is a leading global healthcare market access consultancy that offers health analytics solutions to a broad customer base.